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2 results on '"Miranda Rota, E"'

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

Author

Arce Vargas, F, Furness, AJS, Solomon, I, Joshi, K, Mekkaoui, L, Lesko, MH, Miranda Rota, E, Dahan, R, Georgiou, A, Sledzinska, A, Ben Aissa, A, Franz, D, Werner Sunderland, M, Wong, YNS, Henry, JY, O'Brien, T, Nicol, D, Challacombe, B, Beers, SA, Spain, L, Wotherspoon, A, Francis, N, Smith, M, Strauss, D, Hayes, A, Soultati, A, Stares, M, Lynch, J, Fotiadis, N, Fernando, A, Hazell, S, Chandra, A, Pickering, L, Rudman, S, Chowdhury, S, Swanton, C, Jamal-Hanjani, M, Veeriah, S, Shafi, S, Czyzewska-Khan, J, Johnson, D, Laycock, J, Bosshard-Carter, L, Goh, G, Rosenthal, R, Gorman, P, Murugaesu, N, Hynds, RE, Wilson, G, Birkbak, NJ, Watkins, TBK, McGranahan, N, Horswell, S, Mitter, R, Escudero, M, Stewart, A, Van Loo, P, Rowan, A, Xu, H, Turajlic, S, Hiley, C, Abbosh, C, Goldman, J, Stone, RK, Denner, T, Matthews, N, Elgar, G, Ward, S, Biggs, J, Costa, M, Begum, S, Phillimore, B, Chambers, T, Nye, E, Graca, S, Al Bakir, M, Hartley, JA, Lowe, HL, Herrero, J, Lawrence, D, Hayward, M, Panagiotopoulos, N, Kolvekar, S, Falzon, M, and Borg, E

Subjects
hemic and immune systems, chemical and pharmacologic phenomena
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.

Published
2017

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

Author

Arce Vargas F, Furness AJS, Solomon I, Joshi K, Mekkaoui L, Lesko MH, Miranda Rota E, Dahan R, Georgiou A, Sledzinska A, Ben Aissa A, Franz D, Werner Sunderland M, Wong YNS, Henry JY, O'Brien T, Nicol D, Challacombe B, Beers SA, Turajlic S, Gore M, Larkin J, Swanton C, Chester KA, Pule M, Ravetch JV, Marafioti T, Peggs KS, and Quezada SA

Subjects
Animals, Antibodies, Monoclonal metabolism, Antibodies, Monoclonal therapeutic use, Cell Line, Tumor, Flow Cytometry, Humans, Immunotherapy methods, K562 Cells, Kaplan-Meier Estimate, Lymphocyte Depletion, Mice, Neoplasms pathology, Neoplasms therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor metabolism, Protein Binding immunology, Receptors, IgG immunology, Receptors, IgG metabolism, T-Lymphocytes, Regulatory metabolism, Antibodies, Monoclonal immunology, Immunoglobulin Fc Fragments immunology, Interleukin-2 Receptor alpha Subunit immunology, Neoplasms immunology, Programmed Cell Death 1 Receptor immunology, T-Lymphocytes, Regulatory immunology
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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Published
2017
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