7tps
Crystal structure of ALPN-202 (engineered CD80 vIgD) in complex with PD-L1
Structural highlights
FunctionCD80_HUMAN Involved in the costimulatory signal essential for T-lymphocyte activation. T-cell proliferation and cytokine production is induced by the binding of CD28 or CTLA-4 to this receptor. Publication Abstract from PubMedDespite the recent clinical success of T cell checkpoint inhibition targeting the CTLA-4 and PD-1 pathways, many patients either fail to achieve objective responses or they develop resistance to therapy. In some cases, poor responses to checkpoint blockade have been linked to suboptimal CD28 costimulation and the inability to generate and maintain a productive adaptive anti-tumor immune response. To address this, here we utilize directed evolution to engineer a CD80 IgV domain with increased PD-L1 affinity and fuse this to an immunoglobulin Fc domain, creating a therapeutic (ALPN-202, davoceticept) capable of providing CD28 costimulation in a PD-L1-dependent fashion while also antagonizing PD-1 - PD-L1 and CTLA-4-CD80/CD86 interactions. We demonstrate that by combining CD28 costimulation and dual checkpoint inhibition, ALPN-202 enhances T cell activation and anti-tumor efficacy in cell-based assays and mouse tumor models more potently than checkpoint blockade alone and thus has the potential to generate potent, clinically meaningful anti-tumor immunity in humans. The engineered CD80 variant fusion therapeutic davoceticept combines checkpoint antagonism with conditional CD28 costimulation for anti-tumor immunity.,Maurer MF, Lewis KE, Kuijper JL, Ardourel D, Gudgeon CJ, Chandrasekaran S, Mudri SL, Kleist KN, Navas C, Wolfson MF, Rixon MW, Swanson R, Dillon SR, Levin SD, Kimbung YR, Akutsu M, Logan DT, Walse B, Swiderek KM, Peng SL Nat Commun. 2022 Apr 4;13(1):1790. doi: 10.1038/s41467-022-29286-5. PMID:35379805[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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