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.

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

Glycosylation of MUC1 in cancer progression. Fig.2 Glycosylation of MUC1 in cancer progression.

Perclincal Anti-tumor Activity

Gatipotuzumab

Gatipotuzumab

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.

Gatipotuzumab

Clinical Development Status

Gatipotuzumab

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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.

RESOURCES

Creative Biolabs provides luciferase-based ADCC assay. This Jurkat cell based assay is pioneered by Creative Biolabs, and the methodology is very well accepted by the field. See attached ADCC Reporter Assay Protocol for further details. 

All products and services are for Research Use Only. Do Not use in humans.

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