61 results on '"Ulrich Moebius"'
Search Results
2. 713 Nanrilkefusp alfa, a high-affinity IL-15Rβγ agonist, promotes an innate and adaptive anti-tumour inflammatory environment as single agent or combined with anti-PD-1 in patients with advanced cancers
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Ulrich Moebius, Radek Špíšek, David Béchard, Nada Podzimkova, Irena Adkins, Richard Sachse, Joachim Kiemle-Kallee, Ekaterina Simonova, Lenka Palova Jelinkova, Petr Danek, and Martin Steegmaier
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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3. SOT101 induces NK cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity
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Zuzana Antosova, Nada Podzimkova, Jakub Tomala, Katerina Augustynkova, Katerina Sajnerova, Eva Nedvedova, Milada Sirova, Guy de Martynoff, David Bechard, Ulrich Moebius, Marek Kovar, Radek Spisek, and Irena Adkins
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NK cells ,antibody-dependent cytotoxicity ,interleukin-15 ,immunotherapy ,therapeutic antibodies ,RLI-15 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
SOT101 is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain, representing a promising clinical candidate for the treatment of cancer. SOT101 among other immune cells specifically stimulates natural killer (NK) cells and memory CD8+ T cells with no significant expansion or activation of the regulatory T cell compartment. In this study, we showed that SOT101 induced expression of cytotoxic receptors NKp30, DNAM-1 and NKG2D on human NK cells. SOT101 stimulated dose-dependent proliferation and the relative expansion of both major subsets of human NK cells, CD56brightCD16- and CD56dimCD16+, and these displayed an enhanced cytotoxicity in vitro. Using human PBMCs and isolated NK cells, we showed that SOT101 added concomitantly or used for immune cell pre-stimulation potentiated clinically approved monoclonal antibodies Cetuximab, Daratumumab and Obinutuzumab in killing of tumor cells in vitro. The anti-tumor efficacy of SOT101 in combination with Daratumumab was assessed in a solid multiple myeloma xenograft in CB17 SCID mouse model testing several combination schedules of administration in the early and late therapeutic setting of established tumors in vivo. SOT101 and Daratumumab monotherapies decreased with various efficacy tumor growth in vivo in dependence on the advancement of the tumor development. The combination of both drugs showed the strongest anti-tumor efficacy. Specifically, the sequencing of both drugs did not matter in the early therapeutic setting where a complete tumor regression was observed in all animals. In the late therapeutic treatment of established tumors Daratumumab followed by SOT101 administration or a concomitant administration of both drugs showed a significant anti-tumor efficacy over the respective monotherapies. These results suggest that SOT101 might significantly augment the anti-tumor activity of therapeutic antibodies by increasing NK cell-mediated activity in patients. These results support the evaluation of SOT101 in combination with Daratumumab in clinical studies and present a rationale for an optimal clinical dosing schedule selection.
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- 2022
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4. 563 Pharmacodynamics and pharmacokinetics of SO-C101 in cynomolgus monkeys
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Ulrich Moebius, Radek Špíšek, David Béchard, Nada Podzimkova, Guy de Martynoff, and Irena Adkins
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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5. Supplementary Data from Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343
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Shane Anthony Olwill, Louis Matis, Christine Rothe, Ulrich Moebius, Julia Schüler, Gabriele Matschiner, Alexander Wiedenmann, Andrea Allersdorfer, Corinna Schlosser, Manuela Carola Dürr, Sven Berger, Thomas J. Jaquin, Rachida Siham Bel Aiba, and Marlon J. Hinner
- Abstract
Figure S1: PRS-343 specificity for 4-1BB within TNF receptor superfamily. Seven recombinant human TNF receptor superfamily proteins were purchased from Sino Biological (4-1BB: 10041-H08H, RANK: 16078-H08H, GITR: 13643-H08H, Ox40: 10481-H08H) or R&D Systems (CD30: 6126-CD, TNF-RII: 1089-R2, TNF-RI: 636-R1) and used for determination of PRS-343 selectivity for 4-1BB. Proteins were coated to an ELISA plate, PRS-343 was added in a dilution series and detected via HRP-labeled anti-human IgG Fc antibody. Within the set of tested TNF receptor family proteins, PRS-343 binds exclusively to 4-1BB. Figure S2: Characterization of multiple bispecific formats of a 4-1BB targeting Anticalin protein recombinantly fused to an anti-HER2 antibody (A). ELISA based binding properties of all formats were compared to parental building blocks (C) while the ability to activate T-cells (IL2 induction) was assessed in a co-culture assay. Figure S3: Cytokine release assay with PRS-343. PBMC were isolated from the blood of twelve healthy donors and incubated for 72 hours with PRS-343 either air dried, in soluble form, or wet coated. Four concentrations of PRS-343 in a volume of 50 µl were tested in each setting as indicated in the figure. The anti-CD3 monoclonal antibody OKT3 at three different concentrations served as the positive control, and an IgG4 isotype antibody was the negative control. Supernatant levels of ten cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, GM-CSF, IFN-γ and TNF-α) were analyzed. The figure shows the average response for the ten donors that displayed a significant response to OKT3, and for a selection of the most relevant cytokines. Figure S4: Dose-dependent 4-1BB activation of a 4-1BB over-expressing Jurkat Nf-kB reporter cell line induced by PRS-343 with ON preincubation of the drug in the presence of NCI-N87 (HER2 high), MKN45 (HER2 low) and HepG2 (HER2 null) cell lines, or without tumor cells. Briefly, cancer cells were seeded onto tissue culture plates with PRS-343 (at 10, 1, 0.1 and 0,01 nM) and incubated ON. All plates were then washed twice with PBS. 4-1BB over-expressing Jurkat Nf-kB reporter (at 3:1 ratio) were added to each well. Following a 6 hours incubation, Bio-Glow luciferase reagent was added to each well and luminescence was measured. Figure S5: Fold increase changes of a panel of cytokines induced by human T-cells co-stimulated by PRS-343 in the presence of SKBR-3 (HER2 high) or MCF-7 (HER2 low). Figure S6: h-4-1BB expression in T-cells during co-culture assay. Using a similar set up as described in M&M, purified Pan T-cells (from healthy donors) and SK-BR3 high Her2 expressing cells were co-incubated in the presence of coated anti-CD3 antibody. After 24, 48 and 72 hours of co-incubation, Pan T-cells were collected and 4-1BB expression on CD3 positive cells was assessed by flow cytometry. (A) shows the % of 4-1BB positive T-cells for two donors and (B) shows histogram of h-4-1BB expression on CD3 positive T-cells from two donors (red 24 hours; blue 48 hours; brown 72 hours). Table S1: Relative HER2 cell surface expression on a panel of cell lines. Expression was experimentally determined using a specific anti-HER2-antibody binding capacity (sABC [HER2]) and quantitative indirect immunofluorescence in flow cytometry (QIFIKIT). HER2 surface levels are also provided relative to the level on SKBR3 cells which were chosen as a reference cell line.
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- 2023
6. Supplementary Legend from Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343
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Shane Anthony Olwill, Louis Matis, Christine Rothe, Ulrich Moebius, Julia Schüler, Gabriele Matschiner, Alexander Wiedenmann, Andrea Allersdorfer, Corinna Schlosser, Manuela Carola Dürr, Sven Berger, Thomas J. Jaquin, Rachida Siham Bel Aiba, and Marlon J. Hinner
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Supplementary Legend
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- 2023
7. Data from Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343
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Shane Anthony Olwill, Louis Matis, Christine Rothe, Ulrich Moebius, Julia Schüler, Gabriele Matschiner, Alexander Wiedenmann, Andrea Allersdorfer, Corinna Schlosser, Manuela Carola Dürr, Sven Berger, Thomas J. Jaquin, Rachida Siham Bel Aiba, and Marlon J. Hinner
- Abstract
Purpose:4-1BB (CD137) is a key costimulatory immunoreceptor and promising therapeutic target in cancer. To overcome limitations of current 4-1BB–targeting antibodies, we have developed PRS-343, a 4-1BB/HER2 bispecific molecule. PRS-343 is designed to facilitate T-cell costimulation by tumor-localized, HER2-dependent 4-1BB clustering and activation.Experimental Design:PRS-343 was generated by the genetic fusion of 4-1BB–specific Anticalin proteins to a variant of trastuzumab with an engineered IgG4 isotype. Its activity was characterized using a panel of in vitro assays and humanized mouse models. The safety was assessed using ex vivo human cell assays and a toxicity study in cynomolgus monkeys.Results:PRS-343 targets 4-1BB and HER2 with high affinity and binds both targets simultaneously. 4-1BB–expressing T cells are efficiently costimulated when incubated with PRS-343 in the presence of cancer cells expressing HER2, as evidenced by increased production of proinflammatory cytokines (IL2, GM-CSF, TNFα, and IFNγ). In a humanized mouse model engrafted with HER2-positive SK-OV-3 tumor cells and human peripheral blood mononuclear cells, PRS-343 leads to tumor growth inhibition and a dose-dependent increase of tumor-infiltrating lymphocytes. In IND-enabling studies, PRS-343 was found to be well tolerated, with no overt toxicity and no relevant drug-related toxicologic findings.Conclusions:PRS-343 facilitates tumor-localized targeting of T cells by bispecific engagement of HER2 and 4-1BB. This approach has the potential to provide a more localized activation of the immune system with higher efficacy and reduced peripheral toxicity compared with current monospecific approaches. The reported data led to initiation of a phase I clinical trial with this first-in-class molecule.See related commentary by Su et al., p. 5732
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- 2023
8. Supplementary Figure 2 from Therapeutic Antibodies to Human L1CAM: Functional Characterization and Application in a Mouse Model for Ovarian Carcinoma
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Peter Altevogt, Ulrich Moebius, Jan Endell, Julia Costa, Ricardo Gouveia, Sandra Lüttgau, Marco Pfeifer, Helena Kiefel, Mina Fogel, Gerhard Moldenhauer, and Silke Wolterink
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Supplementary Figure 2 from Therapeutic Antibodies to Human L1CAM: Functional Characterization and Application in a Mouse Model for Ovarian Carcinoma
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- 2023
9. Supplementary Figure 1 from Therapeutic Antibodies to Human L1CAM: Functional Characterization and Application in a Mouse Model for Ovarian Carcinoma
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Peter Altevogt, Ulrich Moebius, Jan Endell, Julia Costa, Ricardo Gouveia, Sandra Lüttgau, Marco Pfeifer, Helena Kiefel, Mina Fogel, Gerhard Moldenhauer, and Silke Wolterink
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Supplementary Figure 1 from Therapeutic Antibodies to Human L1CAM: Functional Characterization and Application in a Mouse Model for Ovarian Carcinoma
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- 2023
10. Supplementary Table 1 from Therapeutic Antibodies to Human L1CAM: Functional Characterization and Application in a Mouse Model for Ovarian Carcinoma
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Peter Altevogt, Ulrich Moebius, Jan Endell, Julia Costa, Ricardo Gouveia, Sandra Lüttgau, Marco Pfeifer, Helena Kiefel, Mina Fogel, Gerhard Moldenhauer, and Silke Wolterink
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Supplementary Table 1 from Therapeutic Antibodies to Human L1CAM: Functional Characterization and Application in a Mouse Model for Ovarian Carcinoma
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- 2023
11. Supplementary Figure 4 from Therapeutic Antibodies to Human L1CAM: Functional Characterization and Application in a Mouse Model for Ovarian Carcinoma
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Peter Altevogt, Ulrich Moebius, Jan Endell, Julia Costa, Ricardo Gouveia, Sandra Lüttgau, Marco Pfeifer, Helena Kiefel, Mina Fogel, Gerhard Moldenhauer, and Silke Wolterink
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Supplementary Figure 4 from Therapeutic Antibodies to Human L1CAM: Functional Characterization and Application in a Mouse Model for Ovarian Carcinoma
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- 2023
12. Supplementary Figure 3 from Therapeutic Antibodies to Human L1CAM: Functional Characterization and Application in a Mouse Model for Ovarian Carcinoma
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Peter Altevogt, Ulrich Moebius, Jan Endell, Julia Costa, Ricardo Gouveia, Sandra Lüttgau, Marco Pfeifer, Helena Kiefel, Mina Fogel, Gerhard Moldenhauer, and Silke Wolterink
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Supplementary Figure 3 from Therapeutic Antibodies to Human L1CAM: Functional Characterization and Application in a Mouse Model for Ovarian Carcinoma
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- 2023
13. Supplementary Materials and Methods from Therapeutic Antibodies to Human L1CAM: Functional Characterization and Application in a Mouse Model for Ovarian Carcinoma
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Peter Altevogt, Ulrich Moebius, Jan Endell, Julia Costa, Ricardo Gouveia, Sandra Lüttgau, Marco Pfeifer, Helena Kiefel, Mina Fogel, Gerhard Moldenhauer, and Silke Wolterink
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Supplementary Materials and Methods from Therapeutic Antibodies to Human L1CAM: Functional Characterization and Application in a Mouse Model for Ovarian Carcinoma
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- 2023
14. Elarekibep (PRS-060/AZD1402): a new class of inhaled Anticalin medicine targeting IL-4Ra for T2 endotype asthma
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Gabriele Matschiner, Mary F. Fitzgerald, Ulrich Moebius, Andreas M. Hohlbaum, Hendrik Gille, Kristian Jensen, Klaus Kirchfeld, Barbara Rattenstetter, Alice Laforge, Rachida S. Bel Aiba, Joe Ciccotosto, Hong Nyugen, Martyn L. Foster, John N. Snouwaert, MyTrang Nguyen, Beverly H. Koller, Louis Matis, Gary P. Anderson, and Shane A. Olwill
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Immunology ,Immunology and Allergy - Abstract
T2 endotype asthma is driven by IL-4 and IL-13 signaling via IL-4Ra, which is highly expressed on airway epithelium, airway smooth muscle and immunocytes in the respiratory mucosa, suggesting potential advantages of an inhalable antagonist. Lipocalin 1 (Lcn1), a 16kD protein abundant in human periciliary fluid, has a robust drug-like structure well-suited to protein engineering, but has never been used to make an inhaled "Anticalin" protein therapeutic.To re-engineer Lcn1 into an inhalable IL-4Ra antagonist and assess its pharmacodynamic/kinetic profile.Lcn1 was systematically modified by directed protein mutagenesis yielding a high affinity, slowly dissociating, long-acting full antagonist of IL-4Ra designated 'PRS-060' with properties analogous to dupilumab, competitively antagonizing IL-4Ra dependent cell proliferation, mucus induction and eotaxin expression in vitro. As PRS-060 displayed exquisite specificity for human IL-4Ra, with no cross-reactivity to rodents or higher primates, we created a new triple-humanized mouse model substituting hIL-4Ra, hIL-4, and hIL-13 at their correct syntenic murine loci to model clinical dosing.Inhaled PRS-060 strongly suppressed acute allergic inflammation indices in triple humanized mice with a duration of action longer than its bulk clearance suggesting it may act locally in the lung.Lcn1 can be re-engineered into the Anticalin antagonist PRS-060, exemplifying a new class of inhaled topical, long-acting therapeutic with potential to treat T2 endotype asthma.
