title: Antibody-drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin.
abstract: Antibody-drug conjugates (ADC) are an attractive approach for the treatment of acute myeloid leukemia and non-Hodgkin lymphomas, which in most cases, are inherently sensitive to cytotoxic agents. CD33 and CD22 are specific markers of myeloid leukemias and B-cell malignancies, respectively. These endocytic receptors are ideal for an ADC strategy because they can effectively carry the cytotoxic payload into the cell. Gemtuzumab ozogamicin (GO, Mylotarg) and inotuzumab ozogamicin consist of a derivative of calicheamicin (a potent DNA-binding cytotoxic antibiotic) linked to a humanized monoclonal IgG4 antibody directed against CD33 or CD22, respectively. Both of these ADCs have a target-mediated pharmacokinetic disposition. GO was the first drug to prove the ADC concept in the clinic, specifically in phase II studies that included substantial proportions of older patients with relapsed acute myeloid leukemia. In contrast, in phase III studies, it has thus far failed to show clinical benefit in first-line treatment in combination with standard chemotherapy. Inotuzumab ozogamicin has shown remarkable clinical activity in relapsed/refractory B-cell non-Hodgkin lymphoma, and it has started phase III evaluation. The safety profile of these ADCs includes reversible myelosuppression (especially neutropenia and thrombocytopenia), elevated hepatic transaminases, and hyperbilirubinemia. There have been postmarketing reports of hepatotoxicity, especially veno-occlusive disease, associated with GO. The incidence is ~2%, but patients who undergo hematopoietic stem cell transplantation have an increased risk. As we steadily move toward the goal of personalized medicine, these kinds of agents will provide a unique opportunity to treat selected patient subpopulations based on the expression of their specific tumor targets.
authors: Biotechnology Unit and Oncology Clinical Research, Pfizer Inc., San Diego, California, USA. alejandro.d.ricart@pfizer.com
authors: Alejandro D
authors: AD
authors: Ricart
mesh_terms: D000617:Aminoglycosides / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D053281:Enediynes / Q000737:chemistry; D000079982:Gemtuzumab; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D000080045:Inotuzumab Ozogamicin; D007951:Leukemia, Myeloid / Q000188:drug therapy; D008228:Lymphoma, Non-Hodgkin / Q000175:diagnosis / Q000188:drug therapy; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology; D063268:Sialic Acid Binding Ig-like Lectin 3; D016896:Treatment Outcome
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; C571163:CD33 protein, human; D053281:Enediynes; D018796:Immunoconjugates; D051918:Sialic Acid Binding Ig-like Lectin 2; D063268:Sialic Acid Binding Ig-like Lectin 3; C489066:calicheamicin enediyne; D000079982:Gemtuzumab; D000080045:Inotuzumab Ozogamicin