A bifunctional antibody–ligand traps --- Y-traps provide new strategy for Cancer Immunotherapy

Scientists found a new class of cancer immunotherapy drugs that fight cancer by make use of immune system more effectively. This novel approach results in a significant decrease of tumor growth, even against cancers that do not respond to existing immunotherapy, published in the journal of Nature Communications.

Naturally, tumor cells can be detected and eliminated by immune system. But almost all cancers evolve to counteract and defeat such immune surveillance through the selection and amplification of immune suppression mechanisms.

Tumors evade the immune system is mainly through the approach of regulatory T cells (Tregs), that can prevent the immune system from attacking cells. Generally, tumors are infiltrated by Tregs, and this is strongly related to poor outcome in multiple cancer types. Many tumors express high levels of a protein that can promote the development of Tregs.

Researchers inferred that turning off Tregs may help immunotherapy work better. However, this is particularly challenging. Tregs are not only induced by the transforming growth factor-β(TGFβ) protein of tumor cells, but make their own TGFβ to maintain their identity and function. In addition, Tregs also make cytotoxic T-lymphocyte associated protein 4 (CTLA-4), which prevents the action of anti-tumor immune cells.

A newly invented class of immunotherapy drugs --- Y-traps solved this problem. An antibody molecule is shaped like a Y with two arms that can be fused to other molecules that can act to “trap” surrounding proteins.



A Y-trap was designed to target CTLA-4 and trap TGFβ, and results showed that this Y-trap disables both CTLA-4 and TGFβ, which allows anti-tumor immune cells to fight the tumor and turns down Treg cells.

Then the team transplanted human cancer cells into mice engineered to have human immune cells. They found that their Y-trap eliminated Treg cells in tumors and slowed the growth of tumors that failed to respond to ipilimumab, a current immunotherapy drug that targets the CTLA-4 protein.

"Tregs have long been a thorn in the side of cancer immunotherapy, and We've finally found a way to overcome this hurdle with this CTLA-4-targeted Y-trap." they said excitedly.

Antibodies to another immune checkpoint protein, PD-1, or its ligand (PD-L1), are a central focus of current cancer immunotherapy. While they work in some patients, they don't work in the vast majority of patients.The research team designed a Y-trap targeting PD-L1 and trapping TGFbeta. Tested against the same engineered mice, they found that their Y-trap works better than just PD-L1-targeting drugs atezolizumab and avelumab. Again, this Y-trap slowed the growth of tumors that previously had not responded to drugs.

Bedi envisions using Y-traps not only for treatment of advanced, metastatic cancers, but also as a neoadjuvant therapy to create a "vaccine" effect -; that is, giving them to patients before surgery to prevent recurrence of the disease.

"These first-in-class Y-traps are just the beginning. We have already invented a whole family of these multifunctional molecules based on the Y-trap technology. Since mechanisms of immune dysfunction are shared across many types of cancer, this approach could have broad impact for improving cancer immunotherapy," says Bedi. "Y-traps could also provide a therapeutic strategy against tumors that resist current immune checkpoint inhibitors."

Find more details, please click https://www.hopkinsmedicine.org/news/media/releases/johns_hopkins_researchers_invent_new_technology_for_cancer_immunotherapy.