20 results on '"Anne Van Abbema"'
Search Results
2. Low-dose self-amplifying mRNA COVID-19 vaccine drives strong protective immunity in non-human primates against SARS-CoV-2 infection
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Amy R. Rappaport, Sue-Jean Hong, Ciaran D. Scallan, Leonid Gitlin, Arvin Akoopie, Gregory R. Boucher, Milana Egorova, J. Aaron Espinosa, Mario Fidanza, Melissa A. Kachura, Annie Shen, Gloria Sivko, Anne Van Abbema, Robert L. Veres, and Karin Jooss
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Multidisciplinary ,COVID-19 Vaccines ,SARS-CoV-2 ,Vaccination ,General Physics and Astronomy ,COVID-19 ,General Chemistry ,Antibodies, Viral ,Antibodies, Neutralizing ,Macaca mulatta ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Spike Glycoprotein, Coronavirus ,Animals ,Humans ,RNA, Messenger - Abstract
The coronavirus disease 2019 (COVID-19) pandemic continues to spread globally, highlighting the urgent need for safe and effective vaccines that could be rapidly mobilized to immunize large populations. We report the preclinical development of a self-amplifying mRNA (SAM) vaccine encoding a prefusion stabilized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein and demonstrate strong cellular and humoral immune responses at low doses in mice and rhesus macaques. The homologous prime-boost vaccination regimen of SAM at 3, 10 and 30 μg induced potent neutralizing antibody (nAb) titers in rhesus macaques following two SAM vaccinations at all dose levels, with the 10 μg dose generating geometric mean titers (GMT) 48-fold greater than the GMT of a panel of SARS-CoV-2 convalescent human sera. Spike-specific T cell responses were observed with all tested vaccine regimens. SAM vaccination provided protective efficacy against SARS-CoV-2 challenge as both a homologous prime-boost and as a single boost following ChAd prime, demonstrating reduction of viral replication in both the upper and lower airways. The SAM vaccine is currently being evaluated in clinical trials as both a homologous prime-boost regimen at low doses and as a boost following heterologous prime.
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- 2021
3. Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model
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Leo Berezhkovsky, Mark Ultsch, Jan Smith, Wade S. Blair, Adam R. Johnson, Calum Macleod, Simon Charles Goodacre, Jason DeVoss, Jun Liang, Kapil Menghrajani, Jim Driscoll, Nico Ghilardi, Wenqian Yang, Steven Magnuson, Karen Williams, Anne van Abbema, Donnie Delarosa, Pawan Bir Kohli, Hieu Nguyen, Kathy Barrett, Steven Shia, Birong Zhang, Sue Sohn, Zhonghua Lin, Christine Chang, Mercedesz Balazs, Priscilla Mantik, Yingjie Lai, Charles Eigenbrot, Vickie Tsui, Amy Sambrone, Ivan Peng, and Lawren C. Wu
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0301 basic medicine ,Imidazopyridine ,Pyridines ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,In vivo ,Psoriasis ,Drug Discovery ,medicine ,Peptide bond ,Humans ,Molecular Biology ,Protein Kinase Inhibitors ,chemistry.chemical_classification ,TYK2 Kinase ,Dose-Response Relationship, Drug ,Molecular Structure ,Kinase ,Aryl ,Organic Chemistry ,Imidazoles ,medicine.disease ,030104 developmental biology ,Enzyme ,chemistry ,Molecular Medicine ,Selectivity ,030215 immunology - Abstract
Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.
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- 2017
4. Design and Discovery of N-(2-Methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers
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Yan Lou, Sharadha Subramanian, Yingyun Wang, Lifeng Wan, John Tellew, Laura Tandeske, Benjamin R. Taft, Kalyani Gampa, Jacob R. Haling, Gisele Nishiguchi, Lina Setti, Alice Rico, Sylvia Ma, Payman Amiri, Mallika Singh, Huw Tanner, Brent A. Appleton, Robert J. Aversa, Sepideh Vaziri, Shenlin Huang, Johanna M. Jansen, Anne Van Abbema, Jing Yuan, Vesselina G. Cooke, Hanne Merritt, Aaron Smith, Wenlin Shao, Valery Polyakov, Fei Feng, Savithri Ramurthy, Matthew Burger, Mulugeta Mamo, Lesley A. Mathews Griner, Vijay Sethuraman, Victoriano Tamez, Michael Patrick Dillon, Emma Lees, Ina Dix, Paul A. Barsanti, Richard Zang, Darrin Stuart, and Mohammad Hekmat-Nejad
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0301 basic medicine ,Proto-Oncogene Proteins B-raf ,Mutant ,Antineoplastic Agents ,medicine.disease_cause ,Crystallography, X-Ray ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Mice ,Structure-Activity Relationship ,0302 clinical medicine ,2,2'-Dipyridyl ,Dogs ,Drug Stability ,Neoplasms ,Drug Discovery ,medicine ,Structure–activity relationship ,Animals ,Humans ,c-Raf ,Molecular Targeted Therapy ,Benzamide ,Chemistry ,Kinase ,Drug discovery ,Small molecule ,Xenograft Model Antitumor Assays ,Rats ,030104 developmental biology ,Biochemistry ,030220 oncology & carcinogenesis ,Drug Design ,Benzamides ,ras Proteins ,Molecular Medicine ,raf Kinases ,KRAS - Abstract
RAS oncogenes have been implicated in30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.
