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

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journal contribution
posted on 17.08.2021, 13:39 by Frederick Arce Vargas, Andrew JS 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 O'Brien, David Nicol, Ben Challacombe, Stephen A Beers, Melanoma TRACERx Consortium, Renal TRACERx Consortium, Lung TRACERx Consortium, Samra Turajlic, Martin Gore, James Larkin, Charles Swanton, Kerry A Chester, Martin Pule, Jeffrey V Ravetch, Teresa Marafioti, Karl S Peggs, Sergio A Quezada
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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