U.K.-based Crescendo Biologics says it has developed a colony of triple-knockout mice that are totally lacking in immunoglobulin heavy chain, kappa light chain, and lambda light chain gene loci and polypeptides. The firm in addition reports on the successful expression of human antibodies in its first-generation yeast artificial chromosome (YAC) construct. Crescendo aims to combine the two technologies to generate its first Crescendo mouse platform.
The company claims triple-knockout mice will have major advantages in comparison with previous knockouts that retain an intact lambda light chain. It suggests that although the lambda light chain accounts for at most 10% of light chains in mouse antibodies, the ability to denude animals of all light chain expression will be critical for the efficient production of human heavy chain antibodies in transgenic mice. The achievement is also central to the firm establishing its platform of VH antibody fragments, which are designed to be the smallest fragments that retain antibody binding.
Crescendo has separately worked with researchers at the Centro Nacional de Biotenologia in Madrid to generate transgenic mice by oocyte microinjection with a 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.
“Today’s announcement marks an important milestone in the development of our highly innovative antibody fragment technology,” states Mike Romanos, Ph.D., Crescendo CSO. “We have successfully delivered what we believe to be a unique asset in our triple-knockout mice, and have also made significant steps in the generation of YACs, which direct the production of human heavy chain antibodies. When combined, and with further developments in our YAC technology, we believe we will have the strongest platform for the generation of new VH fragment therapeutics.”
Established in 2008 to further develop technologies originating at the Babraham Institute, Cambridge, U.K., Crescendo is focused on generating diverse, stable, and optimized human heavy chain (VH) fragments as the basis for a new therapeutic platform. The firm claims that as the smallest functional binding units of an antibody molecule, VH fragments offer several potential advantages over traditional antibodies. These include the potential for topical, oral, and inhaled administration, their stability, and ease of manufacture. Major perceived features of such antibody fragments include the development of bispecifics and formats with effector function, the potential to engineer half-life, and the likely ability to target otherwise inaccessible epitopes, Crescendo suggests.