Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice

Michael J. Mendez, Larry L. Green, Jose R F Corvalan, Xiao Chi Jia, Xiao Dong Yang, Michael L. Gallo, Donna M. Louie, Doris V. Lee, Karen L. Erickson, Jac Luna, Catherine M N Roy, Hadi Abderrahim, Ford Kirschenbaum, Masato Noguchi, Douglas H. Smith, Atsushi Fukushima, Joanna F. Hales, Mitchell H. Finer, C. Geoffrey Davis, Krisztina M. ZseboAya Jakobovits

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Abstract

We constructed two megabase-sized YACs containing large contiguous fragments of the human heavy and kappa (κ) light chain immunoglobulin (Ig) loci in nearly germline configuration, including approximately 66 V(H) and 32 V(κ) genes. We introduced these YACs into Ig-inactivated mice and observed human antibody production which closely resembled that seen in humans in all respects, including gene rearrangement, assembly, and repertoire. Diverse Ig gene usage together with somatic hypermutation enables the mice to generate high affinity fully human antibodies to multiple antigens, including human proteins. Our results underscore the importance of the large Ig fragments with multiple V genes for restoration of a normal humoral immune response. These mice are likely to be a valuable tool for the generation of therapeutic antibodies.

Original languageEnglish
Pages (from-to)146-156
Number of pages11
JournalNature Genetics
Volume15
Issue number2
DOIs
Publication statusPublished - 1 Feb 1997
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Mendez, M. J., Green, L. L., Corvalan, J. R. F., Jia, X. C., Yang, X. D., Gallo, M. L., Louie, D. M., Lee, D. V., Erickson, K. L., Luna, J., Roy, C. M. N., Abderrahim, H., Kirschenbaum, F., Noguchi, M., Smith, D. H., Fukushima, A., Hales, J. F., Finer, M. H., Geoffrey Davis, C., ... Jakobovits, A. (1997). Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nature Genetics, 15(2), 146-156. https://doi.org/10.1038/ng0297-146