26 results on '"Punzalan B"'
Search Results
2. 1 Oral - A radiohapten capture system for CAR T cells that tracks them in vivo and improves efficacy
- Author
-
Kurtz, K., Eibler, L., Dacek, M., Carter, L., Cheal, S., Veach, D., Qureshy, S., Han, J., Reynaud, E., Verma, S., McDevitt, M., Punzalan, B., Vargas, D.B., Santich, B.H., Monette, S., Kesner, A., Cheung, N.K., Larson, S., Scheinberg, D., and Krebs, S.
- Published
- 2022
- Full Text
- View/download PDF
3. 148 Ultrasound Transducer Selection for Identification of B-Lines in Patients With Shortness of Breath
- Author
-
Salazar, L., primary, Punzalan, B., additional, Corujo, O., additional, Fialkovich, J., additional, Chin, S.H., additional, Ali, Z., additional, Radeos, M., additional, and Datta, A., additional
- Published
- 2014
- Full Text
- View/download PDF
4. TU-F-12A-01: Quantitative Non-Linear Compartment Modeling of 89Zr- and 124I- Labeled J591 Monoclonal Antibody Kinetics Using Serial Non-Invasive Positron Emission Tomography Imaging in a Pre-Clinical Human Prostate Cancer Mouse Model
- Author
-
Fung, EK, primary, Cheal, SM, additional, Chalasani, S, additional, Fareedy, SB, additional, Otto, B, additional, Punzalan, B, additional, Humm, JL, additional, Bander, NH, additional, Osborne, JR, additional, Larson, SM, additional, and Zanzonico, PB, additional
- Published
- 2014
- Full Text
- View/download PDF
5. Engineering CAR-T cells for radiohapten capture in imaging and radioimmunotherapy applications.
- Author
-
Kurtz K, Eibler L, Dacek MM, Carter LM, Veach DR, Lovibond S, Reynaud E, Qureshy S, McDevitt MR, Bourne C, Monette S, Punzalan B, Khayat S, Verma S, Kesner AL, Cheung NV, Schöder H, Gajecki L, Cheal SM, Larson SM, Scheinberg DA, and Krebs S
- Subjects
- Positron Emission Tomography Computed Tomography, Tissue Distribution, Immunotherapy, Adoptive methods, Radioisotopes metabolism, T-Lymphocytes metabolism, Radioimmunotherapy, Antineoplastic Agents metabolism
- Abstract
Rationale: The in vivo dynamics of CAR-T cells remain incompletely understood. Novel methods are urgently needed to longitudinally monitor transferred cells non-invasively for biodistribution, functionality, proliferation, and persistence in vivo and for improving their cytotoxic potency in case of treatment failure. Methods: Here we engineered CD19 CAR-T cells ("Thor"-cells) to express a membrane-bound scFv, huC825, that binds DOTA-haptens with picomolar affinity suitable for labeling with imaging or therapeutic radionuclides. We assess its versatile utility for serial tracking studies with PET and delivery of α-radionuclides to enhance anti-tumor killing efficacy in sub-optimal adoptive cell transfer in vivo using Thor-cells in lymphoma models. Results: We show that this reporter gene/probe platform enables repeated, sensitive, and specific assessment of the infused Thor-cells in the whole-body using PET/CT imaging with exceptionally high contrast. The uptake on PET correlates with the Thor-cells on a cellular and functional level. Furthermore, we report the ability of Thor-cells to accumulate cytotoxic alpha-emitting radionuclides preferentially at tumor sites, thus increasing therapeutic potency. Conclusion: Thor-cells are a new theranostic agent that may provide crucial information for better and safer clinical protocols of adoptive T cell therapies, as well as accelerated development strategies., Competing Interests: Competing Interests: MSK has filed for patent protection on behalf of M.M.D., D.R.V., M.R.M., N.K.C., S.M.C., S.M.L., D.A.S., and S.K. for inventions related to the work described in this paper. S.M.C. was named as an inventor on multiple patents filed by MSK, including those licensed to Y-mAbs Therapeutics. N.K.C. has a financial interest in Abpro-Labs, Biotec Pharmacon, Eureka Therapeutics, and Y-mAbs Therapeutics that may work in areas related to this paper. D.A.S. is an advisor to, or owns equity in, IOVA, ATNM, LNTH, Eureka Therapeutics, CoImmune, Atengen, Repertoire, and PFE, which may work in areas related to this paper. S.M.L. reports receiving commercial research grants from Y-mAbs Therapeutics, Genentech, Inc., WILEX AG, Telix Pharmaceuticals Limited, and Regeneron Pharmaceuticals, Inc.; holding ownership interest/equity in Voreyda Theranostics Inc. and Elucida Oncology Inc., and holding stock in Y-mAbs Therapeutics. S.M.L. is the inventor and owner of issued patents both currently unlicensed and licensed by MSK to Samus Therapeutics, Inc., Y-mAbs Therapeutics Inc., and Elucida Oncology, Inc.; is or has served as a consultant to Cynvec LLC, Eli Lilly & Co., Prescient Therapeutics Limited, Advanced Innovative Partners, LLC, Gerson Lehrman Group, Progenics Pharmaceuticals, Inc., and Janssen Pharmaceuticals, Inc. SK has consulted for Telix Pharmaceuticals Ltd. and acknowledges support for investigator services from RayzeBio. The remaining authors report no competing interests., (© The author(s).)
- Published
- 2023
- Full Text
- View/download PDF
6. Efficacy of HER2-Targeted Intraperitoneal 225 Ac α-Pretargeted Radioimmunotherapy for Small-Volume Ovarian Peritoneal Carcinomatosis.
- Author
-
Chung SK, Vargas DB, Chandler CS, Katugampola S, Veach DR, McDevitt MR, Seo SH, Vaughn BA, Rinne SS, Punzalan B, Patel M, Xu H, Guo HF, Zanzonico PB, Monette S, Yang G, Ouerfelli O, Nash GM, Cercek A, Fung EK, Howell RW, Larson SM, Cheal SM, and Cheung NV
- Subjects
- Humans, Animals, Mice, Mice, Nude, Radioisotopes therapeutic use, Cell Line, Tumor, Radioimmunotherapy methods, Peritoneal Neoplasms diagnostic imaging, Peritoneal Neoplasms radiotherapy, Peritoneal Neoplasms drug therapy
- Abstract
Epithelial ovarian cancer (EOC) is often asymptomatic and presents clinically in an advanced stage as widespread peritoneal microscopic disease that is generally considered to be surgically incurable. Targeted α-therapy with the α-particle-emitting radionuclide
225 Ac (half-life, 9.92 d) is a high-linear-energy-transfer treatment approach effective for small-volume disease and even single cells. Here, we report the use of human epidermal growth factor receptor 2 (HER2)225 Ac-pretargeted radioimmunotherapy (PRIT) to treat a mouse model of human EOC SKOV3 xenografts growing as peritoneal carcinomatosis (PC). Methods: On day 0, 105 SKOV3 cells transduced with a luciferase reporter gene were implanted intraperitoneally in nude mice, and tumor engraftment was verified by bioluminescent imaging (BLI). On day 15, treatment was started using 1 or 2 cycles of 3-step anti-HER2225 Ac-PRIT (37 kBq/cycle as225 Ac- Proteus DOTA), separated by a 1-wk interval. Efficacy and toxicity were monitored for up to 154 d. Results: Untreated PC-tumor-bearing nude mice showed a median survival of 112 d. We used 2 independent measures of response to evaluate the efficacy of225 Ac-PRIT. First, a greater proportion of the treated mice (9/10 1-cycle and 8/10 2-cycle; total, 17/20; 85%) survived long-term compared with controls (9/27, 33%), and significantly prolonged survival was documented (log-rank [Mantel-Cox] P = 0.0042). Second, using BLI, a significant difference in the integrated BLI signal area to 98 d was noted between controls and treated groups ( P = 0.0354). Of a total of 8 mice from the 2-cycle treatment group (74 kBq total) that were evaluated by necropsy, kidney radiotoxicity was mild and did not manifest itself clinically (normal serum blood urea nitrogen and creatinine). Dosimetry estimates (relative biological effectiveness-weighted dose, where relative biological effectiveness = 5) per 37 kBq administered for tumors and kidneys were 56.9 and 16.1 Gy, respectively. One-cycle and 2-cycle treatments were equally effective. With immunohistology, mild tubular changes attributable to α-toxicity were observed in both therapeutic groups. Conclusion: Treatment of EOC PC-tumor-bearing mice with anti-HER2225 Ac-PRIT resulted in histologic cures and prolonged survival with minimal toxicity. Targeted α-therapy using the anti-HER2225 Ac-PRIT system is a potential treatment for otherwise incurable EOC., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2023
