Phase 1A, first-in-human study of ARB202, bispecific antibody to CDH17 and CD3, in advanced gastrointestinal malignancies expressing CDH17.

25 Background: Cadherin-17 (CDH17) is a highly specific therapeutic cancer target, of which aberrant expression has been reported in 50-95% in GI tumor samples (including stomach, pancreas, liver/bile duct, rectum, and colon). Normal CDH17 expression is primarily in the water-tight junction between mucosal epithelial cells which is potentially “masked” from the immune system (Feng, Z., et al., Nat Cancer, 2022). A bispecific T-cell engager ARB202 using CD3 to aid the formation of an immunological synapse CDH17 tumor cells and T-cells is being studied. Methods: In an ongoing dose-escalation phase IA part of a continuous study, patients with advanced CD17+ solid tumors are being given up to 3 doses of ARB202 bispecific. In part 1, 28 pts can be treated at dose levels from 0.0003 mg/kg to 10 mg/kg; Based on clinical response intra-dosing of tolerated (higher) doses can occur in for the 2 nd and 3 rd doses. Second and 3 doses are planned at the 4th cohort starting at a dose of 0.010 mg/kg when tissue levels are likely physiologically active. Minimum anticipated biological effect level (MABEL) dosing which is based on the most sensitive in vitro assay is being used to set the initial 3 doses to ensure safety of any T-cell engagement at low levels in circulation. Data cutoff 10.04.23. Results: Colorectal, gastric, pancreatic and cholangiocarcinoma patients have screened positive for CDH17 by semi-automated tissue immunostaining. Seven patients have completed dosing in the first 3 cohorts and have shown tolerability to 0.0003 to 0.003 mg/kg single IV doses. The Cmax measured within 1 hour of dosing has confirmed the circulating PK range of 10-20 ng/ml for the 2 nd cohort and 40-50 ng/ml in the 3 rd cohort consistent with the expected PK of antibody-like volume of distribution. The safety review committee has approved the dose escalation to proceed to the 4th cohort Identifier: NCT05411133. Conclusions: ARB202 a bispecific T-cell engager has shown tolerability up to 40ng/ml Cmax in circulation suggesting no clinically significant CD3 only binding cell activation at these levels. These data allow for higher dosing to achieve tissue ARB202 concentrations where anti-CDH17/CD3 aided synapse formation between tissue tumor cells and T-cells can lead to clinical evidence of bispecific target engagement and their expected effects. Clinical trial information: NCT05411133 .