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- 2022
15. Abstract 3510: SOT201 is a novel targeted IL-15Rbg agonist to alleviate PD-1-mediated immune cell suppression and potentiate anti-tumor efficacy
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Irena Adkins, Zuzana Antosova, Klara Danova, Kamila Hladikova, Katerina Augustynkova, Katerina Sajnerova, Nada Podzimkova, Pavel Marasek, Guy de Martynoff, David Bechard, Ulrich Moebius, and Radek Spisek
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Cancer Research ,Oncology - Abstract
SOT201 is a novel immunocytokine consisting of a monoclonal humanized, Fc silenced antibody against PD-1 fused to a covalent RLI-15 complex of a human IL-15 mutein linked to the high-affinity binding site of the IL-15Rα, the sushi+ domain. SOT201 is developed for immunotherapeutic treatment of various types of cancers. The activity of SOT201 is based on spatiotemporal reinvigorating of anti-tumor immune responses by disrupting co-inhibitory T-cell signaling by blocking PD-1 and synergistically activating adaptive as well as innate immunity by IL-15-mediated signaling via the IL-2/IL-15βγ receptor on T cells, NK, NKT, and γδ T cells. SOT201 showed a superior potentiation of T cell stimulation over pembrolizumab in mixed lymphocyte reaction in vitro. Studies in cynomolgus monkeys showed that decreased affinity of IL-15 mutein in SOT201 for its IL-15Rβγ is well optimized to ensure favorable pharmacokinetic properties while inducing strong CD8+ T cell and NK cell activation and expansion. Synergistic action on CD8+ T cell activation of both anti-PD-1 and RLI-15 moieties was confirmed using mouse surrogate SOT201 molecules in vivo. Strong anti-tumor efficacy after SOT201 treatment was achieved in a human PD-1 transgenic mouse model implanted with the MC38-hPD-L1 cell line. These data represent a promising therapeutic candidate molecule leveraging the synergistic concerted action of anti-PD-1 blockage and simultaneous immune cell activation directed preferentially to the high PD-1+ T cell tumor environment. The therapeutic potential of SOT201 is currently being prepared for evaluation in a Phase I clinical study in metastatic advanced cancer patients as well as for PD-1 resistant/refractory patients as our clinical stage IL-2/IL-15Rβγ agonist SOT101 already showed a clinical benefit in these patients in its ongoing Phase I study. Citation Format: Irena Adkins, Zuzana Antosova, Klara Danova, Kamila Hladikova, Katerina Augustynkova, Katerina Sajnerova, Nada Podzimkova, Pavel Marasek, Guy de Martynoff, David Bechard, Ulrich Moebius, Radek Spisek. SOT201 is a novel targeted IL-15Rbg agonist to alleviate PD-1-mediated immune cell suppression and potentiate anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3510.
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- 2022
16. Abstract CT040: SOT101, an IL-2/IL-15 Rβγ superagonist, in combination with pembrolizumab in patients with advanced solid tumors: Interim safety and efficacy results from the AURELIO-03 dose escalation trial
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Stephane Champiat, Aurelien Marabelle, Vladimir Galvao, Patricia LoRusso, Peter Grell, Philippe Cassier, Carlos Gomez-Roca, Iphigenie Korakis, Aung Naing, Lenka Palova Jelinkova, Irena Adkins, Ulrich Moebius, Richard Sachse, Sascha Tillmanns, David Bechard, Joachim Kiemle-Kallee, and Elena Garralda
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Cancer Research ,Oncology - Abstract
Introduction: SOT101 (previously SO-C101), a fusion protein of IL-15 and the IL-15 receptor α sushi+ domain, was investigated in an open-label, multicenter, dose-escalation study as monotherapy and in combination with pembrolizumab in patients with selected advanced tumors (NCT04234113). Here we report an update on the safety and efficacy of the combination treatment. Methods Dose escalation followed a standard 3+3 design. Objectives were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). The evaluation period for dose-limiting toxicities in each dose step was 21 days. The RP2D was defined as the MTD or a dose below, considering pharmacokinetic and pharmacodynamic parameters. The study is ongoing (data cut-off 26 January 2022). Results: Twenty-one patients with a median of 2 (range 1-6) lines of previous systemic therapies were treated with 1.5, 3.0, 6.0, 9.0, and 12.0 μg/kg of SOT101 subcutaneously in combination with pembrolizumab. The MTD was not yet reached at the ongoing dose level 12.0 µg/kg, which is the RP2D in SOT101 monotherapy. The most common treatment-emergent adverse events were transient and included pyrexia, chills, injection site reaction, anemia, transaminase elevation, vomiting, and lymphopenia. One dose-limiting toxicity with rash, hypotension, and oliguria was reported at 6.0 µg/kg. The event resolved within 2 days and the patient continued with SOT101 at a lower dose. No treatment-related death was reported. One patient achieved a confirmed complete response (CR): mesothelioma at 9.0 µg/kg, on treatment 20 weeks with CR. This patient was immune checkpoint blocker (ICB)-naïve. Four patients achieved a partial response (PR): thyroid gland carcinoma at 3.0 µg/kg, ICB-naïve, on treatment 61 weeks with PR; skin squamous cell carcinoma at 6.0 µg/kg, ICB-relapsed, with PR and disappearance of target lesions, then fluctuating lesions, and on treatment 46 weeks with significant clinical benefit; skin melanoma at 6.0 µg/kg, ICB-relapsed, on treatment 41 weeks with PR; cervical melanoma at 9.0 µg/kg, ICB-pretreated, discontinued treatment after 8 weeks while still on PR. Five patients had confirmed stable disease (SD): anal squamous cell carcinoma (anal SCC) at 1.5 µg/kg, gastric cancer at 3.0 µg/kg, cervical cancer at 6.0 µg/kg, liver cancer at 6.0 µg/kg, and colorectal cancer at 9.0 µg/kg, with 1 patient (anal SCC) having a long-lasting SD over 40 weeks. In this heavily pretreated population, the observed preliminary clinical benefit rate was 63%. Conclusions: SOT101 in combination with pembrolizumab showed a favorable safety profile. Highly promising efficacy signals were reported in ICB-naïve and ICB pre-treated patients, including ICB-resistant tumors. Citation Format: Stephane Champiat, Aurelien Marabelle, Vladimir Galvao, Patricia LoRusso, Peter Grell, Philippe Cassier, Carlos Gomez-Roca, Iphigenie Korakis, Aung Naing, Lenka Palova Jelinkova, Irena Adkins, Ulrich Moebius, Richard Sachse, Sascha Tillmanns, David Bechard, Joachim Kiemle-Kallee, Elena Garralda. SOT101, an IL-2/IL-15 Rβγ superagonist, in combination with pembrolizumab in patients with advanced solid tumors: Interim safety and efficacy results from the AURELIO-03 dose escalation trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT040.
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- 2022
17. 562 SO-C101 induces NK cell cytotoxicity and potentiates antibody-dependent cell cytotoxicity and anti-tumor activity
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David Bechard, Radek Spisek, Ulrich Moebius, Guy de Martynoff, Zuzana Antosova, Irena Adkins, Eva Nedvedova, Nada Podzimkova, and Marketa Jiratova
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Antibody-dependent cell-mediated cytotoxicity ,Chemistry ,medicine.drug_class ,Daratumumab ,Monoclonal antibody ,NKG2D ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Monoclonal ,Cancer cell ,Cancer research ,medicine ,Cytotoxic T cell ,CD8 - Abstract
Background SO-C101 is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain, representing a promising clinical candidate for the treatment of cancer. SO-C101 specifically stimulates natural killer (NK) cells and memory CD8+ T cells with no significant expansion and activation of regulatory T cell compartment. Methods Human NK cell proliferation, the expression of NK cell receptors and ADCC activity of human PBMC after stimulation with SO-C101 in vitro in combination with monoclonal antibodies were detected by flow cytometry. The anti-tumor efficacy of SO-C101 in combination with Daratumumab was assessed in a multiple myeloma SCID xenograft mouse model in vivo. Results In this study, we show that SO-C101 induced proliferation and expansion of both major subsets of human NK cells, CD56brightCD16- and CD56dimCD16+. Furthermore, SO-C101 induced expression of the cytotoxic receptors NKp30 and NKG2D whereas no upregulation of the inhibitory receptors CD158a, CD158b and NKG2A was detected. Both NK cell subsets activated by SO-C101 exhibited cytotoxicity towards cancer cells in vitro. Using human PBMCs, we show that SO-C101 potentiated killing of tumor cells induced by several clinically approved therapeutic monoclonal antibodies such as Cetuximab, Daratumumab and Obinutuzumab in vitro. SO-C101 and Daratumumab monotherapy treatment inhibited tumor growth in vivo, however, their combination showed the strongest anti-tumor efficacy. Specifically, sequential administration of Daratumumab, followed by SO-C101 promoted complete tumor regression, compared to partial anti-tumor responses induced by the respective monotherapies. Conclusions SO-C101 augments the anti-tumor activity of therapeutic antibodies by increasing NK cells mediated antibody-dependent cell cytotoxicity. These results support the evaluation of SO-C101 in combination with monoclonal therapeutic antibodies in clinical studies. Ethics Approval The anti-tumor efficacy studies in mice were approved by the internal ethics board of the respective contract research organization (CRO).
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- 2020
18. Abstract 1204: SO-N102, a novel CLDN18.2-targeting antibody-drug conjugate with strong anti-tumor effect in various solid tumors expressing low target levels
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Ulrich Moebius, Roger R. Beerli, Lukas Bammert, Simona Hoskova, Lenka Sadilkova, Pavel Vopalensky, Radek Spisek, and Iva Valentova
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Antitumor activity ,Cancer Research ,Antibody-drug conjugate ,Oncology ,Chemistry ,Cancer research - Abstract
Claudin (CLDN) 18.2, a member of a large family of transmembrane proteins with distinct functions, has been shown to have a high prevalence, predominantly in gastric and pancreatic cancer. In addition, ectopic expression of CLDN18.2 was described for other cancer types including ovarian, lung, liver and colon, whereas healthy tissue expression is restricted to the stomach. SO-N102 represents a CLDN18.2 targeting antibody-drug conjugate based on a novel proprietary highly specific monoclonal antibody conjugated to a derivative of PNU-159682 using SMACTM technology for the therapy of patients with various CLDN18.2-positive solid tumors, mainly of gastric and pancreatic origin. The CLDN18.2 protein sequence is highly conserved in mammalians with 100% identity in the targeted extracellular loop among rodents, cynomolgus monkey and human. SO-N102 showed excellent specificity for CLDN18.2, strong binding to the target followed by efficient tumor cell killing. Preferential binding to selected patient-derived tumor tissues was observed ex vivo when compared to healthy stomach tissues from mice and cynomolgus monkey. Single-agent therapeutic activity of SO-N102 was demonstrated in 10 patient-derived mouse xenografts models (gastric, pancreatic, liver, colon and lung adenocarcinomas). Complete responses were observed in all models, independent of CLDN18.2 expression levels, ranging from low (IHC1+) to high (IHC3+), with minimum efficacious doses between 0.2 mg/kg and 0.6 mg/kg. An acceptable tolerability profile was observed in preliminary toxicity studies at 10 mg/kg (mouse), 6 mg/kg (rat) and 1 mg/kg (cynomolgus monkey). SO-N102 demonstrated favorable pharmacokinetic properties with half-lives in the range of 8 days and 13 days in cynomolgus monkey and rat, respectively. Stability of SO-N102 without any significant loss of the payload was demonstrated in vitro and in animals. Further toxicology studies in rats and cynomolgus monkeys were initiated, paralleled by process development and manufacturing activities with the plan to initiate the first clinical study with SO-N102 in patients in the first half of 2022. Citation Format: Lenka Kyrych Sadilkova, Iva Valentova, Simona Hoskova, Pavel Vopalensky, Lukas Bammert, Roger Beerli, Ulrich Moebius, Radek Spisek. SO-N102, a novel CLDN18.2-targeting antibody-drug conjugate with strong anti-tumor effect in various solid tumors expressing low target levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1204.
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- 2021
19. Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343
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Manuela Carola Dürr, Sven Berger, Alexander Wiedenmann, Christine Rothe, Rachida Siham Bel Aiba, Ulrich Moebius, Corinna Schlosser, Marlon Hinner, Julia Schüler, Gabriele Matschiner, Louis Matis, Andrea Allersdorfer, Shane Olwill, and Thomas Jaquin
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0301 basic medicine ,Cancer Research ,T cell ,T-Lymphocytes ,Lymphocyte Activation ,Proinflammatory cytokine ,03 medical and health sciences ,Mice ,Tumor Necrosis Factor Receptor Superfamily, Member 9 ,0302 clinical medicine ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Neoplasms ,Antibodies, Bispecific ,medicine ,Animals ,Humans ,biology ,Chemistry ,CD137 ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Humanized mouse ,biology.protein ,Cancer research ,Antibody ,Ex vivo - Abstract
Purpose: 4-1BB (CD137) is a key costimulatory immunoreceptor and promising therapeutic target in cancer. To overcome limitations of current 4-1BB–targeting antibodies, we have developed PRS-343, a 4-1BB/HER2 bispecific molecule. PRS-343 is designed to facilitate T-cell costimulation by tumor-localized, HER2-dependent 4-1BB clustering and activation. Experimental Design: PRS-343 was generated by the genetic fusion of 4-1BB–specific Anticalin proteins to a variant of trastuzumab with an engineered IgG4 isotype. Its activity was characterized using a panel of in vitro assays and humanized mouse models. The safety was assessed using ex vivo human cell assays and a toxicity study in cynomolgus monkeys. Results: PRS-343 targets 4-1BB and HER2 with high affinity and binds both targets simultaneously. 4-1BB–expressing T cells are efficiently costimulated when incubated with PRS-343 in the presence of cancer cells expressing HER2, as evidenced by increased production of proinflammatory cytokines (IL2, GM-CSF, TNFα, and IFNγ). In a humanized mouse model engrafted with HER2-positive SK-OV-3 tumor cells and human peripheral blood mononuclear cells, PRS-343 leads to tumor growth inhibition and a dose-dependent increase of tumor-infiltrating lymphocytes. In IND-enabling studies, PRS-343 was found to be well tolerated, with no overt toxicity and no relevant drug-related toxicologic findings. Conclusions: PRS-343 facilitates tumor-localized targeting of T cells by bispecific engagement of HER2 and 4-1BB. This approach has the potential to provide a more localized activation of the immune system with higher efficacy and reduced peripheral toxicity compared with current monospecific approaches. The reported data led to initiation of a phase I clinical trial with this first-in-class molecule. See related commentary by Su et al., p. 5732
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- 2018
20. Abstract 6686: SO-C101 displays strong anti-tumor effect in TC-1 and TRAMP-C2 tumor mice and in combination with PD-1 blockade prevents tumor development in a NK and CD8+ T cells dependent manner
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Guy de Martynoff, Nada Hradilova, David Bechard, Romana Mikyšková, Ulrich Moebius, Milan Reiniš, Radek Spisek, and Irena Adkins
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Cancer Research ,biology ,Chemistry ,T cell ,Cell ,Interleukin ,Immune system ,medicine.anatomical_structure ,Oncology ,Cancer research ,medicine ,biology.protein ,Cytotoxic T cell ,Antibody ,Receptor ,CD8 - Abstract
SO-C101 (RLI-15) is a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain designed to bypass the need of endogenous IL-15Rα, thereby leveraging the activity of IL-15 in vivo on target immune cells and reducing the toxicity of IL-15 as such. SO-C101 was previously shown to exhibit a potent anti-metastatic activity in Renca, B16F10 melanoma and delayed tumor growth in T cell-based mouse tumor models (CT26, MC38). Here we investigated the anti-tumor efficacy in predominantly natural killer (NK)-cell based mouse tumor models TC-1 and TRAMP-C2. We showed that SO-C101 monotherapy was effective in the treatment of established TC-1 tumors, which was dependent on the presence of both NK and CD8+ T cells, but not CD4+ T cells. In an early treatment setting SO-C101 significantly decreased the rate of tumor development also in dependence on NK and CD8+ T cells. SO-C101 effectively reduced tumor growth in TRAMP-C2 mice in early and advanced treatment settings. However, only in combination with anti-PD-1 antibody treatment the tumor development was prevented in majority of mice. This effect was durable, and the new tumor development was further significantly delayed after a tumor cell re-challenge, which suggests the involvement of memory T cells despite an important NK cell role in anti-tumor efficacy in these models. The efficacy of SO-C101 and anti-PD-1 treatment was not dependent on CD4+ T cells, but mainly on NK and CD8+ T cells. Interestingly, SO-C101 and anti-PD-1 treatment in double NK/CD8+ T cell-depleted mice decreased tumor growth which suggests an involvement of other immune cell populations in the anti-tumor efficacy. SO-C101 stimulated the proliferation and the cytotoxic activity of NK cells and memory CD8+ T cells without significant expansion of regulatory T cells. These data show the importance of various immune cell populations during SO-C101 monotherapy and the treatment in combination with anti-PD-1 antibodies, and set a base for further complex analysis of SO-C101 behavior. The therapeutic potential of SO-C101 is currently being tested in an ongoing Phase I clinical study in cancer patients. Citation Format: Irena Adkins, Romana Mikyskova, Nada Hradilova, Guy de Martynoff, David Bechard, Ulrich Moebius, Milan Reinis, Radek Spisek. SO-C101 displays strong anti-tumor effect in TC-1 and TRAMP-C2 tumor mice and in combination with PD-1 blockade prevents tumor development in a NK and CD8+ T cells dependent manner [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6686.
