The University of Southampton
University of Southampton Institutional Repository

Complex interplay between epitope specificity and isotype dictates the biological activity of anti-human CD40 antibodies

Complex interplay between epitope specificity and isotype dictates the biological activity of anti-human CD40 antibodies
Complex interplay between epitope specificity and isotype dictates the biological activity of anti-human CD40 antibodies

Anti-CD40 monoclonal antibodies (mAbs) that promote or inhibit receptor function hold promise as therapeutics for cancer and autoimmunity. Rules governing their diverse range of functions, however, are lacking. Here we determined characteristics of nine hCD40 mAbs engaging epitopes throughout the CD40 extracellular region expressed as varying isotypes. All mAb formats were strong agonists when hyper-crosslinked; however, only those binding the membrane-distal cysteine-rich domain 1 (CRD1) retained agonistic activity with physiological Fc gamma receptor crosslinking or as human immunoglobulin G2 isotype; agonistic activity decreased as epitopes drew closer to the membrane. In addition, all CRD2-4 binding mAbs blocked CD40 ligand interaction and were potent antagonists. Thus, the membrane distal CRD1 provides a region of choice for selecting CD40 agonists while CRD2-4 provides antagonistic epitopes. CD40 agonist mAbs are being investigated for cancer treatment, whereas antagonistic mAbs are under investigation for the treatment of autoimmune and inflammatory conditions. Yu et al. show that the activity of a CD40 mAb is determined by an interplay between the location of its epitope within CD40 and its isotype.

agonist, antagonist, CD40, crystal structure, epitope, Fc receptors, immunotherapy, isotype, monoclonal antibody, TNFR
1535-6108
664-675
Yu, Xiaojie
44d52374-eacc-4e23-b7da-c881e6d3a5dd
Chan, Hak
b109c93f-7e9a-44ee-ad12-da757b1b11fc
Orr, Christian
f64259af-4120-481a-8e12-11344d005de0
Dadas, Osman
f231026d-4201-40d3-ab10-137ff53f3830
Booth, Steven
c2026d9d-ed93-4b1b-bce5-6b3efc8b8ca5
Dahal, Lekh
1e993a7a-b007-4187-82ea-e28dd3920b66
Penfold, Christine
400d743e-a639-45ea-a027-5b778800f6d3
O'Brien, Lyn
0dea42f9-e160-4929-80db-35001165c280
Mockridge, Christopher
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
French, Ruth
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Duriez, Patrick
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Douglas, Leon
049b5f33-6870-4773-ae34-663489b472ba
Pearson, Arwen R.
701586aa-46d1-4068-b0bf-38eacdd5d61f
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Tews, Ivo
9117fc5e-d01c-4f8d-a734-5b14d3eee8dd
Glennie, Martin
9f6f0eff-4560-48c2-80cd-0ec116110ded
White, Ann L.
dd7e96b0-c826-4495-a2bc-4e3bcde699de
Yu, Xiaojie
44d52374-eacc-4e23-b7da-c881e6d3a5dd
Chan, Hak
b109c93f-7e9a-44ee-ad12-da757b1b11fc
Orr, Christian
f64259af-4120-481a-8e12-11344d005de0
Dadas, Osman
f231026d-4201-40d3-ab10-137ff53f3830
Booth, Steven
c2026d9d-ed93-4b1b-bce5-6b3efc8b8ca5
Dahal, Lekh
1e993a7a-b007-4187-82ea-e28dd3920b66
Penfold, Christine
400d743e-a639-45ea-a027-5b778800f6d3
O'Brien, Lyn
0dea42f9-e160-4929-80db-35001165c280
Mockridge, Christopher
327aef17-4837-4f2a-a93b-3d17cd1a7f9f
French, Ruth
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Duriez, Patrick
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Douglas, Leon
049b5f33-6870-4773-ae34-663489b472ba
Pearson, Arwen R.
701586aa-46d1-4068-b0bf-38eacdd5d61f
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Tews, Ivo
9117fc5e-d01c-4f8d-a734-5b14d3eee8dd
Glennie, Martin
9f6f0eff-4560-48c2-80cd-0ec116110ded
White, Ann L.
dd7e96b0-c826-4495-a2bc-4e3bcde699de

Yu, Xiaojie, Chan, Hak, Orr, Christian, Dadas, Osman, Booth, Steven, Dahal, Lekh, Penfold, Christine, O'Brien, Lyn, Mockridge, Christopher, French, Ruth, Duriez, Patrick, Douglas, Leon, Pearson, Arwen R., Cragg, Mark, Tews, Ivo, Glennie, Martin and White, Ann L. (2018) Complex interplay between epitope specificity and isotype dictates the biological activity of anti-human CD40 antibodies. Cancer Cell, 33 (4), 664-675. (doi:10.1016/j.ccell.2018.02.009).

Record type: Article

Abstract

Anti-CD40 monoclonal antibodies (mAbs) that promote or inhibit receptor function hold promise as therapeutics for cancer and autoimmunity. Rules governing their diverse range of functions, however, are lacking. Here we determined characteristics of nine hCD40 mAbs engaging epitopes throughout the CD40 extracellular region expressed as varying isotypes. All mAb formats were strong agonists when hyper-crosslinked; however, only those binding the membrane-distal cysteine-rich domain 1 (CRD1) retained agonistic activity with physiological Fc gamma receptor crosslinking or as human immunoglobulin G2 isotype; agonistic activity decreased as epitopes drew closer to the membrane. In addition, all CRD2-4 binding mAbs blocked CD40 ligand interaction and were potent antagonists. Thus, the membrane distal CRD1 provides a region of choice for selecting CD40 agonists while CRD2-4 provides antagonistic epitopes. CD40 agonist mAbs are being investigated for cancer treatment, whereas antagonistic mAbs are under investigation for the treatment of autoimmune and inflammatory conditions. Yu et al. show that the activity of a CD40 mAb is determined by an interplay between the location of its epitope within CD40 and its isotype.

Text
Accepted version - Accepted Manuscript
Download (1MB)
Text
1-s2.0-S0022399918300473-main - Version of Record
Available under License Creative Commons Attribution.
Download (455kB)

More information

Accepted/In Press date: 15 February 2018
e-pub ahead of print date: 22 March 2018
Published date: 9 April 2018
Keywords: agonist, antagonist, CD40, crystal structure, epitope, Fc receptors, immunotherapy, isotype, monoclonal antibody, TNFR

Identifiers

Local EPrints ID: 420305
URI: https://eprints.soton.ac.uk/id/eprint/420305
ISSN: 1535-6108
PURE UUID: 61d8d844-feec-4cda-ab7e-427c600ca012
ORCID for Christian Orr: ORCID iD orcid.org/0000-0002-6137-8969
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X
ORCID for Ivo Tews: ORCID iD orcid.org/0000-0002-4704-1139

Catalogue record

Date deposited: 03 May 2018 16:30
Last modified: 22 Mar 2019 05:01

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×