Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy

EBioMedicine

卷:17

Udupi A. Ramagopal¹  Steven C. Almo¹  Eliezer Sylvestre²  Stanley G. Nathenson²  Edith Palmieri²  Eszter Lázár-Molnár²  Chandan Guha³  Indranil Basu³  Lisa Scandiuzzi³  Thomas Quinn³ 

[1] Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA;

[2] Department of Microbiology & Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA;

[3] Department of Radiation Oncology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA;

关键词: PD-1;    Immunotherapy;    High-affinity mutant;    Radio-immunotherapy;    PD-1 Ig fusion protein;   

DOI  :  10.1016/j.ebiom.2017.02.004

来源: DOAJ

【 摘 要 】

Programmed Cell Death-1 (PD-1) is an inhibitory immune receptor, which plays critical roles in T cell co-inhibition and exhaustion upon binding to its ligands PD-L1 and PD-L2. We report the crystal structure of the human PD-1 ectodomain and the mapping of the PD-1 binding interface. Mutagenesis studies confirmed the crystallographic interface, and resulted in mutant PD-1 receptors with altered affinity and ligand-specificity. In particular, a high-affinity mutant PD-1 (HA PD-1) exhibited 45 and 30-fold increase in binding to PD-L1 and PD-L2, respectively, due to slower dissociation rates. This mutant (A132L) was used to engineer a soluble chimeric Ig fusion protein for cell-based and in vivo studies. HA PD-1 Ig showed enhanced binding to human dendritic cells, and increased T cell proliferation and cytokine production in a mixed lymphocyte reaction (MLR) assay. Moreover, in an experimental model of murine Lewis lung carcinoma, HA PD-1 Ig treatment synergized with radiation therapy to decrease local and metastatic tumor burden, as well as in the establishment of immunological memory responses. Our studies highlight the value of structural considerations in guiding the design of a high-affinity chimeric PD-1 Ig fusion protein with robust immune modulatory properties, and underscore the power of combination therapies to selectively manipulate the PD-1 pathway for tumor immunotherapy.

【 授权许可】

Unknown