Characterization of Site-Specifically Conjugated Monomethyl Auristatin E- and Duocarmycin-Based Anti-PSMA Antibody-Drug Conjugates for Treatment of PSMA-Expressing Tumors
| Autor: | Susanne Lütje, Ken Herrmann, Janneke D.M. Molkenboer-Kuenen, Sandra Heskamp, Otto C. Boerman, Giulio Fracasso, Danny Gerrits, Marco Colombatti |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Glutamate Carboxypeptidase II Male Biodistribution Antibody-drug conjugate Immunoconjugates Indoles Single Photon Emission Computed Tomography Computed Tomography monomethyl auristatin E (MMAE) medicine.medical_treatment duocarmycin Medizin Mice Nude Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] prostate-specific membrane antigen (PSMA) urologic and male genital diseases 03 medical and health sciences chemistry.chemical_compound Prostate cancer Duocarmycins Mice All institutes and research themes of the Radboud University Medical Center 0302 clinical medicine Cell Line Tumor medicine Animals Radiology Nuclear Medicine and imaging Tissue Distribution Duocarmycin Chemotherapy biology antibody–drug conjugate Cancer Prostatic Neoplasms prostate cancer medicine.disease Pyrrolidinones Gene Expression Regulation Neoplastic 030104 developmental biology Cell Transformation Neoplastic Monomethyl auristatin E chemistry Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] 030220 oncology & carcinogenesis Cancer research biology.protein Antibody Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] Oligopeptides |
| Zdroj: | The Journal of Nuclear Medicine (1978), 59, 494-501 The Journal of Nuclear Medicine (1978), 59, 3, pp. 494-501 |
| ISSN: | 0161-5505 |
| Popis: | Prostate cancer (PCa) is the most common cancer in men worldwide. In general, PCa responds poorly to chemotherapy. Therefore, antibody-drug conjugates (ADCs) have been developed to specifically deliver highly cytotoxic drugs to the tumor. Because the prostate-specific membrane antigen (PSMA) is overexpressed in PCa, it represents a promising target for ADC-based therapies. The aim of this study was to evaluate the therapeutic efficacy of site-specifically conjugated duocarmycin- and monomethyl auristatin E (MMAE)-based anti-PSMA ADCs with drug-to-antibody ratios (DARs) of 2 and 4. Methods: The glycan group of the anti-PSMA antibody D2B was chemoenzymatically conjugated with duocarmycin or MMAE. Preservation of the immunoreactivity of the antibody on site-specific conjugation was investigated in vitro. Biodistribution and small-animal SPECT/CT imaging (18.5 ± 2.6 MBq) with 25 μg of 111In-labeled ADCs were performed on BALB/c nude mice with subcutaneous PSMA-positive LS174T-PSMA xenografts. Finally, the therapeutic efficacy of the 4 different ADCs was assessed in mice with LS174T-PSMA tumors. Results: The immunoreactivity of the anti-PSMA antibody was preserved on site-specific conjugation. Biodistribution revealed high tumor uptake of all agents. The highest tumor uptake was observed in mice administered with 111In-D2B-DAR2-MMAE, reaching 119.7 ± 37.4 percentage injected dose per gram at 3 d after injection. Tumors of mice injected with 111In-D2B, 111In-D2B-DAR2-duocarmycin, 111In-D2B-DAR4-duocarmycin, 111In-D2B-DAR2-MMAE, and 111In-D2B-DAR4-MMAE could clearly be visualized with small-animal SPECT/CT. In contrast to unconjugated D2B or vehicle, treatment with either of the MMAE-based ADCs, but not with a duocarmycin-based ADC, significantly impaired tumor growth and prolonged median survival from 13 d (phosphate-buffered saline) to 20 and 29 d for DAR2 and DAR4 ADC, respectively. Tumor-doubling time increased from 3.5 ± 0.5 d to 5.2 ± 1.8 and 9.2 ± 2.1 d after treatment with D2B-DAR2-MMAE and D2B-DAR4-MMAE, respectively. Conclusion: The site-specifically conjugated anti-PSMA ADCs D2B-DAR2-MMAE and D2B-DAR4-MMAE efficiently targeted PSMA-expressing xenografts, effectively inhibited tumor growth of PSMA-expressing tumors, and significantly prolonged survival of mice. |
| Databáze: | OpenAIRE |
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