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Interaction with FcyRIIB is critical for the agonistic activity of anti-CD40 monoclonal antibody

White, Ann L., Chan, H.T. Claude, Roghanian, Ali, French, Ruth R., Mockridge, C. Ian, Tutt, Alison L., Dixon, Sandra V., Ajona, Daniel, Verbeek, J. Sjef, Al-Shamkhani, Aymen, Cragg, Mark S., Beers, Stephen A. and Glennie, Martin J. (2011) Interaction with FcyRIIB is critical for the agonistic activity of anti-CD40 monoclonal antibody Journal of Immunology, 187, (4), pp. 1754-1763. (doi:10.4049/jimmunol.1101135). (PMID:21742972).

Record type: Article

Abstract

A high activatory/inhibitory Fc?R binding ratio is critical for the activity of mAb such as rituximab and alemtuzumab that attack cancer cells directly and eliminate them by recruiting immune effectors. Optimal Fc?R binding profiles of other anti-cancer mAb, such as immunostimulatory mAb that stimulate or block immune receptors, are less clear. In this study, we analyzed the importance of isotype and Fc?R interactions in controlling the agonistic activity of the anti-mouse CD40 mAb 3/23. Mouse IgG1 (m1) and IgG2a (m2a) variants of the parental 3/23 (rat IgG2a) were engineered and used to promote humoral and cellular responses against OVA. The mouse IgG1 3/23 was highly agonistic and outperformed the parental Ab when promoting Ab (10-100-fold) and T cell (OTI and OTII) responses (2- to >10-fold). In contrast, m2a was almost completely inactive. Studies in Fc?R knockout mice demonstrated a critical role for the inhibitory Fc?RIIB in 3/23 activity, whereas activatory Fc?R (Fc?RI, -III, and -IV) was dispensable. In vitro experiments established that the stimulatory effect of Fc?RIIB was mediated through Ab cross-linking delivered in trans between neighboring cells and did not require intracellular signaling. Intriguingly, activatory Fc?R provided effective cross-linking of 3/23 m2a in vitro, suggesting the critical role of Fc?RIIB in vivo reflects its cellular distribution and bioavailability as much as its affinity for a particular Ab isotype. In conclusion, we demonstrate an essential cross-linking role for the inhibitory Fc?RIIB in anti-CD40 immunostimulatory activity and suggest that isotype will be an important issue when optimizing reagents for clinical use.

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More information

e-pub ahead of print date: 8 July 2011
Published date: 15 August 2011
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 339295
URI: http://eprints.soton.ac.uk/id/eprint/339295
ISSN: 0022-1767
PURE UUID: ad86723a-d5f7-405d-9538-8e0670ef5b6d
ORCID for Mark S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 28 May 2012 13:56
Last modified: 18 Jul 2017 05:53

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Contributors

Author: Ann L. White
Author: H.T. Claude Chan
Author: Ali Roghanian
Author: Ruth R. French
Author: C. Ian Mockridge
Author: Alison L. Tutt
Author: Sandra V. Dixon
Author: Daniel Ajona
Author: J. Sjef Verbeek
Author: Mark S. Cragg ORCID iD

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