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Human antibodies from transgenic mice

N Lonberg¹, D Huszar

¹GenPharm International Inc., Mountain View, CA 94043, USA.

International Reviews of Immunology

|January 1, 1995

Summary

Researchers created B cell-deficient mice and rescued B cell development using human immunoglobulin transgenes. These mice can produce human monoclonal antibodies, advancing studies on the humoral immune response and immunoglobulin gene expression.

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Area of Science:

Immunology
Molecular Biology
Genetics

Background:

B cells are crucial for adaptive immunity, producing antibodies through immunoglobulin gene rearrangement, somatic mutation, and class switching.
Engineering mice with targeted gene knockouts is a key method for studying immune cell development and function.

Purpose of the Study:

To develop a mouse model capable of producing human monoclonal antibodies.
To investigate the processes of immunoglobulin gene expression, including heavy chain class switching, using human transgenes.

Main Methods:

Homologous recombination in embryonic stem (ES) cells to create B cell-deficient mice lacking endogenous immunoglobulin heavy and kappa light chain genes.
Introduction of human germline-configuration heavy- and kappa light-chain minilocus transgenes to rescue B cell development.
Immunization of engineered mice and subsequent antibody production using hybridoma technology.

Main Results:

B cell development was successfully rescued in mutant mice by human immunoglobulin transgenes.
Transgenes underwent rearrangement, class switching, and somatic mutation upon antigen stimulation, mirroring the humoral immune response.
Human sequence, antigen-specific monoclonal antibodies were generated from immunized mice.
Heavy chain class switching was observed within an autonomous transgene, a previously unrecorded phenomenon.

Conclusions:

The engineered mice serve as a valuable model for studying human immunoglobulin gene expression and the humoral immune response.
This model facilitates the generation of human monoclonal antibodies for therapeutic and research applications.
The study provides novel insights into the mechanisms of immunoglobulin heavy chain class switching in a transgenic context.

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