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

Abstract

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 selectivelymore » manipulate the PD-1 pathway for tumor immunotherapy.« less

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1409617
Report Number(s):
BNL-114669-2017-JA¿¿¿
Journal ID: ISSN 2352-3964
DOE Contract Number:  
SC0012704
Resource Type:
Journal Article
Resource Relation:
Journal Name: EBioMedicine; Journal Volume: 17; Journal Issue: C
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; PD-1; immunotherapy; high-affinity mutant; radio-immunotherapy; PD-1 lg fusion protein

Citation Formats

Lázár-Molnár, Eszter, Scandiuzzi, Lisa, Basu, Indranil, Quinn, Thomas, Sylvestre, Eliezer, Palmieri, Edith, Ramagopal, Udupi A., Nathenson, Stanley G., Guha, Chandan, and Almo, Steven C. Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy. United States: N. p., 2017. Web. doi:10.1016/j.ebiom.2017.02.004.
Lázár-Molnár, Eszter, Scandiuzzi, Lisa, Basu, Indranil, Quinn, Thomas, Sylvestre, Eliezer, Palmieri, Edith, Ramagopal, Udupi A., Nathenson, Stanley G., Guha, Chandan, & Almo, Steven C. Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy. United States. doi:10.1016/j.ebiom.2017.02.004.
Lázár-Molnár, Eszter, Scandiuzzi, Lisa, Basu, Indranil, Quinn, Thomas, Sylvestre, Eliezer, Palmieri, Edith, Ramagopal, Udupi A., Nathenson, Stanley G., Guha, Chandan, and Almo, Steven C. Wed . "Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy". United States. doi:10.1016/j.ebiom.2017.02.004.
@article{osti_1409617,
title = {Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy},
author = {Lázár-Molnár, Eszter and Scandiuzzi, Lisa and Basu, Indranil and Quinn, Thomas and Sylvestre, Eliezer and Palmieri, Edith and Ramagopal, Udupi A. and Nathenson, Stanley G. and Guha, Chandan and Almo, Steven C.},
abstractNote = {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.},
doi = {10.1016/j.ebiom.2017.02.004},
journal = {EBioMedicine},
number = C,
volume = 17,
place = {United States},
year = {Wed Mar 01 00:00:00 EST 2017},
month = {Wed Mar 01 00:00:00 EST 2017}
}