Fc-Engineered Monoclonal Antibodies Refractory to Tumor Immunosuppressive ICAM-1/CD54

Abstract

The ICAM-1/CD54 protein has been found to be a suppressor of antibody-mediated humoral immunity facilitated through its direct binding to the CH3 domain within IgG1 heavy chains. Its binding suppresses antibody immune-effector activity by reducing IgG1 engagement with Fc receptors on effector cells and C1q complement initiating protein. In addition, its binding has the potential to reduce antibody drug conjugate activity by slowing target cell internalization. Engineered antibodies with CH3 region modifications can be generated that reduce or eliminate ICAM-1/CD54 binding leading to antibodies with improved immune-effector activity and antibody drug conjugate killing in the presence ICAM-1/CD54. These antibodies can be useful to treat patients with cancer and inflammatory and infectious diseases exhibiting elevated ICAM-1/CD54 levels.

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