Abstract LB063: Anti-tumor activity in preclinical models utilizing a conditional bispecific redirected activation molecule (COBRA) targeting Her2

Abstract

Abstract Among strategies to recruit cytotoxic T-cells into the tumor micro-environment (TME) are the use of T-cell engager molecules. One such therapeutic modality are molecules that recognize specific tumor associated antigens (TAA) but are activated preferentially in the TME. Conditional Bispecific Redirected Activation molecules (COBRA) are designed to be administered as a prodrug, and cleaved via matrix metalloproteinase to engage with both a tumor TAA and CD3 (Panachi, et.al. MAbs 2020 12(1) 1792130). In this study, we sought to determine the preclinical efficacy of a COBRA molecule targeting the Her2 receptor. Sub-cutaneous xenograft models (SCID mice using adoptive T-cell transfer) were utilized representing various levels of the TAA (HT-55, SNU-16, JIMT-1, and HCC827) to measure both efficacy and mechanism of action (T-cell extravasation). The COBRA molecule was dosed at 0.03, 0.1, 0.3, and 1 mg/kg using a Q3dx7 schedule. A non-cleavable COBRA molecule with the Her2 TAA was included as a control at 1 mg/kg. Efficacy was determined by caliper measurements of sub-cutaneous tumor size twice per week after dosing, and T-cell extravasation into the TME was measured by immunohistochemistry (IHC) at days 10, 19, and termination. IHC data was quantified using HALO imaging software. In our study, we measured dose-dependent tumor regression and/or stasis in all models tested. No anti-tumor activity was measured after dosing with the non-cleavable COBRA molecule. T-cell extravasation as measured by IHC and Halo analysis followed a dose and time dependent course. Comparison of Day 19 T-cell extravasation (one day after the last dose) showed a linear relationship to TAA expression. Our data indicate that treatment with a COBRA molecule in preclinical models with a Her2 TAA results in anti-tumor activity as measured by tumor stasis/regression, and exhibit the expected mechanism of action as evaluated by T-cell extravasation into the TME. Citation Format: Bradley Stringer, Johara Chouitar, Jacqualine Cerbone, Sarah Fortin, Alina Ainbinder, Cassie Kysilovsky, Brittany Scott, Antara Banerjee. Anti-tumor activity in preclinical models utilizing a conditional bispecific redirected activation molecule (COBRA) targeting Her2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB063.