TY  - JOUR
AU  - Kaidun, Polina
AU  - Holzmayer, Samuel
AU  - Greiner, Sarah M
AU  - Seller, Anna
AU  - Tegeler, Christian M
AU  - Hagelstein, Ilona
AU  - Mauermann, Jonas
AU  - Engler, Tobias
AU  - Koch, André
AU  - Hartkopf, Andreas D
AU  - Salih, Helmut
AU  - Märklin, Melanie
TI  - Targeting NKG2DL with Bispecific NKG2D-CD16 and NKG2D-CD3 Fusion Proteins on Triple-Negative Breast Cancer.
JO  - International journal of molecular sciences
VL  - 24
IS  - 17
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - DKFZ-2023-01854
SP  - 13156
PY  - 2023
AB  - Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with a poor response rate to conventional systemic treatment and high relapse rates. Members of the natural killer group 2D ligand (NKG2DL) family are expressed on cancer cells but are typically absent from healthy tissues; thus, they are promising tumor antigens for novel immunotherapeutic approaches. We developed bispecific fusion proteins (BFPs) consisting of the NKG2D receptor domain targeting multiple NKG2DLs, fused to either anti-CD3 (NKG2D-CD3) or anti-CD16 (NKG2D-CD16) Fab fragments. First, we characterized the expression of the NKG2DLs (MICA, MICB, ULBP1-4) on TNBC cell lines and observed the highest surface expression for MICA and ULBP2. Targeting TNBC cells with NKG2D-CD3/CD16 efficiently activated both NK and T cells, leading to their degranulation and cytokine release and lysis of TNBC cells. Furthermore, PBMCs from TNBC patients currently undergoing chemotherapy showed significantly higher NK and T cell activation and tumor cell lysis when stimulated with NKG2D-CD3/CD16. In conclusions, BFPs activate and direct the NK and T cells of healthy and TNBC patients against TNBC cells, leading to efficient eradication of tumor cells. Therefore, NKG2D-based NK and T cell engagers could be a valuable addition to the treatment options for TNBC patients.
KW  - Humans
KW  - Triple Negative Breast Neoplasms: drug therapy
KW  - Triple Negative Breast Neoplasms: genetics
KW  - NK Cell Lectin-Like Receptor Subfamily K: genetics
KW  - Ligands
KW  - Administration, Cutaneous
KW  - Aggression
KW  - NK cell (Other)
KW  - NKG2D (Other)
KW  - T cell (Other)
KW  - TNBC (Other)
KW  - bispecific (Other)
KW  - breast cancer (Other)
KW  - fusion protein (Other)
KW  - immunotherapy (Other)
KW  - NK Cell Lectin-Like Receptor Subfamily K (NLM Chemicals)
KW  - Ligands (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37685962
C2  - pmc:PMC10487695
DO  - DOI:10.3390/ijms241713156
UR  - https://inrepo02.dkfz.de/record/282728
ER  -