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- 2017
5. Lead identification of novel and selective TYK2 inhibitors
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Wade S. Blair, Sue Sohn, Stanley Mark S, Pawan Bir Kohli, Leo Berezhkovskiy, Lawren C. Wu, James P. Driscoll, Charles Eigenbrot, Adam R. Johnson, Vickie Tsui, Birong Zhang, Paul Gibbons, Nico Ghilardi, Yingjie Lai, Jun Liang, Marya Liimatta, Amy Sambrone, Jeremy Murray, Young G. Shin, Jason Halladay, Yisong Xiao, Kathy Barrett, Christine Chang, Maureen Beresini, Steven Shia, Mark Ultsch, Bao Liang, Kapil Menghrajani, Jan Smith, Priscilla Mantik, Anne van Abbema, and Steven Magnuson
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Models, Molecular ,TYK2 Kinase ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Inflammatory Bowel Diseases ,General Medicine ,Hit to lead ,Combinatorial chemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Tyrosine kinase 2 ,Drug Discovery ,Humans ,HATU ,Structure–activity relationship ,Identification (biology) ,Protein Kinase Inhibitors ,ADME - Abstract
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a high-throughput screen for TYK2 inhibitors, revealed pyridine 1 as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity.
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- 2013
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6. Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors
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Sue Sohn, Nico Ghilardi, Priscilla Mantik, Christine Chang, Mercedesz Balazs, Paul Gibbons, Jan Smith, Ivan Peng, Jason DeVoss, Bing-Yan Zhu, Kathy Barrett, Wade S. Blair, Yisong Xiao, Steven Shia, Birong Zhang, Jim Driscoll, Donnie Delarosa, Young G. Shin, Jeremy Murray, Steven Magnuson, Leo Berezhkovsky, Wenqian Yang, Anne van Abbema, Charles Eigenbrot, Lawren C. Wu, Adam R. Johnson, Pawan Bir Kohli, Vickie Tsui, Mark Ultsch, Jason Halladay, Amy Sambrone, Yingjie Lai, Joseph P. Lyssikatos, Yanzhou Liu, Kapil Menghrajani, Jun Liang, and Judy Young
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Models, Molecular ,Administration, Oral ,Aminopyridines ,Biological Availability ,Pharmacology ,Crystallography, X-Ray ,Interferon-gamma ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,Animals ,Structure–activity relationship ,Potency ,4-Aminopyridine ,Benzamide ,Cell potency ,TYK2 Kinase ,chemistry.chemical_classification ,Gene knockdown ,Chemistry ,Janus Kinase 3 ,Stereoisomerism ,Janus Kinase 1 ,Janus Kinase 2 ,STAT4 Transcription Factor ,Interleukin-12 ,Rats ,Enzyme ,Biochemistry ,Tyrosine kinase 2 ,Benzamides ,Microsomes, Liver ,Molecular Medicine ,Protein Binding - Abstract
Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
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- 2013
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7. Discovery of Potent and Selective Pyrazolopyrimidine Janus Kinase 2 Inhibitors
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Janusz J. Kulagowski, Claire Morris, Leslie Lee, Kathy Barrett, Sean P. Flynn, Richard Pastor, Michael Siu, Charles Eigenbrot, Deepak Sampath, Christine Chang, Jane R. Kenny, Aihe Zhou, Jeremy Murray, Joseph P. Lyssikatos, Christopher A. Hurley, Emily J. Hanan, Jeffrey M. Blaney, Wade S. Blair, Tom Rawson, Paul Gibbons, Steven Magnuson, Mark Ultsch, and Anne van Abbema
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Models, Molecular ,Pyrimidine ,Somatic cell ,Mice, SCID ,Pharmacology ,Pyrazolopyrimidine ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,hemic and lymphatic diseases ,Drug Discovery ,STAT5 Transcription Factor ,Animals ,Humans ,Structure–activity relationship ,Tissue Distribution ,Phosphorylation ,Protein Kinase Inhibitors ,Janus kinase 2 ,Molecular Structure ,biology ,Kinase ,food and beverages ,Janus Kinase 2 ,Pyrimidines ,chemistry ,biology.protein ,Molecular Medicine ,Female ,hormones, hormone substitutes, and hormone antagonists - Abstract
The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.
