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Reshaping human antibodies: grafting an antilysozyme activity
M Verhoeyen1, C Milstein, G Winter
1Medical Research Council Laboratory of Molecular Biology, Cambridge, England.
Science (New York, N.Y.)
|March 25, 1988
Summary
Researchers successfully transplanted large protein antigen binding sites from mouse antibodies to human antibodies, overcoming challenges in producing therapeutic human monoclonal antibodies.
Area of Science:
- Immunology
- Molecular Biology
- Biotechnology
Background:
- Therapeutic human monoclonal antibody production is challenging using hybridoma technology.
- "Humanizing" mouse monoclonal antibodies via recombinant DNA techniques offers an alternative approach.
- Previous work demonstrated successful grafting of small hapten binding sites.
Purpose of the Study:
- To investigate the feasibility of transplanting large protein antigen binding sites from mouse to human antibody heavy chains.
- To advance the development of humanized antibodies for therapeutic applications.
Main Methods:
- Utilizing recombinant DNA techniques to transplant hypervariable loops containing binding sites.
- Focusing on the heavy-chain variable domain of mouse antibodies and human myeloma proteins.
- Employing lysozyme as a model protein antigen.
Main Results:
- Successfully transplanted a large binding site for the protein antigen lysozyme from a mouse antibody to a human heavy chain.
- Demonstrated the potential for grafting functional binding sites of significant size.
- Indicated that an induced-fit mechanism may facilitate the success of these constructions.
Conclusions:
- Transplantation of large antigen-binding sites from mouse to human antibodies is achievable.
- This technique holds promise for generating effective humanized therapeutic antibodies.
- Further research into the role of induced-fit mechanisms is warranted.