Development of a HER1/CP2c dual-targeting biopharmaceutical for HER1-overexpressing head and neck cancer

With the development of pharmaceuticals, the death rate due to Cancer continues to decrease. However, the incidence of major cancers remains high. Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent type of non-skin cancers and it predominantly expresses human epidermal growth factor receptor 1 (HER1). To selectively eliminate HNSCC, cetuximab was developed as a HER1 targeting monoclonal antibody (mAb) therapy. Despite approval from the US-FDA, Cetuximab- or other Anticancer drugs-related complications, such as mucosal inflammation, rash, intracranial infections, and neurological deficits, have been reported. In order to address these limitations, we have developed an antibody-drug conjugates (ADCs)-like Anticancer platform called dual-targeting Anticancer therapeutics (DTAT), which consists of a positioning site for mAbs or single-chain fragment variable (scFv) targeting specific antigens and a cell-penetrant cytotoxic payload targeting an oncoprotein CP2c conjugated to a Cleavable Linker sequence (CLS), which is sensed and cleaved by matrix metalloproteinase-11 (MMP-11). Based on this DTAT platform, we generated DTAT-D351, which dual-targets HER1 and CP2c, as an Anticancer biopharmaceutical for HNSCC. Our data showed that DTAT-D351 exhibited high productivity and a strong binding affinity for HER1. Moreover, DTAT-D351 showed high Anticancer potency against HER1-overexpressing Cancer cells and A431 epidermoid squamous carcinoma cells. Moreover, it showed no adverse reactions in immune cells and normal cells. In conclusion, DTAT-D351, herein called Cetuximab scFv-CPTin, is a promising and effective Anticancer agent for the treatment of HER1-overexpressing Cancer cells, including head and neck cancers.

Antibody-drug conjugate (ADC); CP2c; Epidermal growth factor receptor 1 (EGFR1); Epidermoid carcinoma; Head & neck cancer; Human epidermal growth factor receptor 1 (HER1).