HER2 bispecific antibodies are a novel class of therapeutic proteins engineered to target two distinct molecules simultaneously. These specialized antibodies are designed to intercept specific signals that drive cancer growth and progression, representing an advanced approach in targeted cancer therapy.
Understanding HER2
The HER2 protein, or Human Epidermal Growth Factor Receptor 2, is a member of a family of receptors located on the surface of cells. In healthy cells, HER2 plays a role in regulating normal cell growth, division, and differentiation. It functions by forming partnerships with other HER proteins, which then activate signaling pathways inside the cell, promoting these cellular processes.
However, in certain cancers, the gene responsible for producing HER2 can be amplified, leading to an excessive number of HER2 proteins on the cell surface, a condition known as overexpression. When HER2 is overexpressed, it can lead to uncontrolled cell growth and division, contributing to the development and progression of aggressive tumors. This overexpression makes HER2 a significant biomarker and a target for various cancer therapies.
What Makes an Antibody Bispecific
Antibodies are Y-shaped proteins produced by the immune system to identify and neutralize foreign substances, such as bacteria and viruses. Each antibody has specific binding sites that recognize and attach to a unique marker, called an antigen, on the surface of these foreign invaders. This specific binding allows the immune system to target and eliminate harmful entities.
A bispecific antibody is an advanced form of this natural defense mechanism. Unlike traditional antibodies that bind to only one specific antigen, bispecific antibodies are engineered to simultaneously attach to two different targets. This dual-targeting capability is achieved by combining the binding regions from two distinct antibodies into a single molecule. This innovative design allows bispecific antibodies to bridge two different cells or two different molecules on the same cell, opening new possibilities for therapeutic intervention.
How HER2 Bispecific Antibodies Target Cancer
HER2 bispecific antibodies are designed with a dual-targeting strategy to combat cancer cells. One arm of the antibody attaches specifically to the HER2 protein on cancer cells, which often overexpress this receptor. The other arm binds to a different target, such as another receptor on the cancer cell or a molecule on an immune cell like a T-cell.
This dual binding creates a bridge, bringing the immune cell into close proximity with the cancer cell, or simultaneously blocking two different signaling pathways on the cancer cell. For example, some HER2 bispecific antibodies can connect a T-cell, a type of immune cell capable of killing cancer cells, directly to a HER2-positive tumor cell. This direct connection activates the T-cell, prompting it to attack and eliminate the tumor cell without requiring the usual complex immune activation steps. Other bispecific antibodies may target two different regions on the HER2 protein itself, or HER2 and another growth factor receptor like HER3, to more effectively block signals that promote cancer cell growth and survival. This multi-pronged approach aims to enhance anti-cancer effects, potentially overcoming resistance mechanisms that can develop against single-target therapies.
Applications in Cancer Treatment
HER2 bispecific antibodies are being explored for treating various cancers where HER2 overexpression plays a role. These include breast cancer, gastric cancer, gastroesophageal junction cancer, colorectal cancer, and biliary tract cancer. Their use in these cancers stems from HER2 overexpression or amplification being associated with aggressive disease and indicating a need for targeted therapies.
These antibodies are investigated where existing HER2-targeted therapies have limitations or patients have developed resistance. For instance, in breast cancer, HER2 bispecific antibodies are studied to overcome resistance to conventional anti-HER2 treatments. In gastric and gastroesophageal junction cancers, where HER2 overexpression is observed, these antibodies provide a new therapeutic option. Zanidatamab-hrii, a HER2-targeting bispecific antibody, recently received accelerated FDA approval for previously treated, unresectable or metastatic HER2-positive biliary tract cancer, demonstrating clinical impact in this area.