- Full Text
- View/download PDF
7. Intraperitoneal Pretargeted Radioimmunotherapy for Colorectal Peritoneal Carcinomatosis.
- Author
-
Chandler CS, Bell MM, Chung SK, Veach DR, Fung EK, Punzalan B, Burnes Vargas D, Patel M, Xu H, Guo HF, Santich BH, Zanzonico PB, Monette S, Nash GM, Cercek A, Jungbluth A, Pandit-Taskar N, Cheung NKV, Larson SM, and Cheal SM
- Subjects
- Animals, Disease Models, Animal, Humans, Mice, Mice, Nude, Colorectal Neoplasms drug therapy, Peritoneal Neoplasms drug therapy, Radioimmunotherapy methods
- Abstract
Peritoneal carcinomatosis (PC) is considered incurable, and more effective therapies are needed. Herein we test the hypothesis that GPA33-directed intracompartmental pretargeted radioimmunotherapy (PRIT) can cure colorectal peritoneal carcinomatosis. Nude mice were implanted intraperitoneally with luciferase-transduced GPA33-expressing SW1222 cells for aggressive peritoneal carcinomatosis (e.g., resected tumor mass 0.369 ± 0.246 g; n = 17 on day 29). For GPA33-PRIT, we administered intraperitoneally a high-affinity anti-GPA33/anti-DOTA bispecific antibody (BsAb), followed by clearing agent (intravenous), and lutetium-177 (Lu-177) or yttrium-86 (Y-86) radiolabeled DOTA-radiohapten (intraperitoneal) for beta/gamma-emitter therapy and PET imaging, respectively. The DOTA-radiohaptens were prepared from S -2-(4-aminobenzyl)-1,4,7, 10-tetraazacyclododecane tetraacetic acid chelate (DOTA-Bn). Efficacy and toxicity of single- versus three-cycle therapy were evaluated in mice 26-27 days post-tumor implantation. Single-cycle treatment ([
177 Lu]LuDOTA-Bn 111 MBq; tumor dose: 4,992 cGy) significantly prolonged median survival (MS) approximately 2-fold to 84.5 days in comparison with controls ( P = 0.007). With three-cycle therapy (once weekly, total 333 MBq; tumor dose: 14,975 cGy), 6/8 (75%) survived long-term (MS > 183 days). Furthermore, for these treated long-term survivors, 1 mouse was completely disease free (microscopic "cure") at necropsy; the others showed stabilized disease, which was detectable during PET-CT using [86 Y]DOTA-Bn. Treatment controls had MS ranging from 42-52.5 days ( P < 0.001) and 19/20 mice succumbed to progressive intraperitoneal disease by 69 days. Multi-cycle GPA33 DOTA-PRIT significantly prolongs survival with reversible myelosuppression and no chronic marrow (929 cGy to blood) or kidney (982 cGy) radiotoxicity, with therapeutic indices of 12 for blood and 12 for kidneys. MTD was not reached., (©2021 American Association for Cancer Research.)- Published
- 2022
- Full Text
- View/download PDF
8. Imaging of Cancer γ-Secretase Activity Using an Inhibitor-Based PET Probe.
- Author
-
Nie P, Kalidindi T, Nagle VL, Wu X, Li T, Liao GP, Frost G, Henry KE, Punzalan B, Carter LM, Lewis JS, Pillarsetty NVK, and Li YM
- Subjects
- Animals, Female, Humans, Iodine Radioisotopes, Mice, Positron-Emission Tomography, Receptors, Notch metabolism, Tissue Distribution, Amyloid Precursor Protein Secretases, Breast Neoplasms pathology
- Abstract
Purpose: Abnormal Notch signaling promotes cancer cell growth and tumor progression in various cancers. Targeting γ-secretase, a pivotal regulator in the Notch pathway, has yielded numerous γ-secretase inhibitors (GSIs) for clinical investigation in the last 2 decades. However, GSIs have demonstrated minimal success in clinical trials in part due to the lack of specific and precise tools to assess γ-secretase activity and its inhibition in vivo ., Experimental Design: We designed an imaging probe based on GSI Semagacestat structure and synthesized the radioiodine-labeled analogues [
131 I]- or [124 I]-PN67 from corresponding trimethyl-tin precursors. Both membrane- and cell-based ligand-binding assays were performed using [131 I]-PN67 to determine the binding affinity and specificity for γ-secretase in vitro . Moreover, we evaluated [124 I]-PN67 by PET imaging in mammary tumor and glioblastoma mouse models., Results: The probe was synthesized through iodo-destannylation using chloramine-T as an oxidant with a high labeling yield and efficiency. In vitro binding results demonstrate the high specificity of this probe and its ability for target replacement study by clinical GSIs. PET imaging studies demonstrated a significant ( P < 0.05) increased in the uptake of [124 I]-PN67 in tumors versus blocking or sham control groups across multiple mouse models, including 4T1 allograft, MMTV-PyMT breast cancer, and U87 glioblastoma allograft. Ex vivo biodistribution and autoradiography corroborate these results, indicating γ-secretase specific tumor accumulation of [124 I]-PN67., Conclusions: [124 I]-PN67 is a novel PET imaging agent that enables assessment of γ-secretase activity and target engagement of clinical GSIs., (©2021 American Association for Cancer Research.)- Published
- 2021
- Full Text
- View/download PDF
9. COVID-19 vaccine-induced myocarditis: Case report with literature review.
- Author
-
Nassar M, Nso N, Gonzalez C, Lakhdar S, Alshamam M, Elshafey M, Abdalazeem Y, Nyein A, Punzalan B, Durrance RJ, Alfishawy M, Bakshi S, and Rizzo V
- Subjects
- Aged, COVID-19 prevention & control, Echocardiography, Female, Humans, Myocarditis diagnostic imaging, COVID-19 complications, COVID-19 Vaccines adverse effects, Myocarditis etiology
- Published
- 2021
- Full Text
- View/download PDF
10. Corrigendum to "COVID-19 vaccine-induced myocarditis case report with literature review" [Diabetes & Metabolic Syndrome: Clinical Research & Reviews Volume 15, Issue 5, September-October 2021, 102205].
