Antigen-specific human antibodies from mice comprising four distinct genetic modifications

Human sequence monoclonal antibodies, which in theory combine high specificity with low immunogenicity, represent a class of potential therapeutic agents. But nearly 20 years after Köhler and Milstein first developed methods for obtaining mouse antibodies, no comparable technology exists for reliabl...

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Bibliographic Details
Published in:Nature (London) 1994-04, Vol.368 (6474), p.856-859
Main Authors: Lonberg, N, Taylor, L D, Harding, F A, Trounstine, M, Higgins, K M, Schramm, S R, Kuo, C C, Mashayekh, R, Wymore, K, McCabe, J G
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - biosynthesis
Antibodies, Monoclonal - genetics
Antibodies, Monoclonal - immunology
Antibody Specificity
B-Lymphocytes - metabolism
Base Sequence
Bone Marrow Cells
Female
Gene Rearrangement, B-Lymphocyte
Genetics
Humans
Hybridomas
Immunization
Immunogenicity
Immunoglobulin E - biosynthesis
Immunoglobulin E - genetics
Immunoglobulin E - immunology
Immunoglobulin Heavy Chains - genetics
Immunoglobulin Light Chains - genetics
Mice
Mice, Transgenic
Molecular Sequence Data
Mutation
Oligodeoxyribonucleotides
Peritoneal Cavity - cytology
Rodents
Spleen - cytology
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Summary:Human sequence monoclonal antibodies, which in theory combine high specificity with low immunogenicity, represent a class of potential therapeutic agents. But nearly 20 years after Köhler and Milstein first developed methods for obtaining mouse antibodies, no comparable technology exists for reliably obtaining high-affinity human antibodies directed against selected targets. Thus, rodent antibodies, and in vitro modified derivatives of rodent antibodies, are still being used and tested in the clinic. The rodent system has certain clear advantages; mice are easy to immunize, are not tolerant to most human antigens, and their B cells form stable hybridoma cell lines. To exploit these advantages, we have developed transgenic mice that express human IgM, IgG and Ig kappa in the absence of mouse IgM or Ig kappa. We report here that these mice contain human sequence transgenes that undergo V(D)J joining, heavy-chain class switching, and somatic mutation to generate a repertoire of human sequence immunoglobulins. They are also homozygous for targeted mutations that disrupt V(D)J rearrangement at the endogenous heavy- and kappa light-chain loci. We have immunized the mice with human proteins and isolated hybridomas secreting human IgG kappa antigen-specific antibodies.
ISSN:0028-0836
1476-4687