Abstract
RFB4(dsFv)-PE38 is a recombinant immunotoxin in which the variable light domain (V(L)) is disulfide bonded via cysteine residues to the variable heavy domain (V(H)), which in turn is fused to PE38, a mutant form of Pseudomonas exotoxin A. RFB4 binds to CD22, which is a differentiation antigen expressed on the majority of B-cell leukemias and lymphomas. To examine the potential efficacy of RFB4(dsFv)-PE38 when administered at a dose schedule appropriate for phase I testing, mice bearing CA46 human CD22+ Burkitt's lymphoma xenografts were treated on alternate days i.v. for 3 doses (QOD x 3). Complete regressions were observed in 80% and 100% of mice treated with 200 and 275 microg/kg QOD x 3, respectively. The higher dose was 27% of the LD50 and 34% of the LD10 in mice. Because RFB4(dsFv)-PE38 is stable at 37 degrees C, it could also be given by continuous infusion using pumps placed in the peritoneal cavity; complete regressions also resulted from this mode of administration. To study toxicology, a pilot toxicology study of RFB4(dsFv)-PE38 was undertaken in cynomolgus monkeys, which like humans but unlike mice have CD22, which binds RFB4. Doses of 100 and 500 microg/kg i.v. QOD x 3 were well tolerated, indicating that a dose that cured tumors in mice was tolerated by primates. Based on these preclinical results, RFB4(dsFv)-PE38 is being developed for the treatment of patients with CD22-positive leukemias and lymphomas.
MeSH terms
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ADP Ribose Transferases*
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / metabolism
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Antibodies, Monoclonal / pharmacology
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Antigens, CD / immunology*
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Antigens, CD / metabolism
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Antigens, Differentiation, B-Lymphocyte / immunology*
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Antigens, Differentiation, B-Lymphocyte / metabolism
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Bacterial Toxins*
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Burkitt Lymphoma / therapy
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Cell Adhesion Molecules*
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Exotoxins / pharmacology*
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Graft Survival / immunology*
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Humans
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Immunoglobulin Heavy Chains / immunology
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Immunoglobulin Heavy Chains / metabolism
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Immunoglobulin Light Chains / immunology
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Immunoglobulin Light Chains / metabolism
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Immunoglobulin Variable Region / immunology
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Immunoglobulin Variable Region / metabolism
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Immunotoxins / pharmacokinetics
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Immunotoxins / pharmacology*
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Immunotoxins / toxicity
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Lectins*
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Lymphoma, B-Cell / immunology
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Lymphoma, B-Cell / pathology
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Lymphoma, B-Cell / therapy*
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Macaca fascicularis
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Mice
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Mice, Nude
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Neoplasm Transplantation
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Pseudomonas aeruginosa Exotoxin A
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Recombinant Proteins / pharmacology
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Sialic Acid Binding Ig-like Lectin 2
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Transplantation, Heterologous
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Virulence Factors*
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Differentiation, B-Lymphocyte
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Bacterial Toxins
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CD22 protein, human
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Cd22 protein, mouse
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Cell Adhesion Molecules
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Exotoxins
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Immunoglobulin Heavy Chains
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Immunoglobulin Light Chains
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Immunoglobulin Variable Region
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Immunotoxins
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Lectins
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Recombinant Proteins
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Sialic Acid Binding Ig-like Lectin 2
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Virulence Factors
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ADP Ribose Transferases