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

Yuval Avnir, Kristina L. Prachanronarong, Zhen Zhang, Shurong Hou, Eric C. Peterson, Jianhua Sui, Hatem Zayed, Vinodh B. Kurella, Andrew T. McGuire, Leonidas Stamatatos, Brendan J. Hilbert, Markus Frederik Bohn, Timothy F. Kowalik, Jeffrey Jensen, Robert W. Finberg, Jennifer P. Wang, Margaret Goodall, Roy Jefferis, Quan Zhu, Nese Kurt YilmazCelia A. Schiffer, Wayne A. Marasco

Research output: Contribution to journalArticle

7 Scopus citations

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. G6 is an exceptional anti-idiotypic antibody that binds to antibodies encoded by the immunoglobulin heavy chain germline gene IGHV1-69. Yuval 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.

Original languageEnglish (US)
Pages (from-to)3243-3255
Number of pages13
JournalCell Reports
Volume21
Issue number11
DOIs
StatePublished - Dec 12 2017

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Avnir, Y., Prachanronarong, K. L., Zhang, Z., Hou, S., Peterson, E. C., Sui, J., Zayed, H., Kurella, V. B., McGuire, A. T., Stamatatos, L., Hilbert, B. J., Bohn, M. F., Kowalik, T. F., Jensen, J., Finberg, R. W., Wang, J. P., Goodall, M., Jefferis, R., Zhu, Q., ... Marasco, W. A. (2017). Structural Determination of the Broadly Reactive Anti-IGHV1-69 Anti-idiotypic Antibody G6 and Its Idiotope. Cell Reports, 21(11), 3243-3255. https://doi.org/10.1016/j.celrep.2017.11.056