Scientists at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology have developed a novel antibody-drug conjugate (ADC) that combines a natural compound found in soil microbes with cancer-hunting antibodies, showing striking effectiveness against aggressive lymphoma while sparing healthy cells. The research, funded by the National Institutes of Health and published July 1, 2025, in the Journal of the American Chemical Society Au, focuses on diffuse large B cell lymphoma (DLBCL), a non-Hodgkin lymphoma affecting approximately 20,000 people annually in the United States.
Natural Product Discovery and Development
The cancer-killing compound, tiancimycin, was discovered within a historic collection of 125,000 microbial strains housed at the institute's Natural Products Discovery Center. This collection, comprising at least 62,328 actinobacteria, 14,465 other bacteria, and 48,334 unidentified strains, was originally gathered by pharmaceutical company scientists inspired by the discovery of penicillin.
"It would be the ultimate reward if this makes it into the clinic and impacts patient outcomes one day," said Ben Shen, Ph.D., a chemist and member of the UF Health Cancer Center's Cancer Targeting and Therapeutics research program who directs the Natural Products Discovery Center.
Tiancimycins belong to the anthraquinone-fused enediyne (AFE) family of natural products, which exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. However, Shen explained that tiancimycin tested by his team killed lymphoma but risked killing other cells too, necessitating a targeted delivery approach.
Double-Decker Antibody Platform
To address the selectivity challenge, Shen collaborated with former colleague Christoph Rader, Ph.D., to develop the ADC using a unique "double-decker bus" antibody approach. Rader describes this system as having a targeting antibody linked to an active, drug-carrying antibody.
The team 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. This DVD IgG1 platform enables site-specific conjugation and modular antigen-targeting specificity.
"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 said. "It further documents the versatility of this conjugation platform."
Optimization and Target Selection
The conjugation process required two years of chemistry work, with Shen first describing the process in a 2023 publication. Cell-based testing revealed that keto-TNM A exhibited the highest potency among the tiancimycin variants tested.
The researchers selected CD79b as their clinical target, a transmembrane protein that forms part of the B-cell receptor complex. This target is similar to that used by polatuzumab vedotin (Polivy), an FDA-approved ADC for treating diffuse large B-cell lymphoma.
Using various linker chemistries, the team conjugated the novel ADC with keto-TNM A payload to anti-CD79b DVD IgG1. The optimized ADC exhibited potent and selective activity across multiple CD79b-expressing cell lines and, most significantly, patient-derived primary chronic lymphocytic leukemia cells.
Clinical Significance and Future Directions
The research addresses a critical need in lymphoma treatment, where patients face challenges including drug resistance. Cancer may respond well to precision drugs initially, only to become less effective over time, highlighting the need for additional therapeutic options in physicians' arsenals.
The double-decker antibody approach has demonstrated success in laboratory studies with other payloads, including those targeting aggressive breast cancer cells, multiple myeloma, and non-Hodgkin lymphoma 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 involves testing the ADC in mouse models.
"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.
The study included contributions from scientists at The Ohio State University Comprehensive Cancer Center in Columbus, Ohio, with additional authors including Alexander F. Kiefer, Pankajavalli Thirugnanasambantham, Yuan Jin, Andrew D. Steele, Dobeen Hwang, Yanlong Jiang, Ajeeth Adhikari, Dong Yang, Jing Chang, Rakeb Tafesse, and Natarajan Muthusamy.
