Abstract ND04: ABP-102/CT-P72: a novel HER2 x CD3 T cell engager with selective activity for HER2-overexpressing tumors and reduced activity on cells with normal HER2 expression levels

Abstract HER2 is overexpressed in breast, gastric, and other cancers, with limited expression in normal tissues. Impactful HER2-targeted therapeutics include monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates. However, resistance remains an issue. Bispecific antibody T cell engagers (TCEs) have unrealized potential as novel treatments for solid tumors, with notable past successes in hematological malignancies and the encouraging recent FDA approval of tarlatamab for a solid tumor indication. Previous attempts to develop HER2 TCEs have met with toxicity issues. To develop a safer agent, we designed ABP-102/CT-P72, a next-generation HER2 x CD3 tetravalent bispecific (TetraBi) IgG1-[L]-scFv format antibody with selective activity against HER2-overexpressing tumor cells through the reduction of the affinity of each of the bivalent HER2 binding arms to reduce activity against HER2-low cells. ABP-102/CT-P72 is engineered to reduce the potential for on-target, off-tumor toxicity in normal tissues with low HER2 expression, and its IgG-[L]-scFv format features functionally monovalent CD3 binding for T cell engagement. Pre-clinical studies of in vitro activity as well as in vivo efficacy and safety of ABP-102 were performed. In vitro, ABP-102/CT-P72-mediated T cell activation, cytotoxicity, and cytokine release occurred in a HER2-expression level dependent manner. In vivo studies were done using xenograft tumor models implanted with human HER2-expressing cells, followed by application of human PBMCs. ABP-102/CT-P72 demonstrated potent tumor growth inhibition in HER2-overexpressing models (NCI-N87 and BT-474), with reduced tumor growth inhibition in a HER2-low model (HT55), as expected. In the HER2-overexpressing models, ABP-102/CT-P72 displayed up to a two-fold increased tumor growth inhibition compared to a biosimilar of runimotamab, a HER2 x CD3 TCE. ABP-102/CT-P72 was also well tolerated in cynomolgus macaques. Given its selectivity for HER2-overexpressing tumor cells, ABP-102/CT-P72 represents a novel therapeutic approach with the potential to overcome the limitations of current agents by reducing toxicity in HER2-expressing normal tissues and sparing cells with endogenous levels of HER2. With preclinical studies of ABP-102/CT-P72 demonstrating potent efficacy and safety, we expect that this will allow for an expanded therapeutic window in upcoming clinical trials. Abpro and CELLTRION, INC. are co-developing ABP-102, which CELLTRION, INC. has designated under the project code name CT-P72. Citation Format: Adam Pelzek, Shaun Murphy, Sanam Ebtehaj, Marco Muda, James Lulo, Benjamin Barros, Lucy Zhang, Chaohua Zhang, Robert Markelewicz, Bobin Kang, Juhyung Seok, Bokhyeon Im, Riri Kwon, Hyunkyu Choi, Ji-Seon Kang, Jungsun Ahn, Eun Yeong Shim, YeonJung Kim, Jiyoung Shin. ABP-102/CT-P72: a novel HER2 x CD3 T cell engager with selective activity for HER2-overexpressing tumors and reduced activity on cells with normal HER2 expression levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr ND04.