Costoya, Cristobal Javier Costoya; (2023) Role of FcγRs in anti-OX40 based immunotherapies. Doctoral thesis (Ph.D), UCL (University College London).

Text C Costoya Thesis with corrections.pdf - Accepted Version Access restricted to UCL open access staff until 1 January 2025. Download (4MB)

Abstract

The use of immunomodulating monoclonal antibodies to generate anti-tumour immune responses has revolutionised the field of oncology. While antagonistic antibodies targeting the inhibitory pathways of CTLA-4 and PD-1 have shown promising results in many types of cancer, agonistic antibodies have failed to do the same. This thesis show that this is partially due to a poor understanding of the interactions between Fc portions of antibodies and Fc Receptors on innate immune cells and proposes the basis for the rational design of agonistic antibodies in cancer immunotherapy. Using transplantable cancer models in mice, we assessed the impact of 2 different antibody isotypes with different binding affinities to activating FcγRs in an agonistic anti-OX40 antibody. We found that while the weak FcγR engager mouse IgG1 (m1) promotes pan-T cell activation and expansion in the tumour microenvironment, the strong FcγR engager mouse IgG2a (m2a) depletes both regulatory T cells (Treg) and effector CD4+ T cells (Teff) from the tumour microenvironment (TME). These effects are potentiated when anti-OX40 antibodies are combined with anti-PD-1 and anti-PD-L1 therapy, translating in nearly 100% of complete responses when anti-OX40 m1 is used whilst anti-OX40 m2a fails to synergise with anti-PD-1/PD-L1 antibodies. These results support abrogating the Fc effector function in agonistic antibodies to deliver agonistic signalling without off-target depletion of effector populations.

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