Structure-guided development of a high-affinity human Programmed Cell Death-1

Implications for tumor immunotherapy

Eszter Lázár-Molnár, Lisa Scandiuzzi, Indranil Basu, Thomas Quinn, Eliezer Sylvestre, Edith Palmieri, Udupi A. Ramagopal, Stanley G. Nathenson, Chandan Guha, Steven C. Almo

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 selectively manipulate the PD-1 pathway for tumor immunotherapy.

Original languageEnglish (US)
Pages (from-to)30-44
Number of pages15
JournalEBioMedicine
Volume17
DOIs
StatePublished - Mar 1 2017

Fingerprint

Cell death
Immunotherapy
Tumors
Cell Death
Neoplasms
T-cells
Programmed Cell Death 1 Receptor
Fusion reactions
Immunologic Memory
Ligands
Lewis Lung Carcinoma
T-Lymphocytes
Mutagenesis
Mixed Lymphocyte Culture Test
Lymphocytes
Cell Fusion
Radiotherapy
Cell proliferation
Tumor Burden
Dendritic Cells

Keywords

  • High-affinity mutant
  • Immunotherapy
  • PD-1
  • PD-1 Ig fusion protein
  • Radio-immunotherapy

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Structure-guided development of a high-affinity human Programmed Cell Death-1 : Implications for tumor immunotherapy. / Lázár-Molnár, Eszter; Scandiuzzi, Lisa; Basu, Indranil; Quinn, Thomas; Sylvestre, Eliezer; Palmieri, Edith; Ramagopal, Udupi A.; Nathenson, Stanley G.; Guha, Chandan; Almo, Steven C.

In: EBioMedicine, Vol. 17, 01.03.2017, p. 30-44.

Research output: Contribution to journalArticle

Lázár-Molnár, E, Scandiuzzi, L, Basu, I, Quinn, T, Sylvestre, E, Palmieri, E, Ramagopal, UA, Nathenson, SG, Guha, C & Almo, SC 2017, 'Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy', EBioMedicine, vol. 17, pp. 30-44. https://doi.org/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. In: EBioMedicine. 2017 ; Vol. 17. pp. 30-44.
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