Fc-engineering significantly improves the recruitment of immune effector cells by anti-ICAM-1 antibody MSH-TP15 for myeloma therapy
Klausz K, Cieker M, Kellner C, Roesner T, Otte A, Krohn S, Lux A, Nimmerjahn F, Valerius T, Gramatzki M, Peipp M (2021)
Publication Type: Journal article
Publication year: 2021
Journal
Book Volume: 106
Pages Range: 1857-1866
Journal Issue: 7
DOI: 10.3324/haematol.2020.251371
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.
Authors with CRIS profile
Involved external institutions
Universitätsklinikum Schleswig-Holstein (UKSH)
Germany (DE)
Ludwig-Maximilians-Universität (LMU)
Germany (DE)
Germany (DE)
Ludwig-Maximilians-Universität (LMU)
Germany (DE)
How to cite
APA:
Klausz, K., Cieker, M., Kellner, C., Roesner, T., Otte, A., Krohn, S.,... Peipp, M. (2021). Fc-engineering significantly improves the recruitment of immune effector cells by anti-ICAM-1 antibody MSH-TP15 for myeloma therapy. Haematologica, 106(7), 1857-1866. https://doi.org/10.3324/haematol.2020.251371
MLA:
Klausz, Katja, et al. "Fc-engineering significantly improves the recruitment of immune effector cells by anti-ICAM-1 antibody MSH-TP15 for myeloma therapy." Haematologica 106.7 (2021): 1857-1866.
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