Abstract 1871: Novel conditionally active bispecific HER2 x CD3 T cell engager targeting solid tumors

Human epidermal growth factor receptor 2 (HER2) is overexpressed in multiple cancers and is associated with poor prognosis. Despite the outstanding improvement in survival with the introduction of anti-HER2 therapies, therapeutic benefit is limited by many resistance mechanisms and toxicities. Clinical trials of therapeutics redirecting T cell activity to HER2+ tumors have highlighted the apparent risk of on-target, off-tumor adverse effects for this target, as HER2 is also expressed in normal epithelia. Using BioAtla’s Conditionally Active Biologic (CAB) platform, we have developed a HER2 x CAB-CD3 bispecific antibody that was engineered to bind with high affinity to the CD3 receptor and induce T cell activation under conditions that mimic the tumor microenvironment, but with reduced binding in physiological conditions. Both in vitro and in vivo efficacy data for a CAB T cell engager (TCE) targeting HER2 will be presented. Our data will demonstrate that HER2 x CAB-CD3 bispecific antibody promotes cytotoxicity of HER2+ cancer cells in vitro and induces complete regression of tumor growth in vivo. The HER2 x CAB-CD3 bispecific antibody has higher potency in inducing primary T cell activation measured by means of cytokine release and cancer cell cytotoxicity under acidic conditions compared to the non-CAB benchmark bispecific antibody. The generation of CAB bispecific antibodies with activity in the disease microenvironment minimizes on-target, off-tumor toxicities, thereby enabling higher potency-TCEs for targeting drug resistant, low expressing-HER2+ tumors. In summary, the use of CAB technology expands the universe of targets for drug development by generating a new class of potent CAB T-cell engagers with increased safety margin for potentially enhanced therapeutic indices in the clinic. Citation Format: Ana Paula Cugnetti, Haizhen Liu, Patricia McNeeley, Christina Wheeler, Matthew Lucas, Charles Xing, Solmarie Joyner, Kyrie Johnson, Kathryn Woodard, Wei Zhou, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short. Novel conditionally active bispecific HER2 x CD3 T cell engager targeting solid 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 1871.