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- 2020
21. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one
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Andreas Lundqvist, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal Sanz, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Yumeng Mao, John-William Sidhom, Catherine A. Bessell, Jonathan Havel, Jonathan Schneck, Timothy A. Chan, Eliot Sachsenmeier, David Woods, Anders Berglund, Rupal Ramakrishnan, Andressa Sodre, Jeffrey Weber, Roberta Zappasodi, Yanyun Li, Jingjing Qi, Philip Wong, Cynthia Sirard, Michael Postow, Walter Newman, Henry Koon, Vamsidhar Velcheti, Margaret K. Callahan, Jedd D. Wolchok, Taha Merghoub, Lawrence G. Lum, Minsig Choi, Archana Thakur, Abhinav Deol, Gregory Dyson, Anthony Shields, Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Catherine Monaghan, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Sapna P. Patel, Rodabe Amaria, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem W. Overwijk, Chantale Bernatchez, Adi Diab, Erminia Massarelli, Neil H. Segal, Vincent Ribrag, Ignacio Melero, Tara C. Gangadhar, Walter Urba, Dirk Schadendorf, Robert L. Ferris, Roch Houot, Franck Morschhauser, Theodore Logan, Jason J. Luke, William Sharfman, Fabrice Barlesi, Patrick A. Ott, Laura Mansi, Shivaani Kummar, Gilles Salles, Cecilia Carpio, Roland Meier, Suba Krishnan, Dan McDonald, Matthew Maurer, Xuemin Gu, Jaclyn Neely, Satyendra Suryawanshi, Ronald Levy, Nikhil Khushalani, Jennifer Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein, Mark Bucsek, Guanxi Qiao, Cameron MacDonald, Bonnie Hylander, Elizabeth Repasky, Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Kyle Toth, Megan Meek, Elizabeth Garrett-Mayer, Michael Nishimura, Chrystal Paulos, Craig Beeson, Xuezhong Yu, Shikhar Mehrotra, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nicole Scharping, Ashley V. Menk, Rebecca Moreci, Ryan Whetstone, Rebekah Dadey, Simon Watkins, Robert Ferris, Greg M. Delgoffe, Jonathan Peled, Sean Devlin, Anna Staffas, Melissa Lumish, Kori Porosnicu Rodriguez, Katya Ahr, Miguel Perales, Sergio Giralt, Ying Taur, Eric Pamer, Marcel R. M. van den Brink, Robert Jenq, Nicola Annels, Hardev Pandha, Guy Simpson, Hugh Mostafid, Kevin Harrington, Alan Melcher, Mark Grose, Bronwyn Davies, Gough Au, Roberta Karpathy, Darren Shafren, Jacob Ricca, Dmitriy Zamarin, Luciana Batista, Florence Marliot, Angela Vasaturo, Sabrina Carpentier, Cécile Poggionovo, Véronique Frayssinet, Jacques Fieschi, Marc Van den Eynde, Franck Pagès, Jérôme Galon, Fabienne Hermitte, Sean G. Smith, Khue Nguyen, Sruthi Ravindranathan, Bhanu Koppolu, David Zaharoff, Gustavo Schvartsman, Roland Bassett, Jennifer L. McQuade, Lauren E. Haydu, Douglas Kline, Xiufen Chen, Dominick Fosco, Justin Kline, Abigail Overacre, Maria Chikina, Erin Brunazzi, Gulidanna Shayan, William Horne, Jay Kolls, Tullia C. 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June, Saar Gill, Duane Moogk, Shi Zhong, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Alan Frey, Michelle Krogsgaard, Daniel Landi, Kristen Fousek, Malini Mukherjee, Ankita Shree, Sujith Joseph, Kevin Bielamowicz, Tiara Byrd, Nabil Ahmed, Meenakshi Hegde, Sylvia Lee, David Byrd, John Thompson, Shailender Bhatia, Scott Tykodi, Judy Delismon, Liz Chu, Siddiq Abdul-Alim, Arpy Ohanian, Anna Marie DeVito, Stanley Riddell, Kim Margolin, Isabelle Magalhaes, Jonas Mattsson, Michael Uhlin, Satoshi Nemoto, Patricio Pérez Villarroel, Ryosuke Nakagawa, James J. Mule, Adam W. Mailloux, Melinda Mata, Phuong Nguyen, Claudia Gerken, Christopher DeRenzo, Stephen Gottschalk, Mélissa Mathieu, Sandy Pelletier, John Stagg, Simon Turcotte, Nicholas Minutolo, Prannda Sharma, Andrew Tsourkas, Nadine Mockel-Tenbrinck, Daniela Mauer, Katharina Drechsel, Carola Barth, Katharina Freese, Ulrike Kolrep, Silke Schult, Mario Assenmacher, Andrew Kaiser, John Mullinax, MacLean Hall, Julie Le, Krithika Kodumudi, Erica Royster, Allison Richards, Ricardo Gonzalez, Amod Sarnaik, Shari Pilon-Thomas, Morten Nielsen, Anders Krarup-Hansen, Dorrit Hovgaard, Michael Mørk Petersen, Anand Chainsukh Loya, Niels Junker, Charlotte Rivas, Robin Parihar, Cliona M. Rooney, Haiying Qin, Sang Nguyen, Paul Su, Chad Burk, Brynn Duncan, Bong-Hyun Kim, M. Eric Kohler, Terry Fry, Arjun A. Rao, Noam Teyssier, Jacob Pfeil, Nikolaos Sgourakis, Sofie Salama, David Haussler, Sarah A. 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Landis, Sally Koegler, Brooke Hirsch, Roberto Gianani, Jeffrey Kim, Ming-Xiao He, Bingqing Zhang, Nan Su, Yuling Luo, Xiao-Jun Ma, Emily Park, Dae Won Kim, Domenico Copploa, Nishi Kothari, Young doo Chang, Richard Kim, Namyong Kim, Melvin Lye, Ee Wan, Hanna A. Knaus, Sofia Berglund, Hubert Hackl, Judith E. Karp, Ivana Gojo, Leo Luznik, Henoch S. Hong, Sven D. Koch, Birgit Scheel, Ulrike Gnad-Vogt, Karl-Josef Kallen, Volker Wiegand, Linus Backert, Oliver Kohlbacher, Ingmar Hoerr, Mariola Fotin-Mleczek, James M. Billingsley, Yoshinobu Koguchi, Valerie Conrad, William Miller, Iliana Gonzalez, Tomasz Poplonski, Tanisha Meeuwsen, Ana Howells-Ferreira, Rogan Rattray, Mary Campbell, Carlo Bifulco, Keith Bahjat, Brendan Curti, E-K Vetsika, G. Kallergi, Despoina Aggouraki, Z. Lyristi, P. Katsarlinos, Filippos Koinis, V. Georgoulias, Athanasios Kotsakis, Nathan T. Martin, Famke Aeffner, Logan Cerkovnik, Luke Pratte, Rebecca Kim, Joseph Krueger, Amaia Martínez-Usatorre, Camilla Jandus, Alena Donda, Laura Carretero-Iglesia, Daniel E. Speiser, Dietmar Zehn, Nathalie Rufer, Pedro Romero, Anshuman Panda, Janice Mehnert, Kim M. Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Levi Sokol, Mark Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann Silk, Nancy Chan, Melissa Frankel, Michael Kane, Jyoti Malhotra, Joseph Aisner, Howard L. Kaufman, Siraj Ali, Jeffrey Ross, Eileen White, Gyan Bhanot, Shridar Ganesan, Anne Monette, Derek Bergeron, Amira Ben Amor, Liliane Meunier, Christine Caron, Antigoni Morou, Daniel Kaufmann, Moishe Liberman, Igor Jurisica, Anne-Marie Mes-Masson, Kamel Hamzaoui, Rejean Lapointe, Ann Mongan, Yuan-Chieh Ku, Warren Tom, Yongming Sun, Alex Pankov, Tim Looney, Janice Au-Young, Fiona Hyland, Jeff Conroy, Carl Morrison, Sean Glenn, Blake Burgher, He Ji, Mark Gardner, Angela R. Omilian, Wiam Bshara, Omilian Angela, Joseph M. Obeid, Gulsun Erdag, Mark E. Smolkin, Donna H. Deacon, James W. Patterson, Lieping Chen, Timothy N. Bullock, Craig L. Slingluff, John T. Loffredo, Raja Vuyyuru, Sophie Beyer, Vanessa M. Spires, Maxine Fox, Jon M. Ehrmann, Katrina A. Taylor, Alan J. Korman, Robert F. Graziano, David Page, Katherine Sanchez, Maritza Martel, Mariana Petaccia De Macedo, Yong Qin, Alex Reuben, Christine Spencer, Michele Guindani, Adriana Racolta, Brian Kelly, Tobin Jones, Nathan Polaske, Noah Theiss, Mark Robida, Jeffrey Meridew, Iva Habensus, Liping Zhang, Lidija Pestic-Dragovich, Lei Tang, Ryan J. Sullivan, Thomas Olencki, Thomas Hutson, Joanna Roder, Shauna Blackmon, Heinrich Roder, John Stewart, Asim Amin, Marc S. Ernstoff, Joseph I. Clark, Michael B. Atkins, Jeffrey Sosman, David F. McDermott, Harriet Kluger, Ruth Halaban, Mario Snzol, Senait Asmellash, Arni Steingrimsson, Chichung Wang, Kristin Roman, Amanda Clement, Sean Downing, Clifford Hoyt, Nathalie Harder, Guenter Schmidt, Ralf Schoenmeyer, Nicolas Brieu, Mehmet Yigitsoy, Gabriele Madonna, Gerardo Botti, Antonio Grimaldi, Paolo A. Ascierto, Ralf Huss, Maria Athelogou, Harald Hessel, Alexander Buchner, Christian Stief, Gerd Binnig, Thomas Kirchner, Shankar Sellappan, Sheeno Thyparambil, Sarit Schwartz, Fabiola Cecchi, Andrew Nguyen, Charles Vaske, Todd Hembrough, Jan Spacek, Michal Vocka, Eva Zavadova, Helena Skalova, Pavel Dundr, Lubos Petruzelka, Nicole Francis, Rau T. Tilman, Arndt Hartmann, Irena Netikova, Julia Stump, Amanda Tufman, Frank Berger, Michael Neuberger, Rudolf Hatz, Michael Lindner, Rachel E. Sanborn, John Handy, Rudolf M. Huber, Hauke Winter, Simone Reu, Cheng Sun, Weihua Xiao, Zhigang Tian, Kshitij Arora, Niyati Desai, Anupriya Kulkarni, Mihir Rajurkar, Miguel Rivera, Vikram Deshpande, David Ting, Katy Tsai, Adi Nosrati, Simone Goldinger, Omid Hamid, Alain Algazi, Paul Tumeh, Jimmy Hwang, Jacqueline Liu, Lawrence Chen, Reinhard Dummer, Michael Rosenblum, Adil Daud, Tsu-Shuen Tsao, Julia Ashworth-Sharpe, Donald Johnson, Srabani Bhaumik, Christopher Bieniarz, Joseph Couto, Michael Farrell, Mahsa Ghaffari, Antony Hubbard, Jerome Kosmeder, Cleo Lee, Erin Marner, Diana Uribe, Hongjun Zhang, Jian Zhang, Wenjun Zhang, Yifei Zhu, Larry Morrison, Takahiro Tsujikawa, Rohan N. Borkar, Vahid Azimi, Sushil Kumar, Guillaume Thibault, Motomi Mori, Edward El Rassi, Daniel R. Clayburgh, Molly F. Kulesz-Martin, Paul W. Flint, Lisa M. Coussens, Lisa Villabona, Giuseppe V. Masucci, Gary Geiss, Brian Birditt, Qian Mei, Alan Huang, Maribeth A. 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Bauer, Judy S. Wang, Jean K. Lee, Gulam A. Manji, Ragini Kudchadkar, John S. Kauh, Shande Tang, Naomi Laing, Gerald Falchook, Edward B. Garon, Balazs Halmos, Hui Rina, Natasha Leighl, Sung Sook Lee, William Walsh, Konstanin Dragnev, Bilal Piperdi, Luis Paz-Ares Rodriguez, Nabeegha Shinwari, Ziewn Wei, Mary L Maas, Michael Deeds, Adam Armstrong, Tim Peterson, Sue Steinmetz, Thomas Herzog, Floor J. Backes, Larry Copeland, Maria Del Pilar Estevez Diz, Thomas W. Hare, Warner Huh, Byoung-Gie Kim, Kathleen M. Moore, Ana Oaknin, William Small, Krishnansu S. Tewari, Bradley J. Monk, Ashish M. Kamat, Kijoeng Nam, Maria De Santis, Robert Dreicer, Noah M. Hahn, Rodolfo Perini, Arlene Siefker-Radtke, Guru Sonpavde, Ronald de Wit, J. Alfred Witjes, Stephen Keefe, Dean Bajorin, Philippe Armand, John Kuruvilla, Craig Moskowitz, Mehdi Hamadani, Pier Luigi Zinzani, Sabine Chlosta, Nancy Bartlett, Rachel Sabado, Yvonne Saenger, Loging William, Michael Joseph Donovan, Erlinda Sacris, John Mandeli, Andres M. Salazar, John Powderly, Joshua Brody, John Nemunaitis, Leisha Emens, Amita Patnaik, Ian McCaffery, Richard Miller, Ginna Laport, Andrew L. Coveler, David C. Smith, Juneko E. Grilley-Olson, Sanjay Goel, Shyra J. Gardai, Che-Leung Law, Gary Means, Thomas Manley, Kristen A. Marrone, Gary Rosner, Valsamo Anagnostou, Joanne Riemer, Jessica Wakefield, Cynthia Zanhow, Stephen Baylin, Barbara Gitlitz, Julie Brahmer, Sabina Signoretti, Wenting Li, Charles Schloss, Jean-Marie Michot, Wei Ding, Beth Christian, Patricia Marinello, Margaret Shipp, Yana G. Najjar, null Lin, Lisa H. Butterfield, Ahmad A. Tarhini, Diwakar Davar, Hassane Zarour, Elizabeth Rush, Cindy Sander, Siqing Fu, Todd Bauer, Chris Molineaux, Mark K. Bennett, Keith W. Orford, Kyriakos P. Papadopoulos, Sukhmani K. Padda, Sumit A. Shah, A Dimitrios Colevas, Sujata Narayanan, George A. Fisher, Dana Supan, Heather A. Wakelee, Rhonda Aoki, Mark D. Pegram, Victor M. Villalobos, Jie Liu, Chris H. Takimoto, Mark Chao, Jens-Peter Volkmer, Ravindra Majeti, Irving L. Weissman, Branimir I. Sikic, Wendy Yu, Alison Conlin, Janet Ruzich, Stacy Lewis, Anupama Acheson, Kathleen Kemmer, Kelly Perlewitz, Nicole