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(BBSRC DTP) Assessing the role of linker/payload in the stability of protein drug conjugates


Faculty of Biology, Medicine and Health

Manchester United Kingdom Biochemistry Biophysics Chemical Engineering Pharmaceutical Chemistry Pharmacy

About the Project

Antibody-drug conjugates (ADCs) are a new class of advanced drug delivery systems; they combine the benefits of an antibody and a cytotoxic agent, which leads to enhanced efficacy and selectivity for tumour cell killing. There are about 80 ADCs in development; however, the FDA and EMA have approved only four ADCs so far.

The limited number of ADCs on the market is related in parts to the physical and chemical stability of these constructs, which may result in a loss of treatment efficacy via loss of drug, adsorption on the surface of containers or increased aggregation propensity compared to the parent monoclonal antibody. These will affect the product shelf life or in the case of aggregation potentially result in patient immune response.

Both protein, linker and payload will contribute to the interactions between protein drug conjugates, and, consequently their stability; however, these interactions are dependent on experimental parameters such as pH, ionic strength or excipients. This knowledge is scarce now for protein drug conjugates. Thus, the project will aim at defining conditions for the design of protein drug conjugates based on novel linkers.

The specific objectives of this project are to:
1. Synthesise protein drug conjugates containing fluorescent payloads
2. Investigate how formulation conditions especially excipients controls protein-protein interactions especially aggregation depending on the linker and the drug antibody ratio (DAR).
3. Investigate the loss of protein drug conjugates (PDCs) in the context of packaging.
4. To use this data to refine conditions of stability for the formulation as function of linker and DAR and redesign this new class of linkers

The project will involve a broad range of experimental methodologies, ranging from synthesis of the protein drug conjugates, biophysical measurements of protein drug conjugates solution behaviour and intermolecular interactions using light scattering, fluorescent and chromatographic approaches. Training in these experimental methodologies is especially relevant for research and development of any biopharmaceuticals. This multidisciplinary project will be suitable for candidates with a background in chemistry, chemical engineering, biochemistry or related disciplines who wishes to expand their understanding of biopharmaceutical formulation, biophysics.

Alain Pluen: https://www.research.manchester.ac.uk/portal/alain.pluen.html
Sam Butterworth : https://www.research.manchester.ac.uk/portal/sam.butterworth.html
Robin Curtis: https://www.research.manchester.ac.uk/portal/r.curtis.html

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website http://www.manchester.ac.uk/bbsrcdtpstudentships

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of scholarships that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website

References

C. Duerr and W. Friess “Antibody-drug conjugates stability and formulation” Eur. J. Pharm. Biopharm. (2019), 139, 168-176.

S.K. Singh et al. “Antibody-drug conjugates: design, formulation and physicochemical stability” Pharm. Res. (2015), 32, 3541-3571.

C. S. Neumann et al. “Targeted Delivery of Cytotoxic NAMPT Inhibitors Using Antibody–Drug Conjugates” Mol. Cancer Ther. (2018), 17, 2633–2642.

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