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Isotype switching converts anti-CD40 antagonism to agonism to elicit potent antitumor activity

Isotype switching converts anti-CD40 antagonism to agonism to elicit potent antitumor activity
Isotype switching converts anti-CD40 antagonism to agonism to elicit potent antitumor activity
Anti-CD40 monoclonal antibodies (mAbs) comprise agonists and antagonists, which display promising therapeutic activities in cancer and autoimmunity, respectively. We previously showed that epitope and isotype interact to deliver optimal agonistic anti-CD40 mAbs. The impact of Fc engineering on antagonists, however, remains largely unexplored. Here, we show that clinically relevant antagonists used for treating autoimmune conditions can be converted into potent FcγR-independent agonists with remarkable antitumor activity by isotype switching to hIgG2. One antagonist is converted to a super-agonist with greater potency than previously reported highly agonistic anti-CD40 mAbs. Such conversion is dependent on the unique disulfide bonding properties of the hIgG2 hinge. This investigation highlights the transformative capacity of the hIgG2 isotype for converting antagonists to agonists to treat cancer.
CD40, Fc engineering, TNF receptor, agonists, antagonists, antibody, hIgG2, immunostimulatory, immunotherapy, structure function
1535-6108
850-866.e7
Yu, Xiaojie
44d52374-eacc-4e23-b7da-c881e6d3a5dd
Chan, H.T. Claude
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Fisher, Hayden
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Penfold, Christine A.
400d743e-a639-45ea-a027-5b778800f6d3
Kim, Jinny
ea81033c-8f9b-427b-be10-7a320a3f2651
Inzhelevskaya, Tatyana
2d84ec97-18c9-4406-a96b-206c21eae7d5
Mockridge, C. Ian
5b8eea28-f373-4019-8203-1eb79ad1b28b
French, Ruth R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Duriez, Patrick J.
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Douglas, Leon R.
049b5f33-6870-4773-ae34-663489b472ba
English, Vikki
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Verbeek, J. Sjef
115ffb7c-4760-444f-888c-0798469e0b9c
White, Ann L
b8c81272-e959-4acb-bbfe-1adc8a6c43f0
Tews, Ivo
9117fc5e-d01c-4f8d-a734-5b14d3eee8dd
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Yu, Xiaojie
44d52374-eacc-4e23-b7da-c881e6d3a5dd
Chan, H.T. Claude
9b7d97e7-f135-478b-883e-3ff52d49af85
Fisher, Hayden
4ae88aa8-e168-4882-9563-3e5840b32bd6
Penfold, Christine A.
400d743e-a639-45ea-a027-5b778800f6d3
Kim, Jinny
ea81033c-8f9b-427b-be10-7a320a3f2651
Inzhelevskaya, Tatyana
2d84ec97-18c9-4406-a96b-206c21eae7d5
Mockridge, C. Ian
5b8eea28-f373-4019-8203-1eb79ad1b28b
French, Ruth R.
a95ea7a1-7aeb-4c20-998e-fde663613fd1
Duriez, Patrick J.
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Douglas, Leon R.
049b5f33-6870-4773-ae34-663489b472ba
English, Vikki
b0c062ea-d836-4bea-9d46-44c414e11b6e
Verbeek, J. Sjef
115ffb7c-4760-444f-888c-0798469e0b9c
White, Ann L
b8c81272-e959-4acb-bbfe-1adc8a6c43f0
Tews, Ivo
9117fc5e-d01c-4f8d-a734-5b14d3eee8dd
Glennie, Martin J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c

Yu, Xiaojie, Chan, H.T. Claude, Fisher, Hayden, Penfold, Christine A., Kim, Jinny, Inzhelevskaya, Tatyana, Mockridge, C. Ian, French, Ruth R., Duriez, Patrick J., Douglas, Leon R., English, Vikki, Verbeek, J. Sjef, White, Ann L, Tews, Ivo, Glennie, Martin J. and Cragg, Mark S. (2020) Isotype switching converts anti-CD40 antagonism to agonism to elicit potent antitumor activity. Cancer Cell, 37 (6), 850-866.e7. (doi:10.1016/j.ccell.2020.04.013).

Record type: Article

Abstract

Anti-CD40 monoclonal antibodies (mAbs) comprise agonists and antagonists, which display promising therapeutic activities in cancer and autoimmunity, respectively. We previously showed that epitope and isotype interact to deliver optimal agonistic anti-CD40 mAbs. The impact of Fc engineering on antagonists, however, remains largely unexplored. Here, we show that clinically relevant antagonists used for treating autoimmune conditions can be converted into potent FcγR-independent agonists with remarkable antitumor activity by isotype switching to hIgG2. One antagonist is converted to a super-agonist with greater potency than previously reported highly agonistic anti-CD40 mAbs. Such conversion is dependent on the unique disulfide bonding properties of the hIgG2 hinge. This investigation highlights the transformative capacity of the hIgG2 isotype for converting antagonists to agonists to treat cancer.

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More information

Accepted/In Press date: 21 April 2020
e-pub ahead of print date: 21 May 2020
Published date: 8 June 2020
Keywords: CD40, Fc engineering, TNF receptor, agonists, antagonists, antibody, hIgG2, immunostimulatory, immunotherapy, structure function

Identifiers

Local EPrints ID: 441073
URI: http://eprints.soton.ac.uk/id/eprint/441073
ISSN: 1535-6108
PURE UUID: a1a6131d-41d0-478f-a9c6-5843adb58b96
ORCID for Ivo Tews: ORCID iD orcid.org/0000-0002-4704-1139
ORCID for Mark S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 29 May 2020 16:30
Last modified: 21 Apr 2021 04:01

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Contributors

Author: Xiaojie Yu
Author: H.T. Claude Chan
Author: Hayden Fisher
Author: Christine A. Penfold
Author: Jinny Kim
Author: Tatyana Inzhelevskaya
Author: C. Ian Mockridge
Author: Ruth R. French
Author: Patrick J. Duriez
Author: Leon R. Douglas
Author: Vikki English
Author: J. Sjef Verbeek
Author: Ann L White
Author: Ivo Tews ORCID iD
Author: Mark S. Cragg ORCID iD

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