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

作者：Frederick Arce Vargas, Andrew J.S. Furness, Isabelle Solomon, Kroopa Joshi, Leila Mekkaoui, Marta H. Lesko, Enrique Miranda, Rony Dahan, Andrew Georgiou, Anna Śledzińska, Assma Ben Aïssa, Dafne Franz, Mariana Werner Sunderland, Yien Ning Sophia Wong, Jake Y. Henry, Tim O’Brien, David L. Nicol, Ben J Challacombe, Stephen A. Beers, Lavinia Spain, Andrew Charles Wotherspoon, Nicholas Francis, Myles J. F. Smith, D. Strauß, Andrew James Hayes, Aspasia S. Soultati, Mark D. Stares, Lavinia Spain, Joanna Lynch, Nicos Fotiadis, Archana Fernando, Steve Hazell, Ashish Chandra, Lisa M. Pickering, Sarah Maria Rudman, Simon Chowdhury, Charles Swanton, Mariam Jamal‐Hanjani, Selvaraju Veeriah, Seema Shafi, Justyna Czyzewska-Khan, Diana Johnson, Joanne Laycock, Leticia Bosshard‐Carter, Gerald Goh, Rachel Rosenthal, Pat Gorman, Nirupa Murugaesu, Robert E. Hynds, Gareth A. Wilson, Nicolai J. Birkbak, Thomas B.K. Watkins, Nicholas McGranahan, Stuart D. Horswell, Richard Mitter, Mickael Escudero, Aengus Stewart, Peter Van Loo, Andrew Rowan, Hang Xu, Samra Turajlic, Crispin T. Hiley, Christopher Abbosh, Jacki Goldman, Richard Kevin Stone, Tamara Denner, Nik Matthews, Greg Elgar, Sophia Ward, Jennifer Biggs, Marta Freitas Costa, Sharmin Begum, Ben Phillimore, Tim James Chambers, Emma L. Nye, Sofia Graca, Maise Al Bakir, John Anthony Hartley, Helen L. Lowe, Javier Herrero, DAVID B. LAWRENCE, Martin Hayward, Nikolaos Panagiotopoulos, Shyam K. Kolvekar, Mary Falzon, Elaine Borg, Celia Simeon, Gemma Hector, Amy Smith, Marie Aranda, Marco R. Novelli, Dahmane Oukrif, Sam M. Janes, Ricky M. Thakrar, Martin David Forster, Tanya Ahmad, Siow Ming Lee, Dionysis Papadatos-Pastos, Dawn M. Carnell, Ruheena L. Mendes, Jeremy George, Neal Navani, Asia Ahmed, Magali N. Taylor, Junaid Choudhary, Yvonne Jane Summers, Raffaele Califano, Paul W. J. Taylor, Rajesh Shah, Piotr Krysiak, Kendadai Rammohan, Eustace J. Fontaine, Richard Booton, Matthew Evison, Phil Crosbie, Stuart Moss, Faiza Idries, Leena Dennis Joseph, Paul N. Bishop, Anshuman Chaturved, Anne Marie Quinn, Helen M. Doran, Angela Leek, Phil M. Harrison, Katrina M. Moore, Rachael Waddington, Juliette Novasio, Fiona Helen Blackhall, Jane Rogan, Elaine Smith, Caroline Dive, Jonathan D. Tugwood, Ged Brady, Dominic G. Rothwell, Francesca Chemi, Jackie Pierce, Sakshi Gulati, Babu V Naidu, Gerald Langman, Simon Trotter, Mary Bellamy, Hollie Bancroft, Amy Kerr, Salma Bibi Kadiri, Joanne Webb, Gary Middleton, Madava G. Djearaman, Dean A. Fennell, Jacqui Shaw, John P. C. Le Quesne, David A. Moore, Apostolos Nakas, Sridhar Rathinam, William R Monteiro, Hilary E. Marshall, Louise Nelson, Jonathan Bennett, Joan Riley, Lindsay Primrose, Luke J. Martinson, Girija Anand, Sajid Ali Khan, Anita Amadi, Marianne C. Nicolson, Keith M. Kerr, Shirley M. Palmer, Hardy Remmen, J. Richard Miller, Keith Buchan, Mahendran Chetty, Lesley Gomersall, Jason Francis Lester, Alison M. Edwards, Fiona J. E. Morgan, Haydn Adams, Helen E. Davies, Malgorzata Kornaszewska, Richard L. Attanoos, Sara Lock, Azmina Verjee, Mairead MacKenzie, Maggie Wilcox, Harriet Bell, Natasha Iles, Allan K. Hackshaw, Yenting Ngai, Sean G. Smith, Nicole Lee Gower, Christian H. H. Ottensmeier, Serena Chee, Benjamin M. Johnson, Aiman Alzetani, Emily Clare Shaw, Eric Lim, Paulo De Sousa, Monica Tavares Barbosa, Alex Bowman, Simon Jorda, Alexandra J. Rice, Hilgardt Raubenheimer, Chiara Proli, Maria Elena Cufari, John Carlo Ronquillo, Angela Kwayie, Harshil Bhayani, Morag Hamilton, Yusura Bakar, Natalie Mensah, Lyn R. Ambrose, Anand Devaraj, Silviu Buderi, Jonathan Finch, Leire Azcarate, Hema Chavan, Sophie M. Green, Hillaria Mashinga, Andrew Gordon Nicholson, Kelvin Lau, Michael T. Sheaff, Peter Alfons Schmid, John Conibear, Veni Ezhil, Babikir Ismail, Melanie J Irvin-Sellers, Vineet Prakash, Peter Russell, Teresa Light, Tracey Horey, Sarah J. Danson, Jonathan P Bury, John G. Edwards, Jennifer W Hill, Sue Matthews, Yota Kitsanta, Kim Suvarna, Patricia Fisher, Allah Dino Keerio, Michael J. Shackcloth, John R. Gosney, Pieter E. Postmus, Sarah Feeney, Julius Asante-Siaw, Samra Turajlic, Martin Eric Gore, James Larkin, Charles Swanton, Kerry Ann Chester, Martin Pulé, Jeffrey V. Ravetch, Teresa Marafioti, Karl S. Peggs, Sergio A. Quezada · 发表于：Immunity · 年份：2017 · DOI：10.1016/j.immuni.2017.03.013 · 被引用次数：437 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Immune Cell Function and Interaction、Immunotherapy and Immune Responses

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.