Serve as Highly Cytotoxic Payloads in Site-Specific Anticancer Antibody-Drug Conjugates
Tiancimycins are a newly discovered class of enediynes that are ideal payload candidates for anticancer antibody-drug conjugates (ADCs). The substantial toxicity of enediynes limits their use as anticancer drugs unless they can be precisely directed to tumor cells. Monoclonal antibody anti-tumor therapies can target tumors with high precision, but the key to efficacy lies with pairing high precision targeting to tumors with a molecule that has a very high level of cytotoxicity, can be predictably and stably coupled to the monoclonal antibody and can be efficiently and economically synthesized. Tiancimycins are a new class of enediynes that fulfill these criteria.
Antibody-drug conjugates (ADCs) represent a proven therapeutic category of anticancer drugs using the high specificity of monoclonal antibodies to direct a cytotoxic compound to cancerous cells. One of the issues for new ADCs is to ensure more homogeneous conjugates are generated. Random, or at least multiple pathways for conjugation of drug to the antibody, results in a heterogeneous mixture, which in turn can lead to limited efficacy and reduced safety. Existing ADCs employ highly cytotoxic drugs belonging to either the microtubule inhibitor or DNA-damaging families, with most of them using the microtubule inhibitors auristatin and maytansine as the cytotoxic payload. This leaves the antibody-drug conjugates field in need of new cytotoxic agents that are effective against many types of malignant cells, as well as are stable and amenable to rational structural engineering.
Researchers at the University of Florida have discovered tiancimycins, cytotoxins belonging to the enediyne natural product family, to serve as cytotoxic payloads for preparing and developing enediyne-based, site-specific antibody-drug conjugates. Site-specific conjugation of tiancimycins to monoclonal antibodies enables the generation of homogenous antibody-drug conjugates with defined drug-to-antibody ratios.
Application
Tiancimycins, a new class of enediynes, as highly cytotoxic payload candidates for anticancer antibody-drug conjugates
Advantages
- Tiancimycins (TNMs) are highly cytotoxic, making them great candidates for anticancer antibody-drug conjugates
- Very stable in aqueous solutions, facilitating conjugation methods that are compatible with maintaining the activity of antibodies
- Tiancimycins are stable in plasma, enabling a long half-life in systemic circulation of patients
- This natural product is produced by a microorganism, enabling production in sufficient quantities for preclinical and clinical studies and future commercialization
- The producing microorganism is genetically amenable, enabling titer improvement, structural diversity, and rational engineering
Technology
These newly discovered tiancimycins are ideal payload candidates for anticancer antibody-drug conjugates (ADCs). Enediynes are highly cytotoxic natural products and a proven class of anticancer drugs, either as monotherapy or as payloads in antibody-drug conjugates. Tiancimycins (TNMs) can potentially serve as the lead for anticancer drugs or antibody-drug conjugates. TNMs are readily produced in large quantities by a genetically amenable Streptomyces species, enabling ready and economic production for preclinical and clinical studies and future commercialization. Antibody-drug conjugates (ADCs) encompassing the present cytotoxin provide the possibility of selectively ablating cancer cells by combining the specificity of a monoclonal antibody with the delivery of TNMs. TMN are highly cytotoxic and effective against multiple tumor types, with functional groups for linkage, solubility to enable the reaction with antibodies, and prolonged stability in vivo, making them highly effective and versatile antibody-drug conjugate payloads.
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