Bispecific Antibodies Targeting HER2 and HER3

Introduction to HER2

HER2 (human epidermal growth factor receptor 2) is a transmembrane receptor tyrosine kinase encoded by the ERBB2 gene, also known as ERBB2 or NEU. The protein structure of HER2 consists of a ligand-binding extracellular domain, a transmembrane domain and an intracellular domain with kinase activity. HER2 is involved in normal cell growth, differentiation and survival, by forming homodimers or heterodimers with other EGFR family members, activating various signaling pathways, such as RAS/RAF/MEK/ERK, PI3K/AKT and JAK/STAT. HER2 is overexpressed or amplified in various tumors, and is associated with tumor aggressiveness, metastatic potential and poor prognosis. It is an important therapeutic target for malignant tumors such as breast cancer, gastric cancer, ovarian cancer, lung cancer and others.

Introduction to HER3

HER3 (human epidermal growth factor receptor 3) is another transmembrane receptor tyrosine kinase encoded by the ERBB3 gene, also known as ERBB3 or ErbB-3. The protein structure of HER3 is similar to that of HER2, but its intracellular domain lacks or has almost no tyrosine kinase intrinsic activity, and needs to form heterodimers with other EGFR family members to function. HER3 mainly binds to NRG (neuregulin) family ligands, and activates the PI3K/AKT signaling pathway by forming dimers with HER2 or EGFR, promoting cell survival, proliferation and migration. HER3 is overexpressed or activated in various tumors, and is associated with tumor resistance, recurrence and poor prognosis. It is an important therapeutic target for malignant tumors such as breast cancer, colorectal cancer, head and neck squamous cell carcinoma, lung cancer and others.

Signaling Pathways Involved in Bispecific Antibodies Targeting HER2 and HER3

Bispecific antibodies (BsAbs) targeting HER2 and HER3 mainly inhibit tumor growth and survival by blocking the HRG/HER3 signaling pathway. The HRG/HER3 signaling pathway is an important oncogenic signaling pathway that activates the PI3K/AKT signaling pathway, promoting cell cycle progression, inhibiting apoptosis, increasing angiogenesis and metastasis. The HRG/HER3 signaling pathway is also an important mechanism of resistance, by upregulating HER3 expression or secreting HRG, tumor cells can evade treatment targeting EGFR, HER2 or other signaling pathways. BsAbs targeting HER2 and HER3 can inhibit the HRG/HER3 signaling pathway by two mechanisms: one is by blocking the binding of HRG to HER3, and the other is by blocking the dimerization of HER2 and HER3.

Clinical Status of Bispecific Antibodies Targeting HER2 and HER3

So far, three BsAbs targeting HER2 and HER3 have been approved for marketing, namely MCLA-128 and PB4188. The approved BsAbs mainly target breast cancer, gastric cancer, and lung cancer, which are common malignancies with high morbidity and mortality.

Table 1. Approved BsAbs targeting HER2 and HER3.

In addition, there are several BsAbs targeting HER2 and HER3 in different stages of clinical trials. Table 2 lists a representative BsAb and its relevant information. BsAbs targeting HER2 and HER3 in clinical trials are mainly led by companies or research institutions from North America, Europe and Asia.

Table 2. Example of BsAbs targeting HER2 and HER3 in clinical trials.

References

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