Using multiple forms of anti-CTLA-4 antibody, Du et al. discovered that the antitumor mechanism of anti-CTLA-4 surprisingly requires none of the following: blockade of the CTLA-4/B7 interaction, inhibition of B7 trans-endocytosis, upregulation of B7 on dendritic cells, de novo CD8+ T cell priming, or CD4+ T cell activation. Instead, the antitumor effect of anti-CTLA-4 is dependent on the local depletion of Tregs via interactions with the Fc receptor on other host cells and the subsequent antibody-dependent cellular cytotoxicity.
It is assumed that anti-CTLA-4 antibodies cause tumor rejection by blocking negative signaling from B7-CTLA-4 interactions. Surprisingly, at concentrations considerably higher than plasma levels achieved by clinically effective dosing, the anti-CTLA-4 antibody Ipilimumab blocks neither B7 trans-endocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Consequently, Ipilimumab does not increase B7 on dendritic cells (DCs) from either CTLA4 gene humanized (Ctla4 (h/h) ) or human CD34(+) stem cell-reconstituted NSG mice. In Ctla4 (h/m) mice expressing both human and mouse CTLA4 genes, anti-CTLA-4 antibodies that bind to human but not mouse CTLA-4 efficiently induce Treg depletion and Fc receptor-dependent tumor rejection. The blocking antibody L3D10 is comparable to the non-blocking Ipilimumab in causing tumor rejection. Remarkably, L3D10 progenies that lose blocking activity during humanization remain fully competent in inducing Treg depletion and tumor rejection. Anti-B7 antibodies that effectively block CD4 T cell activation and de novo CD8 T cell priming in lymphoid organs do not negatively affect the immunotherapeutic effect of Ipilimumab. Thus, clinically effective anti-CTLA-4 mAb causes tumor rejection by mechanisms that are independent of checkpoint blockade but dependent on the host Fc receptor. Our data call for a reappraisal of the CTLA-4 checkpoint blockade hypothesis and provide new insights for the next generation of safe and effective anti-CTLA-4 mAbs.
Author Info: (1) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. (2) Center for Cancer and Immunology Re
Author Info: (1) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. (2) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. (3) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. (4) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. (5) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. (6) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. (7) OncoImmune, Inc., Rockville, MD, 20852, USA. (8) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. (9) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. (10) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. (11) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. (12) Immutics, Inc., Sunnyvale, CA, 94085, USA. (13) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. (14) Alphamab, Inc., Suzhou, Jiangsu, 215125, China. (15) Alphamab, Inc., Suzhou, Jiangsu, 215125, China. (16) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. pzheng@oncoimmune.com. OncoImmune, Inc., Rockville, MD, 20852, USA. pzheng@oncoimmune.com. (17) Center for Cancer and Immunology Research, Children's Research Institute, Children's National Health System, Washington, DC, 20010, USA. OncoImmune, Inc., Rockville, MD, 20852, USA.
