Both the two FDA-approved antibody-drug conjugates (ADCs) (Adcetris and Kadcyla) and nearly all ADCs in clinical trials are prepared by randomly conjugating drugs to lysine or cysteine residues in the antibody, affording a heterogeneous ADC mixture. Site-specific conjugation is a major recent improvement to ADC development, yielding homogeneous ADCs with greatly improved therapeutic index. Among the 60+ ADCs currently in clinical development, nearly 50 of them use auristatin and maytansine, the two payloads used in Adcetris or Kadcyla, respectively, with the rest using one of only five other drugs. The ADC field is in critical need of new, highly potent, and rapidly acting cytotoxic payloads that are active in many tumor types. We propose in this application to develop new enediyne-based site-specific ADCs for cancer therapy. Specifically, we will focus on tiancimycins (TNMs), which we recently discovered as novel members of the enediyne family of natural products. Our hypotheses are: (i) TNMs are outstanding ADC payload candidates owing to their exquisite potency and validated mode of action, (ii) genetic manipulation of TNM biosynthesis provides outstanding opportunities to produce the most promising TNM analogues to develop the linker chemistry and facilitate site-specific conjugation, (iii) site-specific conjugation of TNMs to engineered thiomabs and selenomabs will generate homogeneous ADCs with defined drug-to-antibody ratios (DARs), and (iv) complementary targeting of HER2 and ROR1 will help evaluate the novel enediyne-based ADCs against current benchmarks and improve therapeutic outcomes for breast cancer patients.
The specific aims for this grant are: (i) manipulation of TNM biosynthesis in Streptomyces sp. CB03234 to produce the most promising TNMs for site-specific conjugation, (ii) production and purification of anti-HER2 and anti-ROR1 thiomabs and selenomabs with 2 engineered cysteine (Cys) and 2 or 1 engineered selenocysteine (Sec) residues, respectively, (iii) development of linker chemistry for site-specific conjugation and delivery of a panel of anti- HER2 and anti-ROR1 thiomab-TNM and selenomab-TNM conjugates, and (iv) evaluation of selectivity and potency of the anti-HER2 and anti-ROR1 thiomab-TNM and selenomab-TNM conjugates against HER2+ and HER2?/ROR1+ breast cancers in both in vitro and in vivo models. The outcomes of this application include (i) fundamental contributions to ADCs and (ii) a panel of anti-HER2 and anti-ROR1 thiomab-TNM and selenomab- TNM conjugates as next-generation ADC therapeutics for cancers. The long-term goal of our research is to discover novel microbial natural products and harness their exquisite cytotoxicity as ADC payloads for anticancer drug discovery.
Breast cancer, a highly heterogeneous disease with treatment response dependent on the subtype, is one of the most common cancer types worldwide, with more than 230,000 estimated new cases and more than 40,000 estimated deaths in 2015 in the U.S. alone. This project aims at developing novel enediyne-based site-specific antibody-drug conjugates as next-generation cancer therapeutics that complementary target HER2 and ROR1, collectively providing new treatment options for at least 50% of breast cancer patients.
|Chang, Chin-Yuan; Yan, Xiaohui; Crnovcic, Ivana et al. (2018) Resistance to Enediyne Antitumor Antibiotics by Sequestration. Cell Chem Biol 25:1075-1085.e4|
|Yan, Xiaohui; Chen, Jian-Jun; Adhikari, Ajeeth et al. (2018) Comparative Studies of the Biosynthetic Gene Clusters for Anthraquinone-Fused Enediynes Shedding Light into the Tailoring Steps of Tiancimycin Biosynthesis. Org Lett 20:5918-5921|
|Liu, Ling; Pan, Jian; Wang, Zilong et al. (2018) Ribosome engineering and fermentation optimization leads to overproduction of tiancimycin A, a new enediyne natural product from Streptomyces sp. CB03234. J Ind Microbiol Biotechnol 45:141-151|
|Yan, Xiaohui; Hindra; Ge, Huiming et al. (2018) Discovery of Alternative Producers of the Enediyne Antitumor Antibiotic C-1027 with High Titers. J Nat Prod 81:594-599|
|Rudolf, Jeffrey D; Chang, Chin-Yuan; Ma, Ming et al. (2017) Cytochromes P450 for natural product biosynthesis in Streptomyces: sequence, structure, and function. Nat Prod Rep 34:1141-1172|
|Peng, Haiyong; Nerreter, Thomas; Chang, Jing et al. (2017) Mining Naïve Rabbit Antibody Repertoires by Phage Display for Monoclonal Antibodies of Therapeutic Utility. J Mol Biol 429:2954-2973|
|Yan, Xiaohui; Chen, Jian-Jun; Adhikari, Ajeeth et al. (2017) Genome Mining of Micromonospora yangpuensis DSM 45577 as a Producer of an Anthraquinone-Fused Enediyne. Org Lett 19:6192-6195|
|Weber, Justus; Peng, Haiyong; Rader, Christoph (2017) From rabbit antibody repertoires to rabbit monoclonal antibodies. Exp Mol Med 49:e305|
|Li, Xiuling; Nelson, Christopher G; Nair, Rajesh R et al. (2017) Stable and Potent Selenomab-Drug Conjugates. Cell Chem Biol 24:433-442.e6|
|Nanna, Alex R; Li, Xiuling; Walseng, Even et al. (2017) Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates. Nat Commun 8:1112|
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