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- 2012
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8. Abstract 724: A novel heterologous prime boost vaccine system drives tumor specific and potent CD8 T cell responses for cancer immunotherapy
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Amy Rachel Rappaport, Kieu Lam, Renee Greer, Hadley Hanson, Petra Schreiner, Leonid Gitlin, Karin Jooss, Ciaran Daniel Scallan, Wade S. Blair, James Heyes, Anne van Abbema, and Gijsbert Grotenbreg
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Cancer Research ,medicine.medical_treatment ,Heterologous ,Biology ,Virology ,Viral vector ,Vaccination ,Immune system ,Oncology ,Cancer immunotherapy ,Antigen ,medicine ,Expression cassette ,Cancer vaccine - Abstract
Tumor-specific neoantigens (TSNAs) are present in a majority of tumor types and are key targets for T cells released by immune checkpoint blockade therapy. Given that TSNAs are non-self antigens, they are particularly attractive cancer vaccine targets. We have developed a potent heterologous prime/boost immunization approach to deliver predicted TSNAs to patients, which is comprised of a replication incompetent chimpanzee adenoviral vector (ChAdV) for the prime vaccination and a self-replicating, synthetic viral vector (srRNA) for repeated boost vaccinations. The ChAdV vector is similar in design to other adenoviral vectors that have demonstrated induction of high titer, polyfunctional and durable CD4 and CD8 T-cell responses against non-self antigens that protected humans against infections. The srRNA vector is based on Venezuelan equine encephalitis virus (VEE), where sequences encoding the structural proteins of VEE were deleted and replaced by a TSNA expression cassette. For delivery in vivo, the srRNA is formulated with a lipid nanoparticle (LNP), which facilitates efficient cellular uptake of the RNA and enhances antigen expression as well as the resulting immune response. We demonstrate that the srRNA vector effectively replicates in vitro and in vivo resulting in durable and high levels of antigen expression. To characterize the vectors in pre-clinical animal models, a prototypical expression cassette that encodes multiple mouse MHC class I tumor antigens as well as Mamu-A01 restricted class I antigens for monitoring immune responses in mice and non-human primates (NHPs) was introduced into both vector systems. We demonstrate that immunization of mice with either vector results in strong antigen-specific CD8 T-cell responses against the encoded murine epitopes. The heterologous prime/boost approach provided a statistically significant survival advantage to tumor bearing mice when compared to untreated mice. The potency of the immunization platform was also assessed in Indian rhesus macaques and the platform demonstrated a quick onset of T-cell responses 1 week post ChAdV prime vaccination with peak T-cell responses against all delivered Mamu-A01 restricted class I antigens at 2-3 weeks. Such ChAdV primed T-cell responses were effectively boosted by the LNP formulated srRNA vector. Co-administration of anti-CTLA4 with the vaccine demonstrated enhanced vaccine induced immune response. These data demonstrate that the heterologous prime/boost platform effectively programs robust T-cell immunity toward encoded non-self antigens in NHPs, which is a highly predictive model of vaccine responses in humans. This vaccine platform is targeted for entry into clinical trials in mid 2018. Citation Format: Wade Blair, Gijsbert Grotenbreg, Ciaran Scallan, Amy Rappaport, Renee Greer, Leonid Gitlin, Kieu Lam, James Heyes, Anne Van Abbema, Hadley Hanson, Petra Schreiner, karin Jooss. A novel heterologous prime boost vaccine system drives tumor specific and potent CD8 T cell responses for cancer immunotherapy [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 724.
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- 2018
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9. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu
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Weihua Song, Daniel E. H. Afar, Peter Burger, Yu-Tzu Tai, Hervé Avet-Loiseau, Wanling Xie, Paul G. Richardson, Claire Mathiot, Audie G. Rice, Anne van Abbema, Xian Feng Li, Kenneth C. Anderson, Lynne Jesaitis, Edie Weller, Ingrid Caras, Alfred Ian Lee, Klaus Podar, Teru Hideshima, Nikhil C. Munshi, Myles B.C. Dillon, Merav Leiba, and Debbie A. Law
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Stromal cell ,medicine.drug_class ,Immunology ,Biology ,Monoclonal antibody ,Biochemistry ,Mice ,Antigen ,Antigens, Neoplasm ,Bone Marrow ,Signaling Lymphocytic Activation Molecule Family ,Cell Adhesion ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,RNA, Messenger ,Receptors, Immunologic ,Cell adhesion ,Antibody-dependent cell-mediated cytotoxicity ,Neoplasia ,Bortezomib ,SLAMF7 ,Antibody-Dependent Cell Cytotoxicity ,Antibodies, Monoclonal ,Cell Biology ,Hematology ,Xenograft Model Antitumor Assays ,Molecular biology ,medicine.anatomical_structure ,Bone marrow ,Stromal Cells ,Multiple Myeloma ,medicine.drug - Abstract
Currently, no approved monoclonal antibody (mAb) therapies exist for human multiple myeloma (MM). Here we characterized cell surface CS1 as a novel MM antigen and further investigated the potential therapeutic utility of HuLuc63, a humanized anti-CS1 mAb, for treating human MM. CS1 mRNA and protein was highly expressed in CD138-purified primary tumor cells from the majority of MM patients (more than 97%) with low levels of circulating CS1 detectable in MM patient sera, but not in healthy donors. CS1 was expressed at adhesion-promoting uropod membranes of polarized MM cells, and short interfering RNA (siRNA) targeted to CS1 inhibited MM cell adhesion to bone marrow stromal cells (BMSCs). HuLuc63 inhibited MM cell binding to BMSCs and induced antibody-dependent cellular cytotoxicity (ADCC) against MM cells in dose-dependent and CS1-specific manners. HuLuc63 triggered autologous ADCC against primary MM cells resistant to conventional or novel therapies, including bortezomib and HSP90 inhibitor; and pretreatment with conventional or novel anti-MM drugs markedly enhanced HuLuc63-induced MM cell lysis. Administration of HuLuc63 significantly induces tumor regression in multiple xenograft models of human MM. These results thus define the functional significance of CS1 in MM and provide the preclinical rationale for testing HuLuc63 in clinical trials, either alone or in combination.
