New Antibody Holds Promise for Treating HER2-Mutated Cancers

Researchers at NYU Langone Health have developed a novel antibody that selectively targets a specific mutation in the HER2 protein, potentially offering a new treatment option for cancer patients with this particular genetic alteration. This breakthrough research was published in the prestigious journal Nature Chemical Biology.

HER2 is a protein often found on the surface of many cell types, playing a crucial role in regulating cell growth. When a single amino acid in the HER2 gene is swapped out, it can trigger uncontrolled cell division and lead to cancer. This specific mutation, known as S310F or S310Y, is a common “hotspot” found in various cancers.

Targeting the Mutation: A New Approach

Current therapies for HER2-positive cancers, such as trastuzumab and pertuzumab, primarily target the full HER2 protein. This can lead to side effects because healthy cells also express the normal HER2 protein.

The new antibody developed by the NYU Langone team, however, is specifically designed to recognize only the mutant HER2, minimizing harm to healthy cells.

“It is generally challenging to develop an antibody that recognizes a single point mutation with high selectivity,” explained Dr. Shohei Koide, lead author of the study and Professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine. “Here we demonstrate the feasibility of developing antibodies that are capable of recognizing a single point mutation in the context of a large antigen, through a carefully designed library sorting strategy and a structure-guided, iterative engineering approach.”

Boosting the Immune Response

To enhance the antibody’s effectiveness, the researchers transformed it into a bispecific T cell engager (BITE). This molecule consists of two parts: one that binds to the mutant HER2 protein and another that binds to T cells, which are immune cells that destroy infected or cancerous cells.

“One end of the antibody sticks to the mutant HER2 on a cancer cell, while the other triggers T cells to kill the cancer cell,” Dr. Koide explained.

Preclinical testing in mice showed that the BITE approach significantly reduced tumor growth without causing severe side effects.

Looking Ahead: Personalized Cancer Therapies

This groundbreaking research opens new avenues for developing highly personalized cancer therapies. Dr. Koide and his team plan to further refine the antibody and explore its potential as a therapeutic for patients with HER2-mutated cancers.

The team also aims to apply this antibody engineering technique to develop targeted therapies for other cancers driven by specific mutations in cell-surface proteins.

“The remarkable selectivity of the antibodies developed in this work offers an optimistic outlook on the strategy of developing antibodies highly selective to other disease-driver mutations in cell-surface proteins,” concluded the researchers in their paper.

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