Abstract 4780: Engineered ICAM-1 refractory trastuzumab improves its therapeutic activity against HER2-positive cancers in native and antibody-drug conjugate (ADC) format

Abstract The ICAM-1 protein has recently been found to bind the CH3 domain of IgG1-type antibodies and suppress their immune effector activity and internalization against ICAM-1 over-expressing cancer cells. Immune effector suppression involves reduced binding of IgG1 to CD16a Fc-γ-activating receptors on NK cells leading to reduced antibody dependent cellular cytotoxicity (ADCC), as well as binding of the complement initiating C1q protein leading to reduced complement dependent cytotoxicity (CDC) via allosteric alteration of the Fc domain. The effect of ICAM-1 on reduced antibody internalization, a requisite for ADC cytotoxicity, due to the physical interaction of the ADC antibody component with cell surface ICAM-1 has shown significant suppression of ADC activity against antigen-positive target cells. To overcome ICAM-1/IgG1 cytotoxic suppression, we identified a consensus motif within the IgG1 CH3 domain when modified leads to ICAM-1 refractory antibodies, thereby restoring maximal immune effector and ADC cytotoxicity of target cells. Here we present the development of an ICAM-1 refractory trastuzumab and its efficacy against HER2 cancer cells over-expressing ICAM-1 in native and ADC format. These data demonstrate the importance of how tumor-produced proteins may negatively impact the cytotoxic effects of tumor-targeting antibodies and offers a novel platform to improve upon the efficacy of antibody-based therapeutics in the presence of immunosuppressive proteins such as ICAM-1. Citation Format: J. Bradford Kline, Luigi Grasso, Nicholas C. Nicolaides. Engineered ICAM-1 refractory trastuzumab improves its therapeutic activity against HER2-positive cancers in native and antibody-drug conjugate (ADC) format [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4780.