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Bispecific NKG2D-CD3 and NKG2D-CD16 Fusion Proteins as Novel Treatment Option in Advanced Soft Tissue Sarcomas.
- Source :
-
Frontiers in immunology [Front Immunol] 2021 Apr 14; Vol. 12, pp. 653081. Date of Electronic Publication: 2021 Apr 14 (Print Publication: 2021). - Publication Year :
- 2021
-
Abstract
- Soft tissue sarcoma (STS) constitutes a rare group of heterogeneous malignancies. Effective treatment options for most subtypes of STS are still limited. As a result, especially in metastatic disease, prognosis is still dismal. The ligands for the activating immunoreceptor NKG2D (NKG2DL) are commonly expressed in STS, but generally absent in healthy tissues. This provides the rationale for utilization of NKG2DL as targets for immunotherapeutic approaches. We here report on the preclinical characterization of bispecific fusion proteins (BFP) consisting of the extracellular domain of the NKG2D receptor fused to Fab-fragments directed against CD3 (NKG2D-CD3) or CD16 (NKG2D-CD16) for treatment of STS. After characterization of NKG2DL expression patterns on various STS cell lines, we demonstrated that both NKG2D-CD16 and NKG2D-CD3 induce profound T and NK cell reactivity as revealed by analysis of activation, degranulation and secretion of IFNγ as well as granule associated proteins, resulting in potent target cell lysis. In addition, the stimulatory capacity of the constructs to induce T and NK cell activation was analyzed in heavily pretreated STS patients and found to be comparable to healthy donors. Our results emphasize the potential of NKG2D-CD3 and NKG2D-CD16 BFP to target STS even in an advanced disease.<br />Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.<br /> (Copyright © 2021 Hagelstein, Lutz, Schmidt, Heitmann, Malenke, Zhou, Clar, Kopp, Jung, Salih, Märklin and Hinterleitner.)
- Subjects :
- Adult
Aged
Antibodies, Bispecific genetics
Antibodies, Bispecific pharmacology
CD3 Complex metabolism
Cell Degranulation drug effects
Cell Degranulation immunology
Cell Line, Tumor
Female
GPI-Linked Proteins antagonists & inhibitors
GPI-Linked Proteins metabolism
Humans
Killer Cells, Natural drug effects
Killer Cells, Natural immunology
Killer Cells, Natural metabolism
Lymphocyte Activation drug effects
Male
Middle Aged
NK Cell Lectin-Like Receptor Subfamily K metabolism
Primary Cell Culture
Protein Domains genetics
Receptors, IgG metabolism
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins isolation & purification
Recombinant Fusion Proteins pharmacology
Sarcoma immunology
T-Lymphocytes drug effects
T-Lymphocytes immunology
T-Lymphocytes metabolism
Young Adult
CD3 Complex antagonists & inhibitors
NK Cell Lectin-Like Receptor Subfamily K genetics
Receptors, IgG antagonists & inhibitors
Recombinant Fusion Proteins therapeutic use
Sarcoma drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 12
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 33936075
- Full Text :
- https://doi.org/10.3389/fimmu.2021.653081