Publication
Radioimmunotherapy of Fibroblast Activation Protein Positive Tumors by Rapidly Internalizing Antibodies
Publisher:
American Association for Cancer Research (AACR)
Date:
14-11-2012
DOI:
10.1158/1078-0432.CCR-12-0644
Abstract: Purpose: Fibroblast activation protein (FAP) is a serine protease that has emerged as a promising target for cancer therapy, either by direct abrogation of its proinvasive activity or by specific targeting of FAP-expressing cells with cytotoxic immunoconjugates. We aimed to select novel human–mouse cross-reactive antibodies and to test suitability for tumor therapy as radioimmunoconjugates in a preclinical model. Experimental Design: Human Fab fragments that bind to human and murine FAP were selected from an antibody phage library. Two candidates (ESC11 and ESC14) were engineered into fully human IgG1 antibodies and further characterized. We investigated the intracellular trafficking of ESC11 and ESC14 in live cells by confocal microscopy and analyzed the biodistribution and therapeutic effects of anti-FAP antibodies labeled with the β-emitting radionuclide 177Lu in a melanoma xenograft nude mouse model. Results were compared with vF19, a humanized variant of an anti-FAP antibody that has been previously used in clinical trials. Results: The two antibodies bound selectively to both human and mouse FAP, with affinities in the low nanomolar range. Binding to FAP-expressing melanoma cells resulted in rapid internalization of FAP-antibody complexes. 177Lu-labeled ESC11 specifically accumulated in melanoma xenografts in vivo, with a higher tumor uptake than ESC14 and vF19. Radioimmunotherapy with 8 MBq 177Lu-labeled anti-FAP antibodies delayed growth of established tumors, whereas 177Lu-ESC11 extended mouse survival more pronounced than 177Lu-ESC14 and 177Lu-vF19. Conclusion: Our results show the potential of ESC11 and ESC14 as potent radioimmunoconjugates or antibody–drug conjugates for diagnostic and therapeutic use in patients with FAP-expressing tumors. Clin Cancer Res 18(22) 6208–18. ©2012 AACR.