Gatipotuzumab

Overview

Gatipotuzumab (PankoMab-GEX^®) is a fully humanized and glycosylated mAb that specifically recognizes a tumor-specific epitope of mucin-1 (TA-MUC1) with potential anti-tumor activity. Gatipotuzumab binds to the TA-MUC1 epitope expressed on the cell surface of tumor cells, activating the immune system to induce ADCC against tumor cells expressing TA-MUC1. TA-MUC1 is demonstrated as an abnormally glycosylated mucin 1 that is overexpressed in epithelial cancer, and glycosylated gatipotuzumab could distinguish between tumor MUC1 and non-tumor MUC1 epitopes. A clinical phase I trial about the efficacy of Gatipotuzumab treating cervical cancer has recently been published.

ADCC Enhancement Technology for Gatipotuzumab

Gatipotuzumab is a novel glycosylation-engineered humanized anti-MUC1 mAb developed to meet the needs of a new reagent with higher activity on MUC1-positive cancers cells. The glycosylation process used to develop this agent is, by altering the glycosylation in the Fc region of the mAb molecule, to significantly enhance immunogenicity and elicit a stronger ADCC / ADCP response.

Fig.1 The two major types of protein glycosylation in cancer progression.

Mechanism of Action of Gatipotuzumab

"Normal" or "healthy" MUC1 has long, complex and branched sugar-based side chains embedded, which usually terminates with fucose residues. The protein core of this conformation is hidden internally so it cannot be recognized by antibodies. On the contrary, cancer-associated MUC1 presents a new epitope of the immune system—a cancer-associated glycoform that is sialylation counterparts of the T and T antigens: Sialyl-T and Sialyl Tn. These sugar epitopes play an important role during antibody molecular recognition, providing a theoretical basis for the application of glyco-engineered anti-MUC1 MAb in the treatment of cancer patients. See figure below for its MOA.

Fig.2 Glycosylation of MUC1 in cancer progression.

Perclincal Anti-tumor Activity

• The overall survival (OS) staining pattern (TA-MUC1 / GPER and TA-MUC1 / ERa) was compared in patients with ovarian cancer. The OS of patients with positive Gatipotuzumab epitope staining was significantly reduced.

• The combination of tamoxifen and Gatipotuzumab reduces the viability of ovarian cancer cell lines.

Clincal Anti-tumor Activity

Gatipotuzumab has been shown to be safe and well tolerated in clinical stage I study, and exhibits good antitumor activity in advanced disease. Clinical benefits were observed on various primary tumors diseases, including 8 of 15 (53%) persentage changes in sum of the longest diameter (SLD) from baseline for ovarian cancer and 3 of 7 (43%) for non-small cell lung cancer (NSCLC). The waterfall diagram of the target lesion baseline changes is shown below.

Clinical Development Status

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References

1. Sabine H.; et al. Potential Interplay of the Gatipotuzumab Epitope TA-MUC1 and Estrogen Receptors in Ovarian Cancer. Int J Mol Sci. 2019, Jan; 20(2): 295.
2. Fiedler W.; et al. A phase I study of PankoMab-GEX, a humanised glyco-optimised monoclonal antibody to a novel tumour-specific MUC1 glycopeptide epitope in patients with advanced carcinomas. European Journal of Cancer. 2016, 63, 55–63.
3. Acres.; et al. Targeted Immunotherapy Designed to Treat MUC1-Expressing Solid Tumour. Cancer Vaccines. 2015, 79–97.
4. Martínez-Sáez, N.; et al. Principles of mucin structure: implications for the rational design of cancer vaccines derived from MUC1-glycopeptides. Chemical Society Reviews. 2015, 46(23), 7154–7175.