CD40/anti-CD40 antibody complexes which illustrate agonist and antagonist structural switches.

Autor:	Argiriadi MA; AbbVie Bioresearch Center, 381 Plantation Street, Worcester, MA, 01605, USA. maria.argiriadi@abbvie.com., Benatuil L; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA., Dubrovska I; AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA., Egan DA; AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA., Gao L; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA., Greischar A; AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA., Hardman J; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA., Harlan J; AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA., Iyer RB; AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA., Judge RA; AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA., Lake M; AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA., Perron DC; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA., Sadhukhan R; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA., Sielaff B; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA., Sousa S; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA., Wang R; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA., McRae BL; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA.
Jazyk:	angličtina
Zdroj:	BMC molecular and cell biology [BMC Mol Cell Biol] 2019 Aug 05; Vol. 20 (1), pp. 29. Date of Electronic Publication: 2019 Aug 05.
DOI:	10.1186/s12860-019-0213-4
Abstrakt:	Background: CD40 is a 48 kDa type I transmembrane protein that is constitutively expressed on hematopoietic cells such as dendritic cells, macrophages, and B cells. Engagement of CD40 by CD40L expressed on T cells results in the production of proinflammatory cytokines, induces T helper cell function, and promotes macrophage activation. The involvement of CD40 in chronic immune activation has resulted in CD40 being proposed as a therapeutic target for a range of chronic inflammatory diseases. CD40 antagonists are currently being explored for the treatment of autoimmune diseases and several anti-CD40 agonist mAbs have entered clinical development for oncological indications. Results: To better understand the mode of action of anti-CD40 mAbs, we have determined the x-ray crystal structures of the ABBV-323 (anti-CD40 antagonist, ravagalimab) Fab alone, ABBV-323 Fab complexed to human CD40 and FAB516 (anti-CD40 agonist) complexed to human CD40. These three crystals structures 1) identify the conformational CD40 epitope for ABBV-323 recognition 2) illustrate conformational changes which occur in the CDRs of ABBV-323 Fab upon CD40 binding and 3) develop a structural hypothesis for an agonist/antagonist switch in the LCDR1 of this proprietary class of CD40 antibodies. Conclusions: The structure of ABBV-323 Fab demonstrates a unique method for antagonism by stabilizing the proposed functional antiparallel dimer for CD40 receptor via novel contacts to LCDR1, namely residue position R32 which is further supported by a closely related agonist antibody FAB516 which shows only monomeric recognition and no contacts with LCDR1 due to a mutation to L32 on LCDR1. These data provide a structural basis for the full antagonist activity of ABBV-323.
Databáze:	MEDLINE
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