Daratumumab and Nanobody-Based Heavy Chain Antibodies Inhibit the ADPR Cyclase but not the NAD+ Hydrolase Activity of CD38-Expressing Multiple Myeloma Cells
| Autor: | Ralf Fliegert, Peter Bannas, Andreas Bauche, Stephan Menzel, Natalie Baum, Friedrich Koch-Nolte, Julia Hambach, Friedrich Haag |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.drug_class Cell CD38 Monoclonal antibody lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine heavy-chain antibodies hemic and lymphatic diseases Hydrolase medicine antibodies Cytotoxicity ecto-enzyme biology Chemistry Daratumumab lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Molecular biology nanobodies multiple myeloma 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis biology.protein NAD+ kinase Antibody NAD+ hydrolase |
| Zdroj: | Cancers, Vol 13, Iss 76, p 76 (2021) Cancers Volume 13 Issue 1 |
| ISSN: | 2072-6694 |
| Popis: | The nucleotides ATP and NAD+ are released from stressed cells as endogenous danger signals. Ecto-enzymes in the tumor microenvironment hydrolyze these inflammatory nucleotides to immunosuppressive adenosine, thereby, hampering anti-tumor immune responses. The NAD+ hydrolase CD38 is expressed at high levels on the cell surface of multiple myeloma (MM) cells. Daratumumab, a CD38-specific monoclonal antibody promotes cytotoxicity against MM cells. With long CDR3 loops, nanobodies and nanobody-based heavy chain antibodies (hcAbs) might bind to cavities on CD38 and thereby inhibit its enzyme activity more potently than conventional antibodies. The goal of our study was to establish assays for monitoring the enzymatic activities of CD38 on the cell surface of tumor cells and to assess the effects of CD38-specific antibodies on these activities. We monitored the enzymatic activity of CD38-expressing MM and other tumor cell lines, using fluorometric and HPLC assays. Our results showed that daratumumab and hcAb MU1067 inhibit the ADPR cyclase but not the NAD+ hydrolase activity of CD38-expressing MM cells. We conclude that neither clinically approved daratumumab nor recently developed nanobody-derived hcAbs provide a second mode of action against MM cells. Thus, there remains a quest for &ldquo double action&rdquo CD38-inhibitory antibodies. |
| Databáze: | OpenAIRE |
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