Abstract 225: TR1801-ADC, an optimized anti cMet PBD ADC with high efficacy in solid tumors of the GI tract and head & neck cancer

Abstract

Abstract cMet is a well-characterized oncogene that is the target of many drugs including small molecule and biologic pathway inhibitors, and more recently, antibody drug conjugates (ADCs). However, clinical benefit from c-Met targeted therapy has been limited up to this point. We developed an optimized c-Met targeted antibody drug conjugate TR1801-ADC that utilized optimization at all steps including specificity, stability, internalization, toxin linkers, conjugation site, PK, and in vivo efficacy. The results were a highly potent c-Met ADC that was superior in comparison to a conventional MMAE (monomethylauristatin E) cMet ADC in potency, efficacy and duration of response. TR1801-ADC is site-specifically conjugated to a PBD-toxin linker and has low picomolar activity in multiple cancer cell lines derived from different solid tumors including lung cancer, colorectal cancer and gastric cancer. The potency of our cMet ADC is independent of MET gene copy number and its activity was high not only in high cMet cell lines but also in medium to low cell lines (100,000 to 40,000 cMet/cell). We identified potential Phase 1 cancer indications based on IHC and cMet H-score from tissue micro arrays (TMAs). 3 cancer indications (gastric, colorectal and head & neck cancer) were chosen based on high abundance of high cMet expression (>20% abundance of H-Score higher than 150) and were used to assess the efficacy of our cMet ADC in PDX models. For each indication 10 PDX (patient-derived xenograft) models were chosen based on their cMet expression. TR1801-ADC was administered in all models as single i.v. dose at 1, 0.5, 0.25 and 0.125 mg/kg. Control ADC was administered at 1mg/kg. Tumor growth inhibition varying from >100% to around 40% was seen in all gastric cancer PDX models with single dose injections of 1 mg/kg and 0.5 mg/kg. Complete tumor regression was seen in 70% of the 1 mg/kg group, in 50% of the 0.5 mg/kg group and in 40% of the 0.25 mg/kg group. TR1801-ADC produced statistically significant growth inhibition in comparison to untreated controls in 9 colorectal cancer PDX models. Complete tumor regression was observed in 40% (4/10) PDX models when treated with 1 mg/kg TR1801-ADC. The further 50% showed partial regression (5/10 models) and one showed no significant tumor response. The head & neck cancer PDX models were in general least sensitive to TR1801-ADC. TR1801-ADC produced statistically significant growth inhibition in comparison to untreated controls in 8/10 head & neck cancer PDX models. Complete tumor regression was observed in 30% (3/10) PDX models when treated with 1 mg/kg TR1801-ADC. 50% showed statistical significant partial regression while two models (20%) showed no significant tumor inhibition. Altogether, TR1801-ADC is a novel highly potent cMet ADC that shows very promising efficacy in PDX models of gastric, colorectal and head & neck cancer with long lasting anti-tumor effect with a single dose. Citation Format: Marco Gymnopoulos, Oscar Betancourt, Vincent Blot, Ryo Fujita, Diana Ly, Sophie Nguyen, Jeanette Snedden, Jose Villicana, Jon Wojciak, Eley Wong, Neki Patel, Francois D'Hooge, Balakumar Vijayakrishnan, Conor Barry, John A. Hartley, Phil W. Howard, Roland Newman, Julia Coronella. TR1801-ADC, an optimized anti cMet PBD ADC with high efficacy in solid tumors of the GI tract and head & neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 225.