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J Nucl Med. 2018 Mar;59(3):494-501. doi: 10.2967/jnumed.117.196279. Epub 2017 Nov 16.

Characterization of Site-Specifically Conjugated Monomethyl Auristatin E- and Duocarmycin-Based Anti-PSMA Antibody-Drug Conjugates for Treatment of PSMA-Expressing Tumors.

Author information

1
Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands susanne.lutje@radboudumc.nl.
2
Clinic for Nuclear Medicine, University Hospital Essen, Essen, Germany; and.
3
Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
4
Department of Medicine, University of Verona, Verona, Italy.

Abstract

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.

KEYWORDS:

antibody–drug conjugate; duocarmycin; monomethyl auristatin E (MMAE); prostate cancer; prostate-specific membrane antigen (PSMA)

PMID:
29146698
DOI:
10.2967/jnumed.117.196279
[Indexed for MEDLINE]
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