Each year SCI’s Scotland group runs a competition where students are invited to write a short article describing how their PhD research relates to SCI’s strapline: where science meets business.
Streamlining Reaction Discovery with Machine Learning: Can we predict the outcome of a reaction without doing it in the lab?
Monoclonal antibody (mAb) therapeutics have taken the pharmaceutical industry by storm, accounting for half of the top ten best selling drugs of 2019, and contributing greatly to the treatment and quality of life of millions of patients. The clinical significance of mAbs can be attributed to their extremely high specificity for their targets, as well as their high solubility and extended in vivo half-life, making them ideal drug compounds.
Due to this surge in interest of antibody therapies, the industry has branched out to research into alternative antibody formats, such as bispecific antibodies (bsAbs). BsAbs offer additional advantages, due to their ability to bind and modulate two different targets simultaneously, enabling novel mechanisms of action and enhanced efficacy of treatment. Diseases such as cancer are multifactorial, thus if a single resistance pathway is blocked via a small molecule or biologic, an alternative pathway may then predominate. Simultaneous interaction of multiple targets therefore can provide enhanced treatments, particularly for cancer patients, in which the unique activities and decreased off-target toxicity of bispecifics could provide superior treatments compared with conventional chemotherapies.
Since the initial development of bsAbs in the 1980s, six have been clinically approved, alongside over 200 currently in clinical trials, highlighting the rapid emergence of this drug class. Despite all these exciting features of bsAbs, a key limitation of bispecific R&D lies in the design process, in which two parent monoclonal antibodies are separately matured and optimised, followed by combination in the final stage to afford the bsAb, which often then requires further optimisation. Not only is this process more time consuming and cost inefficient than initial screening of these constructs in bispecific format, active compounds are sometimes not detected, due to the novel and often unpredictable mechanisms of action exerted by bsAbs.
My PhD research seeks to develop a platform in which bispecific function can be screened in the early stages of the design process, to expediate bispecific discovery. A combination of the rapid kinetics and bio-orthogonal nature of click and conjugation reactions can be harnessed to enable the challenging process of connecting two sterically encumbered proteins, to afford desired bsAbs in high purities and yields, enabling high-throughput production and direct biological analysis.
The modularity of this approach offers additional opportunities, in which the properties of chemical linkers bridging the antibody fragments can be altered, enabling additional exploration into each bispecific construct, in ways not possible via conventional bsAb production techniques. Altering the linker length can provide a series of ‘molecular rulers’, in which the epitopes that the bsAbs bind can be mapped, to zone in on the most optimal distances between binding arms for bispecific function. Further features can also be incorporated within the chemical linkers, such as tags and dyes, to aid in purification and characterisation, or even cytotoxic substances, which could provide a facile method of screening novel bispecific antibody drug conjugates.
The highest cause of attrition within clinical trials is caused by inadequate target validation, therefore improvement in target validation activities is crucial within medicine design. The rapid production of large panels of bsAbs could be utilised within alternative target validation activities, therefore this platform could not only assist in early stage research, but also potentially enhance the bsAb approval success rate.
I aim that the workflow developed within my research can provide an invaluable tool which produces large numbers of bsAbs in an expedient manner, which can be utilised within early stage assays in the development of bsAbs for a host of screening activities, assisting in the acceleration of the bsAb R&D process.
Caitlin Fawcett
PhD student
University of Strathclyde
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