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

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

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.

MeSH terms

  • Amino Acid Sequence
  • Antibodies, Anti-Idiotypic / chemistry*
  • Antibodies, Anti-Idiotypic / genetics
  • Antibodies, Anti-Idiotypic / immunology
  • Antibodies, Monoclonal, Humanized / chemistry*
  • Antibodies, Monoclonal, Humanized / genetics
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Neutralizing / chemistry*
  • Antibodies, Neutralizing / genetics
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / chemistry*
  • Antibodies, Viral / genetics
  • Antibodies, Viral / immunology
  • Antibody Specificity
  • Binding Sites
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Gene Expression
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry*
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics
  • Hemagglutinin Glycoproteins, Influenza Virus / immunology
  • Humans
  • Models, Molecular
  • Orthomyxoviridae / chemistry
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Structure, Secondary
  • Receptors, Antigen, B-Cell / chemistry*
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / immunology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Sequence Alignment
  • Sequence Homology, Amino Acid

Substances

  • Antibodies, Anti-Idiotypic
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Hemagglutinin Glycoproteins, Influenza Virus
  • IGHV1-69 B-cell receptor, human
  • Receptors, Antigen, B-Cell
  • Recombinant Proteins
  • hemagglutinin, human influenza A virus