Genetic engineering of non-human animals for the production of chimeric antibodies
Inventors
Green, Larry • Shizuya, Hiroaki
Assignees
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Publication Number
US-11352444-B2
Publication Date
2022-06-07
Expiration Date
Abstract
The invention provides non-human cells and mammals having a genome encoding chimeric antibodies and methods of producing transgenic cells and mammals. Certain aspects of the invention include chimeric antibodies, humanized antibodies, pharmaceutical compositions and kits. Certain aspects of the invention also relate to diagnostic and treatment methods using the antibodies of the invention.
Core Innovation
The invention relates to a chimeric antibody, or antigen-binding fragment thereof, comprising a chimeric immunoglobulin heavy chain with a human immunoglobulin heavy chain variable region and a chimeric immunoglobulin heavy chain constant region. The constant region comprises a human CH1 domain, a human upper hinge region, a murine CH2 domain, and a murine CH3 domain. The antibody further comprises an immunoglobulin light chain.
The background problem addressed is the need to produce chimeric or humanized antibodies in non-human mammals using genetically engineered Ig loci and transgenic cells. The described platform solves this by functionally inactivating endogenous Ig loci and providing non-endogenous chimeric immunoglobulin locus components, including transgenes that encode chimeric heavy chains and non-endogenous light chains.
The transgenic context is used to generate expression of human or chimeric immunoglobulin in a non-human mammal. Tailored recombination and assembly strategies for engineered Ig loci are described, including site-specific recombinase systems such as CRE/loxP and FLP/frt to assemble and resolve engineered loci, and BAC-based recombineering for synthetic Ig transgenes. Examples described include synthetic human Igλ transgenes, with detection of human Igλ and evidence consistent with somatic mutation and affinity maturation.
Claims Coverage
The independent claim covers the structural composition of a chimeric antibody or antigen-binding fragment with a defined human/murine heavy-chain constant region arrangement and an immunoglobulin light chain. The inventive features include the specific heavy-chain domains and the requirement for an immunoglobulin light chain.
Chimeric heavy chain with human VH and human/murine constant region
A chimeric immunoglobulin heavy chain comprising a human immunoglobulin heavy chain variable region and a chimeric immunoglobulin heavy chain constant region, wherein the constant region comprises a human CH1 domain, a human upper hinge region, a murine CH2 domain, and a murine CH3 domain.
Immunoglobulin light chain with chimeric antibody
An immunoglobulin light chain in the chimeric antibody, or antigen-binding fragment thereof, together with the chimeric immunoglobulin heavy chain.
Overall, the claims are centered on a chimeric antibody or antigen-binding fragment defined by a human heavy-chain variable region combined with a constant region containing human CH1 and upper hinge domains together with murine CH2 and CH3 domains, plus an immunoglobulin light chain.
Stated Advantages
The platform is used to generate expression of human or chimeric immunoglobulin in a non-human mammal.
Detection of human Igλ and evidence consistent with somatic mutation and affinity maturation are described.
Documented Applications
Antibody recovery and display library creation are described.
Pharmaceutical use concepts are described.
Diagnostic use concepts are described.
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