Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab

Udupi A. Ramagopal, Weifeng Liu, Sarah C. Garrett-Thomson, Jeffrey B. Bonanno, Qingrong Yan, Mohan Srinivasan, Susan C. Wong, Alasdair Bell, Shilpa Mankikar, Vangipuram S. Rangan, Shrikant Deshpande, Alan J. Korman, Steven C. Almo

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Rational modulation of the immune response with biologics represents one of the most promising and active areas for the realization of new therapeutic strategies. In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. Ipilimumab is the first-in-class immunotherapeutic for blockade of CTLA-4 and significantly benefits overall survival of patients with metastatic melanoma. Understanding the chemical and physical determinants recognized by these mAbs provides direct insight into the mechanisms of pathway blockade, the organization of the antigen-antibody complexes at the cell surface, and opportunities to further engineer affinity and selectivity. Here, we report the 3.0 A resolution X-ray crystal structure of the complex formed by ipilimumab with its human CTLA-4 target. This structure reveals that ipilimumab contacts the front β-sheet of CTLA-4 and intersects with the CTLA-4:B7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function. The crystallographically observed binding interface was confirmed by a comprehensive cell-based binding assay against a library of CTLA-4 mutants and by direct biochemical approaches. This structure also highlights determinants responsible for the selectivity exhibited by ipilimumab toward CTLA-4 relative to the homologous and functionally related CD28.

Original languageEnglish (US)
Pages (from-to)E4223-E4232
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number21
DOIs
StatePublished - May 23 2017

Fingerprint

Immunotherapy
Neoplasms
Melanoma
Blocking Antibodies
ipilimumab
Antigen-Antibody Complex
Biological Products
Libraries
Immune System
Monoclonal Antibodies
X-Rays
Ligands
Survival
Antibodies
Therapeutics

Keywords

  • Cancer
  • CTLA-4
  • Immunotherapy
  • Ipilimumab
  • X-ray crystallography

ASJC Scopus subject areas

  • General

Cite this

Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab. / Ramagopal, Udupi A.; Liu, Weifeng; Garrett-Thomson, Sarah C.; Bonanno, Jeffrey B.; Yan, Qingrong; Srinivasan, Mohan; Wong, Susan C.; Bell, Alasdair; Mankikar, Shilpa; Rangan, Vangipuram S.; Deshpande, Shrikant; Korman, Alan J.; Almo, Steven C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 21, 23.05.2017, p. E4223-E4232.

Research output: Contribution to journalArticle

Ramagopal, UA, Liu, W, Garrett-Thomson, SC, Bonanno, JB, Yan, Q, Srinivasan, M, Wong, SC, Bell, A, Mankikar, S, Rangan, VS, Deshpande, S, Korman, AJ & Almo, SC 2017, 'Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 21, pp. E4223-E4232. https://doi.org/10.1073/pnas.1617941114
Ramagopal, Udupi A. ; Liu, Weifeng ; Garrett-Thomson, Sarah C. ; Bonanno, Jeffrey B. ; Yan, Qingrong ; Srinivasan, Mohan ; Wong, Susan C. ; Bell, Alasdair ; Mankikar, Shilpa ; Rangan, Vangipuram S. ; Deshpande, Shrikant ; Korman, Alan J. ; Almo, Steven C. / Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 21. pp. E4223-E4232.
@article{2d7ffa9615504e07b4e3040baf4ba44d,
title = "Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab",
abstract = "Rational modulation of the immune response with biologics represents one of the most promising and active areas for the realization of new therapeutic strategies. In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. Ipilimumab is the first-in-class immunotherapeutic for blockade of CTLA-4 and significantly benefits overall survival of patients with metastatic melanoma. Understanding the chemical and physical determinants recognized by these mAbs provides direct insight into the mechanisms of pathway blockade, the organization of the antigen-antibody complexes at the cell surface, and opportunities to further engineer affinity and selectivity. Here, we report the 3.0 A resolution X-ray crystal structure of the complex formed by ipilimumab with its human CTLA-4 target. This structure reveals that ipilimumab contacts the front β-sheet of CTLA-4 and intersects with the CTLA-4:B7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function. The crystallographically observed binding interface was confirmed by a comprehensive cell-based binding assay against a library of CTLA-4 mutants and by direct biochemical approaches. This structure also highlights determinants responsible for the selectivity exhibited by ipilimumab toward CTLA-4 relative to the homologous and functionally related CD28.",
keywords = "Cancer, CTLA-4, Immunotherapy, Ipilimumab, X-ray crystallography",
author = "Ramagopal, {Udupi A.} and Weifeng Liu and Garrett-Thomson, {Sarah C.} and Bonanno, {Jeffrey B.} and Qingrong Yan and Mohan Srinivasan and Wong, {Susan C.} and Alasdair Bell and Shilpa Mankikar and Rangan, {Vangipuram S.} and Shrikant Deshpande and Korman, {Alan J.} and Almo, {Steven C.}",
year = "2017",
month = "5",
day = "23",
doi = "10.1073/pnas.1617941114",
language = "English (US)",
volume = "114",
pages = "E4223--E4232",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "21",

