Monoclonal antibodies (mAbs) are the largest class of biological therapeutics on the market today. Exquisite specificity, high effectivity and minimal side effects make them attractive drug candidates against infectious diseases, inflammatory diseases and even cancer.
The immune systems of humans and higher vertebrates produce billions of antibodies. Each different antibody is highly adapted to bind a specific target. With the right platform, these antibodies are easy to generate – for instance, one may collect B lymphocytes from patients who recovered from a given disease and screen these cells for the suitable antibody leads against targets relevant to the corresponding disease. However, this direct-from-human approach has demonstrated limited utility to date and is difficult to apply to autoimmune disease and cancer.
Although in vitro discovery platforms represent viable approaches to therapeutic antibody discovery, most experts would agree that no such platform has succeeded in recapitulating the performance of a mammalian germinal centre with respect to hypermutation and fine tuning of the match between epitope and paratope in particular.
Learn more about development of monoclonal antibodies from Trianni’s recent White Paper.
Mouse Antibody Platforms and The Trianni Mouse™
Early attempts to use murine mAbs as human therapeutics met with limited success as it quickly became clear that these drugs triggered human anti-mouse immune (HAMA) responses.
Researchers explored ways to reduce antibody immunogenicity by combining murine variable domains and human constant domain sequences in the form of chimeric mAbs. Such chimerica mAbs exhibited lower HAMA responses, but were still highly immunogenic in most cases.
Humanization technologies were subsequently developed as a next step to more human therapeutics with less potential for eliciting HAMA responses. Here, mouse CDR sequences were grafted onto human frameworks with human-to-mouse back mutations then performed to rescue losses in affinity and potency of the humanized sequence vs the parental mouse antibody. Still lower HAMA rates were observed for humanized therapeutic mAbs, but much room for improvement and increased lead generation efficiency remained.
In attempts to develop the ideal human therapeutic antibody discovery technology, the first generation of human transgenic mice were developed. These mice did produce antibodies that were even better tolerated in human patients, but were also immunocompromised compared to their wild-type counterparts. They produced limited portions of the human antibody repertoire and were often unable to mount robust immune responses to targets of interest.
Next-generation human transgenic mice were then designed to be significantly less immunocompromised. These mice make chimeric antibodies with fully-human variable domains and mouse constant domains. The mouse constant domains are swapped for human early on in the lead generation process in order to produce fully-human therapeutic leads. Trianni Mouse™ is the only next-gen transgenic mouse platform that produces a complete human antibody repertoire in a single organism.
In contrast to the other human transgenic mice, which contain large fragments of human genomic DNA, The Trianni Mouse contains immunoglobulin loci carefully designed in silico and produced using advanced DNA synthesis and other cutting-edge techniques.
The endogenous V, D and J antibody gene segments in the Trianni Mouse have been replaced by computationally designed sequences. The resulting transgenic mice exhibit optimal antibody gene expression in driving expression of a complete repertoire of human variable domains.
The variable (V) gene segments in the Trianni Mouse are chimeric – mouse immunoglobulin exons are replaced by human exons while but non-coding (control) genetic elements are of murine origin (Figure 1).
The resulting transgenic mice produce complete human repertoires as humans while providing for wild-type-mouse-like antibody responses to challenge.
Learn more about The Trianni Mouse platform on their technology page.
Trianni Mouse Validation
Validation studies conducted by Trianni, Inc and their pharma partners have shown that The Trianni Mouse exhibits near-normal B cell counts, robust antibody titers and potent, highly developable therapeutic candidates (Figure 2).
Large Pharma evaluation also demonstrates that Trianni Mouse immunization produces mAbs similar to wild-type mice in terms of rate of somatic hypermutation, affinity, specificity and epitope coverage.
Trianni mouse mAbs demonstrate comparable, if not superior, maximal and average potencies compared to wild-type C57BL/6 benchmark mAbs.
Antibody repertoire analyses indicate that all transgene segments are used. Additional validation reveals human-like CDR3 length and amino acid composition (Figure 3).
Trianni mAbs also display high homology to human germline antibody sequences and so provide for minimal immunogenic risk. The “germinality index” of antibodies derived from the Trianni Mouse is typically favourable.
Trianni, Inc Partnerships
Since the official launch of The Trianni Mouse platform in 2014, the company has signed several agreements with large pharma corporations and partnered with a whole range of academic and commercial research teams.
The Trianni Mouse has been licensed for various discovery efforts including those supporting HIV vaccine and cancer immunotherapy research along with a broad spectrum of other therapy areas and indications.
It remains important for Trianni to make their technology accessible to any large pharma, biotech company, or academic investigator – from pharma giants to early stage startups. They work closely with every client to define flexible contract terms.
You can contact Trianni to create a custom partnership that matches your needs via their online form.
To learn more about The Trianni Mouse platform, visit their technology page.