- Author
-
Nassar M, Nso N, Gonzalez C, Lakhdar S, Alshamam M, Elshafey M, Abdalazeem Y, Nyein A, Punzalan B, Durrance RJ, Alfishawy M, Bakshi S, and Rizzo V
- Published
- 2021
- Full Text
- View/download PDF
11. Engineered Cells as a Test Platform for Radiohaptens in Pretargeted Imaging and Radioimmunotherapy Applications.
- Author
-
Dacek MM, Veach DR, Cheal SM, Carter LM, McDevitt MR, Punzalan B, Burnes Vargas D, Kubik TZ, Monette S, Santich BH, Yang G, Ouerfelli O, Kesner AL, Cheung NV, Scheinberg DA, Larson SM, and Krebs S
- Subjects
- Animals, Autoradiography, HEK293 Cells, Humans, Mice, Positron Emission Tomography Computed Tomography, Radiopharmaceuticals pharmacokinetics, Tissue Distribution, Xenograft Model Antitumor Assays, Cell Engineering, Haptens, Radioimmunotherapy methods, Radiopharmaceuticals chemistry
- Abstract
Pretargeted imaging and radioimmunotherapy approaches are designed to have superior targeting properties over directly targeted antibodies but impose more complex pharmacology, which hinders efforts to optimize the ligands prior to human applications. Human embryonic kidney 293T cells expressing the humanized single-chain variable fragment (scFv) C825 (huC825) with high-affinity for DOTA-haptens (293T-huC825) in a transmembrane-anchored format eliminated the requirement to use other pretargeting reagents and provided a simplified, accelerated assay of radiohapten capture while offering normalized cell surface expression of the molecular target of interest. Using binding assays, ex vivo biodistribution, and in vivo imaging, we demonstrated that radiohaptens based on benzyl-DOTA and a second generation "Proteus" DOTA-platform effectively and specifically engaged membrane-bound huC825, achieving favorable tumor-to-normal tissue uptake ratios in mice. Furthermore, [
86 Y]Y-DOTA-Bn predicted absorbed dose to critical organs with reasonable accuracy for both [177 Lu]Lu-DOTA-Bn and [225 Ac]Ac-Pr, which highlights the benefit of a dosimetry-based treatment approach.- Published
- 2021
- Full Text
- View/download PDF
12. γ-Tocotrienol-Loaded Liposomes for Radioprotection from Hematopoietic Side Effects Caused by Radiotherapeutic Drugs.
- Author
-
Lee SG, Kalidindi TM, Lou H, Gangangari K, Punzalan B, Bitton A, Lee CJ, Vargas HA, Park S, Bodei L, Kharas MG, Singh VK, Kishore Pillarsetty NV, and Larson SM
- Subjects
- Animals, Chromans pharmacokinetics, Liposomes, Mice, Radiation-Protective Agents pharmacokinetics, Tissue Distribution, Vitamin E administration & dosage, Vitamin E pharmacokinetics, Vitamin E pharmacology, Chromans administration & dosage, Chromans pharmacology, Hematopoiesis drug effects, Hematopoiesis radiation effects, Radiation-Protective Agents administration & dosage, Radiation-Protective Agents pharmacology, Radiotherapy adverse effects, Vitamin E analogs & derivatives
- Abstract
With the successful development and increased use of targeted radionuclide therapy for treating cancer comes the increased risk of radiation injury to bone marrow-both direct suppression and stochastic effects, leading to neoplasia. Herein, we report a novel radioprotector drug, a liposomal formulation of γ-tocotrienol (GT3), or GT3-Nano for short, to mitigate bone marrow radiation damage during targeted radionuclide therapy. Methods: GT3 was loaded into liposomes using passive loading.
64 Cu-GT3-Nano and3 H-GT3-Nano were synthesized to study the in vivo biodistribution profile of the liposome and GT3 individually. The radioprotection efficacy of GT3-Nano was assessed after acute137 Cs whole-body irradiation at a sublethal (4 Gy), a lethal (9 Gy), or a single high-dose administration of153 Sm-ethylenediamine- N,N,N',N' -tetrakis(methylene phosphonic acid) (EDTMP). Flow cytometry and fluorescence microscopy were used to analyze hematopoietic cell population dynamics and the cellular site of GT3-Nano localization in the spleen and bone marrow, respectively. Results: Bone marrow uptake and retention (percentage injected dose per gram of tissue) at 24 h was 6.98 ± 2.34 for64 Cu-GT3-Nano and 7.44 ± 2.52 for3 H-GT3-Nano. GT3-Nano administered 24 h before or after 4 Gy of total-body irradiation (TBI) promoted rapid and complete hematopoietic recovery, whereas recovery of controls stalled at 60%. GT3-Nano demonstrated dose-dependent radioprotection, achieving 90% survival at 50 mg/kg against lethal 9-Gy TBI. Flow cytometry of the bone marrow indicated that progenitor bone marrow cells MPP2 and CMP were upregulated in GT3-Nano-treated mice. Immunohistochemistry showed that GT3-Nano accumulates in CD105-positive sinusoid epithelial cells. Conclusion: GT3-Nano is highly effective in mitigating the marrow-suppressive effects of sublethal and lethal TBI in mice. GT3-Nano can facilitate rapid recovery of hematopoietic components in mice treated with the endoradiotherapeutic agent153 Sm-EDTMP., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2021
- Full Text
- View/download PDF
13. Alpha radioimmunotherapy using 225 Ac-proteus-DOTA for solid tumors - safety at curative doses.
- Author
-
Cheal SM, McDevitt MR, Santich BH, Patel M, Yang G, Fung EK, Veach DR, Bell M, Ahad A, Vargas DB, Punzalan B, Pillarsetty NVK, Xu H, Guo HF, Monette S, Michel AO, Piersigilli A, Scheinberg DA, Ouerfelli O, Cheung NV, and Larson SM
- Subjects
- Actinium administration & dosage, Actinium pharmacokinetics, Animals, Cell Line, Tumor, Dose-Response Relationship, Radiation, Female, Half-Life, Heterocyclic Compounds, 1-Ring administration & dosage, Heterocyclic Compounds, 1-Ring chemistry, Heterocyclic Compounds, 1-Ring pharmacokinetics, Humans, Indium Radioisotopes administration & dosage, Indium Radioisotopes pharmacokinetics, Mice, Nanoparticles administration & dosage, Nanoparticles chemistry, Neoplasms diagnosis, Neoplasms immunology, Neoplasms pathology, Radioimmunotherapy adverse effects, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacokinetics, Radiotherapy Dosage, Tissue Distribution, Toxicity Tests, Chronic, Xenograft Model Antitumor Assays, Alpha Particles therapeutic use, Neoplasms therapy, Radioimmunotherapy methods, Radiopharmaceuticals administration & dosage, Theranostic Nanomedicine methods
- Abstract
This is the initial report of an α-based pre-targeted radioimmunotherapy (PRIT) using
