Why Human epidermal growth factor receptor 2 (HER2) is an attractive target for ADC

HER2 (Human Epidermal Growth Factor Receptor 2) is a protein that is overexpressed in certain types of cancer, including breast cancer and gastric cancer. It plays a crucial role in promoting cancer cell growth, survival, and proliferation. This overexpression of HER2 makes it an attractive target for various therapeutic approaches, including antibody-drug conjugates (ADCs).

Here are some reasons why HER2 is a good target for ADC:

  1. High expression in cancer cells: HER2 is often overexpressed in cancer cells, particularly in breast cancer. This high expression makes it a specific marker for cancer cells and allows for targeted therapy.
  2. Limited expression in normal tissues: While HER2 is expressed at low levels in normal tissues, it is significantly upregulated in cancer cells. This differential expression pattern minimizes the potential toxicity of ADCs to healthy cells and reduces off-target effects.
  3. Role in cancer progression: HER2 is involved in key signaling pathways that promote cancer cell growth, survival, and metastasis. Inhibiting HER2 signaling can disrupt these pathways and halt cancer progression.
  4. Successful targeted therapies: Targeting HER2 with monoclonal antibodies, such as trastuzumab and pertuzumab, has shown significant clinical benefit in patients with HER2-positive breast cancer. These targeted therapies have established the importance of HER2 as a viable therapeutic target.
  5. Internalization and payload delivery: When an ADC binds to HER2 on the cancer cell surface, the complex is internalized into the cell via receptor-mediated endocytosis. This internalization process allows for efficient delivery of the cytotoxic payload carried by the ADC directly to the cancer cell, enhancing its therapeutic efficacy.
  6. Synergy with chemotherapy: ADCs combine the targeted specificity of monoclonal antibodies with the potent cytotoxic effects of chemotherapy drugs. By delivering chemotherapy directly to HER2-positive cancer cells, ADCs can maximize the efficacy of the cytotoxic payload while minimizing systemic side effects.

Overall, HER2 is a promising target for ADC development due to its high expression in cancer cells, limited expression in normal tissues, and its role in promoting cancer progression. ADCs directed against HER2 offer a targeted therapeutic strategy with the potential to improve treatment outcomes for HER2-positive cancers.

What are the current HER2 targeting drugs on the market?

There are several drugs targeting HER2 that are currently available on the market for the treatment of HER2-positive cancers, particularly breast cancer. Here are some of the notable drugs:

Trastuzumab (Herceptin): Trastuzumab was the first HER2-targeted therapy approved by the U.S. Food and Drug Administration (FDA) in 1998 (source: It is a monoclonal antibody that binds to the HER2 receptor, inhibiting its signaling and promoting immune-mediated destruction of HER2-positive cancer cells. Trastuzumab is used in the treatment of HER2-positive breast cancer, both in the early and advanced stages, as well as in metastatic gastric cancer.

Pertuzumab (Perjeta): Pertuzumab is another monoclonal antibody that targets HER2 (source: It binds to a different domain of the HER2 receptor than trastuzumab, thereby inhibiting the formation of HER2 signaling complexes. Pertuzumab is often used in combination with trastuzumab and chemotherapy for the treatment of HER2-positive metastatic breast cancer and as neoadjuvant therapy for early-stage HER2-positive breast cancer.

Ado-trastuzumab emtansine (T-DM1, Kadcyla): T-DM1 is an antibody-drug conjugate that combines trastuzumab with a cytotoxic payload called emtansine (DM1) (source: . The conjugate binds to HER2 on cancer cells, gets internalized, and releases DM1 to exert its cytotoxic effects. T-DM1 is used for the treatment of HER2-positive metastatic breast cancer that has progressed after prior treatment with trastuzumab and a taxane chemotherapy.

Neratinib (Nerlynx): Neratinib is a small molecule tyrosine kinase inhibitor that irreversibly binds to the intracellular domain of the HER2 receptor, preventing HER2 activation (source: It is indicated for the extended adjuvant treatment of early-stage HER2-positive breast cancer after trastuzumab-based therapy.