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- 2008
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10. CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma
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Shankar Kumar, Gao Liu, Anne van Abbema, Susan Rhodes, Vladimir Vexler, Amulya Nanisetti, Benny P. Shum, John D. Shaughnessy, Melanie Wong, Naoya Tsurushita, Fenghuang Zhan, Shihao Chen, Daniel E. H. Afar, Aparna Draksharapu, Audie Rice, Mahrukh Huseni, David M. W. Powers, Bart Barlogie, Yin Zhang, Balaji Balasa, Marna Williams, Franklin Fuh, Mohamad A. Hussein, Eric D. Hsi, Roxanne Steinle, Susann Szmania, Myles B.C. Dillon, and Frits van Rhee
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Cancer Research ,Plasma Cells ,CD34 ,Mice, SCID ,Biology ,Article ,Mice ,Signaling Lymphocytic Activation Molecule Family ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Receptors, Immunologic ,Elotuzumab ,Multiple myeloma ,Gene Expression Profiling ,SLAMF7 ,Antibody-Dependent Cell Cytotoxicity ,Antibodies, Monoclonal ,medicine.disease ,Xenograft Model Antitumor Assays ,Molecular biology ,Lymphocyte Subsets ,Killer Cells, Natural ,Haematopoiesis ,medicine.anatomical_structure ,Oncology ,Female ,Bone marrow ,Stem cell ,Multiple Myeloma ,CD8 ,medicine.drug - Abstract
Purpose: We generated a humanized antibody, HuLuc63, which specifically targets CS1 (CCND3 subset 1, CRACC, and SLAMF7), a cell surface glycoprotein not previously associated with multiple myeloma. To explore the therapeutic potential of HuLuc63 in multiple myeloma, we examined in detail the expression profile of CS1, the binding properties of HuLuc63 to normal and malignant cells, and the antimyeloma activity of HuLuc63 in preclinical models.Experimental Design: CS1 was analyzed by gene expression profiling and immunohistochemistry of multiple myeloma samples and numerous normal tissues. HuLuc63-mediated antimyeloma activity was tested in vitro in antibody-dependent cellular cytotoxicity (ADCC) assays and in vivo using the human OPM2 xenograft model in mice.Results: CS1 mRNA was expressed in >90% of 532 multiple myeloma cases, regardless of cytogenetic abnormalities. Anti-CS1 antibody staining of tissues showed strong staining of myeloma cells in all plasmacytomas and bone marrow biopsies. Flow cytometric analysis of patient samples using HuLuc63 showed specific staining of CD138+ myeloma cells, natural killer (NK), NK-like T cells, and CD8+ T cells, with no binding detected on hematopoietic CD34+ stem cells. HuLuc63 exhibited significant in vitro ADCC using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. HuLuc63 exerted significant in vivo antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in the mice.Conclusions: These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1 with HuLuc63 for the treatment of multiple myeloma.
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- 2008
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11. A Restricted Role for TYK2 Catalytic Activity in Human Cytokine Responses Revealed by Novel TYK2-Selective Inhibitors
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Hidenobu Kanda, Adam R. Johnson, Christopher A. Hurley, Mark Zak, Yingjie Lai, Kathy Barrett, Janusz J. Kulagowski, Wade S. Blair, Jan Smith, Christine Chang, Wenqian Yang, Sue J. Sohn, Hart S. Dengler, Nicholas Lewin-Koh, Lawren C. Wu, Birong Zhang, Aihe Zhou, Karen Williams, Nico Ghilardi, Jun Liang, Pawan Bir Kohli, Calum Macleod, Steven Magnuson, and Anne van Abbema
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medicine.medical_treatment ,Immunology ,Immunoblotting ,Locus (genetics) ,Biology ,Interleukin-23 ,Mice ,medicine ,Immunology and Allergy ,Animals ,Humans ,Protein Kinase Inhibitors ,TYK2 Kinase ,Janus kinase 1 ,Kinase ,Human patient ,Immunosuppression ,Interleukin-12 ,Cell biology ,Cytokine ,Tyrosine kinase 2 ,Cytokines ,Clinical and Human Immunology ,Tyrosine kinase ,Signal Transduction - Abstract
TYK2 is a JAK family protein tyrosine kinase activated in response to multiple cytokines, including type I IFNs, IL-6, IL-10, IL-12, and IL-23. Extensive studies of mice that lack TYK2 expression indicate that the IFN-α, IL-12, and IL-23 pathways, but not the IL-6 or IL-10 pathways, are compromised. In contrast, there have been few studies of the role of TYK2 in primary human cells. A genetic mutation at the tyk2 locus that results in a lack of TYK2 protein in a single human patient has been linked to defects in the IFN-α, IL-6, IL-10, IL-12, and IL-23 pathways, suggesting a broad role for TYK2 protein in human cytokine responses. In this article, we have used a panel of novel potent TYK2 small-molecule inhibitors with varying degrees of selectivity against other JAK kinases to address the requirement for TYK2 catalytic activity in cytokine pathways in primary human cells. Our results indicate that the biological processes that require TYK2 catalytic function in humans are restricted to the IL-12 and IL-23 pathways, and suggest that inhibition of TYK2 catalytic activity may be an efficacious approach for the treatment of select autoimmune diseases without broad immunosuppression.