225 Ac and its theranostic pair,111 In. We call our novel tumor-targeting DOTA-hapten PRIT system "proteus-DOTA" or "Pr." Herein we report the first results of radiochemistry development, radiopharmacology, and stoichiometry of tumor antigen binding, including the role of specific activity, anti-tumor efficacy, and normal tissue toxicity with the Pr-PRIT approach (as α-DOTA-PRIT). A series of α-DOTA-PRIT therapy studies were performed in three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2), including evaluation of chronic toxicity at ~20 weeks of select survivors. Methods: Preliminary biodistribution experiments in SW1222 tumor-bearing mice revealed that225 Ac could not be efficiently pretargeted with current DOTA-Bn hapten utilized for177 Lu or90 Y, leading to poor tumor uptake in vivo . Therefore, we synthesized Pr consisting of an empty DOTA-chelate for225 Ac, tethered via a short polyethylene glycol linker to a lutetium-complexed DOTA for picomolar anti-DOTA chelate single-chain variable fragment (scFv) binding. Pr was radiolabeled with225 Ac and its imaging surrogate,111 In. In vitro studies verified anti-DOTA scFv recognition of [225 Ac]Pr, and in vivo biodistribution and clearance studies were performed to evaluate hapten suitability and in vivo targeting efficiency. Results: Intravenously (i.v.) administered225 Ac- or111 In-radiolabeled Pr in mice showed rapid renal clearance and minimal normal tissue retention. In vivo pretargeting studies show high tumor accumulation of Pr (16.71 ± 5.11 %IA/g or 13.19 ± 3.88 %IA/g at 24 h p.i. for [225 Ac]Pr and [111 In]Pr, respectively) and relatively low uptake in normal tissues (all average ≤ 1.4 %IA/g at 24 h p.i.). Maximum tolerated dose (MTD) was not reached for either [225 Ac]Pr alone or pretargeted [225 Ac]Pr at administered activities up to 296 kBq/mouse. Single-cycle treatment consisting of α-DOTA-PRIT with either huA33-C825 bispecific anti-tumor/anti-DOTA-hapten antibody (BsAb), anti-HER2-C825 BsAb, or hu3F8-C825 BsAb for targeting GPA33, HER2, or GD2, respectively, was highly effective. In the GPA33 model, no complete responses (CRs) were observed but prolonged overall survival of treated animals was 42 d for α-DOTA-PRIT vs. 25 d for [225 Ac]Pr only ( P < 0.0001); for GD2, CRs (7/7, 100%) and histologic cures (4/7, 57%); and for HER2, CRs (7/19, 37%) and histologic cures (10/19, 56%) with no acute or chronic toxicity. Conclusions: [225 Ac]Pr and its imaging biomarker [111 In]Pr demonstrate optimal radiopharmacologic behavior for theranostic applications of α-DOTA-PRIT. For this initial evaluation of efficacy and toxicity, single-cycle treatment regimens were performed in all three systems. Histologic toxicity was not observed, so MTD was not observed. Prolonged overall survival, CRs, and histologic cures were observed in treated animals. In comparison to RIT with anti-tumor IgG antibodies, [225 Ac]Pr has a much improved safety profile. Ultimately, these data will be used to guide clinical development of toxicity and efficacy studies of [225 Ac]Pr, with the goal of delivering massive lethal doses of radiation to achieve a high probability of cure without toxicity., Competing Interests: Competing Interests: N.K.C reports receiving commercial research grants from Y-mAbs Therapeutics, Inc. in 2015 and Abpro-Labs, Inc. in 2017, holding ownership interest/equity in Y-mAbs Therapeutics and in Abpro-Labs, and owning stock options in Eureka Therapeutics, Inc. N.K.C is the inventor and owner of issued patents licensed by MSK to Y-mAbs Therapeutics, Biotec Pharmacon, and Abpro Labs. These include US patents 6451995, 7507724, 7704973, 7740845, 7666424, 9315585, and multiple pending patents. N.K.C is a scientific advisory board member of Abpro Labs and Eureka Therapeutics. N.K.C, S.M.L, and S.M.C were named as one of the inventors in the following patent applications relating to GPA33: SK2014-074, SK2015-091, SK2017-079, SK2018-045, SK2014-116, SK2016-052, and SK2018-068 filed by MSK. S.M.L reports receiving commercial research grants from Genentech, Inc., WILEX AG, Telix Pharmaceuticals Limited, and Regeneron Pharmaceuticals, Inc.; holding ownership interest/equity in Elucida Oncology, Inc. and Y-mAbs Therapeutics, and holding stock in ImaginAb, Inc. S.M.L is the inventor and owner of issued patents both currently unlicensed and licensed by MSK to Samus Therapeutics, Inc., Elucida Oncology, Inc., and Y-mAbs Therapeutics, Inc. S.M.L serves or has served as a consultant to Cynvec LLC, Eli Lilly & Co., Prescient Therapeutics Limited, Advanced Innovative Partners, LLC, Gerson Lehrman Group, Progenics Pharmaceuticals, Inc., and Janssen Pharmaceuticals, Inc. G.Y and O.O are listed as inventors and receive royalties from patents that were filed by MSK. O.O is an unpaid member of the scientific advisory board of Angiogenex and owns shares in Angiogenex. B.H.S and N.K.C are inventors on US Patent No. 62/502,151. D.A.S is a consultant to, on the board of, and/or has equity in: PGNX, SLS, KLUS, IOVA, PFE, ATNM, Oncopep and Eureka Therapeutics. MSK has filed for patent protection on behalf of D.A.S for technology discussed in this paper. All other authors have no competing interests., (© The author(s).)- Published
- 2020
- Full Text
- View/download PDF
14. Paradigms for Precision Medicine in Epichaperome Cancer Therapy.
- Author
-
Pillarsetty N, Jhaveri K, Taldone T, Caldas-Lopes E, Punzalan B, Joshi S, Bolaender A, Uddin MM, Rodina A, Yan P, Ku A, Ku T, Shah SK, Lyashchenko S, Burnazi E, Wang T, Lecomte N, Janjigian Y, Younes A, Batlevi CW, Guzman ML, Roboz GJ, Koziorowski J, Zanzonico P, Alpaugh ML, Corben A, Modi S, Norton L, Larson SM, Lewis JS, Chiosis G, Gerecitano JF, and Dunphy MPS
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Cell Line, Tumor, Dose-Response Relationship, Drug, Drug Administration Schedule, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Molecular Chaperones metabolism, Molecular Imaging, Neoplasms diagnostic imaging, Neoplasms genetics, Neoplasms pathology, Precision Medicine methods, Protein Interaction Mapping methods, Protein Interaction Maps genetics, Theranostic Nanomedicine methods, Xenograft Model Antitumor Assays, Antineoplastic Agents administration & dosage, Molecular Chaperones antagonists & inhibitors, Neoplasms drug therapy, Protein Interaction Maps drug effects
- Abstract
Alterations in protein-protein interaction networks are at the core of malignant transformation but have yet to be translated into appropriate diagnostic tools. We make use of the kinetic selectivity properties of an imaging probe to visualize and measure the epichaperome, a pathologic protein-protein interaction network. We are able to assay and image epichaperome networks in cancer and their engagement by inhibitor in patients' tumors at single-lesion resolution in real time, and demonstrate that quantitative evaluation at the level of individual tumors can be used to optimize dose and schedule selection. We thus provide preclinical and clinical evidence in the use of this theranostic platform for precision medicine targeting of the aberrant properties of protein networks., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
15. Theranostic pretargeted radioimmunotherapy of internalizing solid tumor antigens in human tumor xenografts in mice: Curative treatment of HER2-positive breast carcinoma.
