FcγRIIB controls antibody-mediated target cell depletion by ITIM-independent mechanisms

Simpson, Alexander P, Roghanian, Ali, Oldham, Robert J, Chan, HT Claude, Penfold, Christine A, Kim, Hyung J, Inzhelevskaya, Tatyana, Mockridge, C Ian, Cox, Kerry L, Bogdanov, Yury D
et al (show 9 more authors) (2022) FcγRIIB controls antibody-mediated target cell depletion by ITIM-independent mechanisms. CELL REPORTS, 40 (3). 111099-.

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Many therapeutic antibodies deplete target cells and elicit immunotherapy by engaging activating Fc gamma receptors (FcγRs) on host effector cells. These antibodies are negatively regulated by the inhibitory FcγRIIB (CD32B). Dogma suggests inhibition is mediated through the FcγRIIB immunoreceptor tyrosine-based inhibition motif (ITIM), negatively regulating immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling from activating FcγR. To assess this, we generated experimental models expressing human (h)FcγRIIB on targets or effectors, lacking or retaining ITIM signaling capacity. We demonstrate that signaling through the hFcγRIIB ITIM is dispensable for impairing monoclonal antibody (mAb)-mediated depletion of normal and malignant murine target cells through three therapeutically relevant surface receptors (CD20, CD25, and OX40) affecting immunotherapy. We demonstrate that hFcγRIIB competition with activating FcγRs for antibody Fc, rather than ITIM signaling, is sufficient to impair activating FcγR engagement, inhibiting effector function and immunotherapy.

Item Type: Article
Uncontrolled Keywords: Animals, Humans, Mice, Receptors, IgG, Antibodies, Monoclonal, Immunotherapy, Signal Transduction
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 25 Oct 2022 15:51
Last Modified: 18 Jan 2023 19:49
DOI: 10.1016/j.celrep.2022.111099
Open Access URL: https://doi.org/10.1016/j.celrep.2022.111099
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3165758