Abstract 4494: Multi-specific cMet x EGFR x VEGF antibody for difficult to treat cancers

Abstract

Abstract Cancers such as TNBC, pancreatic, and gastric are difficult to treat due to diverse etiologies. Several subtypes of these cancers are driven by abnormal EGFR signaling, increased cMET activation, and VEGF linked angiogenesis which are responsible for tumor growth and metastasis. TAVO412, a humanized multi-specific antibody with two distinct anti-EGFR nanobody domains, an anti-cMet Fab arm, and an anti-VEGF ScFv domain, was designed to treat patients with these unmet medical needs. In addition, the Fc domain allows for the heterodimerization, antibody-like pharmacokinetic profile, and additional mutations that enhance the Fc effector functional activity. In preclinical xenograft models, TAVO412 demonstrated strong tumor growth inhibition effects on TNBC, PDAC, GC or NSCLC cell line-derived tumors. The mechanisms of action included selective and potent binding to EGFR, cMet, and VEGF at lower pH values found in the solid tumor environment; effective blocking of EGFR and cMet pathways that drove cancer cell growth and proliferation; shutdown of VEGF mediated angiogenesis; and potent and efficacious Fc effector function that enhanced ADCC, ADCP, and CDC. TAVO412 had better TGI than analogous molecules. TAVO412 also demonstrated strong tumor growth inhibition against NSCLC patient derived xenograft (PDX) models with mutant EGFR and cMet genotypes. Each of the binding arms had cross reactivity with the cynomolgus monkey orthologues allowing the cyno model to be a relevant toxicology model. In the pivotal GLP toxicology study in cynomolgus monkeys, TAVO412 was well tolerated, had no major organ toxicities, observations were mostly consistent with EGFR-related effects and recoverable. In conclusion, TAVO412 was successfully discovered and developed for hard-to-treat solid tumors. This drug is expected to be safe and efficacious in cancer patients. The IND application was approved by the US FDA in October 2022. A first-in-human, 2-Part Phase 1 study to examine the preliminary efficacy, safety, tolerability, pharmacokinetic/pharmacodynamic parameters; maximum tolerated dose/recommended phase 2 dose of TAVO412 will be starting in the first quarter of 2023. Citation Format: Mark Chiu. Multi-specific cMet x EGFR x VEGF antibody for difficult to treat cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4494.