(627a) Engineering Multi-Epitopic Antibodies for Receptor Downregulation

Dysfunction of normal immune system responses contributes to cancer development and progression. A combination of the tumor microenvironment and surface receptor expression on cancer cells inhibits effector T cell activity while simultaneously boosting T_Reg activity. Therefore, immune modulation is a promising avenue for cancer treatment, and is generally accomplished either by therapies which stimulate T effector cell activation or by blockade of immune checkpoint receptors, which are responsible for suppressing T cell activity. Immune checkpoint blockade in particular has demonstrated improved patient outcomes and effects complete cures in some patients across several types of cancer. Selective blockade of natural inhibitory checkpoint receptors, like CTLA-4 and PD-1, increase rates of T-cell activation and provoke anti-tumor responses. However, the percentage of patients who exhibit durable responses to immune checkpoint blockade is limited, highlighting the need for further development in this area. Here we demonstrate the development of multi-epitopic internalizing antibodies targeting immune checkpoint receptors which simultaneously block ligand-mediated activation and downregulate receptor expression from the surface, potentially improving the anti-tumor immune response. By targeting two noncompetitive epitopes on a single receptor, a bispecific antibody can induce receptor cross-linking and clustering in the absence of activation, which increases receptor internalization and suppresses recycling to evoke efficient receptor downregulation.