Opening the door to novel antibody fragment-based therapeutics and diagnostics via a "dual click" strategy

Using antibodies as therapeutics and diagnostics is one of the most exciting and promising areas of research into new healthcare products. Antibodies represent the fastest growing class of therapeutics, with over 20 approved for clinical use to date and over 150 in clinical development. It is estimated that the global market for antibody therapeutics is currently around $40 billion. The power of antibodies lies in their ability to highly specifically bind to a target antigen. This can be exploited to lead to a direct effect, as is the case for the breast cancer drug Herceptin (an antibody) which binds to a protein overproduced on the surface of certain cancer cells, inhibiting cell proliferation. However in many cases naked antibodies alone do not have enough potency. In such cases, the antibody can simply be used as a highly selective targeting device to deliver potent drugs to the site of action (e.g. the cancer cell). Such antibody-drug conjugates (ADCs) are referred to as "Magic-Bullets" due to their ability to seek and destroy diseased cells selectively, and thus greatly reduce the side-effects associated with indiscriminate cytotoxic chemotherapeutics. The chemical attachment of the drug to the antibody is a key technological challenge in the area. The current state of the art is far from ideal, as: (i) drug conjugation is unspecific (leading to very poorly defined conjugates that have unpredictable pharmacological properties such as activity, stability, in vivo lifetimes and side-effects, as well as batch variability; and (ii) they are limited to full antibody conjugation (resulting in major cost issues (precluding there use in the NHS) and a degree of off-site toxicity).

We have recently developed a highly promising new chemical method that allows the attachment of small molecules to specific sites in antibodies, to produce highly defined, stable and fully active conjugates. In this project we aim to deliver a chemistry-led platform which will utilise of our new site-specific chemical methodology to introduce versatile orthogonal handles that will allow us to construct ADCs based on antibody fragments, which are far more economical compared with full antibodies in terms of productions costs and time. Combining site-specific antibody fragment modification with exceptionally versatile small molecules this chemical technology has the ability to overcome many of the existing barriers to ADC development. Moreover, by taking a chemistry approach, there is also the potential to deliver on entirely new antibody fragment-based bispecifics and diagnostics using our innovative strategy. We will exemplify the technology by generating antibody-fragment drug conjugates (for the prospective treatment of breast cancer), antibody fragment-antibody fragment conjugates (as a prospective novel anti-cancer treatment) and antibody fragment-multi-modal imaging conjugates (for improved diagnostic methods). This project has the potential to be transformative to research in the area and to the developments of next generation antibody-based healthcare products.

Antibody-derived therapeutics represent the fastest growing class of pharmaceuticals and are being employed in the treatment of pathological conditions ranging from cancer to inflammatory diseases. The proposed development of a new chemical platform technology for the construction of superior antibody conjugates, based on far more accessible antibody fragments in terms of production cost and time, would have a major impact on the field, and is likely to lead to improved next generation healthcare products and thus have a significant social impact. For example, in the highly promising field of antibody-drug-conjugates (ADCs) for use in oncology it is widely recognised that the non-ideal performance of currently employed chemical conjugation methods and the use of costly full antibody scaffolds are key factors limiting their success and thus further deployment of this approach. Our use of Herceptin as the chosen antibody to exemplify our technology will ensure that the products are of clinical relevance from the outset, for the prospective treatment of breast cancer. In addition to social impact this project would have a significant economic impact. It is estimated that the global market for antibody therapeutics is around $40 billion, which when added to the market of approximately $10 billion for the use antibodies in diagnostics and as reagents in research, leads to an overall market of $50 billion for antibody products. The ability to be able to chemically modify antibody fragments is critical in the field if we are to move towards more economically accessible ADCs. Thus, a generic new approach to the site specific modification of antibody fragments (in place of full antibodies), as proposed here, could become a major contributor in the design of the next generation of antibody therapeutics. Moreover, by taking a chemistry approach, there is also potential to deliver on entirely new antibody fragment-based bispecifics and diagnostics using our innovative dual functionalisation strategy. As a result we suggest the commercial potential for this technology to be extremely significant.