TrasGEX

Overview

TrasGEX (alternative names: Glycooptimised TrastuzuMab-GEX; GT-Mab 7.3-GEX; TrasGEX; TrastuzuMab-GEX) is an anti-HER2 mAb that exhibits increased binding affinity for all FcγRIIIa variants expressed on immune effector cells. Compared to its parent antibody—trastuzumab, defucosylated TrasGEX showed significantly improved cell killing in ADCC-based assays and a higher activity in models in vivo. In addition, TrasGEX is currently being evaluated in clinical phase II trials and has shown good clinical activity in patients with HER2-positive solid tumors.

ADCC Enhancement Technology for Trastuzumab

TrasGEX is a second-generation glycosylated antibody developed to meet the needs of a new therapy exhibiting higher activity on Her2-positive cancers. The glycosylation process used to develop this agent is achieved by reducing the fucosylation in the Fc region of the mAb molecule, resulting in increased binding affinity of the agent for the FcγRIII receptor on immune effector cells.

Mechanism of Action of Trastuzumab

TrasGEX is derived from a parent antibody—trastuzumab. TrasGEX and trastuzumab bind to the same epitope of HER2 and thus, allow for competition and substitution between these two antibodies. Similar to the MOA of trastuzumab, glyco-engineered TrasGEX is thought to exhibit its therapeutic activity against HER2-positive tumors because of:

• Regulating HER2 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.1 Mechanism of action of Trastuzumab.

Glycan Analysis

• Oligosaccharide profile of afucosylated trastuzumab (TrasGEX) and Trastuzumab is shown below.

Binding Affinity Characterization

• Binding characterization of afucosylated trastuzumab (TrasGEX) to mouse and human FcγR in a figure.

ADCC Activity

• TrasGEX showed strongly enhanced ADCC activity in HER2-expressing breast cancer type, compared to trastuzumab.

Preclinical Research

• Afucosylated trastuzumab (TrasGEX) showed superior in vivo efficacy in treating KPL-4 tumor xenografts, compared to trastuzumab. For more details, please click: https://cancerres.aacrjournals.org/content/70/11/4481.

Clinical Anti-tumor Activity

• Strong results was observed on the level of primary tumor, lymph node, metastases and skin lesions, and others. The figure below shows the therapeutic efficacy in the treatment of patients with breast cancer.

• TrasGEX shows a clinical benefit rate (CBR) of 40.5%.

• TrasGEX exhibits activity even at lower doses.

Clinical Development Status

For more detailed information, please do not hesitate to contact us.

References

1. Junttila TT.; et al. Superior In vivo Efficacy of Afucosylated Trastuzumab in the Treatment of HER2-Amplified Breast Cancer. Cancer Research. 2010, 70(11):4481-4489.
2. Walter F.; et al. Phase I study of TrasGEX, a glyco-optimised anti-HER2 monoclonal antibody, in patients with HER2-positive solid tumours[J]. ESMO Open, 2018, 3(4):e000381.
3. Fiedler W.; et al. Phase I study of TrasGEX, a glyco-optimised anti-HER2 monoclonal antibody, in patients with HER2-positive solid tumours. ESMO Open. 2018, 3(4), e000381. doi:10.1136/esmoopen-2018-000381.