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1.
Pharmaceuticals (Basel) ; 16(11)2023 Nov 15.
Article in English | MEDLINE | ID: mdl-38004478

ABSTRACT

Acute myeloid leukemia (AML) is the second most common hematologic malignancy in children. The incidence of childhood AML is much lower than acute lymphoblastic leukemia (ALL), which makes childhood AML a rare disease in children. The role of genetic abnormalities in AML classification, management, and prognosis prediction is much more important than before. Disease classifications and risk group classifications, such as the WHO classification, the international consensus classification (ICC), and the European LeukemiaNet (ELN) classification, were revised in 2022. The application of the new information in childhood AML will be upcoming in the next few years. The frequency of each genetic abnormality in adult and childhood AML is different; therefore, in this review, we emphasize well-known genetic subtypes in childhood AML, including core-binding factor AML (CBF AML), KMT2Ar (KMT2A/11q23 rearrangement) AML, normal karyotype AML with somatic mutations, unbalanced cytogenetic abnormalities AML, NUP98 11p15/NUP09 rearrangement AML, and acute promyelocytic leukemia (APL). Current risk group classification, the management algorithm in childhood AML, and novel treatment modalities such as targeted therapy, immune therapy, and chimeric antigen receptor (CAR) T-cell therapy are reviewed. Finally, the indications of hematopoietic stem cell transplantation (HSCT) in AML are discussed.

2.
Sci Transl Med ; 8(351): 351ra105, 2016 08 10.
Article in English | MEDLINE | ID: mdl-27510901

ABSTRACT

Hematopoietic stem cell (HSC) transplantation can cure diverse diseases of the blood system, including hematologic malignancies, anemias, and autoimmune disorders. However, patients must undergo toxic conditioning regimens that use chemotherapy and/or radiation to eliminate host HSCs and enable donor HSC engraftment. Previous studies have shown that anti-c-Kit monoclonal antibodies deplete HSCs from bone marrow niches, allowing donor HSC engraftment in immunodeficient mice. We show that host HSC clearance is dependent on Fc-mediated antibody effector functions, and enhancing effector activity through blockade of CD47, a myeloid-specific immune checkpoint, extends anti-c-Kit conditioning to fully immunocompetent mice. The combined treatment leads to elimination of >99% of host HSCs and robust multilineage blood reconstitution after HSC transplantation. This targeted conditioning regimen that uses only biologic agents has the potential to transform the practice of HSC transplantation and enable its use in a wider spectrum of patients.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Immunotherapy/methods , Animals , CD47 Antigen/antagonists & inhibitors , CD47 Antigen/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Erythrocytes/metabolism , Flow Cytometry , Hematopoietic Stem Cells/metabolism , Hematopoietic Stem Cells/physiology , Humans , Mice , Mice, Mutant Strains , Receptors, Fc/genetics , Receptors, Fc/metabolism
3.
Clin Cancer Res ; 22(20): 5109-5119, 2016 Oct 15.
Article in English | MEDLINE | ID: mdl-27126995

ABSTRACT

PURPOSE: CD47 is highly expressed on a variety of tumor cells. The interaction of CD47 with signal regulatory protein alpha (SIRPα), a protein on phagocytic cells, transmits a "don't eat me" signal that negatively regulates phagocytosis. CD47-SIRPα antagonists enable phagocytosis by disrupting the inhibitory signal and can synergize with Fc-mediated pro-phagocytic signals for potent elimination of tumor cells. A potential limitation of therapeutic CD47-SIRPα antagonists is that expression of CD47 on normal cells may create sites of toxicity or an "antigen sink." To overcome these limitations and address selective tumor targeting, we developed SIRPabodies to improve the therapeutic benefits of CD47-SIRPα blockade specifically toward tumor. EXPERIMENTAL DESIGN: SIRPabodies were generated by grafting the wild-type SIRPα either to the N-terminus or to the C-terminus of the heavy chain of rituximab. Selective tumor binding was tested using CFSE-labeled human primary CLL cells in the presence of 20-fold excess of human RBCs. NSG mice were transplanted with Raji-luciferase cells and were assigned to controls versus SIRPabody treatment. Cynomolgus nonhuman primates were administered a single intravenous infusion of SIRPabody at 3, 10, or 30 mg/kg. RESULTS: SIRPabodies selectively bound to dual antigen-expressing tumor cells in the presence of a large antigen sink. SIRPabody reduced tumor burden and extended survival in mouse xenograft lymphoma models. SIRPabody caused no significant toxicity in nonhuman primates. CONCLUSIONS: These findings establish SIRPabodies as a promising approach to deliver the therapeutic benefit of CD47-SIRPα blockade specifically toward tumor cells. SIRPabodies may be applied to additional cancer types by grafting SIRPα onto other tumor-specific therapeutic antibodies. Clin Cancer Res; 22(20); 5109-19. ©2016 AACR.


