The Kymouse™ strains have more than 5.4 million base-pairs of the human immunoglobulin genes in their genome — more than any other model.
Their performance is exceptional: virtually every mouse responds to challenge, producing high-titre polyclonal antibodies to a variety of antigens including highly conserved human antigens.
We are improving the value of Kymouse™ platform still further for therapeutic antibody and vaccine discovery through three novel developments.
Using human genes and natural processes to make effective treatments
When immunised with human targets or pathogenic organisms, the Kymouse™ strains mount a normal immune response and mature antibody drugs from their human building blocks. Because the human antibodies are produced through the normal and natural process of maturation, they evolve from molecules with good drug-like properties to drugs with exceptional potency, stability and solubility. Importantly, when these antibody genes are transferred into mammalian expression systems the recombinant molecules are reliably expressed at high levels.
The speed and efficiency with which highly potent antibody drugs are produced by the use of Kymouse™ strains is truly remarkable: in two years since development, the Kymouse™ platform has produced drug panels against more than 25 targets. We no longer need to follow the traditional, very slow and tortuous process of antibody optimisation, involving cycles of modifications to im-prove potency, stability, solubility and manufacturing yields.
Because the Kymouse™ design is modular, we are able to modify it further to support the discovery of highly differentiated antibodies and molecules with modes of action that would be unobtainable with other platforms. We are further developing Kymouse™ to facilitate specific drug-discovery efforts, such as target-locus knockouts and focusing of the repertoire by pre-setting the heavy or light chain to engineer bispecific antibodies. We have also generated mice with an enhanced average CDR3H length which will more effectively deliver antibodies against less-exposed epitopes.
Deep mining of the Kymouse™ antibody repertoire
Our Kymouse™ technology capitalises on the natural processes of the mouse immune system to evolve optimal antibody properties such as high affinities and peak expression, with diversity from the entire human repertoire. Our IntelliSelect™ system captures all that variety and enables us to analyse a vast array of resulting antibodies.
In IntelliSelect™, we capture all relevant antibody sequences from single B-cells, understand their evolutionary relationships and convert them into expression vectors to generate recombinant anti-bodies for high-throughput assays. Because we capture and can analyse the sequence network, we are able to access additional unique antibodies through synthesis. Once a lead has been identi-fied we can deeply mine the repertoire to discover related antibodies with unique and potent thera-peutic properties.
Kymouse™, and Kymouse™ knockout strains further broaden access to all epitopes on drug tar-gets. Ultimately more choice means better product candidates
Finding difficult targets
Knock-in and knockout to produce antibodies directed to conserved regions
Because self-reactive B-cells are deleted during normal development, antibodies recovered are naturally restricted to regions of the antigen that are not conserved between species. However, re-gions of a molecule conserved between species usually are the most important parts of the mole-cule, such as surfaces required for intra-molecular interactions between receptors and ligands or active sites of enzymes.
To generate antibodies to conserved regions, a central part of our technology is to develop Kymouse™ strains in which the relevant part of a target has been deleted (knocked out) or altered. Mice lacking the orthologous protein develop antibodies against all parts of the target molecule.
Our technology developments give us a unique capability and capacity to discover truly innovative drugs, in challenging sectors such as:
- species cross-reactive antibodies, facilitating pre-clinical development;
- antibodies that target unique epitopes, facilitating unique modes of action;
- antibodies that target conserved regions and so are more likely to have functional properties.