Tomuzotuximab

Overview

Tomuzotuximab (or CetuGEX^®; Cetuximab biobetter - Glycotope; GT-MAB 5.2-GEX) is a novel monoclonal antibody (mAb) directed against the epidermal growth factor receptor (EGFR) with optimized and fully human glycosylation. Tomuzotuximab is optimized for glycosylation in its Fc domain to promote antibody-dependent cell-mediated cytotoxicity (ADCC). EGFR is overexpressed on the cell surface in a variety of tumor types and acts under anti-tumor mechanisms: strong ADCC, inhibition of proliferation by receptor blockade, and induction of apoptosis. A clinical phase I dose escalation study involving Tomuzotuxima is ongoing to investigate the efficacy of this antibody in the treatment of metastatic head and neck squamous cell carcinoma.

ADCC Enhancement Technology for Tomuzotuximab

Tomuzotuximab is a glycoengineered second generation antibody of parental cetuximab. The glycosylation process used to develop this agent is achieved by altering the glycosylation in the Fc region of the mAb molecule, resulting in a significant enhancement of immunogenicity and hence a stronger ADCC response.

Fig.1 Site-specific glycoengineering of cetuximab for enhanced ADCC activity.

Mechanism of Action of Tomuzotuximab

Glyco-engineered omuzotuximab is thought to have therapeutic activity against EGFR-positive tumors because of:

• Regulating EGFR signaling, leading to growth retardation or induction of apoptosis or cell death.
• Binding to Fc gamma receptor on improved immune cells to enhance the destruction of EGFR-positive tumor cells.
• Reaction with tumor antigens, which are presented by cells such as macrophage. When taking up antigen, it displays to other cells of the immune system, including T cells.

Fig.2 Mechanism of action of Tomuzotuximab.

Glycan Analysis of Tomuzotuximab

• The glycosylation pattern of glycosylated modified cetuximab (Tomuzotuximab) was verified by LC-MS analysis.

Antigen Binding Characteriztion

• SPR analysis of the FcγRIIIa binding with commercial cetuximab and the glycosylation-modified cetuximab (Tomuzotuximab)

ADCC Activity

• Elimination of fucose leads to an increase in the average ADCC of tomuzotuximab 10-50 times compared to cetuximab.

Clinical Anti-tumor Activity

• The waterfall plot shows the best persentage changes in sum of the longest diameter (SLD) from baseline for the target lesion in 33 patients. Clinical benefit was observed in 16 of 41 patients (39%).

Clinical Development Status

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Reference

1. John P.; et al. Site-selective chemoenzymatic glycoengineering of Fab and Fc glycans of a therapeutic antibody. PNAS. 2018, 115 (47) 12023-12027; first published November 5, 2018.