M. Moxon, Staci Mellinger, Heather McArthur, Trine Juhler-Nøttrup, Jayesh Desai, Ben Markman, Shahneen Sandhu, Hui Gan, Michael L. Friedlander, Ben Tran, Tarek Meniawy, Joanne Lundy, Duncan Colyer, Malaka Ameratunga, Christie Norris, Jason Yang, Kang Li, Lai Wang, Lusong Luo, Zhen Qin, Song Mu, Xuemei Tan, James Song, Michael Millward, Matthew H. G. Katz, Todd W. Bauer, Gauri R. Varadhachary, Nicolas Acquavella, Nipun Merchant, Gina Petroni, Osama E. Rahma, Mei Chen, Yang Song, Markus Puhlmann, Arun Khattri, Ryan Brisson, Christopher Harvey, Jatin Shah, Maria Victoria Mateos, Morio Matsumoto, Hilary Blacklock, Albert Oriol Rocafiguera, Hartmut Goldschmidt, Shinsuke Iida, Dina Ben Yehuda, Enrique Ocio, Paula Rodríguez-Otero, Sundar Jagannath, Sagar Lonial, Uma Kher, Jesus San-Miguel, Moacyr Ribeiro de Oliveira, Habte Yimer, Robert Rifkin, Fredrik Schjesvold, Razi Ghori, Anna Spreafico, Victor Lee, Roger K. C. Ngan, Ka Fai To, Myung Ju Ahn, Quan Sing Ng, Jin-Ching Lin, Ramona F. Swaby, Christine Gause, Sanatan Saraf, Anthony T. C. Chan, Elaine Lam, Nizar M. Tannir, Funda Meric-Bernstam, Matt Gross, Andy MacKinnon, Sam Whiting, Martin Voss, Evan Y. Yu, Mark R. Albertini, Erik A. Ranheim, Jacquelyn A. Hank, Cindy Zuleger, Thomas McFarland, Jennifer Collins, Erin Clements, Sharon Weber, Tracey Weigel, Heather Neuman, Greg Hartig, David Mahvi, MaryBeth Henry, Jacek Gan, Richard Yang, Lakeesha Carmichael, KyungMann Kim, Stephen D. Gillies, Paul M. Sondel, Vivek Subbiah, Lori Noffsinger, Kyle Hendricks, Marnix Bosch, Jay M. Lee, Mi-Heon Lee, Jonathan W. Goldman, Felicita E. Baratelli, Dorthe Schaue, Gerald Wang, Frances Rosen, Jane Yanagawa, Tonya C. Walser, Ying Q. Lin, Sharon Adams, Franco M. Marincola, Paul C. Tumeh, Fereidoun Abtin, Robert Suh, Karen Reckamp, William D. Wallace, Gang Zeng, David A. Elashoff, Sherven Sharma, Steven M. Dubinett, Anna C. Pavlick, Brian Gastman, Brent Hanks, Tibor Keler, Tom Davis, Laura A. Vitale, Elad Sharon, Chihiro Morishima, Martin Cheever, Christopher R. Heery, Joseph W. Kim, Elizabeth Lamping, Jennifer Marte, Sheri McMahon, Lisa Cordes, Farhad Fakhrejahani, Ravi Madan, Rachel Salazar, Maggie Zhang, Christoph Helwig, James L Gulley, Roger Li, John Amrhein, Zvi Cohen, Monique Champagne, Ashish Kamat, M. Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Manel Esteller, Juan Sandoval, Susannah D. Barbee, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Susan Johnson, Johanna Park, Amanda Chen, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges, Rukmini Bhardwaj, Raj K. Puri, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Todd Bartkowiak, Ashvin Jaiswal, Casey Ager, Midan Ai, Pratha Budhani, Renee Chin, David Hong, Michael Curran, William D. Hastings, Maria Pinzon-Ortiz, Masato Murakami, Jason R. Dobson, David Quinn, Joel P. Wagner, Xianhui Rong, Pamela Shaw, Ernesta Dammassa, Wei Guan, Glenn Dranoff, Alexander Cao, Ross B. Fulton, Steven Leonardo, Kathryn Fraser, Takashi O. Kangas, Nadine Ottoson, Nandita Bose, Richard D. Huhn, Jeremy Graff, Jamie Lowe, Keith Gorden, Mark Uhlik, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, Venky Ramakrishna, James Storey, Lawrence J. Thomas, Joel Goldstein, Henry C. Marsh, Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng, Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Thomas Jaquin, Andrea Allersdorfer, Sven Berger, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Olwill A. Shane, Brendan Horton, Stefani Spranger, Dayson Moreira, Tomasz Adamus, Xingli Zhao, Piotr Swiderski, Sumanta Pal, Marcin Kortylewski, Alyssa Kosmides, Kevin Necochea, Kathleen M. Mahoney, Sachet A. Shukla, Nikolaos Patsoukis, Apoorvi Chaudhri, Hung Pham, Ping Hua, Xia Bu, Baogong Zhu, Nir Hacohen, Catherine J. Wu, Edward Fritsch, Vassiliki A. Boussiotis, Gordon J. Freeman, Amy E. Moran, Fanny Polesso, Lisa Lukaesko, Emelie Rådestad, Lars Egevad, Berit Sundberg, Lars Henningsohn, Victor Levitsky, William Rafelson, John L. Reagan, Loren Fast, Pottayil Sasikumar, Naremaddepalli Sudarshan, Raghuveer Ramachandra, Nagesh Gowda, Dodheri Samiulla, Talapaneni Chandrasekhar, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit Dhudashia, Nagaraj Gowda, Murali Ramachandra, Alexander Sankin, Benjamin Gartrell, Kerwin Cumberbatch, Hongying Huang, Joshua Stern, Mark Schoenberg, Xingxing Zang, Ryan Swanson, Michael Kornacker, Lawrence Evans, Erika Rickel, Martin Wolfson, Sandrine Valsesia-Wittmann, Tala Shekarian, François Simard, Rodrigo Nailo, Aurélie Dutour, Anne-Catherine Jallas, Christophe Caux, and Aurélien Marabelle
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Pharmacology ,0303 health sciences ,Cancer Research ,Side effect ,business.industry ,medicine.drug_class ,Immunology ,Phases of clinical research ,Monoclonal antibody ,Phase i study ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Pharmacokinetics ,030220 oncology & carcinogenesis ,Molecular Medicine ,Immunology and Allergy ,Medicine ,In patient ,Programmed death 1 ,business ,030304 developmental biology - Published
- 2016
22. Abstract 3775: Use of RLI-15 a clinical grade fusion protein with IL-15 superagonistic activity for the activation of anti-tumor immune response
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Guy de Martynoff, Ulrich Moebius, Romana Mikyšková, David Bechard, Marek Kovar, Nada Hradilova, Milan Reiniš, Irena Adkins, Jakub Tomala, Lenka Sadilkova, Barbora Tomalova, and Radek Spisek
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Cancer Research ,biology ,business.industry ,Regulatory T cell ,T cell ,Cancer ,medicine.disease ,Immune system ,medicine.anatomical_structure ,Oncology ,Interleukin 15 ,Cancer research ,biology.protein ,Medicine ,Cytotoxic T cell ,Antibody ,business ,CD8 - Abstract
RLI-15, a superagonist fusion protein of interleukin (IL)-15 and the IL-15 receptor α (IL-15Rα) sushi+ domain represents a promising candidate for the induction of anti-tumor immunity. RLI-15 was designed to bypass the need of endogenous IL-15Rα, thereby leveraging the activity of IL-15 in vivo on target immune cells. RLI-15 stimulates the proliferation and the cytotoxic activity of natural killer (NK) cells and memory CD8+ T cells with no significant expansion and activation of regulatory T cell compartment. RLI-15 was previously shown to exhibit a potent anti-metastatic activity in B16F10 melanoma and Renca renal cell carcinoma mouse models. RLI-15 also significantly delayed tumor growth and prolonged survival when combined with anti-PD1 therapy in CT26 and MC38 colon carcinoma models. Here, we report that the combination treatment with clinical-grade RLI-15 and an anti-PD1 antibody leads to a significant anti-tumor efficacy in a TRAMP-C2 prostate cancer mouse model with 70 % of mice remaining tumor free after the treatment. We evaluated the optimal schedule of such combination therapy to set the basis for the design of upcoming clinical trials. We further tested how the administration schedule affects the pharmacodynamics properties of clinical-grade RLI-15 and translates into the anti-tumor efficacy in metastatic Renca and CT26 mouse models. In cynomolgous monkeys, various schedules of administration of RLI-15 showed a dose-dependent expansion of peripheral blood lymphocytes, predominantly of NK cell and memory CD8+ T cell compartments. The toxicity in mice and cynomolgous monkeys was evaluated to determine the maximal tolerated dose of RLI-15. Furthermore, the activity of clinical-grade RLI-15 was tested in vitro on human PBMCs and the superiority over IL-2 and IL-15 stimulatory capacity has been confirmed. The complex analysis of RLI-15 behavior and of the induced anti-tumor immune response will be explored in the design of a planned Phase I clinical study in patients with both solid tumors and hematological malignancies. Citation Format: Irena Adkins, Lenka Sadilkova, Nada Hradilova, Jakub Tomala, Barbora Tomalova, Marek Kovar, Romana Mikyskova, Milan Reinis, Guy de Martynoff, David Bechard, Ulrich Moebius, Radek Spisek. Use of RLI-15 a clinical grade fusion protein with IL-15 superagonistic activity for the activation of anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3775.
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- 2018
23. Efficacy of Oncolytic Herpesvirus NV1020 Can Be Enhanced by Combination with Chemotherapeutics in Colon Carcinoma Cells
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Mihaela Weber, Elfriede Mayer, Martina Muench, Anja Gutermann, Martin Lechmann, Juergen Suehnel, Ulrich Moebius, Claudia Breidenstein, Karin von Dehn-Rothfelser, and Denis Gungor
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Combination therapy ,Colorectal cancer ,Antineoplastic Agents ,Herpesvirus 1, Human ,Virus Replication ,Mice ,In vivo ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Viability assay ,Clonogenic assay ,Molecular Biology ,Mice, Inbred BALB C ,business.industry ,Genetic Therapy ,medicine.disease ,Combined Modality Therapy ,Oncolytic virus ,Oxaliplatin ,Colonic Neoplasms ,Immunology ,Cancer research ,Molecular Medicine ,Fluorouracil ,business ,medicine.drug - Abstract
NV1020, an oncolytic herpes simplex virus type 1, can destroy colon cancer cells by selectively replicating within these cells, while sparing normal cells. NV1020 is currently under investigation in a clinical phase I/II trial as an agent for the treatment of colon cancer liver metastases, in combination with conventional chemotherapeutic agents such as 5-fluorouracil (5-FU), SN38 (the active metabolite of irinotecan), and oxaliplatin. To study the synergy of NV1020 and chemotherapy, cytotoxicity and viral replication were evaluated in vitro by treating various human and murine colon carcinoma cell lines, using a colorimetric viability assay, a clonogenic assay, and a plaque-forming assay. In vivo experiments, using a subcutaneous syngeneic CT-26 tumor model in BALB/c mice, were performed to determine the efficacy of combination therapy. In vitro studies showed that the efficacy of NV1020 on human colon carcinoma cell lines HT-29, WiDr, and HCT-116 was additively or synergistically enhanced in combination with 5-FU, SN38, or oxaliplatin. The sequence of application was not important and effects were still apparent after a 21-day incubation period. Three intra-tumoral treatments with NV1020 (1 x 10(7) plaque-forming units), followed by three subcutaneous treatments with 5-FU (50 mg/kg), resulted in substantially higher inhibition of tumor growth and prolongation of survival compared with monotherapies (NV1020/5-FU vs. NV1020, p = 0.027). On WiDr cells, reduced replication of NV1020, in combination with 5-FU, indicated that additive and synergistic effects of combination therapy must be independent from viral replication. These results suggest that NV1020, in combination with chemotherapy, is a promising therapy for treating patients with metastatic colorectal cancer of the liver. We hypothesize that infection of cells with NV1020 sensitizes the infected cells for the cytotoxic effect of the chemotherapeutics.
