Bioconjugation, the addition of a chemical moiety to a biomolecule, has been used to design new therapeutic agents that harness the power of each element to work cooperatively to target difficult disease types. Antibody-Drug Conjugates (ADCs) are one such example.
ADCs consist of three carefully selected components. Firstly, a monoclonal antibody is chosen whose receptor antigen is found on cells with the target disease state, such as an individual cancer type. At the other end of the conjugate is the warhead, a chemical entity which has been shown to have potency against the target cells, for example a marine natural product. These two components are usually connected by a linker, which can offer the opportunity to modulate physicochemical properties, and can control spatial or temporal release of the warhead. Together, these components make ADCs a valuable alternative to traditional chemotherapy, as the cytotoxin is directed towards the tumour cells, leading to fewer off-site effects.
Several ADCs are now on the market, and others continue to provide promising results in clinical trials.
Spring Group research within the biotherapeutics sub-group focuses on two main areas: linker development, and peptide-drug conjugates.
The linker contributes significantly to the efficacy of an ADC. These can be cleavable, or non-cleavable, depending on the type of cancer cell being targeted. Non-cleavable linkers are the simplest, relying on cellular machinery internalising the connected antibody and then degradation of the ADC within the cell to release the warhead. However, by installing a cleavable linker within the ADC, researchers are able to better control the release of the warhead. Many tumours present a unique microenvironment, often overly acidic, anoxic and reductive, traits which can all be used to initiate cleavage of a drug from an antibody. Additionally, many enzymes are overexpressed within cancer cells, for example proteases such as cathepsin. The Spring Group aims to develop novel linker technologies which will improve drug release within the tumour microenvironment whilst retaining stability of the conjugate elsewhere in the body.
These linkers can also be applied to other biotherapeutics. Following the same format as ADCs, peptide-drug conjugates use a short peptide to recognise their cellular target and thereby direct the drug to the desired site. These have been shown to be effective in the development of novel antimicrobials, a huge unmet need in the modern world. By directing a bacterial efflux pump inhibitor to the surface of bacteria, researchers may be able to reduce the ability of bacteria to expel traditional antibiotics. This may then resensitise bacteria to known antibiotics. Within the Spring Group we use our knowledge of peptides with our linker technologies to develop protein-drug conjugates.
Many of these projects are highly collaborative. We currently have collaborations with Cancer Research UK and the Welch group (Department of Biochemistry, University of Cambridge).