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Cell Therapy & Immunotherapy
Fc-engineering significantly improves the recruitment of immune effector cells by anti-ICAM-1 antibody MSH-TP15 for myeloma therapy
Ferrata Storti Foundation
Haematologica 2021 Volume 106(7):1857-1866
Katja Klausz,1 Michael Cieker,1 Christian Kellner,2 Thies Rösner,1 Anna Otte,1 Steffen Krohn,1 Anja Lux,3 Falk Nimmerjahn,3 Thomas Valerius,1
Martin Gramatzki1 and Matthias Peipp1
1Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, University Hospital Schleswig-Holstein and Christian-Albrechts-University, Kiel; 2Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, University Hospital, LMU Munich, Munich and 3Institute of Genetics, Department of Biology, University of Erlangen-Nürnberg, Erlangen, Germany
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 generat- ed 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.]) Fcγ 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 sub- cutaneous 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.
Introduction
With approval of the monoclonal antibodies (mAb) daratumumab and elotuzum- ab in 2015, antibody-based immunotherapy has entered clinical practice for multi- ple myeloma (MM) patients. While both mAb show therapeutic activity in combi- nation with standard treatment regimens, only daratumumab has significant single- agent activity and is additionally approved as front-line therapy. Increased survival rates and good tolerability are achieved with both mAb, but still not all patients benefit and first drug resistances have been reported.1,2 Thus, there is still a high unmet medical need for myeloma patients.
For homing and growth of malignant plasma cells in the bone marrow (BM), adhesion molecules are of significant importance and ‘hiding’ tumor cells in the BM are believed to induce relapse in myeloma patients.3,4 Therefore, targeting the BM microenvironment and adhesion molecules might be explicitly reasonable for MM therapy.5 For instance, intercellular adhesion molecule-1 (ICAM-1/CD54) is report- ed to be highly expressed on malignant plasma cells and not down-regulated under MM therapy.6 Of note, significantly higher levels of ICAM-1 are expressed on
Correspondence:
MATTHIAS PEIPP
m.peipp@med2.uni-kiel.de
Received: March 11, 2020. Accepted: May 28, 2020. Pre-published: June 4, 2020.
https://doi.org/10.3324/haematol.2020.251371
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