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Cell Rep. 2017 Dec 12;21(11):3243-3255. doi: 10.1016/j.celrep.2017.11.056.

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

Author information

1
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
2
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
3
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
4
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
5
School of Life Sciences, Center for Evolution and Medicine, Arizona State University, Tempe, AZ, USA.
6
Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
7
Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
8
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address: nese.kurtyilmaz@umassmed.edu.
9
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address: celia.schiffer@umassmed.edu.
10
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address: wayne_marasco@dfci.harvard.edu.

Abstract

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.

KEYWORDS:

IGHV polymorphism; VH germline genes; anti-idiotypic antibody; anti-influenza antibodies; chronic lymphocytic leukemia; cross-reactive idiotype; crystal structure; immunoglobulin germline genes; influenza

PMID:
29241550
DOI:
10.1016/j.celrep.2017.11.056
[Indexed for MEDLINE]
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