Cell surface receptor-targeted therapy of acute myeloid leukemia: a review.
Combination chemotherapy produces remissions in patients with acute myeloid leukemia (AML). However, the majority of patients ultimately relapse and die with cytotoxic drug resistant blasts. Novel agents which circumvent resistance are needed. One such class are AML-cell surface targeted proteins. These genetically engineered polypeptides are hybrid molecules composed of two moieties--a haptophore which triggers AML cell binding and a toxophore which kills the cell. The haptophore or ligand portion consists of a monoclonal antibody or antibody fragment or a cytokine. These peptides react with cell surface receptors or antigens on AML cells. The haptophore is genetically or chemically linked to the toxophore. The toxophore may consist of an antibody Fc domain which triggers antibody-dependent cell cytotoxicity, a DNA-damaging cytotoxic drug, a radionuclide or a protein synthesis-inactivating peptide toxin. The toxophore may provide a cell death signal that overcomes standard resistance phenotypes. Further, the targeting provided by the haptophore may reduce normal tissue toxicities. This review describes some of the properties of the cell surface molecular targets, the reactive haptophores and toxophores and how these functional peptides have been optimally combined to kill leukemic blasts in patients with AML.
Frankel
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AE
Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Drive, Winston-Salem, NC 27157, USA.
Sievers
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EL
Scheinberg
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DA
D000208:Acute Disease; D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology* / Q000378:metabolism; D000954:Antigens, Surface / Q000276:immunology* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016923:Cell Death / Q000276:immunology; D002986:Clinical Trials as Topic; D000079982:Gemtuzumab; D006801:Humans; D006825:Hybridomas / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism; D000922:Immunotoxins / Q000627:therapeutic use*; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D007951:Leukemia, Myeloid / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D017493:Leukocyte Common Antigens / Q000276:immunology; D008024:Ligands; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology; D016499:Radioimmunotherapy / Q000379:methods; D063268:Sialic Acid Binding Ig-like Lectin 3
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000954:Antigens, Surface; D000970:Antineoplastic Agents; C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D008024:Ligands; D063268:Sialic Acid Binding Ig-like Lectin 3; C101579:monoclonal antibody M195; D000079982:Gemtuzumab; D017493:Leukocyte Common Antigens