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- 2013
12. Design and evaluation of novel 8-oxo-pyridopyrimidine Jak1/2 inhibitors
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Christine Chang, Pawan Bir Kohli, Anne van Abbema, Kathy Barrett, Steven Shia, Savita Ubhayakar, Mark Zak, Jane R. Kenny, Adam R. Johnson, Paul Gibbons, Micah Steffek, Charles Eigenbrot, Sharada Labadie, Gauri Deshmukh, Marya Liimatta, Wade S. Blair, and Patrick J. Lupardus
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chemistry.chemical_classification ,Cellular activity ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Crystal structure ,Janus Kinase 1 ,Janus Kinase 2 ,Biochemistry ,Molecular Docking Simulation ,Structure-Activity Relationship ,Enzyme ,Pyrimidines ,chemistry ,Drug Discovery ,Molecular Medicine ,Molecule ,Moiety ,Humans ,Molecular Biology ,Protein Kinase Inhibitors - Abstract
A highly ligand efficient, novel 8-oxo-pyridopyrimidine containing inhibitor of Jak1 and Jak2 isoforms with a pyridone moiety as the hinge-binding motif was discovered. Structure-based design strategies were applied to significantly improve enzyme potency and the polarity of the molecule was adjusted to gain cellular activity. The crystal structures of two representative inhibitors bound to Jak1 were obtained to enable SAR exploration.
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- 2013
13. Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2
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Kathy Barrett, Paul Gibbons, Steven Shia, Jane R. Kenny, Mark Zak, Charles Ellwood, Sharada Labadie, Richard James Bull, Chris Hamman, Peter H. Crackett, Peter Gribling, Peter S. Dragovich, Scott Savage, Jiangpeng Liao, Jason DeVoss, Christine Chang, Paroma Chakravarty, Mercedesz Balazs, Wyne P. Lee, Tony Johnson, Rebecca Pulk, Michael F. T. Koehler, Gauri Deshmukh, Marya Liimatta, Janusz J. Kulagowski, Pawan Bir Kohli, Anne van Abbema, Austin John Reeve, Rohan Mendonca, Adam R. Johnson, Ignacio Aliagas, Simon Gaines, Charles Eigenbrot, Yisong Xiao, Nico Ghilardi, Jing Yang, Christopher A. Hurley, Philippe Bergeron, Wade S. Blair, Peter Hewitt, Stuart Ward, Eric Harstad, Micah Steffek, Barbara Avitabile-Woo, Stefan Gradl, Raman Narukulla, and Savita Ubhayakar
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Models, Molecular ,Cell Membrane Permeability ,Membrane permeability ,Stereochemistry ,Pyridines ,Administration, Oral ,Biological Availability ,Stereoisomerism ,Crystallography, X-Ray ,Protein–protein interaction ,Madin Darby Canine Kidney Cells ,Dogs ,Drug Discovery ,Moiety ,Animals ,Humans ,Pyrroles ,Whole blood ,Molecular Structure ,Chemistry ,Imidazoles ,Haplorhini ,Janus Kinase 1 ,Janus Kinase 2 ,Ligand (biochemistry) ,Arthritis, Experimental ,Bioavailability ,Rats ,Isoenzymes ,Antirheumatic Agents ,Microsomes, Liver ,Molecular Medicine ,Collagen ,Selectivity ,Heterocyclic Compounds, 3-Ring - Abstract
Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.
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- 2013
14. Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1
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Adam R. Johnson, Raman Narukulla, Janusz J. Kulagowski, Robert James Maxey, Rina Fong, Stuart Ward, Wade S. Blair, Hazel Joan Dyke, Jane R. Kenny, Marya Liimatta, Nico Ghilardi, Mark Zak, Patrick J. Lupardus, Christopher A. Hurley, Paul Gibbons, Rebecca Pulk, Richard James Bull, Pawan Bir Kohli, Peter H. Crackett, Christine Chang, Savita Ubhayakar, Anne van Abbema, Peter Hewitt, Bohdan Waszkowycz, Gauri Deshmukh, Tony Johnson, and Rohan Mendonca
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Models, Molecular ,Pyridines ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Crystallography, X-Ray ,Biochemistry ,Pharmacokinetics ,Drug Discovery ,JAK1 Inhibitor ,Transferase ,Animals ,Pyrroles ,Molecular Biology ,Cell potency ,Tofacitinib ,Janus kinase 1 ,Chemistry ,Organic Chemistry ,Janus Kinase 1 ,Janus Kinase 2 ,Bioavailability ,Rats ,Kinetics ,Molecular Medicine ,Janus kinase - Abstract
The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).
