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.
Interaction with FcyRIIB is critical for the agonistic activity of anti-CD40 monoclonal antibody
Journal of Immunology, 187, (4), . (doi:10.4049/jimmunol.1101135). (PMID:21742972).
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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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