One of the most promising ways to target powerful cancer drugs to tumors and not healthy cells involves attaching them to a cancer-seeking antibody with a chemical linker. Scientists at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology have spent years developing such precise anti-cancer antibody-drug conjugates.
Research published recently in the Journal of Medicinal Chemistry details the first time a natural product called tiancimycin was effectively connected to this antibody-drug conjugate system. A key feature was invention of the linker molecule needed to connect the antibody to the cancer drug.
The scientists liken antibody-drug conjugates to a biological guided missiles: The antibody is a targeting system that takes aim at the cancer. The potent, toxic compound the scientists employed is similar to a warhead, killing cancer cells by obliterating their DNA. The chemical linker acts like vital missile hardware, connecting the antibody and its chemical payload.
The new antibody-drug conjugate system was developed by teams led by Ben Shen, Ph.D., a chemistry professor and director of the Natural Products Discovery Center at The Wertheim UF Scripps Institute, and antibody expert Christoph Rader, Ph.D., professor of immunology and microbiology, also of The Wertheim UF Scripps Institute.
In leukemia cells, their system worked well, Shen said. The methods they developed offer a promising path for making similar types of cancer-fighting antibody-drug conjugates with complex natural compounds, he added.
“The system we created to connect this natural product to the antibody provides a road map to developing more antibody-drug conjugates with this class of natural products,” Shen said. “The work also showcases the therapeutic potential of the unique collection of natural products housed at the institute, which is available to the wider scientific community.”
The payload for the system, tiancimycin, was discovered within the Natural Products Discovery Center collection. This unique and irreplaceable collection includes more than 122,000 microbial strains that were gathered and purified by scientific groups over nearly a century following the discovery of penicillin and streptomycin, but never fully explored. Each strain has the potential to produce approximately 30 unique chemical natural products, which would dramatically expand the known catalog of such natural compounds, Shen said. More than one-third of all FDA-approved drugs in use today have arisen from natural products such as these, so the collection’s potential to benefit humanity is immense, he added.
Tiancimycin is a member of a chemical family called anthraquinone-fused enediynes, which have generated great interest for their anti-tumor properties, but have yet to make it to the clinic. Building a new, cancer-killing antibody-drug conjugate with them posed several significant scientific hurdles, said Andrew D. Steele, Ph.D., a postdoctoral research associate and co-first author of the paper. The linker molecule cannot alter the properties of either the antibody or the payload, lest the therapeutic lose potency, he said.
“We have shown we can precisely generate antibody-drug conjugates in a manner that is different than what anyone has done in the clinic. This method has the ability to customize every single portion of these systems in a pretty rapid fashion,” Steele said.
The team’s discovery also addresses a longstanding challenge of having to create a new antibody-drug conjugate for different cancers, said Alexander F. Kiefer, Ph.D., a postdoctoral fellow and co-first author of the paper.
“We now are able to address breast cancer or attack leukemia cells. Otherwise, we would need to synthesize an antibody-drug conjugate again and again for each cancer type. This gets us around that problem,” Kiefer said.
After demonstrating effectiveness against leukemia cells in the study, the team plans to move into mouse-model testing. One important future target is breast cancer that is driven by a protein known as human epidermal growth factor receptor 2, or HER2, Kiefer said. About 20% of breast tumors have elevated levels of HER2, according to the American Cancer Society.
Shen said a key takeaway from this paper is that the Natural Products Discovery Center Collection can be efficiently harnessed to produce anti-cancer drug candidates. Designer payloads can be engineered in a way that fine tunes the potency for a given cancer type. Because the collection is available to the wider scientific community, the potential for other research labs to use this resource for drug discovery is exciting, he added.
The searchable database is available at https://npdc.rc.ufl.edu/home. Researchers can freely browse the data and can request strains of interest to further their own research efforts.
Other co-authors of the study are Dobeen Hwang, Ph.D.; Dong Yang, Ph.D.; Christiana N. Teijaro, Ph.D. and Ajeeth Adhikari, Ph.D.
The study is supported by the National Institutes of Health (grants GM134954, CA204484, OD021550 and postdoctoral fellowships GM133114 and GM128345) and a postdoctoral fellowship from the German Research Foundation.
By Doug Bennett and Stacey DeLoye