Complete regression of human B-cell lymphoma xenografts in mice treated with recombinant anti-CD22 immunotoxin RFB4(dsFv)-PE38 at doses tolerated by cynomolgus monkeys.

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.

• Authors: R J Kreitman, Q C Wang, D J FitzGerald, I Pastan
• Journal: International journal of cancer (Int J Cancer) Vol. 81 Issue 1 Pg. 148-55 (Mar 31 1999) ISSN: 0020-7136 [Print] United States
• PMID: 10077166 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antigens, CD
• Antigens, Differentiation, B-Lymphocyte
• Bacterial Toxins
• CD22 protein, human
• Cd22 protein, mouse
• Cell Adhesion Molecules
• Exotoxins
• Immunoglobulin Heavy Chains
• Immunoglobulin Light Chains
• Immunoglobulin Variable Region
• Immunotoxins
• Lectins
• Recombinant Proteins
• Sialic Acid Binding Ig-like Lectin 2
• Virulence Factors
• ADP Ribose Transferases
• Pseudomonas aeruginosa exotoxin A

Topics

• ADP Ribose Transferases
• Animals
• Antibodies, Monoclonal (immunology, metabolism, pharmacology)
• Antigens, CD (immunology, metabolism)
• Antigens, Differentiation, B-Lymphocyte (immunology, metabolism)
• Bacterial Toxins
• Burkitt Lymphoma (therapy)
• Cell Adhesion Molecules
• Exotoxins (pharmacology)
• Graft Survival (immunology)
• Humans
• Immunoglobulin Heavy Chains (immunology, metabolism)
• Immunoglobulin Light Chains (immunology, metabolism)
• Immunoglobulin Variable Region (immunology, metabolism)
• Immunotoxins (pharmacokinetics, pharmacology, toxicity)
• Lectins
• Lymphoma, B-Cell (immunology, pathology, therapy)
• Macaca fascicularis
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Recombinant Proteins (pharmacology)
• Sialic Acid Binding Ig-like Lectin 2
• Transplantation, Heterologous
• Virulence Factors