Defucosylation of Tumor-Specific Humanized Anti-MUC1 Monoclonal Antibody Enhances NK Cell-Mediated Anti-Tumor Cell Cytotoxicity
| Autor: | Yvo F. Graus, Silvie Cloosen, Ying Gong, Valeriia Gulaia, Roel G. J. Klein Wolterink, Gerard M. J. Bos, Femke A I Ehlers, Lotte Wieten, Wilfred T. V. Germeraad |
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| Přispěvatelé: | Interne Geneeskunde, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), MUMC+: DA TI Laboratorium (9), Transplant. Immunology/Tissue Typing lab, MUMC+: DA TI Staf (9), MUMC+: MA Hematologie (9) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
EXPRESSION Cancer Research medicine.drug_class medicine.medical_treatment ENDOCYTOSIS Fc receptor MUC1 CD16 Monoclonal antibody digestive system Article Epitope 03 medical and health sciences NATURAL-KILLER-CELLS 0302 clinical medicine breast cancer Antigen Cancer immunotherapy medicine skin and connective tissue diseases neoplasms antibody therapy RC254-282 Antibody-dependent cell-mediated cytotoxicity natural killer cells biology Chemistry GLYCOSYLATION Neoplasms. Tumors. Oncology. Including cancer and carcinogens biological factors digestive system diseases RECEPTORS 030104 developmental biology Oncology 030220 oncology & carcinogenesis biology.protein Cancer research T-CELLS DOWN-MODULATION Antibody MEMBRANE antibody-dependent cellular cytotoxicity |
| Zdroj: | Cancers, Vol 13, Iss 2579, p 2579 (2021) Cancers Volume 13 Issue 11 Cancers, 13(11):2579. Multidisciplinary Digital Publishing Institute (MDPI) |
| ISSN: | 2072-6694 |
| Popis: | Simple Summary Antibodies with their high specificity to antigens have been widely used in cancer immunotherapy. Natural killer (NK) cells are a group of innate immune cells which have strong cytotoxicity against cancerous cells, virus infected cells, or transformed cells. NK cells express abundant Fc receptors that can bind tumor-specific antibodies, thus allowing them to precisely redirect and eliminate cancer cells. In this study, we demonstrated that NK cells cytotoxicity toward MUC1-positive hematologic and solid tumor can be further enhanced by a humanized 5E5 anti-MUC1 antibody. Furthermore, Fc defucosylation of the antibodies further boosted the kill capacity of NK cells. We believe that our humanized anti-MUC1 antibody is a promising therapeutic candidate for clinical cancer treatment. Abstract Antibodies are commonly used in cancer immunotherapy because of their high specificity for tumor-associated antigens. The binding of antibodies can have direct effects on tumor cells but also engages natural killer (NK) cells via their Fc receptor. Mucin 1 (MUC1) is a highly glycosylated protein expressed in normal epithelial cells, while the under-glycosylated MUC1 epitope (MUC1-Tn/STn) is only expressed on malignant cells, making it an interesting diagnostic and therapeutic target. Several anti-MUC1 antibodies have been tested for therapeutic applications in solid tumors thus far without clinical success. Herein, we describe the generation of fully humanized antibodies based on the murine 5E5 antibody, targeting the tumor-specific MUC1-Tn/STn epitope. We confirmed that these antibodies specifically recognize tumor-associated MUC1 epitopes and can activate human NK cells in vitro. Defucosylation of these newly developed anti-MUC1 antibodies further enhanced antigen-dependent cellular cytotoxicity (ADCC) mediated by NK cells. We show that endocytosis inhibitors augment the availability of MUC1-Tn/STn epitopes on tumor cells but do not further enhance ADCC in NK cells. Collectively, this study describes novel fully humanized anti-MUC1 antibodies that, especially after defucosylation, are promising therapeutic candidates for cellular immunotherapy. |
| Databáze: | OpenAIRE |
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