Scientists at Kymab have engineered mice with the full set of human antibody genes that can produce an enormous range of human antibodies, which can be developed as potent drugs to treat a variety of human diseases such as cancer, autoimmune and infectious diseases.
Published in Nature Biotechnology today, the paper describes the development of Kymouse™, a breakthrough in therapeutic antibody discovery technology and the most ambitious, mouse genome humanisation project undertaken.
Kymab scientists took the approach of moving the vast stretches of DNA of the antibody repertoire into the mouse genome in a series of steps each with a smaller segment of DNA, carefully re-joining them and thereby re-constructing the complete human repertoire in the correct place in the mouse genome.
"This is a remarkable achievement in our journey towards delivering therapeutic antibodies and to facilitate vaccine development," said Professor Allan Bradley, Founder and Chief Scientific Officer of Kymab. "Our team have completed the most ambitious humanisation project of the mouse genome ever undertaken, with 5.4 million bases of human DNA, representing 0.1% of the human genome inserted into the appropriate place in the mouse genome."
Mice with portions of the human antibody repertoire have been developed previously. However, the technology used at the time proved unsuitable for moving the very large stretches of DNA from the human genome into the mouse. As a result their antibody gene repertoires were both incomplete and in the wrong location in the genome.
"Kymab’s highly innovative and technically advanced Kymouse™ platform has overcome the problems which limited previous generations of human antibody generating mice and is a strong foundation on which we can build a global biotechnology company," added Dr David Chiswell, former CEO of Cambridge Antibody Technology and Chairman of Kymab’s Board of Directors.
By using the Kymouse™ technology, Kymab can pursue the targeting of the most challenging drug targets ranging from complicated ion channels and GPCRs to deeply hidden epitopes in heavily glycosylated virus proteins.
"We are delighted to publish our technology in this highly prestigious journal and to present the first professional peer-reviewed publication of transgenic mice with a fully human antibody repertoire," commented Dr Christian Grøndahl, Chief Executive Officer of Kymab. "Antibodies discovered using KymouseTM strains are essentially ready to be developed as drugs. We are building a rich pipeline of first-in-class therapeutics in five areas: haematology, oncology, auto-immunity, pain and cardiovascular disease. This technology offers great potential to advance patient care in diseases with significant unmet medical need."
Antibodies are one of the best-selling classes of drugs today; five of the top ten best selling drugs are antibodies. This is because antibodies are natural products with exquisite specificity and potency, and generally have superior safety profiles. The challenge has been to capture the full human antibody repertoire and to recapitulate all its attributes.
A PDF version of the paper (1.5 MB) can be accessed here.
The Supplementary Material (1.7 MB) is also availabe as a PDF document.
The paper can be accessed at the Nature website:
Notes to editors
About Wellcome Trust Sanger Institute
The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. http://www.sanger.ac.uk/
About Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust’s breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. http://www.wellcome.ac.uk/