Disease relevance of M195

• Humanized IgG1 M195 (HuG1-M195), a complementarity determining region-grafted recombinant monoclonal antibody, is reactive with CD33, an antigen expressed on myelogenous leukemia cells [1].
• M195 is in use in trials for the therapy of acute myelogenous leukemia [1].
• M195 is a murine monoclonal antibody that reacts with CD33, a 67-kD glycoprotein expressed on early myeloid progenitor cells and myeloid leukemia (acute myelogenous leukemia and chronic myelogenous leukemia) cells, but not normal stem cells [2].
• This pattern of reactivity of M195, together with its lack of reactivity with mature granulocytic elements or with adult tissues, make it a candidate for therapy of ANLL in vivo [3].
• In contrast, M195 was positive on only 8% of 51 lymphoblastic leukemias and 1% of 70 other nonmyeloid samples [3].

High impact information on M195

• A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity [2].
• PURPOSE: Mouse monoclonal antibody (mAb) M195 (anti-CD33) is reactive with most myeloid leukemia cells, monocytes, and hematopoietic progenitors, but not with other hematopoietic cells or stem cells nor with nonhematopoietic human tissues [4].
• Thus, the inability of M195 and constructs to kill HL60 targets with human complement is due to the much lower antigen density on HL60 cells compared to CD33+ fibroblasts [5].
• Bone marrow biopsies demonstrated significant dose-related uptake of M195 as early as 1 hour after infusion in all patients, with the majority of the dose found in the marrow [6].
• Ten patients with myeloid leukemias were treated in a phase I trial with escalating doses of mouse monoclonal antibody (mAb) M195, reactive with CD33, a glycoprotein found on myeloid leukemia blasts and early hematopoietic progenitor cells but not on normal stem cells [6].

Chemical compound and disease context of M195

• Dose-escalation trial of M195 labeled with iodine 131 for cytoreduction and marrow ablation in relapsed or refractory myeloid leukemias [4].

Biological context of M195

• Compartmental modeling analysis of antibody pharmacokinetics from a Phase I trial of 131I-labeled monoclonal antibody, M195 (anti-CD33), was used to estimate tumor burden in cases of acute myelogenous leukemia and the absorbed dose in liver, spleen and red marrow [7].

Anatomical context of M195

• Passive immunotherapy using murine anti-CD13 (F23) or anti-CD33 (M195) mAbs was able to eliminate completely the HL-60 cells in the mice, as determined by fluorescence in situ hybridization analysis, colony formation assay, and culture of mouse blood and tissue cells in vitro [8].
• The rapid, specific, and quantitative delivery to the bone marrow and the efficient internalization of M195 into target cells in vivo also suggest that the delivery of other isotopes such as auger or alpha emitters, toxins, or other biologically important molecules into either leukemia cells or normal hematopoietic progenitor cells may be feasible [6].
• L and H chain cDNAs of M195, a murine mAb that binds to the CD33 Ag on normal and leukemic myeloid cells, were cloned [9].
• Specificity of binding of mAb M195 was determined by protein-A red blood cell rosetting assays, immunoabsorption, radioimmunoassays with iodine-125 labeled M195 IgG and F(Ab)'2, and complement cytotoxicity with live human cells and cell lines representing a broad range of lineages and tissues [10].
• A leukemia-selective immunotoxin was constructed by linking recombinant gelonin (rGel), a single chain ribosome inhibitory protein, to recombinant humanized M195 antibody (HuM195), which recognizes the cell-surface protein designated CD33 [11].

Associations of M195 with chemical compounds

• M195 was trace-labeled with iodine-131 (131I) to allow detailed pharmacokinetic and dosimetric studies by serial sampling of blood and bone marrow and whole-body gamma-camera imaging [6].
• Sequential targeted therapy for relapsed acute promyelocytic leukemia with all-trans retinoic acid and anti-CD33 monoclonal antibody M195 [12].
• Re-introducing the glycosylation site in the humanized antibody reduces its binding affinity to that of the murine antibody, while removing the glycosylation site from the murine M195 variable domain increases its affinity [13].

Physical interactions of M195

• Cross-blocking of M195 binding by MY9 and L4F3 (CD33) was demonstrated [3].

Other interactions of M195

• Three different radiolabeled monoclonal antibodies have been evaluated in Phase I/II studies--131I-labeled anti-CD33 (p67) antibody, 213Bi-labeled humanized M195 antibody, and 131I-anti-CD45 antibody [14].
• In mutant M195, O-glycosylation of hIGF-1, but not of yeast proteins chitinase and a-agglutinin, was reduced; in mutant M577 yeast proteins were affected besides hIGF-1 [15].

Analytical, diagnostic and therapeutic context of M195

• Naked antibodies are limited in their ability to kill tumor cells, although studies to date suggest there may be a role in antileukemic therapy for unlabeled anti-CD33 humanized M195 antibody after the tumor burden has been reduced by chemotherapy [14].
• Absorption of M195 onto targets in vivo was demonstrated by biopsy, pharmacology, flow cytometry, and imaging; saturation of available sites occurred at doses greater than or equal to 5 mg/m2 [6].
• Treatment with native HuM195, a humanized version of murine M195, eliminated minimal residual disease detectable by reverse transcription-polymerase chain reaction (RT-PCR) in 50% of patients [16].
• In this paper, we describe the use of radio-labeled M195, a murine IgG2a, anti-CD33 monoclonal antibody, that can be used to effectively cytoreduce AML cells in relapsed patients when tumor burden is high; or to eliminate minimal residual disease and lengthen disease-free survival in patients with APL in remission [17].

References