Abstract 4770: First-in-class anti-TRPV6 antibody as a new therapeutic agent in cancer

Abstract Context: The involvement of calcium signaling in tumor progression has been well documented in the literature. In particular, the calcium channel TRPV6 has been identified as a key player in the physiopathology of solid tumors. At the transcriptomic level, TRPV6 is overexpressed in many cancers such as prostate, pancreatic and ovarian cancers underscoring its potential as a new therapeutic target. While some TRPV6-targeting antagonistic peptides have reached clinical stage, no antibody candidate is currently in development. Leveraging its phage display technology and unique proprietary antibody libraries, Mabqi (France), in collaboration with SATT Nord and PhyCell laboratory (France), has discovered and characterized a first-in-class human anti-TRPV6 antibody "20H3” with high clinical potential. Methods: A comprehensive series of vitro and vivo preclinical studies demonstrated the safety profile, efficacy and clinical relevance of 20H3 antibody, as a new candidate for the treatment of prostate cancer. Results: In vitro studies demonstrated the high affinity and specificity of 20H3 antibody against TRPV6 target. Exploration of antigen-antibody interaction was performed through epitope and paratope mapping and antagonistic activity of 20H3 antibody was validated via calcium flux modulation assays. The excellent developability properties were also demonstrated through thermostability, aggregation and stability assays. In vivo, the 20H3 safety profile was confirmed in mice model. After repeated doses up to 64 mg/kg, no effect on mice body weight and no sign of toxicity in main organs collected were detected. The antitumoral potential of 20H3 antibody was evaluated in three vivo cancer models. As initial positioning is prostate cancer indication, efficacy studies in two xenografted prostate models (LNCaP and VCaP) were performed. In both models, specific tumor targeting and tumor penetration were confirmed and a strong antitumoral efficacy was demonstrated at 4-8 mg/kg with a tumor growth inhibition superior to 60 % and an increased mice survival of 62 %. Interestingly a strong efficacy was also shown in MCA205 sarcoma model. To further elucidate antibody’s mode of action, a comparison between Fc-WT and Fc-silencing format was carried out in immunocompetent and immunodeficient mice models. All together, these results demonstrated that antitumor efficacy is mediated by both paratopic region and Fc region of the antibody that potentializes the effect of the treatment. Finally, the 20H3 clinical relevance was demonstrated by immunohistochemistry studies with positive immunoreactivity in a large proportion of prostate cancer patient samples. Conclusion: The 20H3 antibody is the first anti-TRPV6 antibody under development, with a strong potential to advance rapidly into clinic. The CMC process of 20H3 drug candidate is planned in 2025 and Phase Ia clinical trial is expected to start in early 2027. Citation Format: Lindsay B. Alcaraz, Vincent Roux-Portalez, Aurélien Haustrate, Gautier Robin, Alexia Parmentier, Clément Cordier, Florence Boissière-Michot, Amélie Gudin-de-Vallerin, Evelyne Lopez-Crapez, Gaelle Fromont-Hankard, Tristan Mangeat, Margaux Maurel, Marianne Le Gall, Thierry Chardès, Bruno Robert, Yoann Sottejeau, Diego Tosi, Natacha Prevarskaya, V'yacheslav Lehen'kyi, Bernard Pau, Johanna Marines. First-in-class anti-TRPV6 antibody as a new therapeutic agent in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4770.