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Domain binding and isotype dictate the activity of anti-human OX40 antibodies

Domain binding and isotype dictate the activity of anti-human OX40 antibodies
Domain binding and isotype dictate the activity of anti-human OX40 antibodies
Background Previous data suggests that anti-OX40 mAb can elicit anti-tumor effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory effects on T cells which could evoke therapeutic responses. Human trials with anti-OX40 antibodies have shown that these entities are well tolerated but to date have delivered disappointing clinical responses, indicating that the rules for the optimal use of anti-human OX40 (hOX40) antibodies is not yet fully understood. Changes to timing and dosages may lead to improved outcomes; however, here we focus on addressing the role of agonism versus depleting activity in determining therapeutic outcomes. We investigated a novel panel of anti-hOX40 mAb to understand how these reagents and mechanisms may be optimized for therapeutic benefit.

Methods This study examines the binding activity and in vitro activity of a panel of anti-hOX40 antibodies. They were further evaluated in several in vivo models to address how isotype and epitope determine mechanism of action and efficacy of anti-hOX40 mAb.

Results Binding analysis revealed the antibodies to be high affinity, with epitopes spanning all four cysteine-rich domains of the OX40 extracellular domain. In vivo analysis showed that their activities relate directly to two key properties: (1) isotype—with mIgG1 mAb evoking receptor agonism and CD8+ T-cell expansion and mIgG2a mAb evoking deletion of Treg and (2) epitope—with membrane-proximal mAb delivering more powerful agonism. Intriguingly, both isotypes acted therapeutically in tumor models by engaging these different mechanisms.

Conclusion These findings highlight the significant impact of isotype and epitope on the modulation of anti-hOX40 mAb therapy, and indicate that CD8+ T-cell expansion or Treg depletion might be preferred according to the composition of different tumors. As many of the current clinical trials using OX40 antibodies are now using combination therapies, this understanding of how to manipulate therapeutic activity will be vital in directing new combinations that are more likely to improve efficacy and clinical outcomes.
1-14
Griffiths, Jordana
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Hussain, Khiyam
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Smith, Hannah L
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Sanders, Theodore
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Cox, Kerry L
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Semmrich, Monika
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Mårtensson, Linda
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Kim, Jinny
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Inzhelevskaya, Tatyana
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Penfold, Chris A
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Tutt, Alison L
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Mockridge, C Ian
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Chan, Ht Claude
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English, Vikki
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French, Ruth F
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Teige, Ingrid
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Al-shamkhani, Aymen
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Glennie, Martin J
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Frendeus, Bjorn L
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Willoughby, Jane E
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Cragg, Mark S
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Griffiths, Jordana
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Hussain, Khiyam
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Smith, Hannah L
e97b320e-8bee-4b80-84e5-d7da65e1e723
Sanders, Theodore
27cae67d-cb0e-48c8-bf27-b62f524fb1f5
Cox, Kerry L
7305c27e-9cdc-4e37-b994-ac55d7d1dfd2
Semmrich, Monika
913807d9-6ff8-424e-b616-ede82babb94c
Mårtensson, Linda
93e7b5b8-f383-4ec2-974d-0ede8832aef8
Kim, Jinny
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Inzhelevskaya, Tatyana
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Penfold, Chris A
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Tutt, Alison L
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Mockridge, C Ian
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Chan, Ht Claude
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English, Vikki
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French, Ruth F
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Teige, Ingrid
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Al-shamkhani, Aymen
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Glennie, Martin J
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Frendeus, Bjorn L
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Willoughby, Jane E
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Cragg, Mark S
ec97f80e-f3c8-49b7-a960-20dff648b78c

Griffiths, Jordana, Hussain, Khiyam, Smith, Hannah L, Sanders, Theodore, Cox, Kerry L, Semmrich, Monika, Mårtensson, Linda, Kim, Jinny, Inzhelevskaya, Tatyana, Penfold, Chris A, Tutt, Alison L, Mockridge, C Ian, Chan, Ht Claude, English, Vikki, French, Ruth F, Teige, Ingrid, Al-shamkhani, Aymen, Glennie, Martin J, Frendeus, Bjorn L, Willoughby, Jane E and Cragg, Mark S (2020) Domain binding and isotype dictate the activity of anti-human OX40 antibodies. Journal for Immunotherapy of Cancer, 8 (2), 1-14, [e001557]. (doi:10.1136/jitc-2020-001557).

Record type: Article

Abstract

Background Previous data suggests that anti-OX40 mAb can elicit anti-tumor effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory effects on T cells which could evoke therapeutic responses. Human trials with anti-OX40 antibodies have shown that these entities are well tolerated but to date have delivered disappointing clinical responses, indicating that the rules for the optimal use of anti-human OX40 (hOX40) antibodies is not yet fully understood. Changes to timing and dosages may lead to improved outcomes; however, here we focus on addressing the role of agonism versus depleting activity in determining therapeutic outcomes. We investigated a novel panel of anti-hOX40 mAb to understand how these reagents and mechanisms may be optimized for therapeutic benefit.

Methods This study examines the binding activity and in vitro activity of a panel of anti-hOX40 antibodies. They were further evaluated in several in vivo models to address how isotype and epitope determine mechanism of action and efficacy of anti-hOX40 mAb.

Results Binding analysis revealed the antibodies to be high affinity, with epitopes spanning all four cysteine-rich domains of the OX40 extracellular domain. In vivo analysis showed that their activities relate directly to two key properties: (1) isotype—with mIgG1 mAb evoking receptor agonism and CD8+ T-cell expansion and mIgG2a mAb evoking deletion of Treg and (2) epitope—with membrane-proximal mAb delivering more powerful agonism. Intriguingly, both isotypes acted therapeutically in tumor models by engaging these different mechanisms.

Conclusion These findings highlight the significant impact of isotype and epitope on the modulation of anti-hOX40 mAb therapy, and indicate that CD8+ T-cell expansion or Treg depletion might be preferred according to the composition of different tumors. As many of the current clinical trials using OX40 antibodies are now using combination therapies, this understanding of how to manipulate therapeutic activity will be vital in directing new combinations that are more likely to improve efficacy and clinical outcomes.

Text
Giffiths et al final submission - Accepted Manuscript
Available under License Creative Commons Attribution.
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More information

Accepted/In Press date: 24 November 2020
e-pub ahead of print date: 21 December 2020

Identifiers

Local EPrints ID: 446831
URI: http://eprints.soton.ac.uk/id/eprint/446831
PURE UUID: 1c89d288-c303-4b2d-851a-80f979ed7c88
ORCID for Aymen Al-shamkhani: ORCID iD orcid.org/0000-0003-0727-4189
ORCID for Mark S Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 24 Feb 2021 17:30
Last modified: 26 Nov 2021 02:41

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Contributors

Author: Jordana Griffiths
Author: Khiyam Hussain
Author: Hannah L Smith
Author: Theodore Sanders
Author: Kerry L Cox
Author: Monika Semmrich
Author: Linda Mårtensson
Author: Jinny Kim
Author: Tatyana Inzhelevskaya
Author: Chris A Penfold
Author: Alison L Tutt
Author: C Ian Mockridge
Author: Ht Claude Chan
Author: Vikki English
Author: Ruth F French
Author: Ingrid Teige
Author: Bjorn L Frendeus
Author: Jane E Willoughby
Author: Mark S Cragg ORCID iD

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