[PDF][PDF] Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors

FA Vargas, AJS Furness, I Solomon, K Joshi… - Immunity, 2017 - cell.com
FA Vargas, AJS Furness, I Solomon, K Joshi, L Mekkaoui, MH Lesko, EM Rota, R Dahan
Immunity, 2017cell.com
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 …
Summary
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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