Use of AGS-16M8F as a novel antibody drug conjugate (ADC) for treating renal cancers.

Abstract

e15014 Background: AGS-16 is a novel transmembrane antigen discovered by Agensys using transcription profiling that is expressed in kidney and other cancers. A fully human IgG2k monoclonal antibody that binds to AGS-16 with high affinity was conjugated to the anti-microtubulin drug monomethyl auristatin F (MMAF) via a noncleavable maleimidocaproyl (mc) linker to yield the antibody drug conjugate, AGS-16M8F. Methods: In vitro studies were performed to evaluate the binding affinity, species cross reactivity and cell cytotoxicity of AGS-16M8F. The pharmacokinetics (PK) and anti-tumor activity of AGS-16M8F was evaluated using multiple well-established patient-derived and cell line models of renal clear cell carcinomas. In addition, the expression of AGS-16 protein in patient kidney cancer specimens was confirmed using IHC analysis of individual specimens and tissue microarrays. Results: AGS-16M8F bound with high affinity (Kd = 0.3 nM) to both human and cynomolgus monkey AGS-16. Following cell surface binding, AGS-16M8F was internalized and trafficked to lysosomes where catabolism resulted in the release of active drug metabolite. AGS-16M8F mediated potent cell cytotoxicity in vitro and led to significant and prolonged growth inhibition or complete eradication of multiple, large established renal cancer xenograft models, including those grown orthotopically. Results from pharmacokinetic analyses demonstrated that AGS-16M8F was stable in vivo. Finally, IHC analysis confirmed that AGS-16 was highly expressed in more than 80% of renal cancers including both clear cell and papillary carcinomas. Conclusions: When considered together these data indicate that AGS-16M8F is a promising therapeutic ADC for the treatment of renal and other AGS-16 expressing cancers. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Agensys Inc.