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- 2006
24. Costimulatory T-cell engagement by PRS-343, a CD137 (4-1BB)/HER2 bispecific, leads to tumor growth inhibition and TIL expansion in a humanized mouse model
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Thomas Jaquin, Gabriele Matschiner, Julia Schüler, R.S. Bel Aiba, Corinna Schlosser, Shane A. Olwill, Andrea Allersdorfer, Sven Berger, Ulrich Moebius, Christine Rothe, Alexander Wiedenmann, and Marlon Hinner
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0301 basic medicine ,Cancer Research ,business.industry ,T cell ,CD137 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Humanized mouse ,Immunology ,Cancer research ,Medicine ,Tumor growth inhibition ,business - Published
- 2016
25. Abstract B016: Costimulatory T-cell engagement by PRS-343, a CD137 (4-1BB)/HER2 bispecific, leads to tumor growth inhibition and TIL expansion in humanized mouse model
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Julia Schüler, Ulrich Moebius, Alexander Wiedenmann, Shane Olwill, Marlon Hinner, Corinna Schlosser, Sven Berger, Rachida-Siham Bel Aiba, Christine Rothe, Thomas Jaquin, Gabriele Matschiner, and Andrea Allersdorfer
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Antibody-dependent cell-mediated cytotoxicity ,Cancer Research ,medicine.drug_class ,medicine.medical_treatment ,T cell ,Immunology ,CD137 ,02 engineering and technology ,Biology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Monoclonal antibody ,01 natural sciences ,0104 chemical sciences ,Immune system ,medicine.anatomical_structure ,Cancer immunotherapy ,Humanized mouse ,Cancer research ,medicine ,0210 nano-technology ,CD8 - Abstract
Background: CD137 (4-1BB) is a key costimulatory immunoreceptor and a member of the TNF-receptor (TNFR) superfamily. While multiple lines of evidence show that CD137 is a highly promising therapeutic target in cancer, current mAb-based approaches are not designed to achieve a tumor-target driven activation and may display toxicity and a limited therapeutic window due to peripheral T cell and NK cell activation. To overcome this limitation, we generated PRS-343, a CD137/HER2 bispecific that is designed to promote CD137 clustering by bridging CD137-positive T cells with HER2-positive tumor cells, thereby providing a potent costimulatory signal to tumor antigen-specific T cells. Methods: Anticalin® proteins are 18 kD protein therapeutics derived from human lipocalins. We utilized phage display to generate an Anticalin protein binding to CD137 with high affinity and specificity. PRS-343 was obtained by genetic fusion of the CD137-specific Anticalin protein to a variant of the HER2-targeting monoclonal antibody trastuzumab with an engineered IgG4 backbone. We have shown previously that the bispecific fusion PRS-343 targets CD137 and HER2 in a bispecific manner and efficiently activates T cells ex vivo in the presence of HER2-positive cells. Here, in vivo proof of concept data is presented utilizing a humanized mouse model in immunocompromised mice and the SK-OV-3 cell line as a HER2-positive xenograft. When tumors had reached a predefined size, mice received human PBMC via an intravenous route and weekly intraperitoneal injections of PRS-343 for three weeks. An IgG4 isotype antibody served as the negative control, while a CD137-targeting benchmark antibody and trastuzumab with an engineered IgG4 backbone (“tras-IgG4”) served as controls for monospecific targeting of CD137 and HER2, respectively. Results: PRS-343 activity was investigated at four different weekly doses of PRS-343 (4μg, 20μg, 100μg and 200μg). We found that PRS-343 dose-dependently led to strong tumor growth inhibition compared to treatment with the isotype control, and that the tumor response was accompanied by a significantly higher tumor infiltration with human lymphocytes (hCD45+). Interestingly, the anti-CD137 benchmark neither displayed tumor growth inhibition nor enhanced lymphocyte infiltration into tumors compared to isotype. The tras-IgG4 control was also devoid of lymphocyte infiltration into the tumor, but displayed a tumor growth inhibition comparable to PRS-343. Taken together, these data show that PRS-343 provided dual activity by both increasing the frequency of tumor-infiltrating lymphocytes by bispecific targeting of CD137 and HER2 as well as mediating direct tumor growth inhibition by the direct, monospecific targeting of HER2. Notably, the tumor growth inhibition provided by targeting HER2 did not require any antibody directed cellular cytotoxicity (ADCC) as both PRS-343 and the tras-IgG4 control lack the ability to interact with Fc-gamma receptors on NK cells that ADCC would require. The animal model also allowed investigating the potential safety of PRS-343: While the anti-CD137 benchmark accelerated the onset of graft-versus-host-disease and led to stronger expansion of CD8+ T cells in the peripheral blood compared to the isotype control group, both of these effects were absent for PRS-343. The data therefore support the envisaged mode of action of selective, tumor-localized costimulatory T cell activation, as well as the concept that such an approach may lead to higher efficacy and reduced systemic toxicity compared to conventional anti-CD137 mAbs. Conclusion: We report potent costimulatory T-cell engagement of the immunoreceptor CD137 in a HER2-dependent manner, utilizing the CD137/HER2 bispecific PRS-343. In a humanized mouse model, PRS-343 displays dual activity based on monospecific HER2-targeting and bispecific, tumor-localized costimulation of CD137. Compared to known CD137-targeting antibodies in clinical development, this approach has the potential to provide a more localized activation of the immune system with higher efficacy and reduced peripheral toxicity. The direct, monospecific HER2-targeting activity may provide an additional therapeutic benefit and work in synergy with local CD137 costimulation. The positive functional ex vivo and in vivo data of PRS-343 as well as the excellent developability profile support investigation of its anti-cancer activity in clinical trials. Citation Format: Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Thomas Jaquin, Andrea Allersdorfer, Sven Berger, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Shane A. Olwill. Costimulatory T-cell engagement by PRS-343, a CD137 (4-1BB)/HER2 bispecific, leads to tumor growth inhibition and TIL expansion in humanized mouse model [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B016.
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- 2016
26. Abstract 556: Costimulatory T-cell engagement by the HER2/CD137 bispecific PRS-343 leads to strong antitumor effect in humanized mouse model
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Gabriele Matschiner, Corinna Schlosser, Sven Berger, Marlon Hinner, Ulrich Moebius, Christine Rothe, Alexander Wiedenmann, Andrea Allersdorfer, Rachida-Siham Bel Aiba, and Shane Olwill
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0301 basic medicine ,Cancer Research ,Chemistry ,medicine.drug_class ,T cell ,CD137 ,Monoclonal antibody ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,medicine.anatomical_structure ,Oncology ,In vivo ,030220 oncology & carcinogenesis ,Humanized mouse ,Immunology ,Cancer research ,medicine ,Ex vivo ,Anticalin - Abstract
Background. CD137 (4-1BB) is a key costimulatory immunoreceptor and a member of the TNF-receptor (TNFR) superfamily. While multiple lines of evidence show that CD137 is a highly promising therapeutic target in cancer, current mAb-based approaches are not designed to achieve a tumor-target driven activation and may display toxicity and a limited therapeutic window due to peripheral T cell and NK cell activation. To overcome this limitation, we generated PRS-343, a HER2/CD137 bispecific that is designed to promote CD137 clustering by bridging CD137-positive T cells with HER2-positive tumor cells, thereby providing a potent costimulatory signal to tumor antigen-specific T cells. Methods. Anticalin® proteins are 18 kD protein therapeutics derived from human lipocalins. We utilized phage display to generate an Anticalin protein binding to CD137 with high affinity and specificity. PRS-343 was obtained by genetic fusion of the CD137-specific Anticalin protein to a variant of the HER2-targeting monoclonal antibody trastuzumab with an engineered IgG4 backbone. Results. The bispecific fusion PRS-343 targets CD137 and HER2 with nearly identical affinities compared to the parental building blocks, and is capable of binding both targets simultaneously. We show ex vivo that T cells are efficiently activated when incubated with PRS-343 and HER2-positive cells, and that the activation is HER2-dependent. The in vivo activity of PRS-343 was investigated utilizing a humanized mouse model with a tumor cell-line-derived, HER2-positive xenograft. When tumors had reached a predefined size, mice received human PBMC via an intravenous route and weekly intraperitoneal injections of PRS-343 or controls for three weeks. We found that PRS-343 led to strong tumor growth inhibition and a significantly better response compared to either isotype control or anti-CD137 benchmark mAbs. The data, which include phenotyping of peripheral and intra-tumoral lymphocytes, support the envisaged mode of action of tumor-localized costimulatory T cell activation. Conclusion. We report potent costimulatory T-cell engagement of the immunoreceptor CD137 in a HER2-dependent manner, utilizing the HER2/CD137 bispecific PRS-343. Compared to known CD137-targeting antibodies in clinical development, this approach has the potential to provide a more localized activation of the immune system with higher efficacy and reduced peripheral toxicity. The positive functional ex vivo and in vivo data of PRS-343 as well as the excellent developability profile support investigation of its anti-cancer activity in clinical trials. Citation Format: Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Alexander Wiedenmann, Andrea Allersdorfer, Gabriele Matschiner, Sven Berger, Ulrich Moebius, Christine Rothe, Shane A. Olwill. Costimulatory T-cell engagement by the HER2/CD137 bispecific PRS-343 leads to strong antitumor effect in humanized mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 556.
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- 2016
27. Abstract B023: Costimulatory T-cell engagement via a novel bispecific anti-CD137 /anti-HER2 protein based on Anticalin® technology
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Rachida-Siham Bel Aiba, Gabriele Matschiner, Marlon Hinner, Shane Olwill, Alexander Wiedenmann, Christine Rothe, Andrea Allersdorfer, Corinna Schlosser, and Ulrich Moebius
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Cancer Research ,Phage display ,business.industry ,T cell ,medicine.medical_treatment ,Immunology ,CD137 ,Plasma protein binding ,medicine.anatomical_structure ,Cancer immunotherapy ,Cancer research ,medicine ,Receptor ,business ,Anticalin ,CD8 - Abstract
Background: CD137 is a potent costimulatory immunoreceptor and a member of the TNF-receptor (TNFR) superfamily. The receptor, also known as 4-1BB, is mainly expressed on activated CD4+ and CD8+ T cells, activated B cells, and natural killer (NK) cells. While multiple lines of evidence show that CD137 is a highly promising therapeutic target, current approaches are not designed to achieve a tumor-target driven activation, which may reduce the available therapeutic window via peripheral T cell activation and toxicity. To overcome this limitation, we applied Anticalin® technology to generate a bispecific protein therapeutic binding to CD137 and a differentially expressed tumor target, HER2. Methods: Anticalin® proteins are 18 kD protein therapeutics derived from human lipocalins which enable straight-forward multimeric drug targeting across several formats. We utilized phage display to generate an Anticalin protein binding to CD137 with high affinity and specificity. The CD137-specific Anticalin protein was genetically fused to a Trastuzumab variant, yielding four different constructs covering a range of distances between the binding sites of the T cell-target and the tumor cell target. To minimize Fc-receptor interaction of the resulting bispecific and concomitant potential toxicity towards CD137-positive cells, the backbone of Trastuzumab was switched from IgG1 to an engineered IgG4 isotype. Results: All four bispecific constructs bound the targets CD137 and HER2 with a nearly identical affinity compared to the parental building blocks, and both targets could be simultaneously bound. Compared to non-engineered Trastuzumab, binding to human receptors FcγRI and FcγRIII was significantly reduced, while binding to the neonatal Fc receptor (FcRn) was retained. Functional activity was demonstrated in human T cell activation assays, and shown to be tumor target (HER2) dependent. Conclusion: We report the first bispecific therapeutic protein that targets the potent costimulatory immunoreceptor CD137 in a tumor-target dependent manner, utilizing HER2 as the tumor target. Compared to currently existing CD137-targeting antibodies, this approach has the potential to provide a more localized activation of the immune system with reduced peripheral toxicity. Bispecific T cell engagers based on CD137 and HER2 may have utility in HER2-positive cancers where there is a significant unmet medical need, such as bladder, ovarian and gastric cancer. Citation Format: Marlon J. Hinner, Rachida-Siham Bel Aiba, Alexander Wiedenmann, Corinna Schlosser, Andrea Allersdorfer, Gabriele Matschiner, Christine Rothe, Ulrich Moebius, Shane A. Olwill. Costimulatory T-cell engagement via a novel bispecific anti-CD137 /anti-HER2 protein based on Anticalin® technology. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B023.
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- 2016
28. A Phase I Study Investigating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Activity of the Hepcidin Antagonist PRS-080#022. Results from a Randomized, Placebo Controlled, Double-Blind Study Following Single Administration to Healthy Subjectsa
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Dorine W. Swinkels, Rachel P. L. van Swelm, Werner Feuerer, Edgar Fenzl, Andreas Hohlbaum, and Ulrich Moebius
- Subjects
Volume of distribution ,medicine.medical_specialty ,biology ,medicine.diagnostic_test ,business.industry ,Transferrin saturation ,Immunology ,Area under the curve ,Cmax ,Cell Biology ,Hematology ,Pharmacology ,medicine.disease ,Biochemistry ,Ferritin ,Endocrinology ,Iron-deficiency anemia ,Pharmacokinetics ,Internal medicine ,medicine ,biology.protein ,Serum iron ,business - Abstract
PRS-080#022 is a 20kD AnticalinTM protein linked to 30kD linear poly-ethylene-glycol that specifically binds to human hepcidin 25, thereby inhibiting its activity. PRS-080#022 is developed for the treatment of functional iron deficient anemia associated with chronic kidney disease or cancer. Elevated levels of hepcidin restrict iron availability and contribute to functional iron deficiency and anemia. Thus, antagonizing hepcidin with PRS-080#022 has the potential to improve iron availability and erythropoiesis, thereby avoiding overload with exogenous iron and reducing the administered levels of Erythropoiesis-Stimulating Agents. 48 healthy male subjects were treated in this placebo controlled, double-blind Phase I study with ascending doses of PRS-080#022 in 6 cohorts at 0.08, 0.4, 1.2, 4.0, 8.0, and 16.0 mg/kg. 6 subjects per cohort received PRS-080#022 and 2 subjects received placebo (NCT02340572). Placebo or active treatments were administered by intravenous infusion over 2 hours. Safety, tolerability, the pharmacokinetics of total and free PRS-080#022, serum hepcidin concentrations as well as parameters of iron metabolism (ferritin, serum iron, transferrin saturation, reticulocytes and hemoglobin) were investigated. PRS-080#022 was well tolerated. 39 adverse events (AE) were reported during or after treatment in 22 subjects. All such AEs were mild or moderate and no serious AE was observed. Headache was the most frequently observed AE (10 subjects). Otherwise, no association of AEs to specific organs and no apparent dose dependency or difference between placebo and active treatment were observed. Notably, no hypersensitivity or infusion reactions were noted and vital signs, body temperature and ECG were unchanged. Pharmocokinetics of total PRS-080#022 followed a two-compartment model and was consistent between dose cohorts and within subjects of each cohort (Figure 1). Maximal concentration (Cmax) and area under the time curve (AUC) increased proportionally with dose (Table 1). Cmax was reached about 1 h after the 2 h infusion period (Table 1). The terminal plasma half life (T1/2) of PRS-080#022 ranged from 71 to 81 hours among dose cohorts (Table 1). The volume of distribution was small with 49 to 65 ml/kg, consistent with a distribution mainly to the blood volume. Administration of PRS-080#022 resulted in a decrease of free hepcidin which was observed already 1 h after start of infusion. PRS-080#022 administration induced a transient increase in serum iron concentration and transferrin saturation (TSAT), with both responses exhibiting a comparable time course and at doses of 0.4 mg/kg and higher. TSAT increased to > 90% in individual subjects. Serum iron concentrations reached about 50 µmol/l in individual subjects and did not further increase with dose. Importantly, the time period at which elevated serum iron concentrations and TSAT were observed increased with dose from about 18 h at 0.4 mg/kg to about 120 h at 16 mg/kg PRS-080#022. This is reflected by an increase of the AUC of the serum iron response relative to baseline and placebo (Table 1). In contrast, ferritin levels were largely unaffected by treatment. The excellent safety profile and the confirmed activity of PRS-080#022 on iron metabolism observed in healthy subjects warrants further investigations in anemic patients. A study investigating safety, pharmacokinetics and activity on erythropoiesis in anemic end-stage chronic kidney disease patients is in preparation. aFunded by the European Community FP7 health program grant GA-No. 278408 and supported by the EUROCALIN consortium (www.eurocalin-fp7.eu) Table. Summary of pharmacokinetic and pharmacodynamic parameters PRS-080#022 dose[mg/kg] Pharmacokinetic Parameters (group means ± SD) Pharmacodynamic Parameter(group means ± SD) Cmax[µg/ml] AUC0-inf[h*µg/ml] Tmax[h] T1/2[h] Vss[ml/kg] Serum Iron AUC0-240# [h*µmol/l] 0.08 2.1±0.3 162 ± 17 2.8 ± 0.4 81.2 ± 8.7 56.2 ± 8.0 39 ± 2807 0.4 10.6 ± 1.6 761 ± 163 3.3 ± 1.6 70.5 ± 27.7 54.2 ± 9.8 1174 ± 1150 1.2 33.9 ± 4.4 2264 ±167 2.7 ± 0.8 80.0 ± 10.3 51.3 ± 4.1 958 ± 1178 4.0 120.4 ± 19.6 7491 ± 730 3.7 ± 3.1 73.1 ± 8.9 47.8 ± 5.6 1579 ± 2222 8.0 246.3 ± 56.8 15066 ± 2496 4.3 ± 2.8 79.6 ± 9.7 53.3 ± 9.3 1134 ± 2207 16.0 366.2 ± 40.9 25572 ± 4075 3.0 ± 0.6 80.2 ± 11.6 64.6 ± 14.6 3480 ± 2123 #Response as Area Under the Curve 0-240h over baseline, placebo subtracted Figure 1. Arithmetic mean plasma concentration time profiles of total PRS-080#022 Figure 1. Arithmetic mean plasma concentration time profiles of total PRS-080#022 Disclosures Moebius: Pieris Pharmaceuticals Inc.: Employment. Feuerer:Pieris Pharmaceuticals Inc.: Other: contracted clinical research. Fenzl:Pieris Pharmaceuticals Inc.: Other: contracted clinical research. van Swelm:PIERIS: Other: member of the EU FP7 Eurocalin consortium. Swinkels:PIERIS: Other: member of EU FP7 Eurocalin consortium. Hohlbaum:Pieris Pharmaceuticals Inc.: Employment.