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- 2013
15. Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2
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Paul Gibbons, Wade S. Blair, Sharada Labadie, Janusz J. Kulagowski, Adam R. Johnson, Kathy Barrett, Savita Ubhayakar, Patrick J. Lupardus, Christopher A. Hurley, Philippe Bergeron, Steven Shia, Stuart Ward, Charles Eigenbrot, Gauri Deshmukh, Anne van Abbema, Jeremy Murray, Mark Ultsch, Peter S. Dragovich, Mark Zak, Marya Liimatta, Rebecca Pulk, Pawan Bir Kohli, Nico Ghilardi, Rohan Mendonca, Jane R. Kenny, Christine Chang, and Micah Steffek
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Male ,Models, Molecular ,Stereochemistry ,Pyridines ,Clinical Biochemistry ,Pharmaceutical Science ,Crystallography, X-Ray ,Biochemistry ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,Drug Discovery ,Structure–activity relationship ,Molecule ,Animals ,Humans ,Pyrroles ,Amino acid residue ,Molecular Biology ,Protein Kinase Inhibitors ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,Drug discovery ,Organic Chemistry ,Imidazoles ,Janus Kinase 1 ,Janus Kinase 2 ,Rats ,Sprague dawley ,Enzyme ,chemistry ,Molecular Medicine ,Structure based ,Selectivity - Abstract
Herein we describe our successful efforts in obtaining C-2 substituted imidazo-pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed.
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- 2012
16. Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2
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Philippe Bergeron, Sharada Labadie, Nico Ghilardi, Jeremy Murray, Stuart Ward, Charles Eigenbrot, Pawan Bir Kohli, Scott Savage, Ling Xiao, Janusz J. Kulagowski, Wade S. Blair, Micah Steffek, Tony Johnson, Gauri Deshmukh, Emily J. Hanan, Chris Hamman, Mark Zak, Jiangpeng Liao, Michael F. T. Koehler, Kathy Barrett, Madeleine Rodriguez, Robert James Maxey, Jason DeVoss, Peter S. Dragovich, Rebecca Pulk, Steven Shia, Mark Ultsch, Rohan Mendonca, Anne van Abbema, Yisong Xiao, Zhonghua Lin, Patrick J. Lupardus, Tian Jin, Adam R. Johnson, Stefan Gradl, Christopher A. Hurley, Paul Gibbons, Jane R. Kenny, Marya Liimatta, Savita Ubhayakar, Eric Harstad, Christine Chang, Mercedesz Balazs, and Peter Hewitt
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Models, Molecular ,Stereochemistry ,Biological Availability ,Crystallography, X-Ray ,Cell Line ,Mice ,Structure-Activity Relationship ,Dogs ,In vivo ,Drug Discovery ,Structure–activity relationship ,Potency ,Bioassay ,Animals ,Humans ,ADME ,Chemistry ,Janus Kinase 1 ,Janus Kinase 2 ,In vitro ,Bioavailability ,Rats ,Hepatocytes ,Molecular Medicine ,Biological Assay ,Selectivity ,Heterocyclic Compounds, 3-Ring - Abstract
Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.
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- 2012
17. Development of a new fully human anti-CD20 monoclonal antibody for the treatment of B-cell malignancies
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Anne van Abbema, Gadi Gazit Bornstein, Christophe Quéva, Ping Wang, David C. Blakey, Larry L. Green, Carlos Chavez, Carl I. Webster, Naomi Laing, Sandhya Raja, Ross Stewart, Mohammad Tabrizi, Shenghua Wen, Xiao-Dong Yang, Kiran Ahluwalia, and Orit Foord
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Lymphoma, B-Cell ,medicine.drug_class ,Molecular Sequence Data ,Apoptosis ,Mice, SCID ,Monoclonal antibody ,Antibodies, Monoclonal, Murine-Derived ,Mice ,immune system diseases ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Amino Acid Sequence ,B cell ,Cell Proliferation ,Pharmacology ,CD20 ,Antibody-dependent cell-mediated cytotoxicity ,biology ,Antibody-Dependent Cell Cytotoxicity ,Antibodies, Monoclonal ,medicine.disease ,Antigens, CD20 ,Xenograft Model Antitumor Assays ,Lymphoma ,Leukemia ,Macaca fascicularis ,medicine.anatomical_structure ,Oncology ,Immunology ,biology.protein ,Rituximab ,Antibody ,Peptides ,Epitope Mapping ,medicine.drug - Abstract
Despite the widespread use of rituximab, a chimeric monoclonal antibody with demonstrated efficacy in the treatment of non-Hodgkin's lymphomas, there is a recognized need to develop new agents with improved efficacy. Towards this end, using XenoMouse technology, a fully human IgG1 anti-CD20 monoclonal antibody was generated. This antibody, denoted mAb 1.5.3, evoked enhanced pro-apoptotic activity in vitro, as compared to rituximab, in the Ramos lymphoma cell line. Also, mAb 1.5.3 mediated both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) similar to rituximab in human B-lymphoma lines. Interestingly, mAb 1.5.3 demonstrated superior ADCC compared to rituiximab when FcgammaRIIIa F/F allotype donors were profiled and superior cytolytic activity across multiple human B-lymphoma and chronic B-cell leukemia lines in an in vitro whole blood assay. Furthermore, mAb 1.5.3 exhibited enhanced anti-tumor activity in Ramos, Daudi, and Namalwa tumour xenograft models. Lastly, mAb 1.5.3 produced a superior B-cell depletion profile in lymph node organs and bone marrow as compared to rituximab in a primate pharmacodynamic (PD) model. These findings underscore the potential of mAb 1.5.3 to exhibit improved clinical activity in the treatment of B-cell malignancies compared to rituximab.
