Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies
2018; Cell Press; Volume: 33; Issue: 4 Linguagem: Inglês
10.1016/j.ccell.2018.02.010
ISSN1878-3686
AutoresFrederick 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 Aïssa, Andrew Georgiou, Yien Ning Sophia Wong, Myles Smith, D. Strauß, Andrew Hayes, David Nicol, Tim O'Brien, Linda Mårtensson, Anne Ljungars, Ingrid Teige, Björn Frendéus, Martin Pulé, Teresa Marafioti, Martin Gore, James Larkin, Samra Turajlic, Charles Swanton, Karl S. Peggs, Sergio A. Quezada, Kevin J. Harrington, Alan Melcher, Andrew Wotherspoon, Nick 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, E J Mayer, Jonathon Olsburgh, G. Kooiman, Kevin C. OʼConnor, Grant D. Stewart, Michael Aitchison, Maxine Tran, Nicos Fotiadis, Hema Verma, José I. López, J.F. Lester, Fiona J. E. Morgan, Malgorzata Kornaszewska, Richard Attanoos, Haydn Adams, Helen Davies, Dean A. 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, M. Nicolson, Keith M. Kerr, Shirley Palmer, Hardy Remmen, J. Richard 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, P. W. J. Taylor, Rajesh Shah, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Philip Crosbie, Stuart Moss, Faiza Idries, Juliette Novasio, Leena Dennis Joseph, Paul N. 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 G. Rothwell, Sakshi Gulati, Francesca Chemi, Jonathan Tugwood, Jackie Pierce, David Lawrence, Sophia Ward, Nikolaos Panagiotopoulos, Robert S. George, Davide Patrini, Mary Falzon, Elaine Borg, Reena Khiroya, Mariam Jamal‐Hanjani, Gareth A. Wilson, Nicolai J. Birkbak, Thomas B.K. Watkins, Nicholas McGranahan, Christopher Abbosh, Stuart Horswell, Richard Mitter, Mickael Escudero, Grant D. Stewart, Andrew Rowan, Crispin T. Hiley, Jacki Goldman, Asia Ahmed, Magali N. Taylor, Junaid Choudhary, Penny Shaw, Raju Veeriah, Justyna Czyzewska-Khan, Diana Johnson, Joanne Laycock, Robert E. Hynds, Mariana Werner Sunderland, James L. Reading, Marco Novelli, Dahmane Oukrif, Sam M. Janes, Martin Förster, Tanya Ahmad, Siow Ming Lee, Peter Van Loo, Javier Herrero, John A. Hartley, Richard Stone, Tamara Denner, Marta Costa, Sharmin Begum, Ben Phillimore, Tim Chambers, Emma Nye, Sophia Ward, Greg Elgar, Maise Al-Bakir, Dawn Carnell, R. Mendes, Jeremy George, Neal Navani, Dionysis Papadatos-Pastos, Marco Scarci, Pat Gorman, Helen L. Lowe, Leah Ensell, David A. Moore, Mairead MacKenzie, Maggie Wilcox, Harriet Bell, Allan Hackshaw, Yenting Ngai, Sean Smith, Nicole Gower, Christian H. Ottensmeier, Serena Chee, Benjamin M. Johnson, Aiman Alzetani, Emily Shaw, Eric Lim, Paulo De Sousa, Monica Tavares Barbosa, Andrew G. 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 M. 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 R. Gosney, Pieter E. Postmus, Sarah Feeney, Julius Asante-Siaw, Peter Russell, Teresa Light, Tracey Horey, Kevin Blyth, Craig Dick, Alan Kirk,
Tópico(s)Monoclonal and Polyclonal Antibodies Research
ResumoHighlights•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
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