White mouse in laboratory
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Biocytogen focuses on gene-modified animal model production, generating unique mouse models by replacing murine genes with their human counterparts, such as the fully human antibody mouse, RenMab™.

Set to become the leading platform for human antibody generation, the innovative RenMab™ mouse model utilizes chromosome engineering to remove the entire mouse immunoglobin (Ig) heavy chain region (VDJ), replacing it with the full human heavy chain VDJ counterparts (123-129V, 27D, and 9J) and the entire mouse kappa light chain VJ region with full human kappa VJ counterparts (76V, 5J). This mouse model has been shown to have a similar immune response to the wild type strain as it carries the full human antibody repertoire.

Combining gene-editing technology and the RenMab™ mouse will provide the research community with a different strategy in working with highly homologous proteins between human and mouse, such as G-protein-coupled receptors. Many genes can be knocked out in the RenMab™ mouse model, which will ultimately lead to the generation of a large number of antibody clones for best candidate selection.

Under most circumstances, human drug or antibody candidates recognize only human, not murine, proteins. Therefore, surrogate antibodies are used to test the mechanism of action in mice. However, these surrogate antibodies may not bind to the same epitope or may display different binding affinities leading to misrepresentation of the drug candidate data. For novel targets, Biocytogen’s gene-editing platform can generate target specific humanized mouse models and RenMab™ antibodies simultaneously, reducing the time and effort for target validation and antibody discovery.

RenMab figures 1 and 2
Mouse variable regions of the heavy and k light chains are placed by the human counterparts in situ.

“We plan to continue to develop super-immune mice to greatly benefit the research and pharmaceutical community. Our long-term strategy is to increase the number of antibody drugs developed using RenMab™ along with our target humanized mouse models,” says Yuelei Shen, PhD, the CEO of Biocytogen.

Biocytogen has generated over 1,500 gene-modified mouse models annually for clients using Embryonic Stem cell/Homologous recombination (ESC/HR) and CRISPR/EGE™ (Extreme Genome Editing) gene-editing platforms. The proprietary EGE™ system increases the homologous recombination rate by 10–20-fold over standard CRISPR-Cas9 approach. This technology can accurately edit DNA sequences at almost any genomic locus.

Recently, a line of cytokine/cytokine receptor humanized mouse models were generated, and Biocytogen is planning to expand its unique humanized mouse model portfolio over the next several years. Its immune checkpoint humanized mouse models, such as the human PD-1 model, are used globally for immuno-oncology antibody development, improving overall confidence in candidate selection and risk assessment prior to the clinical phase.

“Our clients tell us that we are ahead of the market. We are able to predict specific needs in the market and invest in the development of these needs in order to have our models available whenever drug candidates need to be tested,” adds Dr. Shen.

Generally, there are two types of human antibody mouse models. In the “knockout plus transgenic” model, the mouse endogenous antibody gene is knocked out and a transgene is randomly inserted into the mouse chromosome. Antibody generation is not well regulated in these models, and the limited number of variable regions ultimately restrict antibody diversity. Biocytogen uses “in situ replacement” technology to replace mouse antibody genes with their human counterparts, in their original, authentic position on the chromosome. In this model, antibody generation is tightly regulated where the variable regions are completely replaced with the human sequences. Chromosome engineering technology, which utilizes in situ replacement, modifies large chromosomal DNA fragments.

With large scale animal breeding capacity, antibody discovery, and preclinical pharmacology services, Biocytogen provides seamless integrated antibody discovery services to the biomedical community for a true one-stop solution from target to IND application.

 

More information about RenMab™ Mouse, is available at: biocytogen.com/renmab-mouse.

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