Lupus Antibody That Penetrates and Kills Cancer Cells Headed to Clinical Trials

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The discovery that one specific lupus antibody, known as 3E10, can penetrate cancer cells and make them sensitive to and killed by standard radiation and chemotherapy methods is getting closer to being investigated in a clinical trial.

Peter M Glazer, MD, PhD, the Robert E. Hunter Professor of Therapeutic Radiology, professor of genetics, and chair of the Department of Therapeutic Radiology, and James Hansen, MD, MS, associate professor of therapeutic radiology, made the discovery nearly a decade ago. Now they have licensed the rights for their antibody discovery to a company, Patrys, Ltd, that has validated the work and developed 3E10 as a cancer therapy for human use. Notably, this technique has shown significant effectiveness in killing cancer cells with DNA repair deficiencies, such as those with mutations in the tumor-suppressing BRCA2 gene that lead to higher rates of breast and ovarian cancer.

“This discovery has unlocked promising new pathways for treatment of BRCA-related cancers that affect so many women around the world,” said Dr Glazer. “We have learned a great deal about how 3E10 interacts with DNA, and we continue to explore how this knowledge could be used to create therapies for other types of difficult-to-treat cancers.”

An earlier human study in Switzerland attempting to use 3E10 as a vaccine for lupus had already demonstrated that it is nontoxic. Phase 1 clinical trials could begin as early as next year, Dr Glazer said, likely for patients with cancers related to mutations of BRCA1/2 genes or of another tumor suppressing gene known as PTEN.

“This is very promising,” Dr Glazer said. “I think it will be important to identify the right subgroup of patients for which this is most effective.”

After publishing the results, Dr Glazer and his colleagues leveraged the data to obtain a pair of large multiyear grants from the National Institutes of Health. With this funding and the help of Yale graduate student Audrey Turchick, the team has discovered that inside a cancer cell, 3E10 sticks to a DNA repair protein called RAD51. This causes the lethality for cancer cells that are deficient in BRCA1 and BRCA2 genes by preventing the cells from conducting the routine DNA repair necessary to sustain themselves.

With ongoing funding from the NIH, Dr Glazer’s team, including structural biologist Franziska Bleichert, PhD, assistant professor, is building on these findings to enhance the anti-cancer potency of 3E10 and develop therapeutic strategies by identifying ways for the antibody to stick more strongly to RAD51.

In addition, an MD/PhD student in the lab, Elias Quijano, helped identify the capacity of 3E10 to bind with RNA — a type of molecule used to carry out DNA instructions — and carry RNA into a cancer cell, potentially with instructions that can kill the cell. Quijano and Drs Glazer, Stephen Squinto, PhD, and Bruce Turner, MD, PhD, co-founded Gennao Bio, a company seeking to develop this method of cancer-fighting therapy.

“This was an unexpected discovery that turns out may be very useful,” Dr Glazer said. “We have some data showing the efficacy of this method against tumors in a laboratory model. It is a versatile platform, because it can deliver different types of RNA in a similar way to how the COVID-19 mRNA vaccines work.”

The research continues, thanks in large part to the investment Women’s Health Research at Yale (WHRY) made so many years ago.

“I think that type of funding is extremely valuable,” Dr Glazer said of his WHRY grant. “It allowed us to do the sets of exploratory experiments we needed to do to demonstrate our approach was viable and get the larger grants. We showed this is feasible, this is promising.”

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Lupus Antibody That Penetrates and Kills Cancer Cells Headed to Clinical Trials.  Appl Rad Oncol. 

By News Release| September 26, 2022

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