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First ‘triple knockout’ mouse announced

Crescendo Biologics Limited has established a colony of engineered mice completely devoid of endogenous antibody polypeptides. These ‘triple knockout’ mice are believed to be unique.

The mice have the immunoglobulin heavy chain, kappa light chain and lambda light chain loci all functionally silenced by large-scale genomic deletion.

This is an important advance over previous knockout mice, which retain intact lambda light chain: although lambda light chain accounts for at most 10% of the light chains in mouse antibodies, Crescendo believes that knockout of all light chain expression is crucial for the efficient generation of human heavy-chain antibodies in transgenic mice.

The new knockout mouse should offer an enhanced background for the generation of new antibody therapeutics and is a key step for Crescendo in establishing their VH antibody fragment platform.

In a parallel development, Crescendo has demonstrated the potential of its first-generation yeast artificial chromosome (YAC) with the successful expression of human antibodies. Working with Professor Lluis Montoliu at the Centro Nacional de Biotecnologia in Madrid, transgenic mice have been generated by oocyte microinjection with a first YAC comprising several human V genes, all human D and J genes and a C region engineered for expression in the absence of light chains.

Crescendo is now working to generate mice that combine its newly developed YAC and the triple knockout mouse to generate a first-generation Crescendo mouse platform.

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