Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies
Authors: Frederick Arce Vargas, Andrew J.S. Furness, Kevin Litchfield, Kroopa Joshi, Rachel Rosenthal, Ehsan Ghorani, Isabelle Solomon, Marta H. Lesko, Nora Ruef, Claire Roddie, Jake Y. Henry, Lavinia Spain, Assma Ben Aissa, Andrew Georgiou, Yien Ning Sophia Wong, Myles Smith, Dirk Strauss, Andrew Hayes, David Nicol, Tim O'Brien, Linda Mårtensson, Anne Ljungars, Ingrid Teige, Björn Frendéus, Martin Pule, Teresa Marafioti, Martin Gore, James Larkin, Samra Turajlic, Charles Swanton, Karl S. Peggs, Sergio A. Quezada, Kevin Harrington, Alan Melcher, Andrew Wotherspoon, Nicholas Francis, Ben Challacombe, Archana Fernando, Steve Hazell, Ashish Chandra, Lisa Pickering, Joanna Lynch, Sarah Rudman, Simon Chowdhury, Karen Harrison-Phipps, Mary Varia, Catherine Horsfield, Alexander Polson, Gordon Stamp, Marie O'Donnell, William Drake, Peter Hill, David Hrouda, Eric Mayer, Jonathan Olsburgh, Gordon Kooiman, Kevin O'Connor, Grant Stewart, Michael Aitchison, Maxine Tran, Nicos Fotiadis, Hema Verma, Jose Lopez, Jason Lester, Fiona Morgan, Malgorzata Kornaszewska, Richard Attanoos, Haydn Adams, Helen Davies, Dean Fennell, Jacqui Shaw, John Le Quesne, Apostolos Nakas, Sridhar Rathinam, William Monteiro, Hilary Marshall, Louise Nelson, Jonathan Bennett, Joan Riley, Lindsay Primrose, Luke Martinson, Girija Anand, Sajid Khan, Marianne Nicolson, Keith Kerr, Shirley Palmer, Hardy Remmen, Joy Miller, Keith Buchan, Mahendran Chetty, Lesley Gomersall, Sara Lock, Babu Naidu, Gerald Langman, Simon Trotter, Mary Bellamy, Hollie Bancroft, Amy Kerr, Salma Kadiri, Joanne Webb, Gary Middleton, Madava Djearaman, Yvonne Summers, Raffaele Califano, Paul Taylor, Rajesh Shah, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Phil Crosbie, Stuart Moss, Faiza Idries, Juliette Novasio, Leena Joseph, Paul Bishop, Anshuman Chaturvedi, Anne Marie Quinn, Helen Doran, Angela leek, Phil Harrison, Katrina Moore, Rachael Waddington, Fiona Blackhall, Jane Rogan, Elaine Smith, Caroline Dive, Ged Brady, Dominic Rothwell, Sakshi Gulati, Francesca Chemie, Jonathan Tugwood, Jackie Pierce, David Lawrence, Martin Hayward, Nikolaos Panagiotopoulos, Robert George, Davide Patrini, Mary Falzon, Elaine Borg, Reena Khiroya, Mariam Jamal-Hanjani, Gareth Wilson, Nicolai Juul Birkbak, Thomas Watkins, Nicholas McGranahan, Christopher Abbosh, Stuart Horswell, Richard Mitter, Mickael Escudero, Aengus Stewart, Andrew Rowan, Crispin Hiley, Jacki Goldman, Asia Ahmed, Magali Taylor, Junaid Choudhary, Penny Shaw, Raju Veeriah, Justyna Czyzewska-Khan, Diana Johnson, Joanne Laycock, Robert Hynds, Mariana Werner Sunderland, James Reading, Marco Novelli, Dahmane Oukrif, Sam Janes, Martin Forster, Tanya Ahmad, Siow Ming Lee, Peter van Loo, Javier Herrero, John Hartley, Richard Kevin Stone, Tamara Denner, Marta Costa, Sharmin Begum, Ben Phillimore, Tim Chambers, Emma Nye, Sophie Ward, Greg Elgar, Maise Al-Bakir, Dawn Carnell, Ruheena Mendes, Jeremy George, Neal Navani, Dionysis Papadatos-Pastos, Marco Scarci, Pat Gorman, Helen Lowe, Leah Ensell, David Moore, Mairead MacKenzie, Maggie Wilcox, Harriet Bell, Allan Hackshaw, Yenting Ngai, Sean Smith, Nicole Gower, Christian Ottensmeier, Serena Chee, Benjamin Johnson, Aiman Alzetani, Emily Shaw, Eric Lim, Paulo De Sousa, Monica Tavares Barbosa, Andrew Nicholson, Alex Bowman, Simon Jordan, 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 Green, Hillaria Mashinga, Kelvin Lau, Michael Sheaff, Peter Schmid, John Conibear, Veni Ezhil, Vineet Prakash, Sarah Danson, Jonathan Bury, John Edwards, Jennifer Hill, Sue Matthews, Yota Kitsanta, Kim Suvarna, Michael Shackcloth, John Gosney, Pieter Postmus, Sarah Feeney, Julius Asante-Siaw, Peter Russell, Teresa Light, Tracey Horey, Kevin Blyth, Craig Dick, Alan Kirk
Journal: Cancer Cell (2018)

Highlights•Anti-CTLA-4 of hIgG1 and hIgG2 isotypes promote depletion of intra-tumoral Treg cells•hIgG2 antibodies mediate in vivo depletion of intra-tumoral Treg cells via CD32a•Anti-CTLA-4 with enhanced Fc effector function improves therapeutic outcomes•The CD16-V158F SNP is associated with response to ipilimumab in inflamed tumorsSummaryWith the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.Graphical abstract