Chemical glycoengineering of therapeutic antibodies

Glycosylation is the most common posttranslational protein modification. Recombinant therapeutic glycoproteins (RTGs) such as monoclonal antibodies (mAbs) are decorated with complex glycans that determine not only their efficacy but also other critical parameters such as in vivo half-life, stability and antigenicity. Efficient, cost effective and flexible methods for the glycoengineering of RTGs are therefore of great interest for biotechnology (Li et al. 2021).

Most existing glycoengineering technologies require the development of optimized cell lines and/or culture conditions. These approaches are time-consuming and expensive, and often based on trial-and-error. An attractive alternative is the addition of small molecule inhibitors of glycosylation to the culture medium during protein production.

The goal of this interdisciplinary project is the development of bespoke small molecules for the rational glycoengineering of monoclonal antibodies and other therapeutic glycoproteins. Building on previous work in the Wagner laboratory (e.g., Pesnot et al. 2010; Jiang et al. 2016), the student will use cutting-edge design strategies for the development of novel glycosylation inhibitors with activity in cells. He/she will design and chemically synthesise a series of target molecules, evaluate their in-vitro activity, and apply them in mAb cell culture systems. He/she will also evaluate the mAB glycoforms in relevant pharmacological assays.

The project is highly interdisciplinary and ideally suited for a student who wants to pursue a career in drug design and development or biotechnology. The student will receive in-depth training in a broad range of experimental techniques as relevant for drug discovery and biotechnology, including computer-assisted inhibitor design, advanced organic synthesis, in-vitro assays, and mammalian cell culture. The project will be carried out in collaboration with Prof Sophia Karagiannis (King’s College London) and the student will benefit from the comprehensive expertise of the supervisory team across medicinal chemistry, organic synthesis, and antibody engineering and pharmacology (e.g., McCraw et al. 2022). The project also offers an ideal opportunity to experience different research environments, including placement opportunities, and to acquire transferable and generic skills in time and project management, science outreach, and knowledge transfer and commercialisation.

It is anticipated that inhibitors developed in this project will create opportunities for knowledge transfer, translation, and commercialisation in the area of drug development and biotechnology. The project will also offer an opportunity for the student to contribute to a range of outreach activities such as the regular delivery of science workshops for school children and lay audiences.

Home applicants must meet the following academic criteria:

1st or 2.1 honours degree in a relevant subject. Relevant subjects include Pharmacy, Pharmaceutical Sciences, Biochemistry, Biological/Biomedical Sciences, Chemistry, Engineering, or a closely related discipline.

International applicants must meet the following academic criteria:

IELTS (or equivalent) of 7.0, a 2.1 honours degree (or equivalent) and a master’s degree in a relevant subject.