A new approach combines biotechnology and immunotherapy to destroy cancer cells

Researchers engineered antibodies to kill treatment-resistant cancer cells.
Ayesha Gulzar
Antibody Immunoglobulin stock photo.
Antibody Immunoglobulin stock photo.


A research team led by scientists at Perlmutter Cancer Center at NYU Langone Health has devised a new strategy to kill cancer cells. The team engineered “bi-specific” antibodies that can bind to cancer-related peptides and “recruit” the “killer cells” of the immune system to destroy treatment-resistant cancer cells.

Cancer drugs called “covalent inhibitors” specifically target proteins inside the cancer cells to block their function. These proteins are then naturally broken down and presented as small fragments (peptides) on cell surfaces by major histocompatibility complex (MHC) molecules to be recognized as foreign by the immune “surveillance” system. These MHC-displayed “flags” can be identified by immune proteins called antibodies. Revolving around this process, the team engineered antibodies that can bind to these MHC flags and recruit killer T cells to destroy cancer cells.

“Even when genetic and other changes frustrate targeted therapies, they often still attach to their target proteins in cancer cells, and this attachment can be used to label those cells for immunotherapy attack,” says co-corresponding study author Shohei Koide, Ph.D., professor in the Department of Biochemistry and Molecular Pharmacology and a member of Perlmutter Cancer Center at NYU Langone. “Further, our system, conceptually, has the potential to increase the efficacy of any cancer drug when attached to the drug’s disease-related target where the combination can be displayed by MHCs.”

Harnessing Display

Published on October 17 in Cancer Discovery, the new study tested the researchers’ approach on two FDA-approved, targeted drugs, Sotorasib and Osimertinib.

Sotorasib, a recently approved drug, works by attaching to an altered form of the protein KRAS called p.G12C, in which a glycine building block is mistakenly replaced by cysteine at position 12 in the protein’s structure. This change is present in about 13 percent of the more than 200,000 patients diagnosed with lung cancer each year in the United States. KRAS encodes a protein switch that regulates growth but becomes “stuck in the ‘on’ mode” when mutated, signaling cells to multiply in tumors continually. Sotarasib effectively blocks this activated signal to start, but cancer cells rapidly become resistant.

In the experiment, researchers grew KRAS mutant cancer cells in a dish and exposed them to the team’s HapImmuneTM antibodies. Once the drug is attached to its target and displayed by MHCs, the modified antibodies recruit T cells and kill the treatment-resistant lung cancer cells.

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The engineered antibodies can also recognize multiple MHC types, and so, in principle, could be deployed in 40–50 percent of the US patient population with tumors bearing KRAS p.G12C.

“Our results further show that the antibodies attach to drug molecules only when presented by MHCs on cells, and so could be used in combination with a drug,” says study co-corresponding author Benjamin G. Neel, MD, Ph.D., director of NYU Langone Health’s Perlmutter Cancer Center. “When used in combination with such antibodies, a given drug would only need to flag cancer cells, not fully inhibit them. This creates the possibility of using drugs at lower doses, potentially, for reducing the toxicity sometimes seen with covalent inhibitors.”

In the future, the team plans to perform animal trials using more pairs of drugs and the disease-related protein fragments they target.

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