111年度育苗「開發針對cetuximab抗藥性癌症的anti-CEACAM6重鏈抗體藥物」

Epidermal growth factor receptor (EGFR) highly expressed on the cancer cell surface is a critical membrane receptor for cancer cell survival, cell cycle changes, tumor angiogenesis, cell migration, and invasion/metastasis. Blocking EGF/EGFR signaling has become a main targeted therapy for advanced stage of CRC (colorectal carcinoma) and HNSCC (head and neck squamous cell carcinoma). Cetuximab is a chimeric IgG1 antibody that specifically recognizes EGFR and is approved to treat advanced stage of CRC and HNSCC in combination with chemotherapy or radiotherapy. However, ~50% of patients develop drug resisitance after treatment for 3-12 months. Although K-RAS and EGFR mutation, and HER2 amplification have been reported to contribute the cetuximab-resistance, there are still a lot of unknown mechanisms for the poor outcome. Therefore, to develop an adjuvant therapy or second-line therapy for cetuximab-resistance is a critical issue. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a glycophosphoinositol (GPI)-anchored protein,
is a heavily-glycosylated tumor antigen. Our previous studies showed that (1) CEACAM6 interacts with EGFR and promotes OSCC metastasis via the complex N-glycans (2) Anti-CEACAM6 heavy chain (HC) Ab antibody (TMU HCAb) from an immune llama library had a better ability to recognize glycosylated CEACAM6 compared to conventional Ab. (3) TMU HCAb inhibited the invasion, migration and EGFR signaling and induced ADCC (antibody dependent cell-mediated
cytotoxicity) against CEACAM6-expressing CRC and OSCC cells. (4) CEACAM6 was highly expressed in the cetuximabresistant OSCC cells and combination of cetuximab and TMU HCAb significantly inhibited CRC tumor growth in a xenograft model. Based on the results, this project aims to develop (1) a second-line TMU HCAb therapy after cetuximab resistance. (2) a combinational treatment of cetuximab andTMU HCAb for CRC and HNSCC.

Our results demonstrated that the combinational treatment of TMU HCAb and cetuximab is more effective in inhibiting tumor growth than monotherapy. Although the humanized TMU hHCAb can recognize recombinant CEACAM6 protein, it is unable to recognize CEACAM6 on the cell membrane. Therefore, we used human IgG1 Chimeric TMU hHCAb antibody to develop an antibody-drug conjugate (ADC). Currently, this ADC has shown promising tumor inhibition effects in mouse xenograft models and performs better than the current clinical treatment regimen. Furthermore, it exhibits specific killing effects on CEACAM6-expressing tumors.