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Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through Fc-engineering

Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through Fc-engineering
Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through Fc-engineering
Agonistic CD27 monoclonal antibodies (mAb) have demonstrated impressive anti-tumour efficacy in multiple preclinical models but modest clinical responses. This might reflect current reagents delivering suboptimal CD27 agonism. Here, using a novel panel of CD27 mAb including a clinical candidate, we investigate the determinants of CD27 mAb agonism. Epitope mapping and in silico docking analysis show that mAb binding to membrane-distal and external-facing residues are stronger agonists. However, poor epitope-dependent agonism could partially be overcome by Fc-engineering, using mAb isotypes that promote receptor clustering, such as human immunoglobulin G1 (hIgG1, h1) with enhanced affinity to Fc gamma receptor (FcγR) IIb, or hIgG2 (h2). This study provides the critical knowledge required for the development of agonistic CD27 mAb that are potentially more clinically efficacious.
2399-3642
Heckel, Franziska
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Turaj, Anna
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Fisher, Hayden
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Chan, H.T. Claude
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Marshall, Michael J.E.
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Dadas, Osman
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Penfold, Christine A.
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Inzhelevskaya, Tatyana
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Mockridge, C. Ian
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Alvarado, Diego
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Tews, Ivo
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Keler, Tibor
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Beers, Stephen
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Cragg, Mark
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Lim, Sean
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Heckel, Franziska
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Turaj, Anna
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Fisher, Hayden
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Chan, H.T. Claude
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Marshall, Michael J.E.
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Dadas, Osman
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Penfold, Christine A.
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Inzhelevskaya, Tatyana
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Mockridge, C. Ian
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Alvarado, Diego
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Tews, Ivo
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Keler, Tibor
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Beers, Stephen
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Cragg, Mark
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Lim, Sean
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Heckel, Franziska, Turaj, Anna, Fisher, Hayden, Chan, H.T. Claude, Marshall, Michael J.E., Dadas, Osman, Penfold, Christine A., Inzhelevskaya, Tatyana, Mockridge, C. Ian, Alvarado, Diego, Tews, Ivo, Keler, Tibor, Beers, Stephen, Cragg, Mark and Lim, Sean (2022) Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through Fc-engineering. Communications Biology, 5 (1), [229]. (doi:10.1038/s42003-022-03182-6).

Record type: Article

Abstract

Agonistic CD27 monoclonal antibodies (mAb) have demonstrated impressive anti-tumour efficacy in multiple preclinical models but modest clinical responses. This might reflect current reagents delivering suboptimal CD27 agonism. Here, using a novel panel of CD27 mAb including a clinical candidate, we investigate the determinants of CD27 mAb agonism. Epitope mapping and in silico docking analysis show that mAb binding to membrane-distal and external-facing residues are stronger agonists. However, poor epitope-dependent agonism could partially be overcome by Fc-engineering, using mAb isotypes that promote receptor clustering, such as human immunoglobulin G1 (hIgG1, h1) with enhanced affinity to Fc gamma receptor (FcγR) IIb, or hIgG2 (h2). This study provides the critical knowledge required for the development of agonistic CD27 mAb that are potentially more clinically efficacious.

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Accepted/In Press date: 17 February 2022
Published date: 14 March 2022
Additional Information: Funding Information: S.H.L. is a co-inventor on a patent application filed (JDM84560P.GBA), receives research funding from and has acted as a consultant to Celldex Therapeutics. F.H. receives research funding from Celldex Therapeutics. M.S.C. is also a co-inventor on patent application filed (JDM84560P.GBA). D.A. and T.K. are employees and shareholders of Celldex Therapeutics. The remaining authors declare no competing interests. Funding Information: We thank Alison L. Tutt for the generation of the CD27 mAb. We would also like to thank the Biomedical Research Facility and pre-clinical unit for animal husbandry. The microscopy work was made possible through the generous funding of an ONI Nanoimager by the Mark Benevolent Fund. This work was funded by a UK Medical Research Council Industrial Collaborative Awards in Science and Engineering (iCASE) studentship, Celldex Therapeutics, Cancer Research UK Advanced Clinician Scientist Fellowship to S.H.L. (A27179) and Cancer Research UK Centre funding (A27452). Funding Information: We thank Alison L. Tutt for the generation of the CD27 mAb. We would also like to thank the Biomedical Research Facility and pre-clinical unit for animal husbandry. The microscopy work was made possible through the generous funding of an ONI Nanoimager by the Mark Benevolent Fund. This work was funded by a UK Medical Research Council Industrial Collaborative Awards in Science and Engineering (iCASE) studentship, Celldex Therapeutics, Cancer Research UK Advanced Clinician Scientist Fellowship to S.H.L. (A27179) and Cancer Research UK Centre funding (A27452). Publisher Copyright: © 2022, The Author(s). Copyright: Copyright 2022 Elsevier B.V., All rights reserved.

Identifiers

Local EPrints ID: 456605
URI: http://eprints.soton.ac.uk/id/eprint/456605
ISSN: 2399-3642
PURE UUID: 942940d3-cae3-4882-b509-5d7e1c0975bd
ORCID for Franziska Heckel: ORCID iD orcid.org/0000-0002-7564-1932
ORCID for Hayden Fisher: ORCID iD orcid.org/0000-0003-0093-0921
ORCID for Stephen Beers: ORCID iD orcid.org/0000-0002-3765-3342
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X

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Date deposited: 05 May 2022 16:50
Last modified: 06 May 2022 02:01

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Contributors

Author: Franziska Heckel ORCID iD
Author: Anna Turaj
Author: Hayden Fisher ORCID iD
Author: H.T. Claude Chan
Author: Michael J.E. Marshall
Author: Osman Dadas
Author: Christine A. Penfold
Author: Tatyana Inzhelevskaya
Author: C. Ian Mockridge
Author: Diego Alvarado
Author: Ivo Tews
Author: Tibor Keler
Author: Stephen Beers ORCID iD
Author: Mark Cragg ORCID iD
Author: Sean Lim

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