- Published
- 2015
29. Abstract C205: Costimulatory T-cell engagement via a novel bispecific anti-CD137 /anti-HER2 protein
- Author
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Marlon Hinner, Gabriele Matschiner, Shane Olwill, Holbrook E Kohrt, Ulrich Moebius, Christine Rothe, Alexander Wiedenmann, Corinna Schlosser, Andrea Allersdorfer, and Rachida-Siham Bel Aiba
- Subjects
Cancer Research ,Tumor microenvironment ,Phage display ,T cell ,CD137 ,Biology ,Molecular biology ,medicine.anatomical_structure ,Oncology ,Cancer research ,medicine ,biology.protein ,Antibody ,Receptor ,Anticalin ,CD8 - Abstract
CD137 is a potent costimulatory immunoreceptor and a member of the TNF-receptor (TNFR) superfamily. The receptor, also known as 4-1BB, is mainly expressed on activated CD4+ and CD8+ T cells, activated B cells, and natural killer (NK) cells. While multiple lines of evidence show that CD137 is a highly promising therapeutic target, current approaches using monospecific antibodies may display a limited therapeutic window due to peripheral T cell and NK cell activation, leading to unwanted toxicity. To overcome this limitation, we have generated a bispecific protein therapeutic designed to achieve a tumor-target driven activation of immune cells via binding to CD137 and to a differentially expressed tumor target, HER2. Anticalin® proteins are 18 kD protein therapeutics derived from human lipocalins. Using phage display technology a CD137-specific Anticalin was identified. The Anticalin was recombinantly fused to a trastuzumab variant at either the C or N terminus of the antibody´s heavy or light chain, yielding four different constructs covering a range of distances between the binding sites of the T cell-target and the tumor cell target. To minimize Fcγ-receptor interaction of the resulting bispecific and concomitant potential toxicity towards CD137-positive cells, the backbone of trastuzumab was switched from IgG1 to an engineered IgG4 isotype. Using ELISA or cell-based assays it was shown that all bispecific constructs bound their targets CD137 and HER2 with similar affinity compared to the parental building blocks, and both targets could be simultaneously bound. Binding to human receptors FcγRI and FcγRIII was significantly reduced in the bispecific constructs compared to non-engineered trastuzumab, while binding to the neonatal Fc receptor (FcRn) was retained. All constructs were shown to have excellent drug-like properties including thermal stability and plasma stability. HER2-dependent agonistic engagement of CD137 was demonstrated in ex-vivo T-cell activation assays utilizing HER2-positive human cell lines. The functional activity of the bispecific constructs was found to be dependent on their geometry. In conclusion, we report the first bispecific therapeutic protein that targets the potent costimulatory immunoreceptor CD137 in a tumor-target dependent manner, utilizing HER2 as the tumor target. Compared to currently existing CD137-targeting antibodies, this approach has the potential to provide a more controlled activation of the immune system in the tumor microenvironment with reduced peripheral toxicity. Bispecific T-cell engagers based on CD137 and HER2 have potential utility in HER2-positive cancers where there is a significant unmet medical need. Citation Format: Marlon J. Hinner, Rachida-Siham Bel Aiba, Alexander Wiedenmann, Corinna Schlosser, Andrea Allersdorfer, Gabriele Matschiner, Christine Rothe, Ulrich Moebius, Holbrook E. Kohrt, Shane A. Olwill. Costimulatory T-cell engagement via a novel bispecific anti-CD137 /anti-HER2 protein. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C205.
- Published
- 2015
30. Costimulatory T cell engagement via a novel bispecific anti-CD137 /anti-HER2 protein
- Author
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Andrea Allersdorfer, Alexander Wiedenmann, Holbrook E Kohrt, Christine Rothe, Corinna Schlosser, Gabriele Matschiner, Shane Olwill, Marlon Hinner, Ulrich Moebius, and Rachida-Siham Bel Aiba
- Subjects
Pharmacology ,Cancer Research ,business.industry ,T cell ,Immunology ,CD137 ,chemical and pharmacologic phenomena ,hemic and immune systems ,SUPERFAMILY ,Bioinformatics ,Cell biology ,medicine.anatomical_structure ,Oncology ,Poster Presentation ,Molecular Medicine ,Immunology and Allergy ,Medicine ,Anti her2 ,Receptor ,business ,Tumor necrosis factor receptor ,CD8 - Abstract
Meeting abstracts CD137 is a potent costimulatory immunoreceptor and a member of the TNF-receptor (TNFR) superfamily. The receptor, also known as 4-1BB, is mainly expressed on activated CD4+ and CD8+ T cells, activated B cells, and natural killer (NK) cells. While multiple lines of evidence show
- Published
- 2015
31. Immune mechanisms underlying HBV persistence
- Author
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Stefan Meuer and Ulrich Moebius
- Subjects
Effector ,T cell ,Immunology ,Biology ,Chronic disease ,Immune system ,medicine.anatomical_structure ,Virology ,medicine ,Viral persistence ,Receptor ,Cell activation ,Immune mechanisms - Abstract
Recent developments in our understanding of molecular mechanisms underlying T cell growth and differentiation have helped to identify previously unknown variables in the host response against virally infected targets. While recognition of viral proteins in HLA-association provides an initial triggering signal for pre-effector cell activation the functional outcome of an immune response is dependent on additional costimulatory signals that are mediated through a set of accessory receptors exposed in the T cell plasma membrane. Availability of such costimulatory signals decides whether T cells will develop into effector cells capable of viral elimination or, alternatively, whether specific tolerance is induced. One important parameter contributing to viral persistence and chronic disease following HBV-infection are secondary immunodeficiencies which mainly exist at the level of accessory receptor stimulation. The elucidation of the molecular basis of acquired immunodeficiencies provides novel perspectives for rational immune reconstitution and efficient antiviral immunity.
- Published
- 1994
32. Therapeutic antibodies to human L1CAM: functional characterization and application in a mouse model for ovarian carcinoma
- Author
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Helena Kiefel, Marco Pfeifer, Júlia Costa, Gerhard Moldenhauer, Silke Wolterink, Ulrich Moebius, Ricardo M. Gouveia, Sandra Lüttgau, P Altevogt, Jan Endell, and Mina Fogel
- Subjects
Cancer Research ,L1 ,medicine.drug_class ,CD1 ,Mice, Nude ,Neural Cell Adhesion Molecule L1 ,CHO Cells ,Cross Reactions ,Monoclonal antibody ,Metastasis ,Epitopes ,Mice ,Cricetulus ,Cell Line, Tumor ,Cricetinae ,medicine ,Animals ,Humans ,Ovarian Neoplasms ,biology ,Cell adhesion molecule ,Gene Expression Profiling ,Antibody-Dependent Cell Cytotoxicity ,Antibodies, Monoclonal ,medicine.disease ,Xenograft Model Antitumor Assays ,Oncology ,Ectodomain ,Cell culture ,Immunoglobulin G ,Immunology ,biology.protein ,Cancer research ,Female ,Antibody - Abstract
Recent work has identified L1CAM (CD171) as a novel marker for human carcinoma progression. Functionally, L1CAM promotes tumor cell invasion and motility, augments tumor growth in nude mice, and facilitates experimental tumor metastasis. These functional features qualify L1 as an interesting target molecule for tumor therapy. Here, we generated a series of novel monoclonal antibodies (mAb) to the L1CAM ectodomain that were characterized by biochemical and functional means. All novel mAbs reacted specifically with L1CAM and not with the closely related molecule CHL1, whereas antibodies to the COOH terminal part of L1CAM (mAb2C2, mAb745H7, pcytL1) showed cross-reactivity. Among the novel mAbs, L1-9.3 was selected and its therapeutic potential was analyzed in various isotype variants in a model of SKOV3ip cells growing i.p. in CD1 nude mice. Only therapy with the IgG2a variant efficiently prolonged survival and reduced tumor burden. This was accompanied by an increased infiltration of F4/80-positive monocytic cells. Clodronate pretreatment of tumor-bearing animals led to the depletion of monocytes and abolished the therapeutic effect of L1-9.3/IgG2a. Expression profiling of tumor-derived mRNA revealed that L1-9.3/IgG2a therapy induced altered expression of cellular genes associated with apoptosis and tumor growth. Our results establish that anti-L1 mAb therapy acts via immunologic and nonimmunologic effector mechanism to block tumor growth. The novel antibodies to L1CAM could become helpful tools for the therapy of L1-positive human carcinomas. Cancer Res; 70(6); 2504–15
- Published
- 2010
33. Human immunodeficiency virus gp120 binding C'C' ridge of CD4 domain 1 is also involved in interaction with class II major histocompatibility complex molecules
- Author
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Stephen C. Harrison, Sheena Abraham, Ulrich Moebius, Linda K. Clayton, Andrew C. Diener, Ellis L. Reinherz, and Juan J. Yunis
- Subjects
Models, Molecular ,CD74 ,Plasma protein binding ,HIV Envelope Protein gp120 ,In Vitro Techniques ,Major histocompatibility complex ,Chlorocebus aethiops ,Cell Adhesion ,Tumor Cells, Cultured ,Animals ,Point Mutation ,Binding site ,Site-directed mutagenesis ,HLA-D Antigens ,Genetics ,chemistry.chemical_classification ,Binding Sites ,Polymorphism, Genetic ,Multidisciplinary ,biology ,MHC Interaction ,chemistry ,CD4 Antigens ,Mutagenesis, Site-Directed ,biology.protein ,Glycoprotein ,Protein Binding ,Research Article - Abstract
Using site-directed mutagenesis informed by high-resolution CD4 structural data, we have investigated the role of residues of the C'C'' ridge region of human CD4 on class II major histocompatibility complex (MHC) binding. This C'C'' ridge is homologous to the CDR2 loop of an immunoglobulin variable domain and is known to contain the binding site for human immunodeficiency virus (HIV) coat glycoprotein gp120. Here we report that this region is also involved in interaction with class II MHC. Exposed positively charged residues Lys-35, Lys-46, and Arg-59 and the exposed hydrophobic residue Phe-43 contribute significantly to class II MHC binding. Moreover, mutations in the buried residues Trp-62 and Ser-49, which support the top and bottom of the C'C'' ridge, respectively, disrupt class II MHC interaction. The HIV binding region appears to involve a restricted area of the larger class II MHC binding site on CD4. Strategies of drug design aimed at interrupting CD4-HIV interaction will need to consider the extensive overlap between class II MHC and HIV gp120 binding surfaces in this region of CD4.
- Published
- 1992
34. The human immunodeficiency virus gp120 binding site on CD4: delineation by quantitative equilibrium and kinetic binding studies of mutants in conjunction with a high-resolution CD4 atomic structure
- Author
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Stephen C. Harrison, Ulrich Moebius, Ellis L. Reinherz, Sheena Abraham, and Linda K. Clayton
- Subjects
Models, Molecular ,Stereochemistry ,Phenylalanine ,Immunology ,Kinetics ,Mutant ,HIV Envelope Protein gp120 ,Biology ,Computer Graphics ,Electrochemistry ,Side chain ,Immunology and Allergy ,Molecule ,Binding site ,chemistry.chemical_classification ,Binding Sites ,Mutagenesis ,Temperature ,Antibodies, Monoclonal ,Articles ,In vitro ,chemistry ,Biochemistry ,CD4 Antigens ,HIV-1 ,Glycoprotein - Abstract
The first immunoglobulin V-like domain of CD4 contains the binding site for human immunodeficiency virus gp120. Guided by the atomic structure of a two-domain CD4 fragment, we have examined gp120 interaction with informative CD4 mutants, both by equilibrium and kinetic analysis. The binding site on CD4 appears to be a surface region of about 900 A2 on the C" edge of the domain. It contains an exposed hydrophobic residue, Phe43, on the C" strand and four positively charged residues, Lys29, Lys35, Lys46, and Arg59, on the C, C', C", and D strands, respectively. Replacement of Phe43 with Ala or Ile reduces affinity for gp120 by more than 500-fold; Tyr, Trp, and Leu substitutions have smaller effects. The four positively charged side chains each make significant contributions (7-50-fold). This CD4 site may dock into a conserved hydrophobic pocket bordered by several negatively charged residues in gp120. Class II major histocompatibility complex binding includes the same region on CD4; this overlap needs to be considered in the design of inhibitors of the CD4-gp120 interaction.
