HER2 As an Ideal Target for Antibody Drugs

The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to approval of the first HER2-targeted drug-the monoclonal antibody trastuzumab-almost 25 years ago. Since then, progress has been swift and the impressive clinical activity across multiple trials with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates that target HER2 has spawned extensive efforts to develop newer platforms and more targeted therapies.

What is HER2?

The human HER2 gene is located on chromosome 17q21 and belongs to the proto-oncogene, which encodes a 185 kD transmembrane protein, referred to as p185, consisting of 1255 amino acids, with positions 720-987 belonging to the tyrosine kinase region, HER2 protein is a transmembrane protein with tyrosine protein kinase activity. Current studies have shown that abnormal HER2 gene expression exists in several tumor types such as breast cancer, ovarian cancer, gastric cancer, uterine cancer, cervical cancer and biliary tract cancer, and the overexpression of HER2 gene is closely related to the degree of cancer progression, and tumors with high HER2 expression show strong metastatic and invasive ability, poor sensitivity to chemotherapy, and easy recurrence.

Specific Structure of HER2 and Its Targeting Sites

The epidermal growth factor receptor family (ERbB family) includes four family members, HER1, HER2, HER3 and HER4, which play important roles in cell growth, development and differentiation. Unlike other family members, HER2 lacks endogenous ligands and activates PI3K, MAPK and JAK/STAT signaling pathways through heterodimerization with other members of the ERBB family to promote cell proliferation and survival.

Fig. 1 Schematic representation of human epidermal growth factor (Erb) family and ligands. (Wang, et al.; 2019)

Antibodies targeting ligands or cytokines act by blocking their binding to receptors, whereas antibodies targeting surface receptors or proteins act by a variety of mechanisms, including blocking receptor-ligand interactions, inter-receptor or co-receptor interactions required for receptor activation, binding to tumor-specific antigens to mediate antibody-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). HER2 has both of these characteristics and is therefore a suitable target for antibody therapy.

This characteristic of HER2, which is overexpressed in tumors and has an extracellular structural domain, makes it an ideal target for antibody drug development. Currently, the main drugs targeting HER2 are monoclonal antibodies, dual antibodies, ADCs, peptide vaccines, antibody mimetic proteins, CAR-T, etc.

Mechanism of Resistance to HER2-Targeted Therapy

Resistance to anti-HER2 therapies may occur via multiple mechanisms, some of which appear to be shared between different agents. A common reason for trastuzumab treatment failure is incomplete inhibition of the HER family of receptors, which can be overcome by dual HER2-targeted therapy or ADCs with potent payloads that have activity even with lower HER2 expression. Effective inhibition of HER2 may also be thwarted by the emergence of HER2-activating mutations. Other resistance mechanisms include generation of p95HER2, a truncated form of HER2 that lacks the ECD that is recognized by anti-HER2 antibodies and Δ16HER2, a splice variant lacking the ECD encoded by exon 16, which leads to stabilization of homodimers and constitutive activation of downstream signaling.

Fig. 2 Select mechanisms of HER2-targeted resistance. (Swain, et al.; 2023)

Next-Generation Therapies for HER2 BC+

The ever-changing face of cancer and its ability to evade existing therapies have underscored the need for continued development of therapeutics based on existing and/or novel platforms and for uncovering new vulnerabilities in resistant tumours. Antibodies targeting alternative HER2 domains or other HER family members have been explored with the goal of achieving a more complete blockade of HER2 and dampening the effects on downstream signalling pathways.

Monoclonal antibodies

Disruption of HER2–HER3 dimerization is important for HER2-driven signalling and is targeted effectively by pertuzumab. The positive results from pertuzumab trials supported a strategy of targeting HER3, which has a crucial role in HER2-mediated tumorigenesis. Several HER3-targeted antibodies have been evaluated in the past decade, mainly targeting the ECD of HER3 (for example, seribantumab and patritumab) and some with modifications to improve ADCC (for example, lumretuzumab, TrasGex) or trap HER3 in an inactive conformation (elgemtumab).

Antibody–drug conjugates

There are more than a dozen HER2-targeted ADCs now in clinical development, with the aim of improving therapeutic index and efficacy. These ADCs differ from the approved agents in cytotoxic payload, DAR, linker or the HER2 epitope targeted.

Tyrosine kinase inhibitors

Targeting the intracellular kinase domain of HER2 using small-molecule inhibitors continues to be investigated with next-generation TKIs. This class of compounds is attractive owing to their unique ability to cross the BBB and BTB.

Bispecific antibodies

Advances in antibody biology and engineering have led to the development of bispecific antibodies that contain two binding sites directed against two separate antigens or conversely, can target two separate epitopes on the same antigen. Bispecific antibodies currently in development include Zanidatamab (ZW25), Zenocutuzumab (MCLA-128), and KN026.

Targeted protein degraders

An emerging technology aims to selectively degrade HER2-expressing cells by coupling targeted protein degraders to a HER2-specific antibody, generating an antibody neodegrader conjugate (AnDC). Conjugating the protein degrader to the HER2 antibody directs the degrader specifically to the cytosol of the target cells.

References:

Wang, J.; et al. Targeted therapeutic options and future perspectives for HER2-positive breast cancer. Signal transduction and targeted therapy. 2019, 4(1): 34.
Swain, S. M.; et al. Targeting HER2-positive breast cancer: Advances and future directions. Nature Reviews Drug Discovery. 2023, 22(2): 101-126.

* For research use only. Not intended for any clinical use.

Quick Inquiry