Cancer Cell
Volume 33, Issue 4, 9 April 2018, Pages 664-675.e4
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Article
Complex Interplay between Epitope Specificity and Isotype Dictates the Biological Activity of Anti-human CD40 Antibodies

https://doi.org/10.1016/j.ccell.2018.02.009Get rights and content
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Highlights

  • Epitope in combination with isotype governs hCD40 mAb activity

  • CRD1 binding mAbs are agonistic as IgG2 or with FcγRIIB crosslinking

  • CRD2-4 binding mAbs display antagonistic properties

  • Structure of receptor complex provides insights into agonistic function

Summary

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.

Keywords

agonist
antagonist
CD40
epitope
crystal structure
Fc receptors
immunotherapy
isotype
monoclonal antibody
TNFR

Cited by (0)

6

Present address: UCB-Celltech, 216 Bath Road, Slough, SL1 3WE, UK

7

Present address: Dstl, Porton Down, Salisbury, SP4 0JQ, UK

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Senior author

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