P165: Enabling natural product payloads for antibody-drug conjugates via biosynthetic engineering

Antibody-drug conjugates (ADCs) represent an innovative therapeutic approach that combine the best of two proven anticancer modalities, the specificity of antibodies and the potency of cytotoxic, small molecule drugs. There are currently about 60 ongoing ADC-based clinical trials and the positive response rates when administered to chemo-refractory cancer patients place ADCs in a promising position to become an important therapeutic class in oncology.

ADC optimization is a complex process reflecting the multifaceted nature of an ADC; there are three key components – monoclonal antibody, linker and cytotoxic small molecule or payload –that require attention when developing ADCs for clinical use. The antibody should specifically bind to antigens highly expressed in tumors but not (or minimally) present in normal tissue. The linker technology should allow drug release only after ADC internalization for maximum potency and minimal toxicity. The method of conjugation will dictate drug loading level and homogeneity and can affect pharmacokinetics, activity and tolerability. Finally, the drug should be highly potent since delivery is limited and dependent on antigen expression level.

Natural products or its derivatives have been in the forefront as payloads. This presentation will discuss the use of biosynthetic engineering tools to overcome potential limitations associated with natural product payloads, such as supply and availability of suitable chemical handles for linker attachment.