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- 2009
18. HuLuc63 in Combination Regimens with Conventional and Targeted Therapies Has Additive and Synergistic Anti-Tumor Activity in Pre-Clinical Models of Myeloma
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Anne van Abbema, Daniel E. H. Afar, Audie Rice, and Myles B.C. Dillon
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Bevacizumab ,Bortezomib ,business.industry ,SLAMF7 ,Immunology ,Cell Biology ,Hematology ,Pharmacology ,medicine.disease ,Biochemistry ,Thalidomide ,In vivo ,medicine ,Elotuzumab ,business ,Multiple myeloma ,Dexamethasone ,medicine.drug - Abstract
Introduction: HuLuc63 is a humanized monoclonal antibody that targets CS1 (CD2 subset 1, CRACC, SLAMF7, CD319), a cell surface glycoprotein that is highly and universally expressed on myeloma cells. In preclinical studies, we have shown that HuLuc63 treatment of mice with multiple myeloma (MM) xenograft tumors resulted in significant in vivo anti-tumor activity that is mediated at least in part by an antibody-dependent cellular cytotoxicity (ADCC) mechanism of action. The purpose of this study was to examine whether using HuLuc63 in combination with a panel of drugs having distinct modes of action (dexamethasone, thalidomide, bevacizumab (Avastin®), bortezomib (Velcade®)) could result in additional therapeutic benefit and provide a rationale for the design of future clinical trials. Methods: HuLuc63 in combination with other agents was tested in vivo for anti-tumor activity using the human L363 and OPM2 xenograft models. SCID mice were implanted subcutaneously with myeloma cells and randomized into different groups (10–15 mice per treatment group) when the average tumor volume reached ∼100 mm3. HuLuc63 was administered via intra-peritoneal injection twice per week at doses of 1–10 mg/kg. Dosing for dexamethasone was 10 mg/kg twice weekly, thalidomide 50 mg/kg daily, bevacizumab twice weekly at 0.5 mg/kg, and bortezomib 1 mg/kg for two dosing cycles, each cycle consisting of twice weekly dosing for 2 weeks followed by a week of rest. Results: The combination of dexamethasone with HuLuc63 showed a statistically significant increase in anti-tumor activity over either agent alone (p < 0.04). Combination with thalidomide only showed a slight enhancement of tumor inhibition when dosed in combination with HuLuc63 but its anti-tumor activity did not reach a statistically significant increase in over that of HuLuc63 alone. Co-treatment of the anti-VEGF anti-angiogenic monoclonal antibody bevacizumab with HuLuc63 resulted in a significant increase in tumor inhibition (p < 0.05) over that observed with either antibody when used as a single agent. The strongest anti-myeloma activity was observed when HuLuc63 was combined with bortezomib, which appeared to result in a synergistic inhibition of tumor cell growth. None of the agents tested changed the CS1 expression level on the myeloma cells or diminished the anti-myeloma activity of HuLuc63. Conclusions: These results suggest that HuLuc63 may be combined with different classes of drugs to enhance its anti-myeloma effects. In particular, agents that may induce apoptosis of myeloma cells (dexamethasone and bortezomib) and anti-angiogenics (bevacizumab) may be of particular interest for future clinical testing. Further preclinical studies using HuLuc63 in combination with other agents are in progress. HuLuc63 is currently being evaluated in a phase I clinical study as monotherapy for the treatment of relapsed/refractory multiple myeloma.
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- 2007
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19. Eradication of Tumors in Pre-Clinical Models of Multiple Myeloma by Anti-CS1 Monoclonal Antibody HuLuc63: Mechanism of Action Studies
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Lynne Jesaitis, Gao Liu, Debbie Law, David M. W. Powers, Ingrid Caras, Susan Rhodes, Melanie Wong, Stacey Lawson, Daniel E. H. Afar, Anne van Abbema, Audie Rice, Yin Zhang, and Myles B.C. Dillon
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Antibody-dependent cell-mediated cytotoxicity ,biology ,medicine.drug_class ,Immunology ,Fc receptor ,Cell Biology ,Hematology ,Monoclonal antibody ,Biochemistry ,Molecular biology ,Fragment crystallizable region ,Mechanism of action ,In vivo ,Monoclonal ,biology.protein ,medicine ,medicine.symptom ,Antibody - Abstract
Introduction: We have recently shown that CS1 (CD2 subset 1, CRACC, SLAMF7), a cell surface glycoprotein of the CD2 family, is uniformly expressed on myeloma cells from multiple myeloma (MM) patients. Based on its high expression in MM and limited expression in normal cells, we propose CS1 as a novel and specific antibody target for the treatment of MM. Methods: A panel of monoclonal anti-CS1 antibodies (mAbs) was generated to identify a potential therapeutic candidate. MAb clones MuLuc63 and MuLuc90 were selected for testing in CS1 positive MM xenograft models in vivo in severe combined immunodeficient mice. HuLuc63, a humanized IgG1 version of MuLuc63, was generated as the potential therapeutic candidate for the treatment of MM. HuLuc63 and Fc-modified versions of HuLuc63 were tested for anti-tumor activity in mouse models vivo. In vitro antibody-dependent cellular cytotoxicity (ADCC) assays were performed to define the potential mechanism of action for HuLuc63. Results: Both MuLuc63 and MuLuc90 exhibited significant in vivo anti-tumor activity