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Generation of Discriminative Human Monoclonal Antibodies from Rare Antigen-specific B Cells Circulating in Blood
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An Engineered Mouse Model That Generates a Diverse Repertoire of Endogenous, High-Affinity Common Light Chain
Yinghui Rong1, I-Ling Chen1, Lance Larrabee1
123andMe, Inc. Therapeutics, 349 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
Antibodies (Basel, Switzerland)
|February 23, 2024
Summary
A new common light chain mouse model supports bispecific antibody discovery. These mice generate diverse antibodies with restricted light chains, suitable for developing novel therapeutics.
Area of Science:
- Immunology
- Biotechnology
- Therapeutic antibody development
Background:
- Bispecific antibodies offer therapeutic advantages over monospecific antibodies.
- A common light chain strategy facilitates the production of bispecific antibodies by pairing antibodies with different antigen specificities.
- Identifying suitable antibody pairs requires efficient methods for generating antibodies with shared light chains.
Purpose of the Study:
- To generate and characterize a novel common light chain (CLC) mouse model.
- To assess the impact of the genetic modification on B-cell development and antibody repertoire diversity.
- To evaluate the utility of this CLC mouse model for bispecific antibody discovery.
Main Methods:
- Generation of a CLC mouse model by replacing the endogenous IGKJ cluster with a modified IGKV10-96/IGKJ1 segment.
- Assessment of B-cell development and antibody repertoire diversity via flow cytometry and sequencing.
- Immunization of CLC mice with ovalbumin and characterization of anti-ovalbumin antibodies, including affinity measurements.
Main Results:
- The genetic modification did not adversely affect B-cell development in the CLC mice.
- The CLC mice produced an antibody repertoire with diverse VH gene segment usage, comparable to wildtype mice.
- Light chain diversity was restricted to the engineered IGKV10-96/IGKJ1 germline, with clonotype diversity matching wildtype levels.
- Antibodies generated in CLC mice exhibited slightly lower affinities than those from wildtype mice but were suitable for bispecific antibody generation.
Conclusions:
- The developed CLC mouse model is viable and does not impair B-cell development or overall antibody repertoire diversity.
- This model effectively restricts light chain usage, facilitating the discovery of antibody pairs for bispecific antibody development.
- The CLC mouse model represents a valuable tool for advancing bispecific antibody therapeutics.
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