With a market value of more than $90bn (€75bn), monoclonal antibodies (mAbs) represent the largest class of biopharmaceutical products on the market today. By 2020, the value of therapeutic antibodies is expected to increase to $125bn (€105bn).
It is unsurprising, therefore, that the industry is focusing much of its energy towards the development of therapeutic mAbs, which can be applied to a wide spectrum of diseases. These include cancer, inflammation, infection, ophthalmologic, cardiovascular and respiratory diseases.
However, researchers face several challenges when working with human mAbs. Not only do they have to cope with a vast variety of antibodies – the human immune system generates billions, each with a different specificity – but they are also confronted with the challenge of creating antibodies that reach the target tissue optimally in order to prevent unwelcome adverse events.
In 2010, a group of scientists decided to rise to these challenges. They founded the biotech company Trianni, Inc. and created a transgenic mouse line that can produce any human antibody in the human antibody repertoire. The company’s platform therefore allows for the isolation of human antibodies against virtually any antigen.
We have had a chat with Matthias Wabl, Ph.D., CEO of Trianni, Inc. We discussed the future of mAbs, the challenges researchers face in the field, and the complex science behind the only transgenic mouse on the market that can produce all human antibodies, The Trianni Mouse™.
Matthias, why are monoclonal antibodies (mAbs) so promising for drug development and what are the challenges within this field?
In recent years, there has been a great upswing in the study and use of therapeutic mAbs. They can enhance or repress immune responses and generally have fewer side effects than traditional therapies. Also, their pharmacokinetics and pharmacodynamics – their fate in and effect on the human body – are more predictable, which can prevent adverse events.
However, non-human antibodies can become a danger to the patient or be rendered useless when they elicit immune responses.
Most researchers focuses on the humanization of antibodies, a process where rodent coding sequences are replaced with human ones. But humanization takes a lot of time and work, with no guaranteed outcome, and this is where transgenic mice come in. They are genetically engineered to efficiently express human mAbs.
Most mice on the market can only express few mAbs. To date, the Trianni Mouse is the only mouse that can produce all human mAbs for therapeutic and research purposes.
Can you tell us a bit more about the unique generation of your transgenic mouse?
There have been several generations of transgenic mice. The first generation were incapable of eliciting robust immune responses to target antigens, because they were immunocompromised compared to their wild-type counterparts. This made it hard to develop complete therapeutic candidates.
Similar problems occurred in several of the second generation of transgenic mice, which either had a limited amount of mAbs they were able to express or were also immunocompromised.
We have used a very different approach in the development of the Trianni Mouse. Its unique characteristic is the computationally designed chimeric human/mouse immunoglobulin loci. These are only subsequently chemically synthesized, which allows for an efficient expression of the full human antibody repertoire and still maintains the mouse’s natural immune response.
What is the science behind the mouse? Why can it produce all antibodies in the human antibody repertoire?
To date, the Trianni Mouse is the only transgenic mouse platform that can produce all human antibodies in one single organism. At the same time, it reacts to an antigen in the same way as a wild-type mouse does.
We designed the specific immunoglobulin loci that I mentioned above, to include a human variable region that contains all genetic information needed to produce all human antibodies. The V genes’ coding part – the exons – are of human origin and code for the antibodies. The non-coding control sequences are of mouse origin.
Next, we chemically synthesized the designed DNA sequences. These were then inserted in place of the corresponding loci in the mouse genome. Within this newly inserted cassette, the so-called V genes are chimeric.
As a result, the Trianni Mouse can produce antibodies just like humans, which is great for researchers studying and developing therapeutic mAbs.
What makes your technology a key player in the production of mAbs?
There are four characteristics that are important here. First, transgenic mouse platforms should not have residual mouse antibodies, and the Trianni Mouse lacks all gene segments that encode mouse antibody variable regions.
Second, the transgenic mouse should contain the full human antibody repertoire. Until now, the Trianni Mouse is the only platform that expresses that repertoire.
Third, the human antibody genes should be stably integrated into the mouse genome at the endogenous site. As the Trianni Mouse human antibody repertoire is encoded at the correct chromosomal locations, it guarantees a stable and efficient antibody synthesis.
Lastly, the immunoglobulin loci in the Trianni Mouse are designed to contain human antibody-coding DNA embedded in the mouse non-coding regulatory DNA. This enables the wild-type-like immune responses, which earlier generations of transgenic mice lack.
What are the benefits for scientists using your platform, compared to other types of antibody production platforms?
Currently, in-vitro platforms cannot yet reproduce the affinity maturation – the process in which antibodies become better binders over time – that takes place in the lymph nodes and spleen, the germinal centers, of the mouse.
As a consequence, the clinical antibody pipeline has become heavily skewed towards human antibodies from in-vivo platforms. Among these in-vivo platforms is the Trianni Mouse with which scientists can study the full human antibody repertoire.
It enables them to obtain antibodies that are equivalent or better than those of wild-type mice in terms of titers, ligand-blocking activities, cross-reactivity, affinity, reformatting, diversity, and hybridoma fusion parameters.
What are the clinical and research applications?
Five of the top 10 most successful drugs in 2016, were antibodies for the therapy in oncology and autoimmune diseases. But antibody therapy is being extended to almost all other diseases. These applications include infectious diseases, chronic inflammation, asthma, macular degeneration, osteoporosis and neurological diseases.
It is the reason why the Trianni Mouse is the premier antibody platform of large, medium and small pharmaceutical and biotech companies. Also researchers at top institutions use the Trianni Mouse to study the immune response to HIV and influenza, and the generation of broadly neutralizing antibodies, for example.
How do you see the Trianni Mouse developing in the future?
The standard Trianni Mouse reproduces the human repertoire of the standard four-chain antibodies comprising heavy and light chains. There will be five next generation Trianni Mice, adding bells and whistles to the Trianni Mouse antibody platform.
One Trianni Mouse will allow the sorting of specific antibody-producing plasma cells, which will make hybridoma fusion and other technologies unnecessary.
A second mouse will produce heavy chain only, which can access cryptic antigens.
A third mouse will produce antibodies with extended complementary-determining regions 3 (CDR3), which are a part of antibodies’ variable chains. Extended CDR3 regions are important in broadly neutralizing antibodies.
A fourth mouse will lack central B cell tolerance and will thus be able to generate antibodies to evolutionary conserved epitopes. These epitopes are physiologically and pharmacologically the most important ones.
Lastly, a fifth mouse will produce bispecific antibodies in-vivo that can be immediately tested in functional assays. To date, in order to construct bispecific antibodies one has to first identify two desired specificities independently and then put them together in a single molecule.
Exhausted by other platforms that provide sub-par results in your antibody discovery research? Then it may be time to try The Trianni Mouse which allows you to source all human antibodies against virtually any antigen in one single organism. Have a look at what they do and learn more!
Images via Monique Guilbault, ustas7777777, Rost9, Liya Graphics, Juan Gaertner, molekuul_be, CI Photos/ Shutterstock.com
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