Novel Tiancimycins (TNMs) Antibody Drug Conjugates (ADCs) for Anticancer Therapeutics

项目总结

Project Summary The antibody-drug conjugate (ADC) field has emerged as the next-generation therapeutic option for targeting and delivering highly cytotoxic drugs to tumors. The rapid growth in this area is seen in the more than 60 ADCs currently in clinical trials and the four FDA-approved drugs Adcetris® in 2011, Kadcyla® in 2013, and most recently Besponsa®, and Mylotarg® in 2017. Currently within the ADC field there are two major issues that need to be overcome: (i) random conjugation and varying drug-to-antibody ratios (DAR), and (ii) small molecule drugs as payloads. Nearly all the ADCs in clinical trials and the two approved drugs use random conjugation linking the payload to lysine or cysteine residues present within the antibody. This results in heterogenous ADCs with DARs between 0 and 8. The lack of uniformity leads to issues in pharmacokinetics and safety. One way to overcome this is site-specific conjugation through specific residues within the antibody. Furthermore, the currently small molecules being used as payloads for ADCs is limited and new, highly potent, and rapidly active small molecules are needed. Our hypotheses are (i) production of tiancimycins (TNMs) and TNM analogs and structure-activity relationship (SAR) studies, (ii) development of linker chemistry for site-specific conjugation of the TNMs, (iii) evaluation of the panel of anti-HER and anti-ROR1 thiomab- and DVD-TNMs against HER2+/ROR1- and HER2- /ROR1+ breast cancers cell lines for direct comparison of these novel enediyne-based ADCs to current benchmarks as well as development into next-generation ADCs for breast cancer lacking current therapeutic options. The specific aims for this application are (i) production, isolation, and fermentation of TNMs via manipulation of TNM biosynthesis in Streptomyces sp. CB03234 and chemical diversification, (ii) development and optimization of linker chemistry for site-specific conjugation of TNM to a panel of anti-HER2 and anti-ROR1 thiomabs and DVDs, and (iii) evaluation of potency and selectivity of TNM analogs and TNM conjugates against HER2+/ROR1- and HER2-/ROR1+ breast cancer cells in vitro. The outcomes of this application include advancements in the ADC field including new enediyne payloads, new site-specific conjugation techniques, and new anti-HER2 and anti-ROR1 thiomab- and DVD-TNM ADCs for the development of next-generation ADC therapies for breast cancer. The long-term goal of this research is to identify innovative cytotoxic natural products to utilize as small molecule payloads for ADCs to afford novel anticancer drugs.