- Author
-
Cheal SM, Xu H, Guo HF, Patel M, Punzalan B, Fung EK, Lee SG, Bell M, Singh M, Jungbluth AA, Zanzonico PB, Piersigilli A, Larson SM, and Cheung NV
- Subjects
- Animals, Antigens, Neoplasm metabolism, Breast Neoplasms pathology, Disease Models, Animal, Heterografts, Humans, Mice, Mice, Nude, Neoplasm Transplantation, Octreotide administration & dosage, Treatment Outcome, Antibodies, Neoplasm administration & dosage, Breast Neoplasms therapy, Molecular Targeted Therapy methods, Octreotide analogs & derivatives, Organometallic Compounds administration & dosage, Radioimmunotherapy methods, Receptor, ErbB-2 metabolism, Theranostic Nanomedicine methods
- Abstract
In recent reports, we have shown that optimized pretargeted radioimmunotherapy (PRIT) based on molecularly engineered antibody conjugates and
177 Lu-DOTA chelate (DOTA-PRIT) can be used to cure mice bearing human solid tumor xenografts using antitumor antibodies to minimally internalizing membrane antigens, GPA33 (colon) and GD2 (neuroblastoma). However, many solid tumor membrane antigens are internalized after antibody binding and it is generally believed that internalizing tumor membrane antigens are not suitable targets for PRIT. In this study, we tested the hypothesis that DOTA-PRIT can be performed successfully to target HER2, an internalizing membrane antigen widely expressed in breast, ovarian, and gastroesophageal junction cancers. Methods: DOTA-PRIT was carried out in athymic nude mice bearing BT-474 xenografts, a HER2-expressing human breast cancer, using a three-step dosing regimen consisting of sequential intravenous administrations of: 1) a bispecific IgG-scFv (210 kD) format (BsAb) carrying the IgG sequence of the anti-HER2 antibody trastuzumab and the scFv "C825" with high-affinity, hapten-binding antibody for Bn-DOTA (metal) (BsAb: anti-HER2-C825), 2) a 500 kD dextran-based clearing agent, followed by 3)177 Lu-DOTA-Bn. At the time of treatment, athymic nude mice bearing established subcutaneous BT-474 tumors (medium- and smaller-sized tumors with tumor volumes of 209 ± 101 mm3 and ranging from palpable to 30 mm3 , respectively), were studied along with controls. We studied single- and multi-dose regimens. For groups receiving fractionated treatment, we verified quantitative tumor targeting during each treatment cycle using non-invasive imaging with single-photon emission computed tomography/computed tomography (SPECT/CT). Results: We achieved high therapeutic indices (TI, the ratio of radiation-absorbed dose in tumor to radiation-absorbed dose to critical organs, such as bone marrow) for targeting in blood (TI = 28) and kidney (TI = 7), while delivering average radiation-absorbed doses of 39.9 cGy/MBq to tumor. Based on dosimetry estimates, we implemented a curative fractionated therapeutic regimen for medium-sized tumors that would deliver approximately 70 Gy to tumors, which required treatment with a total of 167 MBq177 Lu-DOTA-Bn/mouse (estimated absorbed tumor dose: 66 Gy). This regimen was well tolerated and achieved 100% complete responses (CRs; defined herein as tumor volume equal to or smaller than 4.2 mm3 ), including 62.5% histologic cure (5/8) and 37.5% microscopic residual disease (3/8) at 85 days (d). Treatment controls showed tumor progression to 207 ± 201% of pre-treatment volume at 85 d and no CRs. Finally, we show that treatment with this curative177 Lu regimen leads to a very low incidence of histopathologic abnormalities in critical organs such as bone marrow and kidney among survivors compared with non-treated controls. Conclusion: Contrary to popular belief, we demonstrate that DOTA-PRIT can be successfully adapted to an internalizing antigen-antibody system such as HER2, with sufficient TIs and absorbed tumor doses to achieve a high probability of cures of established human breast cancer xenografts while sparing critical organs of significant radiotoxicity., Competing Interests: Competing Interests: N.K. Cheung reports receiving commercial research grants from Y-mabs Therapeutics and Abpro-Labs Inc.; holding ownership interest/equity in Y-Mabs Therapeutics Inc., holding ownership interest/equity in Abpro-Labs, and owning stock options in Eureka Therapeutics. NKC is the inventor and owner of issued patents both currently unlicensed and licensed by MSK to Ymabs Therapeutics, Biotec Pharmacon, and Abpro-labs. NKC is an advisory board member for Abpro-Labs and Eureka Therapeutics. SM Larson reports receiving commercial research grants from Genentech, Wilex, Telix and Regeneron; holding ownership interest/equity in Voreyda Theranostics Inc. and Elucida Oncology Inc, and holding stock in ImaginAb. SML is the inventor and owner of issued patents both currently unlicensed and licensed by MSK to Samus Therapeutics and Elucida Oncology Inc. SML is or has been consultant to Cynvec, Eli Lilly, Prescient, Advanced Innovative Partners, Gerson Lehrman, Progenics and Janssen Pharmaceuticals. All other authors have no competing interests.- Published
- 2018
- Full Text
- View/download PDF
16. Copper-64 labeled liposomes for imaging bone marrow.
- Author
-
Lee SG, Gangangari K, Kalidindi TM, Punzalan B, Larson SM, and Pillarsetty NVK
- Subjects
- Animals, Bone Marrow metabolism, Drug Compounding, Isotope Labeling, Male, Mice, Mice, Nude, Tissue Distribution, Bone Marrow diagnostic imaging, Copper Radioisotopes, Liposomes chemical synthesis, Liposomes chemistry, Liposomes metabolism, Liposomes pharmacokinetics, Positron Emission Tomography Computed Tomography methods
- Abstract
Introduction: Bone marrow is the soft tissue compartment inside the bones made up of hematopoietic cells, adipocytes, stromal cells, phagocytic cells, stem cells, and sinusoids. While [
18 F]-FLT has been utilized to image proliferative marrow, to date, there are no reports of particle based positron emission tomography (PET) imaging agents for imaging bone marrow. We have developed copper-64 labeled liposomal formulation that selectively targets bone marrow and therefore serves as an efficient PET probe for imaging bone marrow., Methods: Optimized liposomal formulations were prepared with succinyl PE, DSPC, cholesterol, and mPEG-DSPE (69:39:1:10:0.1) with diameters of 90 and 140nm, and were doped with DOTA-Bn-DSPE for stable64 Cu incorporation into liposomes., Results: PET imaging and biodistribution studies with64 Cu-labeled liposomes indicate that accumulation in bone marrow was as high as 15.18±3.69%ID/g for 90nm liposomes and 7.01±0.92%ID/g for 140nm liposomes at 24h post-administration. In vivo biodistribution studies in tumor-bearing mice indicate that the uptake of 90nm particles is approximately 0.89±0.48%ID/g in tumor and 14.22±8.07%ID/g in bone marrow, but respective values for Doxil® like liposomes are 0.83±0.49%ID/g and 2.23±1.00%ID/g., Conclusion: Our results indicate that our novel PET labeled liposomes target bone marrow with very high efficiency and therefore can function as efficient bone marrow imaging agents., Competing Interests: The authors declare no competing financial interests., (Copyright © 2016 Elsevier Inc. All rights reserved.)- Published
- 2016
- Full Text
- View/download PDF
17. Targeting of radiolabeled J591 antibody to PSMA-expressing tumors: optimization of imaging and therapy based on non-linear compartmental modeling.
