Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study evaluated the ability of daniplestim, a high affinity interleukin 3 receptor agonist, to enhance the hematopoietic response of Mpl ligand (Mpl-L) administration in nonhuman primates following severe, radiation-induced myelosuppression. Rhesus monkeys were total body x-irradiated (TBI) to 600 cGy, midline tissue dose. Beginning on day 1 post-TBI, animals were s.c. administered daniplestim (100 microg/kg bid; n = 4), Mpl-L (10 microg/kg qd; n = 3), daniplestim (100 microg/kg bid) plus Mpl-L (10 microg/kg qd) (n = 4) or 0.1% autologous serum (AS) (n = 11) for 18 days. CBCs were monitored for 60 d after TBI. The duration of thrombocytopenia (platelet count; PLT <20,000/microl) was significantly decreased by the administration of daniplestim (6.5 d, p = .01), Mpl-L (3.0 d, p = .003) and the coadministered daniplestim/Mpl-L (1.3 d, p = .001) compared to controls (10.4 d). As monotherapy Mpl-L but not daniplestim significantly improved the PLT nadir (21,000/microl, p = .023 and 5,000/microl, p = .266, respectively) compared to the control (3,000/microl). The combined administration of daniplestim and Mpl-L significantly improved the PLT nadir (28,000/microl, p = .007) compared to both the control cohort (3,000/microl) and the daniplestim only cohort (5,000/microl, p = .043). Recovery of PLT to preirradiation values occurred earlier in the daniplestim only (d 21) or the daniplestim/Mpl-L cohorts (d 18) than in the Mpl-L only or control cohorts (d 28, d 29, respectively). The administration of daniplestim or Mpl-L alone neither shortened the duration of neutropenia (ANC<500/microl) compared to the controls (15.8 d, 16.0 d versus 16.2 d, respectively), nor improved the recovery time of neutrophils to baseline values (d 22, d 25, and d 23, respectively). The ANC nadir was significantly improved by daniplestim alone but not Mpl-L administration (76/microl, p = .001 and 50/microl, p = .093, respectively) compared to the controls (8/microl). Coadministration of daniplestim and Mpl-L significantly improved the ANC nadir (196/microl, p = .001) compared to either the AS- or the monotherapy-treated cohorts. Also the duration of neutropenia observed in the AS-controls (16.2 d) was significantly reduced in the daniplestim/Mpl-L cohort (10.8 d, p = .002). The combined administration of daniplestim and Mpl-L significantly improved hematopoietic recovery and further enhanced the stimulatory effect of cytokine monotherapy, as well as reducing clinical support requirements after radiation-induced bone marrow myelosuppression.
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PMID:The combined administration of daniplestim and Mpl ligand augments the hematopoietic reconstitution observed with single cytokine administration in a nonhuman primate model of myelosuppression. 1101 86

The treatment of patients with acute myeloid leukemia (AML) with targeted immunotherapy is challenged by the heterogeneity of the disease and a lack of tumor-exclusive antigens. Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen receptor (CAR)-engineered T-cells (CAR-T-cells), a therapy that has been highly successful in the treatment of B-cell leukemia and lymphoma. However, CD33 and CD123 are present on hematopoietic stem cells, and targeting with CAR-T-cells has the potential to elicit long-term myelosuppression. C-type lectin-like molecule-1 (CLL1 or CLEC12A) is a myeloid lineage antigen that is expressed by malignant cells in more than 90% of AML patients. CLL1 is not expressed by healthy Hematopoietic Stem Cells (HSCs), and is therefore a promising target for CAR-T-cell therapy. Here, we describe the development and optimization of an anti-CLL1 CAR-T-cell with potent activity on both AML cell lines and primary patient-derived AML blasts in vitro while sparing healthy HSCs. Furthermore, in a disseminated mouse xenograft model using the CLL1-positive HL60 cell line, these CAR-T-cells completely eradicated tumor, thus supporting CLL1 as a promising target for CAR-T-cells to treat AML while limiting myelosuppressive toxicity.
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PMID:Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia. 2907 54

Previous studies have demonstrated the radioprotective efficacy of scorpion venom peptide, fraction II (SVPII) from the venom of Buthus martensii Karsch. In the present study, the SVP-B5 polypeptide, which is one of the active components of SVPII, was purified using a two-step chromatographic process. SVP-B5 significantly promoted the proliferation of irradiated M-NFS-60 mouse-derived myelocytic leukemia cells. In addition, SVP-B5 effectively and persistently promoted hematopoietic recovery and expansion of hematopoietic cells after irradiation as demonstrated by cobblestone area forming cell and long-term bone marrow culture assays. Treatment of M-NFS-60 cells with SVP-B5 upregulated the expression of interleukin 3 receptor and activated the Janus kinase-2/signal transducer and activator of transcription 5 signaling pathway. In conclusion, the present study demonstrated that SVP-B5 has growth factor-like properties and may be used as a therapeutic modality in the recovery of severe myelosuppression, which is a common side effect of radiotherapy.
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PMID:SVP-B5 peptide from Buthus martensii Karsch scorpion venom exerts hyperproliferative effects on irradiated hematopoietic cells. 2920 Dec 18

The outlook for patients with refractory/relapsed acute myeloid leukemia (AML) remains poor, with conventional chemotherapeutic treatments often associated with unacceptable toxicities, including severe infections due to profound myelosuppression. Thus there exists an urgent need for more effective agents to treat AML that confer high therapeutic indices and favorable tolerability profiles. Because of its high expression on leukemic blast and stem cells compared with normal hematopoietic stem cells and progenitors, CD123 has emerged as a rational candidate for molecularly targeted therapeutic approaches in this disease. Here we describe the development and preclinical characterization of a CD123-targeting antibody-drug conjugate (ADC), IMGN632, that comprises a novel humanized anti-CD123 antibody G4723A linked to a recently reported DNA mono-alkylating payload of the indolinobenzodiazepine pseudodimer (IGN) class of cytotoxic compounds. The activity of IMGN632 was compared with X-ADC, the ADC utilizing the G4723A antibody linked to a DNA crosslinking IGN payload. With low picomolar potency, both ADCs reduced viability in AML cell lines and patient-derived samples in culture, irrespective of their multidrug resistance or disease status. However, X-ADC exposure was >40-fold more cytotoxic to the normal myeloid progenitors than IMGN632. Of particular note, IMGN632 demonstrated potent activity in all AML samples at concentrations well below levels that impacted normal bone marrow progenitors, suggesting the potential for efficacy in AML patients in the absence of or with limited myelosuppression. Furthermore, IMGN632 demonstrated robust antitumor efficacy in multiple AML xenograft models. Overall, these findings identify IMGN632 as a promising candidate for evaluation as a novel therapy in AML.
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PMID:A CD123-targeting antibody-drug conjugate, IMGN632, designed to eradicate AML while sparing normal bone marrow cells. 2966 55