Subject(s)
Antibodies, Bispecific/pharmacology , Antineoplastic Agents/pharmacology , CD47 Antigen/antagonists & inhibitors , Receptors, Immunologic/antagonists & inhibitors , Rituximab/pharmacology , Animals , Antibodies, Bispecific/immunology , Antigens, Differentiation/chemistry , Antigens, Differentiation/immunology , Antineoplastic Agents/chemistry , CD47 Antigen/immunology , Cell Line, Tumor , Humans , Macaca fascicularis , Male , Mice , Phagocytosis , Receptors, Immunologic/chemistry , Receptors, Immunologic/immunology , Rituximab/chemistry
4.
PLoS One ; 10(9): e0137345, 2015.
Article in English | MEDLINE | ID: mdl-26390038

ABSTRACT

CD47 is a widely expressed cell surface protein that functions as a regulator of phagocytosis mediated by cells of the innate immune system, such as macrophages and dendritic cells. CD47 serves as the ligand for a receptor on these innate immune cells, SIRP-alpha, which in turn delivers an inhibitory signal for phagocytosis. We previously found increased expression of CD47 on primary human acute myeloid leukemia (AML) stem cells, and demonstrated that blocking monoclonal antibodies directed against CD47 enabled the phagocytosis and elimination of AML, non-Hodgkin's lymphoma (NHL), and many solid tumors in xenograft models. Here, we report the development of a humanized anti-CD47 antibody with potent efficacy and favorable toxicokinetic properties as a candidate therapeutic. A novel monoclonal anti-human CD47 antibody, 5F9, was generated, and antibody humanization was carried out by grafting its complementarity determining regions (CDRs) onto a human IgG4 format. The resulting humanized 5F9 antibody (Hu5F9-G4) bound monomeric human CD47 with an 8 nM affinity. Hu5F9-G4 induced potent macrophage-mediated phagocytosis of primary human AML cells in vitro and completely eradicated human AML in vivo, leading to long-term disease-free survival of patient-derived xenografts. Moreover, Hu5F9-G4 synergized with rituximab to eliminate NHL engraftment and cure xenografted mice. Finally, toxicokinetic studies in non-human primates showed that Hu5F9-G4 could be safely administered intravenously at doses able to achieve potentially therapeutic serum levels. Thus, Hu5F9-G4 is actively being developed for and has been entered into clinical trials in patients with AML and solid tumors (ClinicalTrials.gov identifier: NCT02216409).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , CD47 Antigen/immunology , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antibody Affinity , Antineoplastic Agents/immunology , Antineoplastic Agents/pharmacokinetics , Female , Haplorhini , Humans , Leukemia, Myeloid, Acute/pathology , Macaca fascicularis , Mice , Mice, Inbred BALB C , Phagocytosis/drug effects , Rituximab/therapeutic use , Tumor Cells, Cultured
5.
MAbs ; 7(5): 946-56, 2015.
Article in English | MEDLINE | ID: mdl-26083076

ABSTRACT

Agents that block the anti-phagocytic signal CD47 can synergize with pro-phagocytic anti-tumor antigen antibodies to potently eliminate tumors. While CD47 is overexpressed on cancer cells, its expression in many normal tissues may create an 'antigen sink' that could minimize the therapeutic efficacy of CD47 blocking agents. Here, we report development of bispecific antibodies (BsAbs) that co-target CD47 and CD20, a therapeutic target for non-Hodgkin lymphoma (NHL), that have reduced affinity for CD47 relative to the parental antibody, but retain strong binding to CD20. These characteristics facilitate selective binding of BsAbs to tumor cells, leading to phagocytosis. Treatment of human NHL-engrafted mice with BsAbs reduced lymphoma burden and extended survival while recapitulating the synergistic efficacy of anti-CD47 and anti-CD20 combination therapy. These findings serve as proof of principle for BsAb targeting of CD47 with tumor-associated antigens as a viable strategy to induce selective phagocytosis of tumor cells and recapitulate the synergy of combination antibody therapy. This approach may be broadly applied to cancer to add a CD47 blocking component to existing antibody therapies.


Subject(s)
Antibodies, Bispecific/pharmacology , Antibodies, Monoclonal/pharmacology , Antigens, CD20/immunology , CD47 Antigen/immunology , Lymphoma, Non-Hodgkin/immunology , Animals , Antibodies, Bispecific/immunology , Antibodies, Monoclonal/immunology , Antibody Affinity , Humans , Immunoglobulin G/immunology , Immunoglobulin G/pharmacology , Mice , Polymerase Chain Reaction , Surface Plasmon Resonance , Xenograft Model Antitumor Assays
6.
Sci Rep ; 3: 2234, 2013.
Article in English | MEDLINE | ID: mdl-23868657

ABSTRACT

Giant magnetoresistive (GMR) nanosensors provide a novel approach for measuring protein concentrations in blood for medical diagnosis. Using an in vivo mouse radiation model, we developed protocols for measuring Flt3 ligand (Flt3lg) and serum amyloid A1 (Saa1) in small amounts of blood collected during the first week after X-ray exposures of sham, 0.1, 1, 2, 3, or 6 Gy. Flt3lg concentrations showed excellent dose discrimination at ≥ 1 Gy in the time window of 1 to 7 days after exposure except 1 Gy at day 7. Saa1 dose response was limited to the first two days after exposure. A multiplex assay with both proteins showed improved dose classification accuracy. Our magneto-nanosensor assay demonstrates the dose and time responses, low-dose sensitivity, small volume requirements, and rapid speed that have important advantages in radiation triage biodosimetry.


Subject(s)
Biosensing Techniques , Blood Proteins , Nanotechnology , Radiation, Ionizing , Radiometry , Animals , Biomarkers/blood , Biosensing Techniques/instrumentation , Biosensing Techniques/standards , Dose-Response Relationship, Radiation , Female , Male , Membrane Proteins/blood , Mice , Reproducibility of Results , Serum Amyloid A Protein , Time Factors
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