About the Project
University of Manchester Supervisor: Prof Jeremy Derrick. A*STAR Supervisor: Samuel Gan (BII).
Human monoclonal antibodies are used as drugs to treat a wide range of diseases, including inflammatory conditions, such as arthritis, and cancer. During purification and storage, antibodies are frequently subject to posttranslational modifications, such as oxidation and deamidation. These chemical changes can have deleterious consequences; first, they can impair the ability of the antibody to function as a drug, by blocking binding to its therapeutic target molecule. Second, such changes can cause aggregation, a phenomenon whereby protein molecules bind together noncovalently into irregular structures; aggregates can grow to micron dimensions, and are often insoluble. Aggregation leads to losses during industrial production, and also has the potential to exacerbate an immune response in the patient. This project seeks to develop better ways to improve the predictability of the modification of various antibody structural elements, by oxidation and deamidation, in antibodies and antibody fragments. It will integrate experimental measurements of these modifications to antibodies with studies of aggregation using dynamic light scattering and biophysical characterization, amongst other approaches. Using molecular modelling and computation, predictive methods will be developed, which will be validated against experimental data. Ultimately, such methods could be used during biopharmaceutical drug development to improve yield and efficacy during treatment.
References
Palmer B, Angus K, Taylor L, Warwicker J, Derrick JP. (2008) Design of stability at extreme alkaline pH in streptococcal protein G. J Biotechnol. 134,222-30
Ratanji, K.D., Derrick, J.P., Dearman, R.J., and Kimber, I. (2014). Immunogenicity of therapeutic proteins: Influence of aggregation. J Immunotoxicol 11, 99-109.
Ratanji, K., Dearman, R., Kimber, I., Thorpe, R., Wadhwa, M., and Derrick, J. (2016). Subvisible aggregates of immunogenic proteins promote a Th1-type response. Toxicol Sci 153, 258-270.
Su CTTC*, Ling WL*, Lua WH, Poh JJ, Gan SKE. (2017) The role of Antibody Vκ Framework 3 region towards Antigen binding: serendipitous effects on recombinant production and Protein L binding. Scientific Reports, 19 June 2017 Vol 7. No: 3766 d10.1038/s41598-017-02756-3.
Lua WH*, Gan SKE*,#, Lane DP, Verma CS# (2015). A search for synergy in the binding kinetics of Trastuzumab and Pertuzumab whole and F(ab) to Her2. NPJ Breast Cancer. Vol1: Article 15012 (2015). doi: 10.1038/npjbcancer.2015.12. *Joint first author. # Joint corresponding.
Karagiannis P, Singer J, Hunt J, Gan SKE, Rudman SM, Mechtcheriakova D, Knittelfelder R, Daniels TR, Hobson PS, Beavil AJ, Spicer S, Nestle F, Penichet ML, Gould HJ, Jensen-Jarolim E, Karagiannis SN. Characterisation of an engineered trastuzumab IgE antibody and effector cell mechanisms targeting HER2/ neu -positive tumour cells in Cancer Immunology, Immunotherapy, 2009 Jun;58(6):915-30.
Gan SKE, Hunt J, Marsh PJ, Beavil, AJ, Harries, HE. Method (Recombinant human Ig production). – International Publication Number WO 2009/150426 A2. *Main Inventor.