TR1801-ADC: A Potent cMet PBD Antibody-Drug Conjugate for GI and Head & Neck Solid Tumors

A novel antibody drug conjugate (ADC), TR1801-ADC, has been developed to target the cMet oncogene, which is implicated in various solid tumors. This conjugate has undergone comprehensive optimization to enhance its specificity, stability, internalization, and overall efficacy. Compared to traditional MMAE-based cMet ADCs, TR1801-ADC demonstrates superior potency and a more enduring response. It is conjugated to a PBD-toxin linker and exhibits low picomolar activity against multiple cancer cell lines, including those from lung, colorectal, and gastric cancers. Its effectiveness is not dependent on the MET gene copy number and is robust across a range of cMet expression levels.

Potential Phase 1 cancer indications for TR1801-ADC were identified through immunohistochemistry (IHC) and cMet H-scores from tissue microarrays. Three cancer types—gastric, colorectal, and head & neck—were selected for further study due to high cMet expression levels. Patient-derived xenograft (PDX) models were used to evaluate the ADC's efficacy at varying doses. In gastric cancer models, TR1801-ADC showed tumor growth inhibition rates exceeding 100% and complete tumor regression in a significant proportion of cases. Colorectal cancer models also responded well, with complete and partial regression observed. However, head & neck cancer models were less sensitive, though still showing significant growth inhibition and some complete tumor regression.

Overall, TR1801-ADC is a promising new cMet ADC with high potency and long-lasting anti-tumor effects in PDX models of gastric, colorectal, and head & neck cancers, warranting further investigation.