- Author
-
Fung EK, Cheal SM, Fareedy SB, Punzalan B, Beylergil V, Amir J, Chalasani S, Weber WA, Spratt DE, Veach DR, Bander NH, Larson SM, Zanzonico PB, and Osborne JR
- Abstract
Background: We applied a non-linear immunokinetic model to quantitatively compare absolute antibody uptake and turnover in subcutaneous LNCaP human prostate cancer (PCa) xenografts of two radiolabeled forms of the humanized anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 ((124)I-J591 and (89)Zr-J591). Using the model, we examined the impact of dose on the tumor and plasma positron emission tomography (PET)-derived time-activity curves. We also sought to predict the optimal targeting index (ratio of integrated-tumor-to-integrated-plasma activity concentrations) for radioimmunotherapy., Methods: The equilibrium rates of antibody internalization and turnover in the tumors were derived from PET images up to 96 h post-injection using compartmental modeling with a non-linear transfer rate. In addition, we serially imaged groups of LNCaP tumor-bearing mice injected with (89)Zr-J591 antibody doses ranging from antigen subsaturating to saturating to examine the suitability of using a non-linear approach and derived the time-integrated concentration (in μM∙hours) of administered tracer in tumor as a function of the administered dose of antibody., Results: The comparison of (124)I-J591 and (89)Zr-J591 yielded similar model-derived values of the total antigen concentration and internalization rate. The association equilibrium constant (k a) was twofold higher for (124)I, but there was a ~tenfold greater tumoral efflux rate of (124)I from tumor compared to that of (89)Zr. Plots of surface-bound and internalized radiotracers indicate similar behavior up to 24 h p.i. for both (124)I-J591 and (89)Zr-J591, with the effect of differential clearance rates becoming apparent after about 35 h p.i. Estimates of J591/PSMA complex turnover were 3.9-90.5 × 10(12) (for doses from 60 to 240 μg) molecules per hour per gram of tumor (20 % of receptors internalized per hour)., Conclusions: Using quantitative compartmental model methods, surface binding and internalization rates were shown to be similar for both (124)I-J591 and (89)Zr-J591 forms, as expected. The large difference in clearance rates of the radioactivity from the tumor is likely due to differential trapping of residualizing zirconium versus non-residualizing iodine. Our non-linear model was found to be superior to a conventional linear model. This finding and the calculated activity persistence time in tumor have important implications for radioimmunotherapy and other antibody-based therapies in patients.
- Published
- 2016
- Full Text
- View/download PDF
18. The qTSN4 Effect on Flag Leaf Size, Photosynthesis and Panicle Size, Benefits to Plant Grain Production in Rice, Depending on Light Availability.
- Author
-
Fabre D, Adriani DE, Dingkuhn M, Ishimaru T, Punzalan B, Lafarge T, Clément-Vidal A, and Luquet D
- Abstract
Increasing rice yield potential is essential to secure world food supply. The quantitative trait locus qTSN4 was reported to achieve yield increases by enhancing both source and sink capacity. Three greenhouse experiments and one field experiment in the Philippines were conducted to study near-isogenic lines (NILs) in two genetic backgrounds, subjected to treatments with restricted light resources through shading (greenhouse) or population density (field and greenhouse). A consistent promotion of flag leaf width, leaf area and panicle size in terms of spikelet number was observed in the presence of qTSN4, regardless of environment. However, grain production per plant was enhanced only in one greenhouse experiment. An in-depth study demonstrated that increased flag leaf size in the presence of qTSN4 was associated with increased photosynthetic rates, along with lower SLA and greater N content per leaf weight and per area. This was emphasized under low light situation as the qTSN4-NILs did not express shade acclimation traits in contrast with the recipient varieties. The authors conclude that qTSN4 is a promising subject for further physiological studies, particularly under limited radiation. However, the QTL alone may not be a reliable source of increased yield potential because its effects at the plant and population scale are prone to genotype × environment interactions and the increased panicle size is compensated by the adaptive plasticity of other morphological traits.
- Published
- 2016
- Full Text
- View/download PDF
19. Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity ⁸⁶Y- or ¹⁷⁷Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates.
- Author
-
Cheal SM, Xu H, Guo HF, Lee SG, Punzalan B, Chalasani S, Fung EK, Jungbluth A, Zanzonico PB, Carrasquillo JA, O'Donoghue J, Smith-Jones PM, Wittrup KD, Cheung NV, and Larson SM
- Subjects
- Animals, Antibodies, Bispecific immunology, Colorectal Neoplasms radiotherapy, Immunoconjugates immunology, Immunoglobulin G immunology, Lutetium therapeutic use, Mice, Radiopharmaceuticals immunology, Single-Chain Antibodies immunology, Single-Chain Antibodies therapeutic use, Xenograft Model Antitumor Assays, Yttrium Radioisotopes therapeutic use, Antibodies, Bispecific therapeutic use, Antibody Affinity, Colorectal Neoplasms diagnostic imaging, Immunoconjugates therapeutic use, Membrane Glycoproteins immunology, Radioimmunotherapy, Radiopharmaceuticals therapeutic use
- Abstract
Purpose: GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn-(radiolanthanide metal) complex., Methods: PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens (177)Lu-or (86)Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model., Results: Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq (177)Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm(3)) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 - 3.0 based on time to 500-mm(3) tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten (86)Y-DOTA-Bn., Conclusion: We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts.
- Published
- 2016
- Full Text
- View/download PDF
20. Pairwise comparison of 89Zr- and 124I-labeled cG250 based on positron emission tomography imaging and nonlinear immunokinetic modeling: in vivo carbonic anhydrase IX receptor binding and internalization in mouse xenografts of clear-cell renal cell carcinoma.
- Author
-
Cheal SM, Punzalan B, Doran MG, Evans MJ, Osborne JR, Lewis JS, Zanzonico P, and Larson SM
- Subjects
- Animals, Antigens, Neoplasm immunology, Carbonic Anhydrase IX, Carbonic Anhydrases immunology, Cell Line, Tumor, Humans, Kinetics, Mice, Protein Binding, Tissue Distribution, Xenograft Model Antitumor Assays, Antibodies, Monoclonal pharmacokinetics, Antigens, Neoplasm metabolism, Carbonic Anhydrases metabolism, Carcinoma, Renal Cell diagnostic imaging, Iodine Radioisotopes pharmacokinetics, Positron-Emission Tomography, Zirconium pharmacokinetics
- Abstract
Purpose: The PET tracer, (124)I-cG250, directed against carbonic anhydrase IX (CAIX) shows promise for presurgical diagnosis of clear-cell renal cell carcinoma (ccRCC) (Divgi et al. in Lancet Oncol 8:304-310, 2007; Divgi et al. in J Clin Oncol 31:187-194, 2013). The radiometal (89)Zr, however, may offer advantages as a surrogate PET nuclide over (124)I in terms of greater tumor uptake and retention (Rice et al. in Semin Nucl Med 41:265-282, 2011). We have developed a nonlinear immunokinetic model to facilitate a quantitative comparison of absolute uptake and antibody turnover between (124)I-cG250 and (89)Zr-cG250 using a human ccRCC xenograft tumor model in mice. We believe that this unique model better relates quantitative imaging data to the salient biological features of tumor antibody-antigen binding and turnover., Methods: We conducted experiments with (89)Zr-cG250 and (124)I-cG250 using a human ccRCC cell line (SK-RC-38) to characterize the binding affinity and internalization kinetics of the two tracers in vitro. Serial PET imaging was performed in mice bearing subcutaneous ccRCC tumors to simultaneously detect and quantify time-dependent tumor uptake in vivo. Using the known specific activities of the two tracers, the equilibrium rates of antibody internalization and turnover in the tumors were derived from the PET images using nonlinear compartmental modeling., Results: The two tracers demonstrated virtually identical tumor cell binding and internalization but showed markedly different retentions in vitro. Superior PET images were obtained using (89)Zr-cG250, owing to the more prolonged trapping of the radiolabel in the tumor and simultaneous washout from normal tissues. Estimates of cG250/CAIX complex turnover were 1.35 - 5.51 × 10(12) molecules per hour per gram of tumor (20 % of receptors internalized per hour), and the ratio of (124)I/(89)Zr atoms released per unit time by tumor was 17.5., Conclusion: Pairwise evaluation of (89)Zr-cG250 and (124)I-cG250 provided the basis for a nonlinear immunokinetic model which yielded quantitative information about the binding and internalization of radioantibody bound to CAIX on tumor cells in vivo. (89)Zr-cG250 is likely to provide high-quality PET images and may be a useful tool to quantify CAIX/cG250 receptor turnover and cG250-accessible antigen density noninvasively in humans.
