ICAM‐1 Is Overexpressed by Cancers and Negatively Impacts Antibody‐Based Therapies Including Antibody–Drug Conjugates

Abstract

ABSTRACTHumoral immunity utilizes antibodies and immune effector cells to mediate dysregulated cancer cell killing. These mechanisms are referred to as Humoral Immuno‐Oncology (HIO). HIO immunosuppression is mediated by tumor‐produced proteins called HIO factors. Using a combination of patient serum analysis and literature searches, we screened a number of samples to determine if they suppressed HIO. Herein, we identified that ICAM‐1 (intercellular adhesion molecule 1) can bind IgG1‐type antibodies and suppress their immune effector activity. Through a series of mutagenesis, we identified a unique motif within the IgG1CH3 domain essential for ICAM‐1 binding, which inhibits antibody‐dependent cellular cytotoxicity and complement‐dependent cytotoxicity. Conservative amino acid substitutions within the CH3 domain were able to abrogate ICAM‐1 binding and overcome ICAM‐1 mediated immune effector suppression. Additionally, isogenic tumor cell lines with silenced ICAM‐1 expression were more susceptible to antibody–drug conjugate (ADCs) cytotoxicity than parental cells. This effect appeared to correlate with membrane ICAM‐1 binding to the IgG1 component that reduced ADC internalization, a function important for maximal target cell killing. These findings highlight a novel mechanism by which tumors can suppress the host's immune system for survival and offer new concepts for engineering antibody‐based therapeutics that are refractory to ICAM‐1 immunosuppression.