MET alterations can act as an oncogenic driver in non-small cell lung cancer (NSCLC) and elevated cMET expression occurs in many cancers. Antibody drug conjugates targeting cMET (cMET-ADCs) have been developed as a strategy to treat cMET+ tumors irrespective of dependency on cMET signaling. cMET- ADCs have shown promising clinical activity, but largely in a subset of NSCLC patients having the highest cMET levels, indicating tumor cMET levels may be limiting for efficacy. We sought to create an ADC with the potential to benefit a broader population of patients including those expressing moderate cMET levels. Here, we describe MYTX-011, an ADC incorporating the clinically validated vcMMAE linker-payload conjugated to a novel, pH-dependent anti-cMET antibody. We hypothesized that engineering the antibody to rapidly lose affinity at acidic endosomal pH would boost ADC uptake and efficacy in cMET+ tumor cells by avoiding non-productive ADC recycling. We conducted mutagenesis of anti-cMET antibodies, screening for variants that selectively lost binding under acidic conditions, and, in parallel, assessed antibody internalization in cell-based assays. The resulting lead humanized IgG1 antibody was conjugated to vcMMAE at engineered cysteine residues (DAR=2) to create MYTX-011, which exhibited rapid dissociation from cMET at pH5.4 but retained high affinity binding at pH7.4 and 6.4. MYTX-011 showed markedly higher (>3 fold) internalization in cMET+ tumor cells and broader, more potent cytotoxicity across a large panel of cMET+ cancer cell lines in vitro compared to a matched ADC based on the unmodified parent antibody lacking pH-dependent binding, or an in-house version of a clinical stage cMET ADC. These findings translated in vivo where MYTX-011 showed superior efficacy (>3 fold based on dose titration) in NSCLC xenograft models with high (EBC-1) or only moderate cMET expression levels (H1373, H1975) compared to the matched parent ADC or an in-house version of a clinical stage cMET ADC. PK and toxicity studies in cynomolgus monkeys revealed that MYTX-011 exhibited favorable PK characteristics, and a toxicity profile similar to previously described MMAE-based ADCs. Together, these findings highlight the potential of MYTX-011 as a therapeutic candidate for treating a broader range of cMET+ malignancies than other cMET-ADCs.

Citation Format: Nimish Gera, Kyle Fitzgerald, Vijay Ramesh, Purvi Patel, Lena Kien, Deepak Kanojia, Simon Aoyama, Federico Colombo, Amit Deshpande, William Comb, Thomas Chittenden, Brian Fiske. MYTX-011: A novel cMET-targeting antibody drug conjugate (ADC) engineered to increase on-target uptake in and efficacy against cMET expressing tumors. [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 5000.