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Although the fully humanized CD33 antibody lintuzumab induced complete remission in individual patients in single-agent phase I and II clinical trials, no survival was found in phase III clinical trials in which it was combined with a triple chemotherapy regimen. benefit
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Embodiment 1
[0325] Example 1 - Epigenetic modifying drugs as sensitizers of CD33-targeting compound-induced cytotoxicity
[0326] The level of CD33 expression was identified as a key variable for the degree of activity of CD33-targeting compounds described herein, such as AMG330, against human AML cells. Therefore, it was surprising to observe epigenetic modification drugs such as histone deacetylase (HDAC) inhibitors or DNA methyltransferase (DNMT) I inhibitors as sensitizers for AMG330-induced cytotoxicity potential.
[0327] For the experimental setup, monocytes were collected from healthy adult volunteers via leukapheresis and T cells were enriched by magnetic cell sorting (Pan T Cell Isolation Kit II; Miltenyi Biotec, Auburn, CA). Thawed cell aliquots were labeled with 3 μM CellVue Burgundy (eBioscience, San Diego, CA) according to the manufacturer's instructions.
[0328] Human bone marrow OCI-AML3, KG-1a, ML-1, NB4, TF-1 and HL-60 cells were maintained as previously described (...
Embodiment 2
[0333] CD33 up-regulation on Example 2-AML cells increases AMG 330-mediated lysis efficacy
[0334] Hydroxyurea
[0335] CD33 upregulation on AML cell lines:
[0336] AML cell lines HL-60, PL21, OCI-AML3, KG1a, and MV4-11 were seeded at 1 × 10^6 cells / ml on day 0 in 24-well plates. Cells were left untreated (UT) or treated with 10 μM (H1) or 100 μM (H2) hydroxyurea (Sigma) for three consecutive days (day 0, day 1 and day 2). On day 3, cells were harvested, counted and analyzed for changes in CD33 surface expression levels by flow cytometry.
[0337] image 3 and Table 2 show the upregulation of CD33 in a concentration-dependent manner on HL-60 and PL21 AML cells.
[0338] Table 2: CD33MFI ratios of HL-60 and PL21 AML cells determined by flow cytometry after incubation with / without hydroxyurea.
[0339] CD33 MFI ratio UT H1 H2 HL-60 134.9 171.3 210.0 PL21 166.9 177.9 191.8
[0340] Upregulation of CD33 on primary AML cells:
[0341] Th...
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Abstract
The present invention provides a combination epigenetic factors and bispecific compounds targeting CD33 and CD3 in the treatment of myeloid leukemia, wherein the epigenetic factor is selected from thegroup consisting of histone deacetylase (HDAC) inhibitors, DNA methyltransferase (DNMT) I inhibitors,hydroxyurea, Granulocyte-Colony Stimulating Factor (G-CSF), histone demethylase inhibitors and ATRA (All Trans-retinoic acid). Accordingly, the invention provides a pharmaceutical composition comprising a CD33 targeting compound and at least one epigenetic factor and an epigenetic factor for use in the amelioration and / or treatment of a myeloid leukemia, wherein the epigenetic factor increases the responsiveness of a patient to a CD33 targeting compound. Moreover, the invention provides the use of at least one an epigenetic factor for increasing the responsiveness of a myeloid leukemia patient to a treatment with a CD33 targeting compound, a method for the treatment of a myeloid leukemia,the method comprising the administration of at least one epigenetic factor and a CD33 targeting compound to a patient in the need thereof and a kit comprising a pharmaceutical composition of the invention or an epigenetic factor of the invention and a bispecific CD33 targeting compound.
Description
technical field [0001] The present invention provides a combination of an epigenetic factor and a bispecific compound targeting CD33 and CD3 for the treatment of myeloid leukemia, wherein the epigenetic factor is selected from the group consisting of histone deacetylase (HDAC) inhibitors, DNA alpha DNMT I inhibitors, hydroxyurea, granulocyte colony-stimulating factor (G-CSF), histone demethylase inhibitors, and ATRA (all-trans retinoic acid). Therefore, the present invention provides a pharmaceutical composition comprising a CD33 targeting compound and at least one epigenetic factor, and provides the epigenetic factor for improving and / or treating myeloid leukemia in which the epigenetic factor is increased in patients Responsiveness to CD33 Targeting Compounds. Furthermore, the present invention provides the use of at least one epigenetic factor for increasing the responsiveness of a myeloid leukemia patient to treatment with a CD33 targeting compound; a method for treating ...
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