}

TY - JOUR

T1 - Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab

AU - Ramagopal, Udupi A.

AU - Liu, Weifeng

AU - Garrett-Thomson, Sarah C.

AU - Bonanno, Jeffrey B.

AU - Yan, Qingrong

AU - Srinivasan, Mohan

AU - Wong, Susan C.

AU - Bell, Alasdair

AU - Mankikar, Shilpa

AU - Rangan, Vangipuram S.

AU - Deshpande, Shrikant

AU - Korman, Alan J.

AU - Almo, Steven C.

PY - 2017/5/23

Y1 - 2017/5/23

N2 - Rational modulation of the immune response with biologics represents one of the most promising and active areas for the realization of new therapeutic strategies. In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. Ipilimumab is the first-in-class immunotherapeutic for blockade of CTLA-4 and significantly benefits overall survival of patients with metastatic melanoma. Understanding the chemical and physical determinants recognized by these mAbs provides direct insight into the mechanisms of pathway blockade, the organization of the antigen-antibody complexes at the cell surface, and opportunities to further engineer affinity and selectivity. Here, we report the 3.0 A resolution X-ray crystal structure of the complex formed by ipilimumab with its human CTLA-4 target. This structure reveals that ipilimumab contacts the front β-sheet of CTLA-4 and intersects with the CTLA-4:B7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function. The crystallographically observed binding interface was confirmed by a comprehensive cell-based binding assay against a library of CTLA-4 mutants and by direct biochemical approaches. This structure also highlights determinants responsible for the selectivity exhibited by ipilimumab toward CTLA-4 relative to the homologous and functionally related CD28.

AB - Rational modulation of the immune response with biologics represents one of the most promising and active areas for the realization of new therapeutic strategies. In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. Ipilimumab is the first-in-class immunotherapeutic for blockade of CTLA-4 and significantly benefits overall survival of patients with metastatic melanoma. Understanding the chemical and physical determinants recognized by these mAbs provides direct insight into the mechanisms of pathway blockade, the organization of the antigen-antibody complexes at the cell surface, and opportunities to further engineer affinity and selectivity. Here, we report the 3.0 A resolution X-ray crystal structure of the complex formed by ipilimumab with its human CTLA-4 target. This structure reveals that ipilimumab contacts the front β-sheet of CTLA-4 and intersects with the CTLA-4:B7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function. The crystallographically observed binding interface was confirmed by a comprehensive cell-based binding assay against a library of CTLA-4 mutants and by direct biochemical approaches. This structure also highlights determinants responsible for the selectivity exhibited by ipilimumab toward CTLA-4 relative to the homologous and functionally related CD28.

KW - Cancer

KW - CTLA-4

KW - Immunotherapy

KW - Ipilimumab

KW - X-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=85019540641&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019540641&partnerID=8YFLogxK

U2 - 10.1073/pnas.1617941114

DO - 10.1073/pnas.1617941114

M3 - Article

VL - 114

SP - E4223-E4232

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 21

ER -