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

Int J Cancer. 1999 Mar 31;81(1):148-55. doi: 10.1002/(sici)1097-0215(19990331)81:1<148::aid-ijc24>3.0.co;2-l.

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

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

Substances

  • 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
  • toxA protein, Pseudomonas aeruginosa