New strategies for therapeutic antibodies – synthetic bispecific antibodies & antibody-drug conjugates with controlled drug loading. general methods for unexplored adcs and personalised therapies.
Antibody-Drug Conjugates (ADCs) are revolutionary next-generation therapeutics. The number of ADCs in the clinic is constantly growing with four of them having now reached the market. Despite this great promise, the complex structure of antibodies results in drawbacks for their reliable modification to construct ADCs, thus impairing the full potential of ADCs. One of the major reasons for clinical failure is that it is hard to control the drug to antibody ratio (DAR) to obtain homogeneous structures. Furthermore, current synthetic methods give access to ADCs with a DAR limited to values of 2, 4 and 8, thus lowering the variety of species being tested and possibilities to balance their toxicity.  Hence, new synthetic methods giving access to homo- or hetero-functional ADCs with a high control of the DAR would be tremendous progress; being highly impactful to the ADC field and related patient outcomes.   Here, we propose innovative methods to functionalise antibodies. Based on a well-established, patented disulfide bond re-bridging method, and orthogonal click ligations, we will finely control antibody modification. This will yield: 1) Mono-functional ADCs with highly controlled DAR, including odd DARs (DAR 1, DAR 3...). This is fundamental to determine the optimal ratio between drug loading and hydrophobicity to obtain the best therapeutic activity. 2) Hetero-functional ADCs with controlled amount and site of functionalisation with different payloads. This includes production of DAR 1+1, DAR 1+1+1…several combinations of payloads are possible, paving the way to promising multi-therapies. 3) Fully synthetic bi-specific antibodies. Our method provides an unprecedented way to obtain bi-specific antibodies in a controlled and adaptable fashion from native antibodies, i.e. without requiring bioengineering.   The project addresses unmet needs in the therapeutic antibody field and could bring unprecedented outlooks to this booming sector.