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Antibodies to Costimulatory Receptor 4-1BB Enhance Anti-tumor Immunity via T Regulatory Cell Depletion and Promotion of CD8 T Cell Effector Function

Buchan, Sarah L.; Dou, Lang; Remer, Marcus; Booth, Steven G.; Dunn, Stuart N.; Lai, Chester; Semmrich, Monika LU ; Teige, Ingrid LU ; Mårtensson, Linda LU and Penfold, Christine A., et al. (2018) In Immunity 49(5). p.958-970
Abstract

The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcγR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells,... (More)

The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcγR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells, followed by either agonistic anti-4-1BB IgG1 or anti-PD-1 mAb augmented anti-tumor responses in multiple solid tumor models. An antibody engineered to optimize both FcγR-dependent Treg cell depleting capacity and FcγR-independent agonism delivered enhanced anti-tumor therapy. These insights into the effector mechanisms of anti-4-1BB mAbs lay the groundwork for translation into the clinic.

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@article{0b047e58-76d1-4962-a994-373381b64d4b,
  abstract     = {<p>The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcγR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells, followed by either agonistic anti-4-1BB IgG1 or anti-PD-1 mAb augmented anti-tumor responses in multiple solid tumor models. An antibody engineered to optimize both FcγR-dependent Treg cell depleting capacity and FcγR-independent agonism delivered enhanced anti-tumor therapy. These insights into the effector mechanisms of anti-4-1BB mAbs lay the groundwork for translation into the clinic.</p>},
  author       = {Buchan, Sarah L. and Dou, Lang and Remer, Marcus and Booth, Steven G. and Dunn, Stuart N. and Lai, Chester and Semmrich, Monika and Teige, Ingrid and Mårtensson, Linda and Penfold, Christine A. and Chan, H. T.Claude and Willoughby, Jane E. and Mockridge, C. Ian and Dahal, Lekh N. and Cleary, Kirstie L.S. and James, Sonya and Rogel, Anne and Kannisto, Päivi and Jernetz, Mats and Williams, Emily L. and Healy, Eugene and Verbeek, J. Sjef and Johnson, Peter W.M. and Frendéus, Björn and Cragg, Mark S. and Glennie, Martin J. and Gray, Juliet C. and Al-Shamkhani, Aymen and Beers, Stephen A.},
  issn         = {1074-7613},
  keyword      = {4-1BB,agonism,cancer,combination,depletion,immunotherapy,PD-1,TNFR,Treg cell,tumor},
  language     = {eng},
  number       = {5},
  pages        = {958--970},
  publisher    = {Cell Press},
  series       = {Immunity},
  title        = {Antibodies to Costimulatory Receptor 4-1BB Enhance Anti-tumor Immunity via T Regulatory Cell Depletion and Promotion of CD8 T Cell Effector Function},
  url          = {http://dx.doi.org/10.1016/j.immuni.2018.09.014},
  volume       = {49},
  year         = {2018},
}