Characterization of site-specifically conjugated monomethyl auristatin E- and duocarmycin-based anti-PSMA antibody-drug conjugates for treatment of PSMA-expressing tumors

Rationale: 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. As 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-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 upon site-specific conjugation was investigated in vitro. Biodistribution and microSPECT/CT imaging (18.5 ± 2.6 MBq) with 25 µg of (111)In-labeled ADCs were performed in BALB/c nude mice with s.c. PSMA(+) LS174T-PSMA xenografts. Finally, the therapeutic efficacy of the four different ADCs was assessed in mice with LS174T-PSMA tumors. Results: The immunoreactivity of the anti-PSMA antibody was preserved upon site-specific conjugation. Biodistribution revealed high tumor uptake of all agents, highest tumor uptake was observed in mice administered with (111)In-DTPA-D2B-DAR2-MMAE, reaching 119.7 ± 37.4 %ID/g at 3 days p.i. Tumors of mice injected with (111)In-DTPA-D2B, (111)In-DTPA-D2B-DAR2-duocarmycin, (111)In-DTPA-D2B-DAR4-duocarmycin, (111)In-DTPA-D2B-DAR2-MMAE, and (111)In-DTPA-D2B-DAR4-MMAE could clearly be visualized with microSPECT/CT. In contrast to unconjugated D2B or vehicle, treatment with either MMAE-based ADC, but not with a duocarmycin-based ADC, significantly impaired the tumor growth and prolonged median survival from 13 days (PBS) to 20 and 29 days for DAR2 and DAR4 ADC, respectively. Tumor doubling time increased from 3.5 ± 0.5 days to 5.2 ± 1.8 and 9.2 ± 2.1 days 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.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2017 Nov 16 [Epub ahead of print]

Susanne Lütje, Danny Gerrits, Janneke D Molkenboer-Kuenen, Ken Herrmann, Giulio Fracasso, Marco Colombatti, Otto C Boerman, Sandra Heskamp

University Hospital Essen, Germany., Radboud university medical center, Netherlands., Department of Medicine, University of Verona, Italy., Radboud University Medical Center, Netherlands.


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