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

FcγRIIB controls antibody-mediated target cell depletion by ITIM-independent mechanisms
FcγRIIB controls antibody-mediated target cell depletion by ITIM-independent mechanisms
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.
B cells, CP: Immunology, Fc receptors, FcγRIIB, ITIM, Treg, cancer, depletion, immunotherapy, monoclonal antibody
2211-1247
Simpson, Alexander Patrick
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Roghanian, Ali
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Oldham, Robert James
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Chan, Claude
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Penfold, Christine
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James, Sonya
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Bogdanov, Yury
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Mockridge, Christopher
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Kim, Hyung
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Inzhelevskaya, Tatyana
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Beers, Stephen
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Cragg, Mark
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Simpson, Alexander Patrick
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Roghanian, Ali
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Oldham, Robert James
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Chan, Claude
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Penfold, Christine
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James, Sonya
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Bogdanov, Yury
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Mockridge, Christopher
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Kim, Hyung
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Inzhelevskaya, Tatyana
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Beers, Stephen
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Cragg, Mark
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Simpson, Alexander Patrick, Roghanian, Ali, Oldham, Robert James, Chan, Claude, Penfold, Christine, James, Sonya, Bogdanov, Yury, Mockridge, Christopher, Kim, Hyung, Inzhelevskaya, Tatyana, Beers, Stephen and Cragg, Mark (2022) FcγRIIB controls antibody-mediated target cell depletion by ITIM-independent mechanisms. Cell Reports, 40 (3), [111099]. (doi:10.1016/j.celrep.2022.111099).

Record type: Article

Abstract

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.

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Accepted/In Press date: 23 June 2022
Published date: 19 July 2022
Additional Information: Funding Information: We thank members of the Antibody and Vaccine Group and BioInvent International for useful discussions and the pre-clinical unit staff for animal husbandry. Funding was from Blood Cancer UK (award numbers 12050 and 14043 ), CRUK (award numbers A18087 , A24721 , A25139 ), and BioInvent International . A.P.S was supported by an iCASE studentship from the BBSRC ( 1943869 ) in association with GSK. Funding Information: We thank members of the Antibody and Vaccine Group and BioInvent International for useful discussions and the pre-clinical unit staff for animal husbandry. Funding was from Blood Cancer UK (award numbers 12050 and 14043), CRUK (award numbers A18087, A24721, A25139), and BioInvent International. A.P.S was supported by an iCASE studentship from the BBSRC (1943869) in association with GSK. A.P.S. designed and performed experiments, analyzed and interpreted data, and wrote the manuscript. A.R. designed and performed experiments, supervised data collection, analyzed and interpreted data, and edited the manuscript. R.O. H.T.C. K.L.C. Y.B. S.J. and L.N.D. designed and performed experiments. C.P. J.K. T.I. I.M. and A.T. generated or provided key reagents or performed and analyzed research. D.R. and P.M. helped design the study, supervised data collection, and discussed and interpreted data. I.T. helped design the study, supervised data collection, and discussed and interpreted data. B.F. S.A.B. and M.S.C. designed the study, supervised data collection, discussed and interpreted data, and wrote the manuscript. M.S.C. acts as a consultant for a number of biotech companies, being retained as a consultant for BioInvent International, and has received research funding from BioInvent International, GSK, UCB, iTeos, and Roche. S.A.B. has acted as a consultant for a number of biotechs and receives institutional support for grants and patents from BioInvent. A.R. receives institutional support for grants and patents from BioInvent International. D.R. and P.M. are employees of GSK. I.T. and B.F. are employees of BioInvent International. This work is related to patent family EP3263602A1 concerning the combined use of FcγRIIB and CD20-specific antibodies as well as US 11001638 and WO2019020774-A2/A3, relating to OX40 and 4-1BB. Publisher Copyright: © 2022 The Author(s)
Keywords: B cells, CP: Immunology, Fc receptors, FcγRIIB, ITIM, Treg, cancer, depletion, immunotherapy, monoclonal antibody

Identifiers

Local EPrints ID: 469109
URI: http://eprints.soton.ac.uk/id/eprint/469109
ISSN: 2211-1247
PURE UUID: 78a7488a-0bfe-4ba8-9678-d1d9abdb82d3
ORCID for Ali Roghanian: ORCID iD orcid.org/0000-0003-1316-4218
ORCID for Robert James Oldham: ORCID iD orcid.org/0000-0002-8007-1145
ORCID for Claude Chan: ORCID iD orcid.org/0000-0003-0530-9480
ORCID for Yury Bogdanov: ORCID iD orcid.org/0000-0003-4667-5890
ORCID for Stephen Beers: ORCID iD orcid.org/0000-0002-3765-3342
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 06 Sep 2022 18:49
Last modified: 17 Mar 2024 03:45

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Contributors

Author: Alexander Patrick Simpson
Author: Ali Roghanian ORCID iD
Author: Robert James Oldham ORCID iD
Author: Claude Chan ORCID iD
Author: Christine Penfold
Author: Sonya James
Author: Yury Bogdanov ORCID iD
Author: Christopher Mockridge
Author: Hyung Kim
Author: Tatyana Inzhelevskaya
Author: Stephen Beers ORCID iD
Author: Mark Cragg ORCID iD

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