Prostate cancer (PCa) is the most common cancer in men worldwide. In advanced stages of the disease, PCa responds poorly to chemotherapy. Therefore, antibody-drug-conjugates (ADCs) have been developed to allow specific and improved delivery of highly cytotoxic drug to the tumor. As the pros-tate-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 monometh-yl auristatin E (MMAE)-based anti-PSMA ADCs with drug-anti-body-ratios (DARs) of 2 and 4. Materials and Methods: The anti-PSMA antibody D2B was chemoenzymatically conjugated with duocarmycin or monomethyl auristatin E (MMAE) via the glycosylated site of the antibody. Preservation of the immuno-reactivity of the antibody upon site-specific conjugation was investigated in vitro. Biodistribution studies and microSPECT/CT imaging (18.5 ± 2.6 MBq) with 25 μg of 111In-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 s.c. LS174T-PS-MA tumors. Results: The immunoreactivity of the anti-PSMA antibody was preserved upon site-specific conjugation with the drugs. Biodistribution revealed high tumor uptake of all ADCs. 111In-DTPA-D2B-DAR2-MMAE showed the highest tumor uptake, reaching 119.7 ± 37.4 %ID/g at 3 days p.i.. Tumors of mice treated with 111In-DTPA-D2B, 111In-DTPA-D2B-DAR2-duo-carmycin, 111In-DTPA-D2B-DAR4-duocarmycin, 111In-DTPA-D2B-DAR2-MMAE, and 111In-DTPA-D2B-DAR4-MMAE could clearly be visualized with microSPECT/CT. In contrast to ‘naked’ D2B or vehicle, D2B-DAR2-duocarmycin and D2B-DAR4-duocarmy-cin, treatment with D2B-DAR2-MMAE and D2B-DAR4-MMAE significantly impaired the tumor growth and prolonged medi-an survival from 13 days (PBS) to 20 and 29 days, respectively. Tumor doubling time increased from 3.5 ± 0.5 days to 5.2 ± 1.8 and 9.2 ± 2.1, after treatment with D2B-DAR2-MMAE and D2B-DAR4-MMAE, respectively. Conclusion: The site-specifi-cally 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.
|Titolo:||Characterization of In-111-labeled site-specifically conjugated anti-PSMA antibody-drug conjugates for treatment of PSMA-expressing tumors|
FRACASSO, Giulio [Investigation]
COLOMBATTI, Marco [Funding Acquisition]
|Data di pubblicazione:||2017|
|Appare nelle tipologie:||01.05 Abstract in rivista|
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