Lapatinib (Tykerb/Tyverb): Lapatinib is another small molecule tyrosine kinase inhibitor that targets both HER2 and EGFR (Epidermal Growth Factor Receptor) (source: It inhibits the signaling pathways mediated by these receptors and is approved for use in combination with capecitabine or letrozole for the treatment of HER2-positive metastatic breast cancer.

These drugs have revolutionized the treatment of HER2-positive cancers and have significantly improved outcomes for patients with these types of tumors.

Why Linker plays a crucial role in HER2 ADC drug research

In the context of HER2-targeted drugs, such as antibody-drug conjugates (ADCs), the linker plays a crucial role in connecting the monoclonal antibody and the cytotoxic payload. The linker serves multiple purposes in HER2 drugs, including:

  1. Stability: The linker should be stable in circulation to prevent premature release of the cytotoxic payload. It needs to withstand the physiological conditions and enzymatic degradation in the bloodstream, ensuring the intact ADC reaches the tumor site.
  2. Selective release: The linker should facilitate the selective release of the cytotoxic payload inside the target cancer cells. Once the ADC binds to HER2 receptors on cancer cells, the linker needs to be cleaved or disrupted, allowing for payload release within the target cell.
  3. Internalization: The linker may have a role in promoting internalization of the ADC-HER2 complex into the cancer cell. Internalization ensures the ADC is efficiently delivered into the target cell, allowing for payload release in the intracellular environment.
  4. Payload stability and activity: The linker should maintain the stability and activity of the cytotoxic payload during circulation and release. It should protect the payload from degradation or inactivation until it reaches the intended site of action.
  5. Pharmacokinetics: The linker can influence the pharmacokinetic properties of the ADC, such as its half-life, clearance, and distribution. The choice of linker can impact the systemic exposure and tissue distribution of the ADC, which can affect its efficacy and toxicity profile.

The design and selection of the linker in HER2 drugs are critical for achieving optimal therapeutic outcomes. Various linker types, such as cleavable linkers, non-cleavable linkers, or protease-sensitive linkers, can be utilized based on the desired mechanism of payload release and the specific characteristics of the cytotoxic agent being used.

Common linkers used in HER2 drug conjugates

The linker types used in HER2-targeted drugs, particularly antibody-drug conjugates (ADCs), can vary depending on the specific drug design and the intended mechanism of payload release. Here are some common linker types that have been used in HER2 drugs:

  1. Cleavable linkers: Cleavable linkers are designed to be sensitive to specific intracellular conditions or enzymatic activity within the cancer cell. They allow for the selective release of the cytotoxic payload once the ADC is internalized. Cleavable linkers can be designed to be sensitive to factors such as low pH, reducing conditions, or specific enzymes present in the target cell’s lysosomes or cytoplasm. Click here for a full collection of cleavable linkers.
  2. Non-cleavable linkers: Non-cleavable linkers are more stable and resistant to degradation compared to cleavable linkers. These linkers rely on other mechanisms, such as lysosomal degradation or receptor-mediated recycling, for payload release. Non-cleavable linkers are generally more stable during circulation, reducing the premature release of the payload before reaching the target cells.
  3. Protease-sensitive linkers: Some linkers are designed to be sensitive to specific proteases present in the tumor microenvironment or within the target cancer cells. These proteases can cleave the linker and release the cytotoxic payload. Protease-sensitive linkers provide an additional level of specificity by utilizing the unique protease profiles associated with the tumor cells. Click here to see a full collection of protease-sensitive linkers
  4. Self-immolative linkers: Self-immolative linkers undergo an intramolecular rearrangement upon internalization, leading to the release of the cytotoxic payload. These linkers can be designed to be triggered by various stimuli, such as pH or enzymatic activity, resulting in payload release within the target cell.

The selection of a specific linker type depends on various factors, including the desired mechanism of payload release, the stability required during circulation, and the characteristics of the cytotoxic payload being used. The goal is to achieve optimal payload release and therapeutic efficacy while minimizing off-target effects and systemic toxicity.

As one of the major linker technology companies, AxisPharm has more than 5000 high-quality bioconjugation linkers in our San Diego warehouse. Please click here to find out how our diversified linkers can meet your research needs. We also provide custom synthesis and bioconjugation services to support ADC and AOC research and development. Click here to learn how our custom linker synthesis and bioconjugation service can benefit your ADC research.

Related articles reading:

Related Posts