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Discovery and preclinical characterization of the antagonist anti-PD-L1 monoclonal antibody LY3300054

Li, Y;Carpenito, C;Wang, G;Surguladze, D;Forest, A;Malabunga, M;Murphy, M;Zhang, Y;Sonyi, A;Chin, D;Burtrum, D;Inigo, I;Pennello, A;Shen, L;Malherbe, L;Chen, X;Hall, G;Haidar, JN;Ludwig, DL;Novosiadly, RD;Kalos, M;

Modulation of the PD-1/PD-L1 axis through antagonist antibodies that block either receptor or ligand has been shown to reinvigorate the function of tumor-specific T cells and unleash potent anti-tumor immunity, leading to durable objective responses in a subset of patients across multiple tumor types. Here we describe the discovery and preclinical characterization of LY3300054, a fully human IgG1 monoclonal antibody that binds to human PD-L1 with high affinity and inhibits interactions of PD-L1 with its two cognate receptors PD-1 and CD80. The functional activity of LY3300054 on primary human T cells is evaluated using a series of in vitro T cell functional assays and in vivo models using human-immune reconstituted mice. LY3300054 is shown to induce primary T cell activation in vitro, increase T cell activation in combination with anti-CTLA4 antibody, and to potently enhance anti-tumor alloreactivity in several xenograft mouse tumor models with reconstituted human immune cells. High-content molecular analysis of tumor and peripheral tissues from animals treated with LY3300054 reveals distinct adaptive immune activation signatures, and also previously not described modulation of innate immune pathways. LY3300054 is currently being evaluated in phase I clinical trials for oncology indications.