HER-3 ADC Research and Development Progress

Although the combination therapy of immune checkpoint inhibitor combined with ADC is currently being favored by major pharmaceutical companies, there is no relevant clinical trial of HER-3 ADC combined with immune checkpoint inhibitor carried out worldwide.

HER-3 and Tumor Treatment

Human epidermal growth factor receptor (HER) proteins are a family of receptor tyrosine kinases consisting of four highly homologous members: epidermal growth factor receptor (EGFR, also known as ERBB1/HER-1), HER-2 (ERBB2), HER-3 (ERBB3), and HER-4 (ERBB4). HER-3, as one of the HER family members, not only induces tumorigenesis alone, but also synergistically induces tumorigenesis, metastatic progression, and drug resistance with other family members.

Fig. 1 HER-3 dimerization and signaling cascade.¹

HER-3 is expressed in a variety of solid tumors, including breast cancer, lung cancer, etc. HER-3 can activate signaling pathways such as PI3K/AKT, MAPK, JAK/STAT, etc., and the activation of these signaling pathways has been associated with resistance to various drugs. Therefore, HER-3 is an important therapeutic target.

Drug development for HER-3 targets is based on several principles:

• Locking HER-3 in a "bound" state
• Capturing its high-affinity ligand, the neuromodulin (NRG)
• Blocking the ligand binding site
• Promoting the internalization of HER-3
• Blocking the heterodimerization of HER-3 with other members of the HER family
• Promoting immune cell clearance of HER-3-expressing tumor cells

Advances in HER-3 ADC Drug Development

Currently, there are no HER-3 targeted ADCs approved globally. Only 17 HER-3 ADCs in the world, and only 6 have entered the clinic. The exploration of indications mainly focuses on non-small cell lung cancer, breast cancer, esophageal cancer and other solid tumors.

• The antibody portion of an developed ADC drug targeting HER-3 is a HER-3 monoclonal antibody, covalently coupled to a topoisomerase I inhibitor via linker. By binding to HER-3 on the surface of cancer cells, it is endocytosed into the cell to release the inhibitor, which in turn exerts a cytotoxic effect and kills cancer cells.
• The world's exclusive recombinant humanized ADC targeting EGFR/HER-3 dual targets independently developed can simultaneously bind EGFR and HER-3 on tumor cells to achieve simultaneous blockade of two tumor-related targets, thus obtaining targeting and enhanced anti-tumor activity.
• An ADC product targeting HER-3 developed consists of a novel humanized anti-HER-3 monoclonal antibody covalently linked to a proprietary DNA topoisomerase I inhibitor via a maleimide cleavable linker.

At Creative Biolabs, we acknowledge the potential impact that HER-3 ADCs can bring about in oncology. We remain devoted to innovation and implementation of ground-breaking technologies in immune checkpoint research. Please do not hesitate to contact us with your particular needs.

Reference

1. Haikala, et al. "Thirty years of HER3: from basic biology to therapeutic interventions." Clinical Cancer Research 27.13 (2021): 3528-3539.

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