Exclusive: The man behind the next generation antibody discovery platform

Last year IONTAS, a biotechnology company focused on antibody discovery and development, entered into a licensing agreement with Bristol Myers Squibb for its proprietary mammalian display. John McCafferty, nuclease directed mammalian display inventor and co-inventor of antibody phage display, told Lu Rahman about this breakthrough work.

The company operates as a single group comprised of three brands, FairJourney Biologics and IONTAS, and came together in 2020 to offer services and technology licencing associated with antibody discovery. As of February 2021, FlowEighteen 38 has been added to the portfolio of brands and focuses on the generation of research reagent antibodies, and the purification and characterisation of therapeutic antibodies. All three brands are positioned to ensure they solve the problems their partners may experience in progressing an antibody through the discovery stage.

The antibodies the company discovers can be derived from many sources, be that fully validated naïve libraries from humans and llamas or immune libraries from a range of sources. In all cases it applies screening technologies based on phage display, for which Sir Greg Winter received the Nobel prize for chemistry in 2018, or the next generation mammalian display platform.

Following on from phage display, John McCafferty and his team have invented nuclease directed mammalian display. The platform leverages the benefits of phage display and the ability to generate large antibody libraries displayed on the surface of mammalian cells. As well as generating an abundance of antibodies that bind a desired target, the technology also addresses ‘developability’ issues early in the discovery process. Using gene editing technologies, single antibody genes can be integrated into the genome of mammalian cells and screened in their millions. As the system can be used with cells lines commonly applied to antibody manufacturing, those antibodies that are seen to present well on the surface of the cells, correlate with good biophysical properties. These properties are important in reducing risk of late development failure and costly delays as antibodies progress into manufacturing

Recently IONTAS has embarked upon a number of interesting projects including the identification of highly potent anti-COVD-19 antibodies as a part of the Bioindustry Association (BIA) anti-COVID-19 antibody consortium. Other service-based projects, have included generating immuno-oncology antibodies that redirect the immune system in the treatment of cancer, and a collaboration with big pharma to implement mammalian display at the pharma’s facility.

LR: It seems that collaboration is a key part of the way the company operates. Why is this important?

JM: An understanding of our partner’s needs is the direct route to success, such a philosophy can only work if collaboration is at the foundation of the relationship. Fundamentally, we do not look at ourselves as a service company, we look at ourselves as problem solvers. Furthermore, offering flexibility in our collaborative approach allows us to respond to any issues that may arise as, be that as a specific one-off project, an FTE based discovery team, or the transfer of technologies to a third party.

LR: Why are antibody treatments promising (especially potentially being a bridge before vaccines arrive) 

JM: In the context of the COVID-19 pandemic, antibodies offer an immediate route to treatment for those not vaccinated and where a vaccine is ineffective.  These treatments are not preventative but can act as an immediate therapy mopping up any circulating virus mitigating symptoms and allowing time for a patient’s own immune system to inactivate the virus. Looking further ahead, the use of phage display and mammalian display, may also allow a broad repertoire of antibodies to be discovered that could offer therapies against new variants of the disease.

LR: Can mammalian display technology help big pharma with cost-efficiencies by identifying the most potent antibodies, and so significantly reducing time and money spent on antibodies that might be difficult to scale up?

JM: The ability to manufacture an antibody is an expensive and long process and any delays in this can impact the development economics significantly. One of the common delays associated with antibodies concerns the intrinsic biophysical properties of the antibodies (developability profile). Poor developability profiles can lead to issues such as aggregation and if these aggregates induce immunogenicity whilst in the clinic, the risk of late stage failure is increased. Mammalian display not only identifies potent antibodies, but also identifies those with good biophysical properties, therefore conferring a lower risk of failure due to developability. Our aim is to generate antibody candidates that do not require significant development or re-engineering post discovery. Mammalian display fulfils these aims and allows the discovery of the right antibody early in the discovery process.

LR: What can researchers learn from your work and the approaches you take?  

JM: Primarily the ability to screen very large libraries and reduce developability risk during antibody discovery will save time and money in the post-research development of an antibody therapeutic. We see the use of mammalian display as the bridge that spans some of the traditional risks in the transition from R&D into manufacturing.

LR: Where do you see the antibody market in the next five years – where are the key opportunities? 

JM The antibody market is so diverse that opportunities will be in many areas. The expansion of bispecific, or multi specific antibodies will be significant. These are more complex molecules that are known to be difficult to manufacture, so use of the right development tools, which consider developability in the process, will be essential in the rapid advancement into the clinic. In addition, the redirecting of the immune system will also be an area of expansion. These therapies may use antibodies to target cells or direct specific sets of immune cells to areas of disease. Such therapies will require highly specific molecules to exploit their full potential. These classes of antibody directed therapies offer great potential for effective therapies in a range of indications.



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