Laboratory preparation of a deglycosylated ricin toxin A chain containing immunotoxin directed against a CD7 T lineage differentiation antigen for phase I human clinical studies involving T cell malignancies

J Immunol Methods. 1996 Oct 16;197(1-2):69-83. doi: 10.1016/0022-1759(96)00127-5.

Abstract

An immunotoxin consisting of a monoclonal antibody specific for CD7, a cell surface determinant expressed on T acute lymphocytic leukemia (T-ALL) blast cells, was linked to the potent plant toxin deglycosylated ricin toxin A chain (dgRTA) and is currently under evaluation in phase I clinical trials. Scale-up production of this immunotoxin, called DA7, was simplified using a two-step purification protocol that resulted in a highly purified immunotoxin meeting FDA criteria for IND approval. The anti-CD7 antibody, 3Ale, an IgG2b, was coupled to toxin using two different heterobifunctional cross-linkers, (1) N-succinimidyl-3-(2-pyridyl-dithiolproprionate) (SPDP), considered a standard croslinker and (2) 4-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio)tolu ene (SMPT), designed to hinder the in vivo breakdown of the toxin/antibody disulfide bond. Since experiments revealed that SPDP-DA7 had similar pharmacokinetics and biodistribution in mice and higher yields than DA7 made with a hindered cross-linker, SPDP-DA7 was scaled up for clinical study. Yield of SPDP-DA7 was 25% relative to starting material. Fractions were collected containing a toxin: antibody ratio of 1:1 to 4:1 rather than only a 1:1 ratio since studies showed that this heterogenous fraction was just as toxic to proliferating CD7-expressing leukemia cells as a homogeneous 1:1 fraction. In vitro, the concentration of heterogenous SPDP-DA7 selectively inhibiting 50% activity (IC50) of the CD7+ CEM cell line was 0.01 microgram/ml to 0.05 microgram/ml for inhibiting activated T cells or T cell lines. In vivo, SPDP-DA7 showed a significant anti-tumor effect against CEM cells administered to scid/scid mice, but even more importantly was effective against primary T cell leukemias taken from patients and injected into scid/scid mice.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / isolation & purification
  • Antigens, CD7 / immunology*
  • Clinical Trials, Phase I as Topic
  • Dose-Response Relationship, Immunologic
  • Humans
  • Immunotherapy
  • Immunotoxins / isolation & purification*
  • Immunotoxins / pharmacokinetics
  • Leukemia, Experimental / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, SCID
  • Molecular Weight
  • Neoplasm Transplantation
  • Ricin / chemistry*
  • T-Lymphocytes / immunology*
  • Transplantation, Heterologous

Substances

  • Antibodies, Monoclonal
  • Antigens, CD7
  • Immunotoxins
  • Ricin