Crescendo Transgenic Platform
Heavy chain antibodies (HCAb, i.e. immunoglobulin which lacks light chains) occur naturally in camelids and sharks, and have been developed as a source of VH fragments, which are then humanised prior to therapeutic development. Critical to the ability of these species to secrete functional HCAb is the absence of CH1 domains from heavy chain immunoglobulin. The Crescendo transgenic mouse comprises engineered human heavy chain immunoglobulin genes (IgH), in order to produce human heavy chain antibodies in response to immunisation. This in vivo route will provide a faster more predictable route to high affinity human VH fragments than camelid or in vitro technologies.
Our approach originates from the work of a leading pioneer in the field of human antibody transgenic mice, Dr Marianne Brüggemann, and depends on generating mice devoid of endogenous murine immunoglobulin heavy and light chain expression. These mice are then crossed with transgenic mice containing a large yeast artificial chromosome (YAC) construct comprising the human heavy chain immunoglobulin (IgH) V, D and J genes linked to human or murine C genes engineered for secretion in the absence of light chains.
Crescendo is working with leading academic groups in YAC construction and transgenesis to generate a pipeline of mice towards the best-in-class human HCAb mouse. These will comprise YAC constructs with increasing numbers of human V genes linked to a murine C region.
