Structural Determination of the Broadly Reactive Anti- IGHV1-69 Anti-idiotypic Antibody G6 and Its Idiotope

Summary

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.

Graphical Abstract

Highlights

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  G6 binds to a subset of IGHV1-69 germline-based anti-influenza Abs

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  The structure of humanized G6 with a IGHV1-69 anti-influenza Ab is reported

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  Various binding assays further define the G6 cross-reactive binding idiotope

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  The core binding idiotope of G6 is deduced

Abstract

G6 is an exceptional anti-idiotypic antibody that binds to antibodies encoded by the immunoglobulin heavy chain germline gene IGHV1-69. Avnir et al. describe how G6 binds to its cross-reactive idiotope by a set of binding assays and by solving the structure of humanized-G6 complexed with an IGHV1-69-anti-influenza Ab.