In:
Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5551-5551
Kurzfassung:
Immunotherapy is a promising option for cancer treatment. Our previous studies demonstrated that DKK1 is widely expressed by various tumor cells including multiple myeloma (MM) and other hematological malignancies but not normal tissues, and DKK1 peptide (such as P20 and P66v, which bind with HLA-A2 molecule) specific cytotoxic T cells specifically kill myeloma and other cancer cells that express DKK1 and HLA-A2, but not HLA-A2+ normal cells, indicating that DKK1+ tumor cells naturally express these peptides, in the context of HLA-A2 molecules, on their surface. To develop cancer therapeutic antibodies, DKK1 peptide P20-HLA-A2 monomer was synthesized and used to immunize mice. Hybridomas secreting monoclonal antibodies (mAbs) recognizing soluble and cell surface-expressed DKKl P20-HLA-A2 complex were obtained and analyzed. The mAbs bind specifically with DKK1-expressing, HLAA2+ cancer cells but not DKK1-expressing, HLA-A2- cancer cells or DKK1- HLA-A2+ normal blood cells. The mAbs exhibited potent in vitro tumoricidal activity on HLA-A2+DKK1+ U266 multiple myeloma cells, HLA-A2+DKK1+ PC-3 prostate cancer cells and T2 cells loaded with DKK1-P20 peptides. Our results also showed that the anti-DKK1-HLA-A2 mAbs effectively lysed cancer cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which were correlated with and dependent on the surface expression of DKK1-HLA-A2 complex on cancer cells. Furthermore, anti-DKK1/HLA-A2 mAbs were also active and therapeutic in vivo. In MM xenografted SCID mouse model, the mAbs were able to eradicate U266 MM cells and more than 60% of mAb-treated mice survived for 3 months, while control mice all died within 2 months. Toxicity and safety assay in MM xenografted A2-SCID mouse model showed that the mAbs had no significant negative effects on different normal tissues. Therefore, these results support clinical development of anti- DKK1-HLA-A2 mAbs as therapeutic agents to treat hematological malignancies and possibly solid tumors that express surface DKK1-HLA-A2. Disclosures No relevant conflicts of interest to declare.
Materialart:
Online-Ressource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2019-123541
Sprache:
Englisch
Verlag:
American Society of Hematology
Publikationsdatum:
2019
ZDB Id:
1468538-3
ZDB Id:
80069-7
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