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Development of a HER1/CP2c dual-targeting biopharmaceutical for HER1-overexpressing head and neck cancer
Kyu Tae Byun1, Junmin Cho1, Boram Kim1
1Department of Biotechnology and Research Institute for Biomedical and Health Science (RIBHS), College of Biomedical and Health Science, Konkuk University, Chungju, 27478, Republic of Korea.
Abstract:
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.
Insights
A new dual-targeting therapy, DTAT-D351 (Cetuximab scFv-CPTin), effectively targets HER1 and CP2c in head and neck cancers. This promising agent shows high potency against cancer cells with no adverse effects on normal cells.
Area of Science:
- Oncology
- Biotechnology
- Pharmacology
Background:
- Head and neck squamous cell carcinoma (HNSCC) remains a significant health concern, despite advancements in cancer treatment.
- Current therapies like cetuximab, while targeting human epidermal growth factor receptor 1 (HER1), can cause severe side effects.
- There is a need for more targeted and safer therapeutic strategies for HNSCC.
Purpose of the Study:
- To develop a novel dual-targeting anticancer therapeutic platform, called dual-targeting anticancer therapeutics (DTAT).
- To create DTAT-D351, a specific agent targeting both HER1 and oncoprotein CP2c for HNSCC treatment.
- To evaluate the efficacy and safety of DTAT-D351 in preclinical models.
Main Methods:
- Development of the DTAT platform utilizing antibody-drug conjugate principles with a cleavable linker sequence (CLS) activated by matrix metalloproteinase-11 (MMP-11).
- Generation of DTAT-D351, incorporating a HER1-targeting single-chain fragment variable (scFv) and a CP2c-targeting cytotoxic payload.
- Assessment of DTAT-D351's binding affinity to HER1, anticancer potency against HER1-overexpressing and A431 cells, and its effects on immune and normal cells.
Main Results:
- DTAT-D351 demonstrated high productivity and strong binding affinity for HER1.
- The agent exhibited significant anticancer potency against HER1-overexpressing cancer cells and A431 epidermoid squamous carcinoma cells.
- DTAT-D351 showed no adverse reactions in immune cells and normal cells, indicating a favorable safety profile.
Conclusions:
- DTAT-D351, also known as Cetuximab scFv-CPTin, is a highly effective dual-targeting therapeutic agent.
- This novel biopharmaceutical shows promise for treating HER1-overexpressing cancers, including head and neck cancers.
- The DTAT platform offers a potential advancement in targeted cancer therapy with improved safety.
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