We will perform this proposed project to address one of the overarching challenges “Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival.” Antibody Drug Conjugates (ADCs) represent a rapidly growing and extensively potent class of anticancer therapeutics. ADCs deliver potent anticancer drugs selectively to tumors while avoiding healthy tissues. In this way, the ADC format allows for the use of highly active drugs that have been too toxic to use for cancer treatment. Many ADCs including Food and Drug Administration (FDA)-approved Kadcyla (for breast cancer treatment) and about 60 ADCs in clinical trials are currently being used in cancer therapy with remarkable success. An appropriate chemical linker between the antibody and the highly active drug provides a specific bridge, enabling selective delivery and precise release of the highly active drug only at the tumor sites.

Despite extensive efforts to improve ADC linker technology, most ADC linkers developed to date load only single cytotoxic drugs. The clinical potential of ADC linkers that can load two or more different drugs remains unexplored because of the lack of efficient and versatile methods enabling such multiple loading. Recently, we developed an efficient method using a multi-loading ADC linker enabling simple and easy installation of two molecules onto an antibody. Based on this success, we hypothesize that the multi-loading strategy using properly designed ADC linkers will lead to next-generation ADCs for combating the cancer drug resistance and heterogeneity issues in breast cancer treatment. We envisage that ADCs loading two different drugs with distinct antitumor or tumor-targeting mechanisms can kill a broad scope of breast cancer cells including those resistant to either of the two drugs without attacking healthy tissues.

In this project, we will prepare such dual-loading ADCs using our new method and evaluate their specificity for and anticancer efficacy against drug-sensitive and -resistant breast cancer cells using cell-based assays and mouse models of breast cancer. The drug resistance and tumor heterogeneity are unsolved issues leading to discontinuation of medication and recurrence of malignancy in breast cancer chemotherapy. Thus, successful completion of this project will validate the new concept "hybrid ADCs" as an innovative approach for overcoming such unsolved issues and establish a novel ADC platform providing a number of valuable additions to the current list of drug candidates to be tested in the future clinical studies.