- Published
- 2014
- Full Text
- View/download PDF
21. Evaluation of glycodendron and synthetically modified dextran clearing agents for multistep targeting of radioisotopes for molecular imaging and radioimmunotherapy.
- Author
-
Cheal SM, Yoo B, Boughdad S, Punzalan B, Yang G, Dilhas A, Torchon G, Pu J, Axworthy DB, Zanzonico P, Ouerfelli O, and Larson SM
- Subjects
- Animals, Carbohydrate Sequence, Cell Line, Tumor, Drug Delivery Systems, Drug Stability, Heterografts, Humans, Mice, Molecular Structure, Positron-Emission Tomography, Colonic Neoplasms diagnosis, Colonic Neoplasms radiotherapy, Coordination Complexes chemistry, Coordination Complexes therapeutic use, Dextrans chemistry, Dextrans therapeutic use, Molecular Imaging, Radioimmunotherapy, Radioisotopes chemistry
- Abstract
A series of N-acetylgalactosamine-dendrons (NAG-dendrons) and dextrans bearing biotin moieties were compared for their ability to complex with and sequester circulating bispecific antitumor antibody streptavidin fusion protein (scFv4-SA) in vivo, to improve tumor-to-normal tissue concentration ratios for multistep targeted (MST) radioimmunotherapy and diagnosis. Specifically, a total of five NAG-dendrons employing a common synthetic scaffold structure containing 4, 8, 16, or 32 carbohydrate residues and a single biotin moiety were prepared (NAGB), and for comparative purposes, a biotinylated-dextran with an average molecular weight of 500 kD was synthesized from amino-dextran (DEXB). One of the NAGB compounds, CA16, has been investigated in humans; our aim was to determine if other NAGB analogues (e.g., CA8 or CA4) were bioequivalent to CA16 and/or better suited as MST reagents. In vivo studies included dynamic positron-emission tomography (PET) imaging of (124)I-labeled-scFv4-SA clearance and dual-label biodistribution studies following MST directed at subcutaneous (s.c.) human colon adenocarcinoma xenografts in mice. The MST protocol consists of three injections: first, a scFv4-SA specific for an antitumor-associated glycoprotein (TAG-72); second, CA16 or other clearing agent; and third, radiolabeled biotin. We observed using PET imaging of the (124)I-labeled-scFv4-SA clearance that the spatial arrangement of ligands conjugated to NAG (i.e., biotin linked with an extended spacer, referred to herein as long-chain (LC)) can impact the binding to the antibody in circulation and subsequent liver uptake of the NAG-antibody complex. Also, NAGB CA32-LC or CA16-LC can be utilized during MST to achieve comparable tumor-to-blood ratios and absolute tumor uptake seen previously with CA16. Finally, DEXB was equally effective as NAGB CA32-LC at lowering scFv4-SA in circulation, but at the expense of reducing absolute tumor uptake of radiolabeled biotin.
- Published
- 2014
- Full Text
- View/download PDF
22. N-acetylgalactosamino dendrons as clearing agents to enhance liver targeting of model antibody-fusion protein.
- Author
-
Yoo B, Cheal SM, Torchon G, Dilhas A, Yang G, Pu J, Punzalan B, Larson SM, and Ouerfelli O
- Subjects
- Acetylgalactosamine pharmacokinetics, Animals, Dendrimers pharmacokinetics, Female, Iodine Radioisotopes, Mice, Recombinant Fusion Proteins blood, Single-Chain Antibodies blood, Streptavidin genetics, Acetylgalactosamine metabolism, Dendrimers metabolism, Liver metabolism, Recombinant Fusion Proteins metabolism, Single-Chain Antibodies metabolism
- Abstract
Dendrimer clearing agents represent a unique class of compounds for use in multistep targeting (MST) in radioimmunotherapy and imaging. These compounds were developed to facilitate the removal of excess tumor-targeting monoclonal antibody (mAb) prior to administration of the radionuclide to minimize exposure of normal tissue to radiation. Clearing agents are designed to capture the circulating mAb, and target it to the liver for metabolism. Glycodendrons are ideally suited for MST applications as these highly branched compounds are chemically well-defined, thus advantageous over heterogeneous macromolecules. Previous studies have described glycodendron 3 as a clearing agent for use in three-step MST protocols, and early in vivo assessment of 3 showed promise. However, synthetic challenges have hampered its availability for further development. In this report we describe a new sequence of chemical steps which enables the straightforward synthesis and analytical characterization of this class of dendrons. With accessibility and analytical identification solved, we sought to evaluate both lower and higher generation dendrons for hepatocyte targeting as well as clearance of a model protein. We prepared a series of clearing agents where a single biotin is connected to glycodendrons displaying four, eight, sixteen or thirty-two α-thio-N-acetylgalactosamine (α-SGalNAc) units, resulting in compounds with molecular weights ranging from 2 to 17 kDa, respectively. These compounds were fully characterized by LCMS and NMR. We then evaluated the capacity of these agents to clear a model (131)I-labeled single chain variable fragment antibody-streptavidin ((131)I-scFv-SAv) fusion protein from blood and tissue in mice, and compared their clearing efficiencies to that of a 500 kDa dextran-biotin conjugate. Glycodendrons and dextran-biotin exhibited enhanced blood clearance of the scFv-SAv construct. Biodistribution analysis showed liver targeting/uptake of the scFv-SAv construct to be 2-fold higher for compounds 1 to 4, as well as for the 500 kDa dextran, over saline. Additionally, the data suggest the glycodendrons clear through the liver, whereas the dextran through reticuloendothelial system (RES) metabolism.
- Published
- 2013
- Full Text
- View/download PDF
23. In vivo imaging of Bcr-Abl overexpressing tumors with a radiolabeled imatinib analog as an imaging surrogate for imatinib.
- Author
-
Glekas AP, Pillarsetty NK, Punzalan B, Khan N, Smith-Jones P, and Larson SM
- Subjects
- Animals, Benzamides, Catalytic Domain, Cell Line, Tumor, Crystallography, X-Ray methods, Dose-Response Relationship, Drug, Humans, Imatinib Mesylate, K562 Cells, Mice, Models, Chemical, Models, Molecular, Neoplasm Transplantation, Protein Binding, Time Factors, Fusion Proteins, bcr-abl metabolism, Piperazines chemistry, Piperazines pharmacology, Pyrimidines chemistry, Pyrimidines pharmacology
- Abstract
Unlabelled: Imatinib mesylate is a tyrosine kinase inhibitor that was approved by the U.S. Food and Drug Administration in 2001 for treatment of many different stages of chronic myeloid leukemia and in 2002 for treatment of gastrointestinal stromal tumors. Imatinib is known to inhibit the dysregulated proliferation of chronic myeloid leukemia, which is associated with the Bcr-Abl kinase; in gastrointestinal stromal tumors, imatinib is known to act via c-Kit kinase inhibition. The objective of this study was to synthesize an (18)F-labeled analog of imatinib not as a primary imaging agent but rather as a tracer for in vivo drug distribution and tracer concentration that can be used as a PET imaging surrogate for imatinib., Methods: Molecular modeling studies based on the crystal structure of imatinib bound to the active site of Abl were performed for designing the fluorinated analog. A 2-fluoroethyl analog of imatinib (SKI696) was synthesized using well-established procedures. The selectivity and binding affinity of SKI696 were compared with those of imatinib in vitro. Mice bearing K562 tumor xenografts, which are known to overexpress Bcr-Abl, were imaged with (18)F-SKI696 PET. A biodistribution study was also performed on K562 tumor-bearing mice to which our radiolabeled tracer was administered., Results: The kinase assay verified that imatinib and SKI696 bind to the same targets with similar affinities. The feasibility of using (18)F-SKI696 as a PET agent was examined in vivo, and (18)F-SKI696 PET was shown to visualize K562 tumor xenografts in nude mice. The tumor was visible on PET 1 h after injection, with uptake of 1% of the injected dose. Biodistribution studies in K562-bearing mice were also performed, and the uptake of (18)F-SKI696 (percentage injected dose per gram) for each organ was calculated., Conclusion: The results of the binding assay showed that SKI696 has selectivity and binding affinity comparable to imatinib. Small-animal PET of K562 tumor-bearing mice using (18)F-SKI696 as a PET agent displayed promising tumor uptake and tumor-to-nontarget contrast. Because (18)F-SKI696 has been taken up in vivo by tumors that overexpress Bcr-Abl, we are exploring a possible role for identifying tumors that will respond to imatinib before therapy.
