Buchan, Sarah, Dou, Lang, Remer, Marcus, Booth, Steven, Dunn, Stuart N, Lai, Chester, Semmrich, Monika, Teige, Ingrid, Martensson, Linda, Penfold, Christine, Chan, H.T. Claude, Willoughby, Jane, Mockridge, C. Ian, Dahal, Lekh, Rogel, Anne, Kannisto, Paivi, Jernetz, Mats, Williams, Emily L, Healy, Eugene, Verbeek, J. Sjef, Johnson, Peter, Frendeus, Bjorn, Cragg, Mark, Glennie, Martin, Gray, Juliet, Al-Shamkhani, Aymen and Beers, Stephen (2018) Antibodies to costimulatory receptor 4-1BB enhance anti-tumor immunity via T regulatory cell depletion and promotion of CD8 T cell effector function. Immunity, 49 (5), 958-970.e7. (doi:10.1016/j.immuni.2018.09.014).
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, 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. Buchan et al. reveal dual anti-tumor activities for antibodies to the co-stimulatory receptor 4-1BB, which depend on antibody isotype and FcγR availability. Sequential scheduling of anti-4-1BB and checkpoint blockade mAbs, and antibodies engineered to harness both Treg cell depleting and effector cell agonism properties show potent anti-tumor activity in preclinical models, laying the groundwork for translation into the clinic.
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