Identification and validation of anti-TMEFF2-Auristatin E conjugated antibodies in the treatment of prostate cancer

Abstract

2557 Background: Current treatments for advanced stage prostate cancer are largely ineffectual, resulting in high mortality and morbidity. Experimental strategies to fulfill this unmet medical need include the use of toxin-based antibody-drug conjugates (ADCs) to specifically target cancer cells in vivo. Using gene expression profiling, TMEFF2 was identified as being selective to prostate cancer and was validated as a target suitable for an ADC approach using pre-clinical xenograft models in vivo. Methods: A panel of antibodies specific to TMEFF2 protein was generated. One antibody was selected on the basis of affinity and in vitro functionality as an ADC to undergo further analysis in vivo. Results: TMEFF2, a gene encoding a plasma membrane protein with 2 follistatin-like domains and one EGF-like domain, was found to exhibit a restricted normal tissue expression profile and was determined to be highly over-expressed in prostate cancer. A monoclonal antibody (mAb) raised against TMEFF2 was used in immunohistochemistry (IHC) of clinical specimens confirming significant TMEFF2 protein expression in 73% of primary prostate tumors. The exquisite tissue specificity of TMEFF2 followed by the over expression in prostate cancer, allowed for the use of an ADC based therapeutic strategy. We used an Auristatin-E conjugated anti-TMEFF2 mAb, Pr1-vcMMAE, to evaluate the effect on human prostate cancer xenograft tumors grown in male severe combined immunodeficient (SCID) mice. Treatment of SCID mice bearing LNCaP and CWR22 tumors, both of which express TMEFF2, with doses of 3 to 10 mg/kg of ADC resulted in significant and sustained tumor growth inhibition. No overt in vivo toxicity was observed with either murine or humanized ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with murine TMEFF2 protein, indicating a high safety profile. Conclusions: The TMEFF2 protein exhibits the desired expression profile for an ADC target. Our data on significant tumor growth inhibition in the in vivo treatment models support humanized Pr1-vcMMAE as a novel therapeutic for the treatment of prostate cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Protein Design Labs, Inc. Protein Design Labs, Inc. Protein Design Labs, Inc.