Department of Biochemistry and Molecular Pharmacology; Schiffer Lab; Department of Medicine; Department of Microbiology and Physiological Systems
Biochemistry | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Structural Biology | Therapeutics
The heavy chain IGHV1-69 germline gene exhibits a high level of polymorphism and shows biased use in protective antibody (Ab) responses to infections and vaccines. It is also highly expressed in several B cell malignancies and autoimmune diseases. G6 is an anti-idiotypic monoclonal Ab that selectively binds to IGHV1-69 heavy chain germline gene 51p1 alleles that have been implicated in these Ab responses and disease processes. Here, we determine the co-crystal structure of humanized G6 (hG6.3) in complex with anti-influenza hemagglutinin stem-directed broadly neutralizing Ab D80. The core of the hG6.3 idiotope is a continuous string of CDR-H2 residues starting with M53 and ending with N58. G6 binding studies demonstrate the remarkable breadth of binding to 51p1 IGHV1-69 Abs with diverse CDR-H3, light chain, and antigen binding specificities. These studies detail the broad expression of the G6 cross-reactive idiotype (CRI) that further define its potential role in precision medicine.
IGHV polymorphism, VH germline genes, anti-idiotypic antibody, anti-influenza antibodies, chronic lymphocytic leukemia, cross-reactive idiotype, crystal structure, immunoglobulin germline genes, influenza
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Copyright 2017 The Authors. Open Access funded by the US Department of Defense (DoD) or performed by an employee of DoD. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI of Published Version
Cell Rep. 2017 Dec 12;21(11):3243-3255. doi: 10.1016/j.celrep.2017.11.056. Link to article on publisher's site
Avnir, Yuval; Prachanronarong, Kristina L.; Hou, Shurong; Hilbert, Brendan J.; Bohn, Markus-Frederik; Kowalik, Timothy F.; Finberg, Robert W.; Wang, Jennifer P.; Yilmaz, Nese Kurt; Schiffer, Celia A.; and Marasco, Wayne A., "Structural Determination of the Broadly Reactive Anti-IGHV1-69 Anti-idiotypic Antibody G6 and Its Idiotope" (2017). Schiffer Lab Publications. 17.
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