compared to isotype control antibodies in the L363 MM xenograft model. MuLuc63 was significantly more potent, resulting in rapid tumor eradication in most of the animals for the length of the study (~4 months). Based on these results, MuLuc63 was humanized to generate HuLuc63, which exhibited similar affinity for CS1 when compared to the mouse parent antibody. In two different MM xenograft models, L363 and OPM2, HuLuc63 exhibited significant anti-tumor activity resulting in tumor eradication in a high proportion of animals. To investigate the mechanism of action, two modified versions of HuLuc63 were tested in xenograft models. One version, HuLuc63-Ala,Ala, exhibits a mutation in the Fc region that decreases the ability to interact with the Fc receptor on natural killer (NK) cells. The second version, HuLuc63-LF, exhibits low levels of fucosylation in the Fc region that would result in increased binding to the Fc receptor. Compared to HuLuc63, the LF version exhibited significantly better in vivo anti-tumor activity towards, while the Ala,Ala mutant exhibited no anti-tumor activity. These data indicate that the Fc region of HuLuc63 is critical for its anti-tumor activity, and suggest ADCC as a possible mechanism of action. In vitro, HuLuc63 exhibits substantial ADCC towards L363 and OPM2 cells. The activity was dose-dependent, with increasing cytotoxicity being observed with concentrations ranging from 0.01μg/mL to10 μg/mL. Conclusions: These pre-clinical data support HuLuc63 as a new therapeutic for the treatment of MM and suggest that ADCC is part of the mechanism of action. HuLuc63 will be entering a phase I clinical study for multiple myeloma.
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- 2006
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20. Killing of Drug-Sensitive and Resistant Myeloma Cells and Disruption of Their Bone Marrow Stromal Interaction by HuLuc63, a Novel Humanized Anti-CS1 Monoclonal Antibody
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Nikhil C. Munshi, Audie Rice, Paul G. Richardson, Weihua Song, Robert L. Schlossman, Anne van Abbema, Peter C. Burger, Yu-Tzu Tai, Xian-Feng Li, Daniel E. H. Afar, and Kenneth C. Anderson
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Antibody-dependent cell-mediated cytotoxicity ,Stromal cell ,business.industry ,Bortezomib ,SLAMF7 ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Molecular biology ,medicine.anatomical_structure ,Antigen ,medicine ,Cytotoxic T cell ,Bone marrow ,business ,Multiple myeloma ,medicine.drug - Abstract
Introduction: Current monoclonal antibody (mAb) therapies for multiple myeloma (MM) have had limited success due to narrow target expression across MM patient samples. A preferred strategy would be to develop cytotoxic human mAbs against novel antigens that are highly expressed in MM cells yet have limited expression in other cell types. CS1 (CD2 subset 1, CRACC, SLAMF7), a member of the CD2 family of cell surface glycoproteins, was found to be highly expressed in myeloma cells. In this study, we investigated the anti-myeloma activity of HuLuc63, a novel humanized anti-CS1 mAb. Methods: Microarray expression profiling was used to determine the CS1 mRNA levels in CD138-expressing myeloma cells from 101 MM patient samples. For detection of CS1 protein, flow cytometry was performed using the anti-CS1 mAb HuLuc63. Functional characterization of HuLuc63 was performed by assessing antibody-dependent cellular cytotoxicity (ADCC) and by assessing MM and bone marrow stromal cell (BMSC) interactions. Results: CS1 mRNA was expressed in CD138 cells from more than 96% (97/101) of MM patients. Flow cytometric analysis confirmed that protein expression mirrors the mRNA profile. Importantly, CS1 is also present in 12 MM cell lines that are either drug-sensitive or resistant. HuLuc63, but not an isotype control antibody, induced ADCC in a CS1-specific, dose-dependent manner against CD138-expressing MM lines and patient MM cells including dexamethasone (dex)-sensitive MM1S and dex-resistant MM1R cells. Significantly, HuLuc63 triggered autologous ADCC against CS1-expressing CD138-purified tumor cells from 11 MM patients resistant to conventional or novel therapies such as bortezomib (Velcade®) and an HSP90 inhibitor. Since CS1 may regulate cell adhesion, we next studied whether HuLuc63 alters MM cell adhesion to BMSCs. HuLuc63 inhibited MM cell adhesion to BMSCs in a dose-dependent manner, whereas human control IgG did not. However, the presence of BMSC appeared to reduce HuLuc63-induced cell lysis against MM1S and MM1R cells. Since the immunomodulatory drug lenalidomide (Revlimid®) enhances NK cell function, we further tested whether HuLuc63-induced ADCC against MM cells is augmented by lenalidomide. Pretreatment with lenalidomide markedly enhanced NK-cell-mediated lysis of autologous patient MM cells triggered by HuLuc63. Conclusions: We show that the new MM antigen, CS1, is expressed in myeloma cells from more than 96% of MM patients. The novel humanized anti-CS1 mAb, HuLuc63, induced significant cytotoxicity against MM cells including drug-resistant cells, and inhibited their interaction with BMSCs. These data suggest that HuLuc63 may have clinical utility in a spectrum of MM patients including those newly diagnosed with the disease as well as patients with late stage refractory disease.
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- 2006
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