Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2017 Apr 16

PMID 28410988

Citations 221

Authors

Frederick Arce Vargas

Andrew J S Furness

Isabelle Solomon

Kroopa Joshi

Leila Mekkaoui

Marta H Lesko

Enrique Miranda Rota

Rony Dahan

Andrew Georgiou

Anna Sledzinska

Assma Ben Aissa

Dafne Franz

Mariana Werner Sunderland

Yien Ning Sophia Wong

Jake Y Henry

Tim OBrien

David Nicol

Ben Challacombe

Stephen A Beers

Samra Turajlic

Martin Gore

James Larkin

Charles Swanton

Kerry A Chester

Martin Pule

Jeffrey V Ravetch

Teresa Marafioti

Karl S Peggs

Sergio A Quezada

Affiliations

Soon will be listed here.

Abstract

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.

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