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Functional Antagonism of Human CD40 Achieved by Targeting a Unique Species-Specific Epitope.

Abstract：

:Current clinical anti-CD40 biologic agents include both antagonist molecules for the treatment of autoimmune diseases and agonist molecules for immuno-oncology, yet the relationship between CD40 epitope and these opposing biological outcomes is not well defined. This report describes the identification of potent antagonist domain antibodies (dAbs) that bind to a novel human CD40-specific epitope that is divergent in the CD40 of nonhuman primates. A similarly selected anti-cynomolgus CD40 dAb recognizing the homologous epitope is also a potent antagonist. Mutagenesis, biochemical, and X-ray crystallography studies demonstrate that the epitope is distinct from that of CD40 agonists. Both the human-specific and cynomolgus-specific molecules remain pure antagonists even when formatted as bivalent Fc-fusion proteins, making this an attractive therapeutic format for targeting hCD40 in autoimmune indications.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Yamniuk AP,Suri A,Krystek SR,Tamura J,Ramamurthy V,Kuhn R,Carroll K,Fleener C,Ryseck R,Cheng L,An Y,Drew P,Grant S,Suchard SJ,Nadler SG,Bryson JW,Sheriff S

doi

10.1016/j.jmb.2016.05.014

subject

Has Abstract

pub_date

2016-07-17 00:00:00

pages

2860-79

issue

14

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(16)30169-3

journal_volume

428

pub_type

杂志文章

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