Show simple item record

dc.contributor.authorSallin, Michelle Ann
dc.date.accessioned2014-01-22T15:05:21Z
dc.date.available2014-07-09T12:07:56Z
dc.date.issued2013
dc.identifier.urihttp://hdl.handle.net/10713/3653
dc.descriptionUniversity of Maryland, Baltimore. Molecular Medicine. Ph.D. 2013en_US
dc.description.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.en_US
dc.language.isoen_USen_US
dc.subject4-1BBen_US
dc.subjectCD137en_US
dc.subjectFc gamma receptoren_US
dc.subject.meshAntibodies, Monoclonal--therapeutic useen_US
dc.subject.meshReceptors, IgGen_US
dc.subject.meshTumor Necrosis Factor Receptor Superfamily, Member 9en_US
dc.titleDefining the Role of Fc-Fc Gamma Receptor Interactions in the Anti-Tumor Function of Anti-CD137 Monoclonal Antibody Therapyen_US
dc.typedissertationen_US
dc.contributor.advisorStrome, Scott E.
dc.identifier.ispublishedNoen_US
dc.description.urinameFull Texten_US
refterms.dateFOA2019-02-21T02:02:35Z


Files in this item

Thumbnail
Name:
Sallin_umaryland_0373D_10465.pdf
Size:
2.713Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record