- Published
- 2011
- Full Text
- View/download PDF
24. Optimizing tumor targeting of the lipophilic EGFR-binding radiotracer SKI 243 using a liposomal nanoparticle delivery system.
- Author
-
Medina OP, Pillarsetty N, Glekas A, Punzalan B, Longo V, Gönen M, Zanzonico P, Smith-Jones P, and Larson SM
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Cell Line, Tumor, Humans, Liposomes, Mice, Mice, Nude, Neoplasms drug therapy, Radiopharmaceuticals pharmacokinetics, Antineoplastic Agents administration & dosage, ErbB Receptors antagonists & inhibitors, ErbB Receptors metabolism, Neoplasms diagnostic imaging, Positron-Emission Tomography, Radiopharmaceuticals administration & dosage
- Abstract
Positron emission tomography (PET) of epidermal growth factor receptor (EGFR) kinase-specific radiolabeled tracers could provide a means for non-invasively characterizing EGFR expression and signaling activity in patients' tumors before, during, and after therapy with EGFR inhibitors. Towards this goal, our group has developed PET tracers which irreversibly bind to EGFR. However, tumor uptake is relatively low because of both the lipophilicity of such tracers (e.g. the morpholino-[124I]-IPQA [SKI 212243]), with octanol-to-water partition coefficients of up to 4, and a short dwell time in the blood and significant hepatobiliary clearance and intestinal reuptake. Liposomal nanoparticle delivery systems may favorably alter the pharmacokinetic profile and improve tumor targeting of highly lipophilic but otherwise promising cancer imaging tracers, such as the EGFR inhibitor SKI 243. SKI 243 is therefore an interesting model molecule for incorporation into lipid-based nanoparticles, as it would not only improve their solubility but also increase the circulation time, availability and, potentially, targeting of tumors. In the current study, we compared the pharmacokinetics and tumor targeting of the bare EGFR kinase-targeting radiotracer SKI 212243 (SKI 243) with that of the same tracer embedded in liposomes. SKI 243 and liposomal SKI 243 are both taken up by tumor xenografts but liposomal SKI 243 remained in the blood longer and consequently exhibited a 3- to 6-fold increase in uptake in the tumor among several other organs., (Copyright © 2010 Elsevier B.V. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
25. 2-18F-Fluoropropionic acid as a PET imaging agent for prostate cancer.
- Author
-
Pillarsetty N, Punzalan B, and Larson SM
- Subjects
- Acetates chemistry, Acetates pharmacokinetics, Animals, Carbon Radioisotopes chemistry, Male, Mice, Octanols chemistry, Radioactive Tracers, Tissue Distribution, Water chemistry, Fluorocarbons chemistry, Fluorocarbons pharmacokinetics, Positron-Emission Tomography methods, Propionates chemistry, Propionates pharmacokinetics, Prostatic Neoplasms diagnostic imaging
- Abstract
Unlabelled: There is a high interest in developing an (18)F-labeled PET tracer that can aid in diagnosis and therapy monitoring of prostate cancer. In the current study, we have evaluated the potential of 2-(18)F-fluoropropionic acid ((18)F-FPA) as a PET tracer for imaging prostate cancer., Methods: (18)F-FPA was synthesized starting from methyl-2-bromopropionate. Small-animal PET studies were performed on mice with CWR22rv1, PC-3, DU-145, and LNCaP prostate xenografts, and comparison of imaging characteristics of (18)F-FPA with (18)F-FDG uptake is reported. Biodistribution studies with (18)F-FPA were performed on mice with CWR22rv1 xenografts and compared with (14)C-acetate., Results: (18)F-FPA was synthesized in 44% overall radiochemical yield (decay-corrected). Small-animal PET studies revealed that (18)F-FPA can delineate both androgen-dependent and androgen-independent prostate xenografts with high tumor-to-background ratios. Comparative imaging studies demonstrate the superior performance of (18)F-FPA over (18)F-FDG for imaging prostate cancer, with excellent tumor-to-background contrast. Biodistribution studies show that tumor uptake of the tracer was 5.52 +/- 0.35, 5.53 +/- 0.42, 5.74 +/- 0.54, and 5.34 +/- 0.19 percentage injected dose (%ID) per gram at 1, 2, 3, and 4 h, respectively, after injection. The %ID/g values for (18)F-FPA and (14)C-acetate 1 h after tail vein injection were 7.08 +/- 0.80 and 0.36 +/- 0.08 in tumor, and the corresponding tumor-to-muscle ratios were 1.94 and 2.06, respectively., Conclusion: The data presented here indicate that (18)F-FPA accumulates in prostate cancers with high tumor-to-background ratios. (18)F-FPA has potential for use in the clinical diagnosis of prostate cancer in humans.
- Published
- 2009
- Full Text
- View/download PDF
26. Sensitive in vivo imaging of T cells using a membrane-bound Gaussia princeps luciferase.
- Author
-
Santos EB, Yeh R, Lee J, Nikhamin Y, Punzalan B, Punzalan B, La Perle K, Larson SM, Sadelain M, and Brentjens RJ
- Subjects
- Animals, Cell Membrane enzymology, Coleoptera enzymology, Flow Cytometry, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, SCID, Sensitivity and Specificity, Signal Transduction, Luciferases genetics, T-Lymphocytes cytology
- Abstract
We developed a new approach to bioluminescent T cell imaging using a membrane-anchored form of the Gaussia luciferase (GLuc) enzyme, termed extGLuc, which we could stably express in both mouse and human primary T cells. In vitro, extGLuc+ cells emitted significantly higher bioluminescent signal when compared to cells expressing GLuc, Renilla luciferase (RLuc) or membrane-anchored RLuc (extRLuc). In vivo, mouse extGLuc+ T cells showed higher bioluminescent signal when compared to GLuc+ and RLuc+ T cells. Application of this imaging approach to human T cells genetically modified to express tumor-specific chimeric antigen receptors (CARs) enabled us to show in vivo CAR-mediated T cell accumulation in tumor, T cell persistence over time and concomitant imaging of T cells and tumor cells modified to express firefly luciferase. This sensitive imaging technology has application to many in vivo cell-based studies in a wide array of mouse models.
- Published
- 2009
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.