LONDON – The advent of mice that produce the full range of human antibodies is set to trigger an explosion in new therapies for human diseases and to revolutionize vaccine research.

Derived from embryonic stem cells into which all the genes encoding the entire human antibody repertoire have been inserted, the mice are fertile and apparently normal in every other way. The antibodies the animals produce have all the properties desired for therapeutic antibodies, studies suggest.

The breakthrough ends years, if not decades, of attempts aimed at finding a way to produce fully humanized antibodies for therapeutic use.

Kymab Ltd., of Cambridge, UK, the biopharmaceutical company that has produced the mice, was formed as a spinout company from the Wellcome Trust Sanger Institute of Hinxton, UK. Kymab has developed a program, Kymab Access, to foster collaboration with academic researchers who want to search for and develop new human monoclonal antibody therapeutics.

“Using these mice, you can get an antibody that you don’t need to modify further before developing it as a drug that will have highly predictable clinical benefits,” Allen Bradley, chief scientific officer of Kymab, told BioWorld Today.

Christian Grondahl, CEO of Kymab, said the company is building “a rich pipeline of first-in-class therapeutics” in five areas: hematology, oncology, autoimmunity, pain and cardiovascular disease.

“This technology offers great potential to advance patient care in diseases with significant unmet medical need,” he said.

Bradley and his collaborators reported the development of the transgenic “Kymouse” in a paper in the March 16, 2014, edition of Nature Biotechnology: “Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery.”

Previous attempts at producing humanized antibodies from animals have had mixed results, although some strategies have led to successful commercial products. Major problems included not being able to “mature” the antibodies, a process needed for the molecules to be able to bind tightly to their targets; and insertion of the human genes at random in the mouse genome, rather than in the correct place, so that expression of the human genes remained unreliable.

As gene engineering technology advanced, however, the Kymab/Sanger group decided that the way forward lay in transferring all the human antibody variable genes into the mouse genome, in front of the mouse antibody constant genes. They then moved the mouse variable genes to another location in the genome so that these would not be used. They devised a strategy of moving the enormous stretches of DNA involved section by section rather than in one huge chunk. They rejoined the sections in the mouse genome, thus recreating the entire human antibody repertoire in the correct place in the mouse genome.

The Nature Biotechnology paper describes how the mouse was made, as well as tests carried out to evaluate the properties of the human antibodies that the mice manufacture.

“The antibody loci are absolutely enormous,” Bradley said. “They cover about 3 million base pairs of DNA sequence. The remarkable thing is that despite the many DNA engineering steps made on the embryonic stem cells, we get a mouse at the end of it that has no defects in its immune system, or in any other aspects of its biology – and that this mouse produces antibodies that have fully human variable regions. That is unheard of in this field.”

Experiments showed that the antibodies are made by normal B cells and that the mice responded as expected to immunizations. The antibodies created are derived from the entire human repertoire. Plus, they are matured as normally happens, in such a way as to have normal affinity with their targets.

Bradley said in order to scale up production of individual antibodies, the first step is to isolate the B cells that are producing the desired molecule and use these to make monoclonal antibodies. After screening the monoclonal antibodies for those with desirable properties, it is then possible to scale up production of the selected antibodies. Before being able to put the molecules to therapeutic use, it is also necessary to replace the murine constant region of the antibody with the human constant region; an easy task.

According to a statement released by Kymab, the company is using the Kymouse for internal drug discovery programs and in partnership with pharmaceutical companies. Kymab said it signed its first Kymouse antibody discovery agreement with Novo Nordisk AS, of Bagsvaerd, Denmark, last year.

The company predicts that the transgenic mouse will make it possible to target some of the most challenging drug targets, from complicated ion channels and G-protein coupled receptors, to hidden epitopes in heavily glycosylated viral proteins.

The other strand of research that will benefit from the development of the Kymouse is vaccine research.

“Historically, one of the big problems in vaccine development is that if you put an antigen into a mouse or a rabbit, for example, their antibody response does not predict what the human antibody response to that antigen would be,” Bradley said. “With the Kymouse, you can put in an antigen and see what the human response would be – whether that antigen elicits a protective immune response or not. The ability to do this is going to dramatically speed up vaccine research into almost any infectious disease.”