Project Title:

Development of homobifunctional chemical linkers for the generation of bivalent and bispecific antibody constructs

Project Summary:

The ability of antibodies to bind almost any biological target with high specificity and avidity has resulted in antibody-based therapeutics becoming an essential tool in modern medicine. However, traditional antibody therapeutics are monospecific and there remains scope for broadening their therapeutic impact. This can be achieved by generating non-natural bispecific antibodies which can bind two separate antigens. Bispecific antibodies allow for the multifactorial nature of diseases to be targeted, enhancing their therapeutic effect. The expression of fusion protein constructs can be challenging for a variety of reasons, including the necessity for N- to C-terminal fusion, which can lead to decreased biological activity of the fusion construct. Expression of fusion bsAb constructs is also marred by poor yields, incorrect folding, and instability of the conjugates with concomitant detrimental effects on biological activity. A generalised chemical linking strategy could help to generate dimeric constructs in a rapid, consistent manner from the corresponding monomers without the need to express a peptide linked fusion protein, a process that may require optimisation for individual constructs. My research focuses on producing dimeric constructs using a chemical linking strategy to allow modular construction of bivalent antibodies targeting a variety of disease related antigens. It is hoped that the constructs generated will give us an insight into the molecular basis of conditions such as Alzheimer’s disease.