Cancer-hunting antibodies coupled with a natural compound (NP) found in soil microbes proved a powerful combination against an aggressive type of blood cancer, according to a new study from scientists at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology.[1]
Natural products elicit potent and unique biological activities. They have shown great promise as cancer-killing compounds. Among them are anthraquinone-fused enediyne (AFE) natural products, such as tiancimycins (TNMs) which exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. Tiancimycins were found within a historic collection of soil microbes housed at the institute.
As a proof-of principle, an antibody-drug conjugate or ADC, linking an antibody to a tiancimycin payload, developed by the research team at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, demonstrated a striking ability to kill aggressive lymphomas while ignoring healthy, non-cancerous cells in blood samples donated by cancer patients.[2]
Tiancimycins are expected to be exploited as novel, emerging, payload candidates with exceptional potency and a validated DNA-damaging mechanism of action (MoA) for the next generation of anticancer ADCs. emerging payload candidates..[2]
Diffuse large B cell lymphoma
The study, funded by the National Institutes of Health (NIH), focused on diffuse large B cell lymphoma (DLBCL), a non-Hodgkin lymphoma that affects around 20,000 people annually in the United States and is one of the more common, and aggressive, sub-types of white blood cell cancers.
The study results were published in the July 1, 2025 edition of the Journal of the American Chemical Society Au.[1]
Getting it into the Clinic
“It would be the ultimate reward if this makes it into the clinic and impacts patient outcomes one day,” noted professor Ben Shen, Ph.D., a chemist who is a member of the UF Health Cancer Center’s Cancer Targeting and Therapeutics research program.
Shen who directs the Department of Molecular Medicine, at the Natural Products Discovery Center, oversees a historic collection of more than 125,000 microbial strains of which at least 62,328 are actinobacteria, 14,465 other bacteria, and 48,334 unidentified, gathered long ago by pharmaceutical company scientists who were inspired by the discovery of penicillin.
Benefiting cancer patients
Cancer patients have recently benefited from the emergence of precision cancer treatments, which are targeted to specific genetic mutations. Still, patients face many challenges, especially the threat of drug resistance. Someone’s cancer may respond well to a precision drug for a while, only for it to become less effective over time.
Patients who have lymphomas, which have many sub-types, need more treatment options. That’s why doctors need – and are searching for – more precision therapies in their arsenal.
Antibody-drug Conjugates
Shen explained that tiancimycin tested by his team killed lymphoma, but risked killing other cells, too. Tethering it to a cancer-seeking antibody offered a way to direct a drug specifically where it was needed.
In this development process, Shen teamed up with a former colleague from The Wertheim UF Scripps Institute, Christoph Rader, Ph.D., to make the antibody-drug conjugates,
Rader describes the antibody the scientists used to deliver the natural product as a ‘double-decker bus,’ with a targeting antibody linked to an active, drug-carrying antibody. This double-decker antibody approach has been used successfully in lab studies with other payloads, too, Rader noted, including payloads that vanquished aggressive breast cancer cells, multiple myeloma and non-Hodgkin lymphoma cells.
“The compatibility of the conjugation platform with novel payloads discovered in the Natural Products Discovery Center at The Wertheim UF Scripps Institute is exciting and is paving the way to next-generation ADCs for cancer therapy,” Rader noted.
“It further documents the versatility of this conjugation platform,” he added.
Linking the tiancimycin to Rader’s antibodies required two years of chemistry work. Shen first described that process in a paper published in 2023.[3]
Development
Shen and Rader developed a dual variable domain monoclonal immunoglobulin G1 (DVD IgG1), an engineered protein that combines the function and specificity of two monoclonal antibodies in one molecular entity. DVD IgG1 enable site-specific conjugation and modular antigen-targeting specificity.
Once payload and antibodies were successfully conjugated, the team’s cell-based testing revealed which form of tiancimycin would be most effective against the cancer. Keto-TNM A exhibited the highest potency among the TNMs.
Using a variety of linker chemistries, they conjugated a novel ADC. CD79b, a transmembrane protein that forms part of the B-cell receptor complex, which is similar to the clinical target for polatuzumab vedotin (Polivy®; Genentech/Roche), an FDA-approved ADC designed to treat diffuse large B-cell lymphoma, was chosen as the clinical target used.
The optimized ADC, which includes a keto-TNM A-payload conjugated to anti-CD79b DVD IgG1, exhibited potent and selective activity across multiple CD79b-expressing cell lines and, most significantly, patient-derived primary chronic lymphocytic leukemia cells.
“The process and the platform the team developed to create this ADC could prove valuable in developing next-generation immunotherapies that target various cancers and mutations,” Shen said.
His next step is to test the ADC in mice.
“Taken together, the data suggest that this combination of engineered payload, linking chemistry and double-decker antibodies could one day offer a promising new option for lymphoma patients,” Shen concluded..
Scientists from The Ohio State University Comprehensive Cancer Center in Columbus, Ohio, also contributed to the study.
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Highlights of prescribing information
Polatuzumab vedotin (Polivy®; Genentech/Roche)[Prescribing Information]
Reference
[1] Kiefer AF, Thirugnanasambantham P, Jin Y, Steele AD, Hwang D, Jiang Y, Adhikari A, Yang D, Chang J, Tafesse R, Rader C, Muthusamy N, Shen B. Second Generation Tiancimycin-Based Antibody–Drug Conjugates Enabled by Highly Efficient Semi-synthetic Approach Specifically Targeting B-Cell Malignancies. ACS Au 2025. DOI 10.1021/jacsau.5c00353
[2] Yan X, Ge H, Huang T, Hindra, Yang D, Teng Q, Crnovčić I, Li X, Rudolf JD, Lohman JR, Gansemans Y, Zhu X, Huang Y, Zhao LX, Jiang Y, Van Nieuwerburgh F, Rader C, Duan Y, Shen B. Strain Prioritization and Genome Mining for Enediyne Natural Products. mBio. 2016 Dec 20;7(6):e02104-16. doi: 10.1128/mBio.02104-16. PMID: 27999165; PMCID: PMC5181780.
[3] Steele AD, Kiefer AF, Hwang D, Yang D, Teijaro CN, Adhikari A, Rader C, Shen B. Application of a Biocatalytic Strategy for the Preparation of Tiancimycin-Based Antibody-Drug Conjugates Revealing Key Insights into Structure-Activity Relationships. J Med Chem. 2023 Jan 26;66(2):1562-1573. doi: 10.1021/acs.jmedchem.2c01771. Epub 2023 Jan 4. PMID: 36599039; PMCID: PMC11660660.
An edited version of the article was published in ADC Review | J. of Antibody-drug Conjugates.
Featured image: Research Assistant Professor Dong Yang, Ph.D., incubates the microbe strains to increase the quantities needed for their studies. Photo courtesy: © 2025 Scott Wiseman. Used with permission.
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