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

Authors: 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 Nicol, Ben Challacombe, Stephen A. Beers, Samra Turajlic, Martin Gore, James Larkin, Charles Swanton, Kerry Chester, Martin Pulé, Jeffrey V. Ravetch, Teresa Marafioti, Karl S. Peggs, Sergio A. Quezada, Lavinia Spain, Andrew Wotherspoon, Steve Hazell, Myles Smith, D. Strauß, Andrew J. Hayes, Aspasia Soultati, Mark Stares, Lavinia Spain, Joanna Lynch, Nicos Fotiadis, Archana Fernando, Steve Hazell, Ashish Chandra, Lisa Pickering, Sarah 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 Horswell, Richard Mitter, Mickael Escudero, Aengus Stewart, Peter Van Loo, Andrew Rowan, Hang Xu, Samra Turajlic, Crispin T. Hiley, Christopher Abbosh, Jacki Goldman, Richard Stone, Tamara Denner, Nik Matthews, Greg Elgar, Sophia Ward, Jennifer Biggs, Marta Costa, Sharmin Begum, Ben Phillimore, Tim Chambers, Emma Nye, Sofia Graca, Maise Al Bakir, John A. Hartley, Helen L. Lowe, Javier Herrero, David Lawrence, Dahmane Oukrif, Nikolaos Panagiotopoulos, Shyam Kolvekar, Mary Falzon, Elaine Borg, Celia Simeon, Gemma Hector, Amy Smith, Marie Aranda, Marco Novelli, Dahmane Oukrif, Sam M. Janes, Ricky M. Thakrar, Martin Förster, Tanya Ahmad, Siow Ming Lee, Dionysis Papadatos-Pastos, Dawn Carnell, R. Mendes, Jeremy George, Neal Navani, Asia Ahmed, Magali N. Taylor, Junaid Choudhary, Yvonne Summers, Raffaele Califano, P. W. J. Taylor, Rajesh Shah, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Philip Crosbie, Stuart Moss, Faiza Idries, Leena Dennis Joseph, Jane Rogan, Anshuman Chaturved, Anne Marie Quinn, Helen Doran, Angela Leek, Phil Harrison, Katrina Moore, Rachael Waddington, Juliette Novasio, Fiona Blackhall, Jane Rogan, Elaine Smith, Caroline Dive, Jonathan Tugwood, Ged Brady, Dominic G. Rothwell, Francesca Chemi, Jackie Pierce, Sakshi Gulati, Babu Naidu, Gerald Langman, Simon Trotter, Mary Bellamy, Hollie Bancroft, Amy Kerr, Salma Kadiri, Joanne Webb, Gary Middleton, Madava Djearaman, Dean A. Fennell, Jacqui Shaw, John Le Quesne, David A. Moore, Apostolos Nakas, Sridhar Rathinam, William Monteiro, Hilary Marshall, Louise Nelson, Jonathan Bennett, Joan Riley, Lindsay Primrose, Luke Martinson, Girija Anand, Sajid Khan, Anita Amadi, M. Nicolson, Keith M. Kerr, Shirley Palmer, Hardy Remmen, J. Richard Miller, Keith Buchan, Mahendran Chetty, Lesley Gomersall, J.F. Lester, Alison Edwards, Fiona J. E. Morgan, Haydn Adams, Helen Davies, Malgorzata Kornaszewska, Richard Attanoos, Sara Lock, Azmina Verjee, Mairead MacKenzie, Maggie Wilcox, Harriet Bell, Natasha Iles, Allan Hackshaw, Yenting Ngai, Sean G. Smith, Nicole Gower, Christian H. Ottensmeier, Serena Chee, Benjamin M. Johnson, Aiman Alzetani, Emily Shaw, Eric Lim, Paulo De Sousa, Monica Tavares Barbosa, Alex Bowman, Simon Jorda, Alexandra Rice, Hilgardt Raubenheimer, Chiara Proli, Maria Elena Cufari, John Carlo Ronquillo, Angela Kwayie, Harshil Bhayani, Morag Hamilton, Yusura Bakar, Natalie Mensah, Lyn Ambrose, Anand Devaraj, Silviu Buderi, Jonathan Finch, Leire Azcarate, Hema Chavan, Sophie M. Green, Hillaria Mashinga, Andrew G. Nicholson, Kelvin Lau, Michael Sheaff, Peter Schmid, John Conibear, Veni Ezhil, Babikir Ismail, Melanie Irvin-Sellers, Vineet Prakash, Peter Russell, Teresa Light, Tracey Horey, Sarah Danson, Jonathan Bury, John Edwards, Jennifer Hill, Sue Matthews, Yota Kitsanta, Kim Suvarna, Patricia Fisher, Allah Dino Keerio, Michael Shackcloth, John R. Gosney, Pieter E. Postmus, Sarah Feeney, Julius Asante-Siaw - Immunity 2017 cited by 430

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.