Wistar scientists have developed a new type of bispecific T-cell engager (BTE) that is effective against ovarian cancer in preclinical studies. This is a major advance for this type of immunotherapy, which has been used successfully against blood cancers, but has so far been less effective against solid tumors.
Researchers have developed a new “knob-in-to-hole” platform for delivering BTE. This manipulates the antibody’s “knob” to force it to match the antibody’s “hole”, resulting in a perfect locking of the two puzzle pieces for a precise fit.
They showed that DNA-based technology can be used to deliver BTE. This is a powerful approach that can significantly reduce manufacturing costs and patient treatment burden. They also developed a method to deliver BTE targeting two different antigens in a single dose, an important strategy to overcome therapeutic resistance.
“I think this is a major advance for the field of bispecific antibodies,” said Pratik S. Bhojnagarwala, Ph.D., a postdoctoral fellow in the lab of David B. Weiner, Ph.D., in the Center for Vaccine and Immunotherapy at the Wistar Institute and lead author of the study. “This is important for ovarian cancer, where new treatment options are really needed, but it has broad applications for other solid tumors as well.”
Bispecific T-cell engagers are powerful immunotherapies whose clinical use has increased significantly over the past decade. They help the immune system fight cancer by physically capturing and binding cancer cells and disease-fighting T cells. This redirects the killing activity of T cells against cancer cells.
Existing BTEs have been ineffective against solid tumors such as ovarian cancer because they have short half-lives and are rapidly cleared from the body. Additionally, solid tumors are more heterogeneous than blood cancer cells, making it easier to evade BTEs that target a single antigen on the cancer cell surface. New technology solves both problems.
The first key innovation is the use of a DNA-based delivery platform to make a patient’s own muscle tissue act like a “factory” to produce BTE directly within the body. The knob-in-to-hole design that the researchers adapted for DNA delivery further improves the half-life of BTE and increases its duration. This approach is more affordable, easier to manufacture, requires no refrigeration, and requires fewer doses and lasts longer, Bhojnagarwala explained.
The researchers also showed that this platform can be used to simultaneously deliver two different BTEs. This is a more effective approach to target the diverse antigens found in solid tumors.
Demonstrating that these highly complex molecules can be delivered in vivo in a mouse model was a very exciting achievement, demonstrating their potential as next-generation tools to improve patient outcomes. Treatments may be cheaper, the body’s muscle cells continue to produce the therapeutic drug, and fewer doses may be needed without the need for multiple doses. ”
Pratik S. Bhojnagarwala, first author
The researchers showed in preclinical models that the new BTE lasted longer in the body and was more effective at slowing tumor growth. The researchers also conducted a study in the lab showing that the drug also had an effect on cells from human ovarian cancer patients. Another experiment showed that the treatment could be made more effective when combined with immune checkpoint inhibition, an immunotherapy commonly used for solid tumors.
Next, the researchers plan to test the therapy in more sophisticated models of human cells, bringing it one step closer to human clinical trials. They also hope to study it against other cancer targets.
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Reference magazines:
Bhojnagarwala, P.S. others. (2026) Efficient in vivo assembly of DNA-encoded multivalent BTEs for dual antigen targeting to expand therapeutic efficacy in ovarian cancer. Molecular therapy. DOI: 10.1016/j.ymthe.2026.05.019. https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(26)00406-5
