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Human antibodies from transgenic animals

Abstract

Laboratory mice provide a ready source of diverse, high-affinity and high-specificity monoclonal antibodies (mAbs). However, development of rodent antibodies as therapeutic agents has been impaired by the inherent immunogenicity of these molecules. One technology that has been explored to generate low immunogenicity mAbs for in vivo therapy involves the use of transgenic mice expressing repertoires of human antibody gene sequences. This technology has now been exploited by over a dozen different pharmaceutical and biotechnology companies toward developing new therapeutic mAbs, and currently at least 33 different drugs in clinical testing—including several in pivotal trials—contain variable regions encoded by human sequences from transgenic mice. The emerging data from these trials provide an early glimpse of the safety and efficacy issues for these molecules. Nevertheless, actual product approval, the biggest challenge so far, is required to fully validate this technology as a drug discovery tool. In the future, it may be possible to extend this technology beyond rodents and use transgenic farm animals to directly generate and produce human sequence polyclonal sera.

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Figure 1: Evolution of therapeutic antibody technology and progress to the clinic5,6,7,15,21,22.

Katie Ris

Figure 2: Three sources of diversity contribute to antibody repertoires: combinatorial, junctional and somatic.

Katie Ris

Figure 3: Human immunoglobulin sequences introduced in the germ line of mice comprising endogenous Ig heavy-chain and κ-light-chain gene inactivations (A39, B55, C42, D36, E35, F22, G21, H43).

Katie Ris

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Acknowledgements

I thank Don Drakeman for comments and Michelle Temple for assistance with the manuscript.

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Correspondence to Nils Lonberg.

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The author is an employee of, and has a financial interest, in Medarex, Inc.

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Lonberg, N. Human antibodies from transgenic animals. Nat Biotechnol 23, 1117–1125 (2005). https://doi.org/10.1038/nbt1135

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