Defining the Role of Fc-Fc Gamma Receptor Interactions in the Anti-Tumor Function of Anti-CD137 Monoclonal Antibody Therapy
AuthorSallin, Michelle Ann
AdvisorStrome, Scott E.
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AbstractAgonistic monoclonal antibodies (mAbs) directed against the co signaling molecule CD137 (4-1BB) elicit potent anti-tumor immunity in mice. This enhanced anti-tumor immunity has traditionally been thought to result from the ability of the Fab portion of anti-CD137 mAb to function as a CD137L analogue. Although engagement of CD137 by anti-CD137 mAbs has the potential to cross-link the Fc fragments, mediating Fc engagement of low to moderate affinity Fc gamma receptors (FcγR), the relative import of such Fc-FcγR interactions in mediating CD137 associated anti-tumor immunity is unknown. In order to address this knowledge gap, we studied the ability of rat anti-mouse CD137 mAb (2A) to mediate the anti-tumor response against the EL4E7 lymphoma in WT and FcγR<super>-/-</super> strains. We hypothesized that Fc interactions through activating FcγRs would enhance the anti-tumor immune response elicited by anti-CD137 mAb. 2A treated Fcγ chain deficient mice have improved anti-tumor immunity against EL4E7 lymphoma relative to WT mice, which can be completely recapitulated in FcγRIII<super>-/-</super> mice. We tested the hypothesis using the MC38 colon carcinoma, but did not find the same enhanced anti-tumor immune response in the FcγRIII<super>-/-</super> mice as in the EL4E7 lymphoma. Kinetic experiments to analyze the immune response in the tumor bearing 2A treated FcγRIII<super>-/-</super> mice identified an increase in splenic CD8β<super>+</super> T cell and dendritic cell (DC) populations compared to WT mice and IgG controls. There was a significant increase in the number of DCs expressing CD40, CD80, and CD86 molecules in the 2A treated FcγRIII<super>-/-</super> mice suggesting the potential for more effective antigen presentation compared to WT mice. The increased numbers of splenic CD8β<super>+</super> T cell and dendritic cell (DC) populations in the 2A treated FcγRIII<super>-/-</super> mice significantly correlated with the tumor volume on Day 16. Collectively, these data suggest FcγRIII ligation negatively regulates anti-CD137 mAb stimulation of DCs with a secondary increase in CD8β<super>+</super> T cells involved in the anti-tumor immune response. Our results demonstrate an unexpected inhibitory role for FcγRIII in the anti-tumor function of anti-CD137 mAb in the EL4E7 lymphoma, and underscore the need to consider antibody isotype when engineering therapeutic mAbs.
DescriptionUniversity of Maryland, Baltimore. Molecular Medicine. Ph.D. 2013
Fc gamma receptor
Antibodies, Monoclonal--therapeutic use
Tumor Necrosis Factor Receptor Superfamily, Member 9