Strength in Antibody Technology
One of the U.K.’s strengths is in delivering technology to improve development and manufacturing of antibody therapeutics. The U.K. has capacity and specialist expertise in ADCs, and it’s where some U.S. pharmas and biotechs, including ADC heavyweight Seattle Genetics, are actively choosing to have their antibody conjugation processes performed.
Two companies that illustrated this technical strength at the conference were Oxford BioTherapeutics and Kymab.
Harry Lamble, Ph.D., director of business development at Oxford BioTherapeutics, presented his company’s use of its Oxford Genome Anatomy Project (OGAP®) database, a discovery platform that integrates proteomic data on three-quarters of the human proteome, with genetic and clinical information across 50 different human tissue types and 60 diseases including 25 forms of cancer.
“Using the information in our OGAP database in collaboration with a number of antibody technology firms including BMS, Amgen, and Alere, we have generated novel antibodies to treat cancer,” said Dr. Lamble.
“A number of our lead programs are currently in preclinical development, including ADCs to treat gastric, lung, and other cancers.” Dr. Lamble showed mouse Xenograft data for two programs, which demonstrated that a single 2 mg/kg dose arrested tumor growth during the period of observation in established disease models.
“We view ADCs as transformational and recently entered a collaboration with Seattle Genetics to develop ADCs. Seattle’s recent successes with its ADC—Adcetris for treating Hodgkin lymphoma—indicates that this class of drug could be highly efficacious for treating cancers,” Dr. Lamble concluded.
Tom Shepherd, Ph.D., chief business officer at Kymab, a spin-out from The Wellcome Trust Sanger Institute in Cambridge, presented interesting information on his firm’s transgenic mouse platform, Kymouse™. According to Dr. Shepherd, of the nine fully humanized monoclonal antibodies marketed as therapies, seven are derived from transgenic mouse platforms.
“The first-generation transgenic mice for antibody production in the 1990s carried human genes coding a proportion of the variable and constant region of antibodies randomly integrated into the genome, and these mice could make human monoclonal antibodies,” Dr. Shepherd commented. “However, they suffered from a suboptimal immune response due to deficient signaling of the human constant region, and only carried a proportion of the human genes.”
Subsequently, Regeneron learned from Abgenix and Medarex and kept the mouse constant region, added more human gene diversity, and ensured the gene integration was in the right place, but the lambda light chain was still missing. Therefore, these earlier mice don’t provide the full spectrum of functional human immunoglobin diversity.
“We developed Kymouse because we felt there was a place for improved transgenic mice. Our mouse will contain over 2.5-megabases of human genes in its genome with the entire functional human immunoglobin V, D, and J gene repertoire, including the human heavy kappa and lambda chain genes, which we believe will result in the production of improved monoclonal antibodies."
In addition to Kymouse, Kymab is also making a new ES cell bank from Kymouse, which it will use to make knock-out and knock-in mice for specific drug targets.
“It would normally take years to cross a knock-out mouse with a fully human antibody transgenic mouse; we can do this in a fraction of the time in vitro using the new ES bank,” Dr. Shepherd claimed. “The Kymouse KO version will eliminate immune tolerance to highly conserved targets, previously an issue with mouse immunization, and Kymouse KI will allow preclinical in vivo testing of the antibodies produced by Kymouse.”