- Published
- 1992
35. The CD3 zeta cytoplasmic domain mediates CD2-induced T cell activation
- Author
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Tiiu E. Gennert, Philippe Moingeon, Ellis L. Reinherz, David J. McConkey, Booma D. Yandava, Frank D. Howard, and Ulrich Moebius
- Subjects
Antigens, Differentiation, T-Lymphocyte ,Cytoplasm ,CD3 Complex ,CD8 Antigens ,T-Lymphocytes ,CD3 ,T cell ,Molecular Sequence Data ,Immunology ,CD2 Antigens ,Receptors, Antigen, T-Cell ,Lymphocyte Activation ,Jurkat cells ,medicine ,Humans ,Immunology and Allergy ,Phosphorylation ,Receptors, Immunologic ,Base Sequence ,biology ,T-cell receptor ,Articles ,Molecular biology ,Intracellular signal transduction ,Transmembrane domain ,medicine.anatomical_structure ,biology.protein ,Tyrosine ,Signal transduction ,CD8 - Abstract
CD2-mediated T lymphocyte activation requires surface expression of CD3-Ti, the T cell receptor (TCR) for antigen major histocompatibility complex protein. Given the importance of CD3 zeta in TCR signaling, we have directly examined the ability of the CD3 zeta cytoplasmic domain to couple CD2 to intracellular signal transduction pathways. A cDNA encoding a chimeric protein consisting of the human CD3 zeta cytoplasmic domain (amino acid residues 31-142) fused to the CD8 alpha extracellular and transmembrane domains (amino acid residues 1-187) was transfected into a CD2+CD3-CD8- variant of the human T cell line Jurkat. The resulting transfectants expressed the CD8 alpha/CD3 zeta chimeric receptor at the cell surface in the absence of other TCR subunits. Stimulation of these transfectants with anti-T11(2) + anti-T11(3) monoclonal antibodies (mAbs) initiated both a prompt cytosolic free calcium ([Ca2+]i) rise and protein tyrosine kinase activation. Stimulation with either intact anti-T11(2) + anti-T11(3) mAbs or purified F(ab')2 fragments resulted in interleukin 2 (IL-2) secretion. In contrast, control cell lines transfected with a cDNA encoding wild-type CD8 alpha, and thus lacking surface expression of the CD3 zeta cytoplasmic domain, failed to show any [Ca2+]i rise, protein tyrosine kinase activation, or IL-2 secretion after identical stimulation. These data directly establish the CD3 zeta cytoplasmic domain as a necessary and sufficient component of the CD3-Ti complex involved in T lymphocyte activation through CD2. Moreover, they show that CD2 signaling can function in the absence of Fc receptors.
- Published
- 1992
36. Structure and Interactions of CD4
- Author
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Ulrich Moebius, J Liu, Thomas P. J. Garrett, Ellis L. Reinherz, Y Yan, Stephen C. Harrison, and Jia-huai Wang
- Subjects
HLA-D Antigens ,Molecular Structure ,In Vitro Techniques ,business.industry ,Chemistry ,Molecular Sequence Data ,Structure (category theory) ,Plasma protein binding ,Computational biology ,HIV Envelope Protein gp120 ,Biochemistry ,Protein Structure, Tertiary ,Text mining ,Protein structure ,CD4 Antigens ,Genetics ,Humans ,Amino Acid Sequence ,business ,Molecular Biology ,Peptide sequence ,Protein Binding - Published
- 1992
37. Hepatocellular expression of lymphocyte function—associated antigen 3 in chronic hepatitis
- Author
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Karl-Hermann Meyer zum Büschenfelde, Michael Manns, Hans-Peter Dienes, Frank Autschbach, Ulrich Moebius, W. Thoenes, Stefan Meuer, and Georg Hess
- Subjects
Hepatitis ,Hepatology ,T cell ,Lymphocyte ,CD58 ,Autoimmune hepatitis ,Biology ,medicine.disease ,medicine.anatomical_structure ,Immune system ,Immunology ,medicine ,IL-2 receptor ,Viral hepatitis - Abstract
T lymphocyte-mediated cytolytic immune reactions are considered a major cause of hepatocyte injury in chronic viral and autoimmune hepatitis. To further investigate local immune responses, we studied the expression of lymphocyte antigens and cell-cell interaction molecules known to be involved in effector-target cell interactions by light and electron microscopy in liver biopsy specimens from patients with chronic viral and autoimmune hepatitis. CD8+ lymphocytes were found to be the predominant population of cells in the inflammatory infiltrate in chronic hepatitis B and non-A, non-B hepatitis. In contrast, CD4+ cells constituted a comparably higher proportion of cells and were more numerous than CD8+ cells in chronic autoimmune hepatitis. In both viral and autoimmune hepatitis, a substantial portion of lymphocytes expressed activation antigens such as T11/3 (CD2R) and IL-2-R (CD25). Lymphocyte function-associated antigen-3 (CD58), which mediates lymphocyte adhesion and activation and is the natural ligand of the CD2/T11 lymphocyte surface receptor, could be demonstrated on endothelial cells and hepatocytes. Hepatocellular lymphocyte function-associated antigen-3 expression in chronic hepatitis showed membranous and cytoplasmic staining of hepatocytes and had a positive correlation with the degree of inflammatory activity. These results suggest that effector-target interactions between hepatocytes and lymphocytes mediated by the lymphocyte function-associated antigen-3/CD2 pathway play a role in chronic inflammatory liver disease. Possible functional consequences of this interaction include enhancement of antigen-specific immune reactions and antigen-independent mechanisms of T cell activation, which may contribute considerably to the degree of inflammatory activity and tissue damage in chronic hepatitis.
- Published
- 1991
38. Expression of different CD8 isoforms on distinct human lymphocyte subpopulations
- Author
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Gabriela Kober, Ulrich Moebius, Anne Lise Griscelli, Thierry Hercend, and Stefan Meuer
- Subjects
Antigens, Differentiation, T-Lymphocyte ,CD3 Complex ,CD8 Antigens ,T cell ,Lymphocyte ,Immunology ,T-cell receptor ,Receptors, Antigen, T-Cell ,Antibodies, Monoclonal ,Alpha (ethology) ,T lymphocyte ,Biology ,Peptide Mapping ,Precipitin Tests ,Molecular biology ,Natural killer cell ,medicine.anatomical_structure ,Antigens, CD ,T-Lymphocyte Subsets ,medicine ,Humans ,Immunology and Allergy ,Beta (finance) ,CD8 - Abstract
Human CD8+ lymphocyte subpopulations were analyzed for their expression of CD8 alpha and CD8 beta subunits. Investigations with uncloned peripheral blood lymphocytes as well as cloned human natural killer and T cell subpopulations demonstrate that CD3- natural killer cells, T cell receptor gamma/delta, and CD4+CD8+ T cell clones express exclusively CD8 alpha gene products. Structural analysis of CD8 molecules demonstrates that CD8 alpha+/beta- T lymphocytes surface express 75-kDa CD8 alpha/alpha homodimers whereas CD8 alpha/beta lymphocytes express concomittantly two CD8 isoforms of different molecular masses (67 kDa and 75 kDa, respectively). Peptide mapping of these latter two isoforms suggests that CD8 is expressed as alpha/alpha homodimers and alpha/beta heterodimers on CD8 alpha/beta+ cells. Importantly, we found that the two CD8 isoforms behave functionally different. Thus, in contrast to CD8 alpha/beta+/CD8 alpha/alpha+ T lymphocytes, cytolytic activity of CD8 alpha/beta-/CD8 alpha/alpha+ T cell clones was not inhibited by anti-CD8 monoclonal antibodies and the latter were not induced to proliferate following CD3/CD8 cross-linking.
- Published
- 1991
39. T cell receptor gene rearrangements of T lymphocytes infiltrating the liver in chronic active hepatitis B and primary biliary cirrhosis (PBC): Oligoclonality of PBC-derived T cell clones
- Author
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G Kober, K H Meyer zum Büschenfelde, S. Meuer, Michael Manns, Ulrich Moebius, and Georg Hess
- Subjects
Adult ,Antigens, Differentiation, T-Lymphocyte ,CD8 Antigens ,T-Lymphocytes ,T cell ,Biliary cirrhosis ,Immunology ,Biology ,Gene Rearrangement, T-Lymphocyte ,Autoimmune Diseases ,Primary biliary cirrhosis ,Antigen ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Aged ,Hepatitis, Chronic ,Hepatitis ,Liver Cirrhosis, Biliary ,T-cell receptor ,T lymphocyte ,Middle Aged ,medicine.disease ,Clone Cells ,Phenotype ,medicine.anatomical_structure ,Liver ,CD4 Antigens ,Female - Abstract
Immunological events are involved in the pathophysiology of chronic active hepatitis as indicated from the accumulation of T lymphocytes at the site of tissue damage. We generated T cell clones from liver biopsies of 3 patients with chronic active hepatitis B and 2 patients with primary biliary cirrhosis. These T cell clones (n = 84) were analyzed by means of T cell receptor (TcR) beta gene rearrangements to determine whether the infiltrate consists of a polyclonal or oligoclonal T cell population. The vast majority (62 of 64) of T cell clones from three different patients with chronic active hepatitis B showed no identical rearrangements of the TcR beta chain genes. In marked contrast, in both patients with primary biliary cirrhosis, T cell clones established were of limited diversity. Thus 5 out of 10 and 2 out of 10 T cell clones from one patient and 3 out of 9 and 2 out of 9 T cell clones from the second patient, respectively, showed identical TcR beta gene rearrangements. These data suggest that a clonal dominance is characteristic for local T cell responses in autoimmune liver disease such as primary biliary cirrhosis whereas in virus-induced chronic active hepatitis T cell activation occurs polyclonally.
- Published
- 1990
40. Simultaneous ligation of CD5 and CD28 with monoclonal antibodies restores impaired immunostimulatory function in human renal cell carcinoma
- Author
-
Ulrich Moebius, Annette Habicht, Stefan Meuer, Michael Siebels, and Geeske C Meyer
- Subjects
Urology ,T cell ,T-Lymphocytes ,CD1 ,chemical and pharmacologic phenomena ,Biology ,CD5 Antigens ,Lymphocyte Activation ,Interferon-gamma ,CD28 Antigens ,MHC class I ,medicine ,Tumor Cells, Cultured ,Cytotoxic T cell ,Humans ,Antigen-presenting cell ,Carcinoma, Renal Cell ,MHC class II ,Tumor Necrosis Factor-alpha ,Antibodies, Monoclonal ,MHC restriction ,Molecular biology ,Kidney Neoplasms ,medicine.anatomical_structure ,biology.protein ,Immunization ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
Tumor cells, including renal cell carcinoma (RCC) cells, do not effectively stimulate T lymphocyte responses against specific antigens presented on their surface. Reasons for this low immunogenicity may include low or absent expression of MHC class I and/or class II molecules, as well as accessory and costimulatory molecules. We used tumor cell pretreatment with cytokines, together with monoclonal antibodies (mAbs) directed at receptors for costimulatory molecules, to render RCC cells immunostimulatory. Interferon-gamma or tumor necrosis factor-alpha pretreatment enhanced expression of MHC class I and class II molecules, as well as CD54, but had only minimal effects on T cell activation. A CD28 mAb, or an even more effective combination of CD28 and CD5 mAb, induced strong primary proliferative responses of allogeneic resting T lymphocytes. Cytokine pretreatment further augmented this T cell response in vitro and allowed T cell expansion and establishment of T cell lines. Stimulation of T cells with autologous RCC cells resulted in a similar T cell activation but with the expansion of cytolytic T cells directed at autologous MHC class II molecules. These experiments demonstrate that cytokines combined with costimulatory mAbs are useful for increasing the immunogenicity of tumor cells. They also indicate. however, that autologous MHC class II expression on tumor cells, together with strong costimulation, may lead to the activation of autoreactive T cells.
- Published
- 2002
41. Potential of CD80-transfected human breast carcinoma cells to induce peptide-specific T lymphocytes in an allogeneic human histocompatibility leukocyte antigens (HLA)-A2.1+-matched situation
- Author
-
Ulrich Moebius, B. Gückel, Geeske C Meyer, Stefan Meuer, W. Rudy, Richard Batrla, and Diethelm Wallwiener
- Subjects
Cancer Research ,Time Factors ,T-Lymphocytes ,Breast Neoplasms ,Cell Count ,Human leukocyte antigen ,Immunoenzyme Techniques ,Interferon-gamma ,Antigen ,HLA Antigens ,Tumor Cells, Cultured ,Humans ,Molecular Biology ,Pan-T antigens ,Chemistry ,Tumor Necrosis Factor-alpha ,Transfection ,Histocompatibility ,Cell culture ,Immunology ,Cancer research ,B7-1 Antigen ,Molecular Medicine ,Interleukin-2 ,Tumor necrosis factor alpha ,Interleukin-4 ,CD80 - Abstract
Allogeneic human histocompatibility leukocyte antigen (HLA)-matched tumor cell lines that have been made immunogenic by the transfer of genes encoding for costimulatory molecules such as CD80 are considered to be potential vaccines for the induction of systemic immune reactions in cancer patients. We used a human HLA-A2.1+ CD80-transfected breast carcinoma cell line (KS-CD80) and investigated in vitro the efficiency at which antigen (Ag)-specific responses were induced following the stimulation of allogeneic HLA-A2.1-matched T lymphocytes. The influenza matrix protein M1 was used as a model Ag. It was either endogenously expressed or exogenously loaded as a peptide (matrix protein), and the frequency of the generated specific T cells was determined. The expression of CD80 in KS cells was required for an effective activation and expansion of Ag-specific T cells. This response was augmented following the pretreatment of KS-CD80 cells with interferon-gamma and tumor necrosis factor-alpha. Interleukin-4 (IL-4), IL-7, and IL-12 further increased T-cell expansion. IL-7 was best at supporting the generation of T cells with Ag specificity. This investigation demonstrates that allogeneic CD80+ tumor cells can induce Ag-specific, HLA-restricted T lymphocytes at a high frequency. Our study supports the use of allogeneic cell lines for the induction of specific T-cell responses in tumor patients.
- Published
- 1999
42. T cell activation by monoclonal antibodies bound to tumor cells by a cell surface displayed single-chain antibody
- Author
-
Ulrich Moebius, Melvyn Little, and Hans-Jürgen Rode
- Subjects
CD3 Complex ,medicine.drug_class ,T cell ,CD3 ,T-Lymphocytes ,Immunology ,Gene Expression ,chemical and pharmacologic phenomena ,Biology ,Monoclonal antibody ,CD5 Antigens ,Lymphocyte Activation ,Cell membrane ,CD28 Antigens ,medicine ,Tumor Cells, Cultured ,Immunology and Allergy ,Humans ,Immunoglobulin Fragments ,Oxazoles ,Oxazolone ,CD28 ,Antibodies, Monoclonal ,Drug Synergism ,Molecular biology ,medicine.anatomical_structure ,Cell culture ,biology.protein ,B7-1 Antigen ,CD5 ,Hapten ,Haptens ,Cell Division - Abstract
Tumor cells often lack the costimulatory molecules necessary for T cell activation. However, the transformation of cells with more than one stimulatory molecule is a difficult procedure. We therefore developed a retroviral vector for the expression of a cell membrane anchored single-chain antibody fragment (scFv) directed against the hapten 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one (phOx). Proteins and peptides can be readily modified with this hapten, thus, enabling them to be bound to cells with the cell surface displayed anti-phOx scFv. To test combinations of surface-bound stimulatory molecules on T cell activation, SK-Mel63 human melanoma cells expressing the membrane anchored anti-phOx scFv were incubated with phOx-labeled mAbs against CD3, CD28 and CD5. Cells presenting a given mixture of modified anti-CD3 and anti-CD28 molecules stimulated T cell activation better than any single antibody and a given mixture of anti-CD3, anti-CD28 and anti-CD5 provided a stimulatory response higher than the best double combination. However, the relative concentrations are very important and must be carefully chosen. Concentrations of antibodies giving good T cell responses when used alone can block synergistic effects.
