title: 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.
authors.affiliation: Department of Molecular Discovery Technologies, Bristol-Myers Squibb, Princeton, NJ 08543, USA. Electronic address: aaron.yamniuk@bms.com.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Yamniuk
authors.affiliation: Department of Discovery Biology, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: Anish
authors.initials: A
authors.lastname: Suri
authors.affiliation: Department of Molecular Discovery Technologies, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Krystek
authors.affiliation: Department of Molecular Discovery Technologies, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: James
authors.initials: J
authors.lastname: Tamura
authors.affiliation: Department of Molecular Discovery Technologies, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: Vidhyashankar
authors.initials: V
authors.lastname: Ramamurthy
authors.affiliation: Department of Discovery Biology, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Kuhn
authors.affiliation: Department of Discovery Biology, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Carroll
authors.affiliation: Department of Discovery Biology, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fleener
authors.affiliation: Department of Molecular Discovery Technologies, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: Rolf
authors.initials: R
authors.lastname: Ryseck
authors.affiliation: Department of Molecular Discovery Technologies, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Molecular Discovery Technologies, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: Yongmi
authors.initials: Y
authors.lastname: An
authors.affiliation: Domantis, 315 Cambridge Science Park, Cambridge CB4 0WG, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Drew
authors.affiliation: Domantis, 315 Cambridge Science Park, Cambridge CB4 0WG, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.affiliation: Department of Discovery Biology, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Suchard
authors.affiliation: Department of Discovery Biology, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Nadler
authors.affiliation: Department of Molecular Discovery Technologies, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Bryson
authors.affiliation: Department of Molecular Discovery Technologies, Bristol-Myers Squibb, Princeton, NJ 08543, USA. Electronic address: steven.sheriff@bms.com.
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D018360:Crystallography, X-Ray / Q000379:methods; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D008252:Macaca fascicularis
chemical_list: D019013:CD40 Antigens; D000939:Epitopes
keywords: CD40; X-ray structure; autoimmune disease; domain antibody; therapeutic