Immunomodulatory antibodies activate antitumor responses through multiple mechanisms. These include activation of T cells through the inhibition of negative T cell regulators (known as checkpoint blockade), as well as through the engagement of T cell costimulatory receptors with agonistic antibodies. Antibodies which block CTLA-4 function through inhibition of ligand binding were observed to derive much of their anti-tumor activity through the engagement of activating Fc receptors (Selby et al. Cancer Imm Res 2013; Simpson et al. J Exp Med 2013). This activity was due to the depletion of CTLA-4-positive regulatory T cells uniquely at the tumor site. Related observations for agonistic antibodies to GITR and OX40 (Bulliard et al. J Exp Med 2013, Bulliard et al. Immunol Cell Biol 2014) have led to the reevaluation of the mechanism of action of many immunomodulatory antibodies. We have extended the study of the role of immunoglobulin isotype on the mechanism of action of antibodies to a variety of negative regulators, including PD-1 and PD-L1, and multiple costimulatory molecules, including CD137. In addition, the role of human IgG2 hinge variants on the properties of immunomodulatory antibodies has also been studied. These results have significant impact on the design of therapeutic antibodies. The development of antibodies in which specific T cell functions are targeted will lead to superior choices in considerations for combination cancer immunotherapy.
Citation Format: Alan J. Korman. Antitumor activity of immunomodulatory antibodies. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA03.
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