- Published
- 1999
43. Strong immunogenic potential of a B7 retroviral expression vector: generation of HLA-B7-restricted CTL response against selectable marker genes
- Author
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Dirk Jung, S. Cayeux, Julia Karbach, Thomas Blankenstein, Christine Hilmes, Christoph Huber, Alexander Knuth, Elke Jaeger, Ulrich Moebius, and Barbara Seliger
- Subjects
Genetic Markers ,T cell ,Genetic Vectors ,Lymphocyte Activation ,HLA-B7 Antigen ,Immune system ,Retrovirus ,Antigens, Neoplasm ,Genetics ,medicine ,Tumor Cells, Cultured ,Humans ,Molecular Biology ,Carcinoma, Renal Cell ,Selectable marker ,Expression vector ,biology ,Histocompatibility Antigens Class I ,Gene Transfer Techniques ,Genetic Therapy ,Acquired immune system ,biology.organism_classification ,Molecular biology ,Kidney Neoplasms ,medicine.anatomical_structure ,Retroviridae ,Cell culture ,Thymidine kinase ,Cancer research ,B7-1 Antigen ,Molecular Medicine ,T-Lymphocytes, Cytotoxic - Abstract
The stimulation of a specific immune response is an attractive goal in cancer therapy. Gene transfer of co-stimulatory molecules and/or cytokine genes into tumor cells and the injection of these genetically modified cells leads to tumor rejection by syngeneic hosts and the induction of tumor immunity. However, the development of host immune response could be either due to the introduced immunomodulatory genes or due to vector components. In this study, human renal cell carcinoma cell lines were modified by a retrovirus to express the co-stimulatory molecule B7-1 together with the hygromycin/thymidine kinase fusion protein (HygTk) as positive and negative selection markers. These B7-1-transduced renal cell carcinoma cell lines were able significantly to activate allogeneic T cell proliferation. The cytolytic activity of these T cells was determined by employing several transduced and nontransduced renal cell carcinoma cell lines as targets. Evidence for a strong vector-specific T cell reactivity induced by the Hyg/Tk protein was obtained in autologous renal cell carcinoma systems. Antibody blocking experiments as well as peptide binding assays demonstrated an HLA-B7-restricted T cell response directed against both the Hyg and the Tk genes. Thus, the vector itself may mask the generation of immune reactivity against tumor antigens and may even detract from it. Vectors with immunogenic potential may be useful for tumor vaccination via cross priming in vivo, whereas antivector reactivities would be detrimental in situations where gene defects are being corrected and where long term expression of a therapeutic protein is required.
- Published
- 1998
44. Construction of Immunogenic Tumor Cell Surfaces by Somatic Gene Transfer
- Author
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Stefan Meuer, Ulrich Moebius, Brigitte Gückel, M. Lindauer, and W. Rudy
- Subjects
biology ,Clonal anergy ,Chemistry ,Effector ,Somatic cell ,Cell ,Major histocompatibility complex ,Molecular biology ,medicine.anatomical_structure ,Antigen ,MHC class I ,biology.protein ,medicine ,Receptor - Abstract
A contemporary model of T-lymphocyte activation (two-signal hypothesis) strongly suggests that in addition to recognition of peptide/MHC and, thus, tumor antigens by the T-cell antigen receptor, costimulatory signals are required for optimal T-cell clonal expansion and their differentiation into effector cells (Mueller et al. 1989; Schwartz 1990). Receptors for costimulatory signals have been identified and defined, among which CD 2, CD 11/18, CD 28, CD 4, and CD 8 appear to play important roles. Their respective ligands/coreceptors are CD 58, CD 54, CD 80/CD 86, MHC II, and MHC I, respectively.
- Published
- 1998
45. Induction of Antigen-Specific T Cells by Allogeneic CD80 Transfected Human Carcinoma Cells
- Author
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W. Rudy, Geeske C Meyer, Stefan Meuer, R. Batrla, Diethelm Wallwiener, Brigitte Gückel, and Ulrich Moebius
- Subjects
CD40 ,biology ,Chemistry ,T cell ,Interleukin 21 ,medicine.anatomical_structure ,Immune system ,Antigen ,medicine ,biology.protein ,Interleukin 12 ,Cancer research ,Cytotoxic T cell ,CD80 - Abstract
Most tumor cells seem to be characterized by multiple genetic alterations. The products of these alterations can represent specific tumor antigens, which are processed in-tracellularly and presented towards T cells in association with HLA molecules. Tumor-specific antigens can be derived from viruses, mutated proteins or products of chromosomal translocation only presented in tumor cells only as well as from unaltered, overexpressed proteins [rev. in 1]. Therefore, tumors can be specifically recognized and destinguished from normal tissue by the immune system. However, tumor cells are also known to be merely weakly immunogenic and not capable of effectively inducing immune responses. An explanation for the failure of tumor cells to elicit an immune response is their inability to provide costimulatory signals to T lymphocytes. Presentation of tumor antigens in the absence of costimulatory molecules is believed to prevent T cell activation and induce a state of specific tolerance towards the tumor [2,3].
- Published
- 1998
46. Detection of cytosine deaminase in genetically modified tumor cells by specific antibodies
- Author
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Karin Haack, Johannes Gebert, Ulrich Moebius, M. V. Knebel Doeberitz, Ch. Herfarth, and H. K. Schackert
- Subjects
medicine.drug_class ,Blotting, Western ,Gene Expression ,Enzyme-Linked Immunosorbent Assay ,Nucleoside Deaminases ,Monoclonal antibody ,Flow cytometry ,Cytosine Deaminase ,Mice ,Antibody Specificity ,Genetics ,medicine ,Animals ,Molecular Biology ,Antiserum ,Mice, Inbred BALB C ,biology ,medicine.diagnostic_test ,Cytosine deaminase ,Gene Transfer Techniques ,Antibodies, Monoclonal ,Suicide gene ,Flow Cytometry ,Fusion protein ,Molecular biology ,Immunohistochemistry ,Precipitin Tests ,Polyclonal antibodies ,biology.protein ,Molecular Medicine ,Rabbits ,Antibody - Abstract
Bacterial cytosine deaminase (CD) converts the non-toxic prodrug 5-fluorocytosine (5-FC) into 5-fluorouracil (5-FU), which is toxic for mammalian cells. Therefore, the CD gene is used in cancer gene therapy to achieve high local concentration of a toxic metabolite without significant systemic toxicity. To allow the detection of CD expression at the protein level, we raised both polyclonal rabbit antisera and a monoclonal antibody (mAb) against a histidine-tagged CD fusion protein. The specificity of the polyclonal antisera and the mAb was confirmed by immunohistochemistry, immunoblot analysis, and immunoprecipitation using CD-expressing tumor cell lines. Furthermore, the antibodies can be used for ELISA assays and flow cytometry. Finally, the CD protein could be demonstrated in frozen tissue sections of CD-modified tumors in a rat tumor model using the anti-CD serum. With these antibodies, CD expression can now be monitored throughout in vitro and in vivo gene transfer studies, including clinical protocols relying on the CD suicide gene strategy.
- Published
- 1997
47. Cytosine deaminase gene as a potential tool for the genetic therapy of colorectal cancer
- Author
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Franz Oberdorfer, Johannes Gebert, Ulrich Moebius, Marcus Lindauer, Uwe Haberkorn, Christian Herfarth, H. K. Schackert, and Simon Rowley
- Subjects
Colorectal cancer ,Genetic enhancement ,R Factors ,Genetic Vectors ,Molecular Sequence Data ,Flucytosine ,Nucleoside Deaminases ,Biology ,medicine.disease_cause ,Transfection ,Polymerase Chain Reaction ,Cytosine Deaminase ,Bystander effect ,medicine ,Escherichia coli ,Tumor Cells, Cultured ,Humans ,Cloning, Molecular ,Gene ,Cloning ,Base Sequence ,Cell Death ,Cytosine deaminase ,General Medicine ,Genetic Therapy ,medicine.disease ,Oncology ,Cell culture ,Immunology ,Cancer research ,Interleukin-2 ,Surgery ,Fluorouracil ,Colorectal Neoplasms ,Glioblastoma - Abstract
The bacterial enzyme cytosine deaminase (CD) catalyzes the conversion of 5-fluorocytosine (5-FC) to the lethal 5-fluorouracil (5-FU) and so provides a useful system for selective killing of gene-modified mammalian tumor cells. Cloning of the CD gene from Escherichia coli and expression in human tumor cell lines enabled these cells to convert 3H-labeled 5-FC into 3H-5-FU. Two CD-expressing human tumor cell lines (adenocarcinoma cell line KM12 and glioblastoma cell line T1115) became 200-fold more sensitive to 5-FC than the nonexpressing parental cell lines. At least 90% of the cells are killed within 7 days. CD-expressing cells are able to kill nonexpressing cells when grown in the same culture flask (bystander effect). The CD gene may be used as a suicide system for in situ chemotherapy or as a safety mechanism abrogating the expression of other genes. © 1996 Wiley-Liss, Inc.
- Published
- 1996
48. Development of immunogenic colorectal cancer cell lines for vaccination: expression of CD80 (B7.1) is not sufficient to restore impaired primary T cell activation in vitro
- Author
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W. Rudy, P. Galmbacher, Johannes Gebert, Stefan Meuer, H. K. Schackert, M. Lindauer, A. Habicht, and Ulrich Moebius
- Subjects
Cancer Research ,Lymphocyte ,T cell ,T-Lymphocytes ,chemical and pharmacologic phenomena ,Major histocompatibility complex ,Lymphocyte Activation ,Immune system ,HLA-DR3 Antigen ,Antigens, Neoplasm ,medicine ,Tumor Cells, Cultured ,Cytotoxic T cell ,Humans ,Melanoma ,biology ,Gene Transfer Techniques ,Cytolysis ,medicine.anatomical_structure ,Oncology ,Genes ,Cell culture ,Immunology ,Cancer research ,biology.protein ,B7-1 Antigen ,Cytokines ,Lymphocyte Culture Test, Mixed ,Colorectal Neoplasms ,CD80 - Abstract
The capacity of colorectal carcinoma and melanoma cell lines to induce primary versus effector T lymphocyte activation in vitro was investigated. Established epithelial tumour cell lines derived from colorectal carcinoma and melanoma did not activate a primary proliferative response of resting T lymphocytes in allogeneic mixed lymphocyte tumour cell cultures (MLTCs). In contrast, the same tumour cells were effectively lysed by preactivated cytolytic T cell clones. This demonstrates that tumour cells are impaired in inducing a primary immune response but are susceptible to effector immune responses. Attempts at improving primary T cell activation revealed that exogenous cytokines, including interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2), were not effective. Expression of CD80 (B7.1), by transfecting a CD80 cDNA into the melanoma cell line SkMel63, improved T cell proliferation considerably. In contrast, CD80 expression in two colorectal carcinoma cell lines (SW480, SW707) did not result in T cell activation. This was not due to lack of class II MHC expression on SW480 since coexpression of a HLA-DR3 alloantigen and CD80 had no effect. Our data suggest that de novo CD80 expression is not, in general, sufficient to improve primary T cell activation by human tumour cells.
- Published
- 1995
49. Limited T-cell receptor diversity in liver-infiltrating lymphocytes from patients with primary biliary cirrhosis
- Author
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Sergio Roman-Roman, Laurent Ferradini, Ulrich Moebius, Stefan Meuer, Anita Diu, Delphine Delorme, Monique Claudon, Thierry Hercend, Catherine Genevée, and Françoise Praz
- Subjects
Male ,Subfamily ,Base Sequence ,Liver Cirrhosis, Biliary ,Receptors, Antigen, T-Cell, alpha-beta ,Immunology ,T-cell receptor ,Molecular Sequence Data ,T lymphocyte ,Biology ,Middle Aged ,medicine.disease ,Molecular biology ,Primary biliary cirrhosis ,medicine ,Immunology and Allergy ,Humans ,Female ,Amino Acid Sequence ,Receptor ,Gene ,Peptide sequence ,Alpha chain ,Aged - Abstract
Primary biliary cirrhosis is associated with the presence of high-titer anti-mitochondrial autoantibodies as well as T-cell infiltration of the liver, suggesting the involvement of autoimmune mechanisms. We have studied here the sequences of T-cell receptor alpha and beta chains expressed by T-cell clones derived from liver-infiltrating lymphocytes of two patients with primary biliary cirrhosis. Among the eight clones studied from the first patient, four expressed the same member of the V beta 6 subfamily, associated with either V alpha 4 (three clones) or V alpha 21 (one clone) gene segment. Two other clones expressed an identical V beta 12 transcript, and two in-frame alpha chain transcripts, involving V alpha 2 and V alpha 7 gene segments. From the second patient, eight out of the nine clones were found to rearrange V beta 17-J beta 2.1 and V alpha 3 gene segments. The remaining clone expressed distinct T-cell receptor chains, involving V beta 9 and V alpha 11 gene segments. As deduced from the analysis of their junctional regions, the eight T-cell clones expressing V beta 17/V alpha 3 gene segments derived from only three different T cells. Furthermore, conserved amino acid motifs were found to be encoded in both the alpha and the beta-chain junctional regions. Together, these data show a local amplification of unique T lymphocytes in both patients. The use of identical V beta J beta and V alpha gene segments with similar junctional sequences by three different cells, evidenced in one of the two cases, strengthens the view that liver-infiltrating T lymphocytes are selected locally by autoantigens in PBC.
- Published
- 1993
50. Delineation of an extended surface contact area on human CD4 involved in class II major histocompatibility complex binding
- Author
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Stephen C. Harrison, Ulrich Moebius, Peter Pallai, and Ellis L. Reinherz
- Subjects
Models, Molecular ,Protein Conformation ,Molecular Sequence Data ,Fluorescent Antibody Technique ,Major histocompatibility complex ,Transfection ,Protein Structure, Secondary ,Domain (software engineering) ,Cell Line ,Protein structure ,Antigen ,Antigens, CD ,Animals ,Amino Acid Sequence ,Binding site ,Site-directed mutagenesis ,Peptide sequence ,Genetics ,HLA-D Antigens ,Multidisciplinary ,Binding Sites ,biology ,MHC Interaction ,Recombinant Proteins ,CD4 Antigens ,biology.protein ,Biophysics ,Mutagenesis, Site-Directed ,Research Article - Abstract
We describe a detailed mapping of the class II major histocompatibility complex (MHC) binding site using site-directed mutagenesis in conjunction with high-resolution CD4 structural data. Residues on all lateral surfaces of domain 1 and the neighboring portions of domain 2 participate in contacting class II MHC. Thus, in addition to the C'C" ridge that forms the human immunodeficiency virus type 1 gp120 binding site, apparent MHC contacts extend over the BED face of domain 1 and across the interdomain groove onto the FG loop of domain 2. Several models of the CD4/class II MHC interaction accounting for the extent of the CD4 surface involved are discussed, including the possibility that CD4 may contact more than one class II MHC molecule using different surfaces.
- Published
- 1993
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