Abstract
Despite several therapeutic advances, patients with multiple myeloma (MM) require additional treatment options since no curative therapy exists yet. In search of a novel therapeutic antibody, we previously applied phage display with myeloma cell screening and developed TP15, a single-chain fragment variable targeting intercellular adhesion molecule 1 (ICAM-1/CD54). In order to more precisely evaluate the antibody's modes of action, fully human immunoglobulin G1 antibody variants were generated bearing the wild-type (MSH-TP15) or mutated fragment crystallizable (Fc-engineered [Fc-eng.]) region to either enhance (MSH-TP15 Fc-eng.) or prevent (MSH-TP15 Fc knockout [Fc k.o.]) Fc gamma receptor binding. Especially MSH-TP15 Fc-eng. induced significant antibody-dependent cell-mediated cytotoxicity against malignant plasma cells by recruiting natural killer cells and engaged macrophages for antibody-dependent cellular phagocytosis of tumor cells. Binding studies with truncated ICAM-1 demonstrated MSH-TP15 binding to ICAM-1 domain 1-2. Importantly, MSH-TP15 and MSH-TP15 Fc-eng. both prevented myeloma cell engraftment and significantly prolonged survival of mice in an intraperitoneal xenograft model. In the subcutaneous model MSH-TP15 Fc-eng. was superior to MSH-TP15, whereas MSH-TP15 Fc k.o. was not effective in either of the models - reflecting the importance of Fc-dependent mechanisms of action also in vivo. The efficient recruitment of immune cells and the observed anti-tumor activity of the Fc-engineered MSH-TP15 antibody hold significant potential for myeloma immunotherapy.
| Item Type: | Journal article |
|---|---|
| Faculties: | Medicine |
| Subjects: | 600 Technology > 610 Medicine and health |
| ISSN: | 0390-6078 |
| Language: | English |
| Item ID: | 99583 |
| Date Deposited: | 05. Jun 2023, 15:32 |
| Last Modified: | 17. Oct 2023, 15:01 |
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