Cell Surface Receptor-Targeted Therapy of Acute Myeloid Leukemia: A Review

Abstract

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.

The folate receptor: What does it promise in tissue-targeted therapeutics?

“…Targeted therapies based on antibody conjugates, such as immunotoxins, have frequently yielded encouraging results in the treatment of leukemias [107][108][109][110][111][112][113][114]. Moreover, tumortargeted immunoliposomes have yielded encouraging results in preclinical studies [115][116][117][118][119].…”

Adult acute myeloid leukaemia

“…Monoclonal antibodies offer the possibility of increasing response with minimal additional toxicity [203,204]. CD33 is found on 90% of AML blast cells but not on stem cells.…”

Phage display-based generation of novel internalizing antibody fragments for immunotoxin-based treatment of acute myeloid leukemia

“…8 The main drawback of the antigens listed above is that they are not exclusive to AML cells and are also presented on normal cells. 9 Drugs targeting these antigens therefore cause toxicity and severe side effects, so there is an urgent need to identify tumor-associated antigens that are overexpressed on AML cells, but not expressed in vital tissues and organs.…”