Recombinant single-chain immunotoxins against T and B cell leukemias.

Abstract

Interleukin 2 (IL2) receptors (IL2R's) are found on malignant cells in many human leukemias and lymphomas and are expressed by activated T cells in many autoimmune disorders. Anti-Tac(Fv), a single-chain protein composed of the variable heavy and light domains of the anti-IL2R monoclonal antibody anti-Tac, can be genetically fused to derivatives of Pseudomonas exotoxin (PE) or diphtheria toxin (DT) to form potent immunotoxins. We have shown that anti-Tac(Fv) binds to low affinity IL2R's on fresh chronic lymphocytic leukemia (CLL) and adult T-cell leukemia (ATL) cells and can target either toxin to kill those cells. Anti-Tac(Fv)-PE40, containing the truncated form of PE without its binding domain, was cytotoxic to malignant cells from 8 of 8 ATL patients tested, with IC50's ranging from 0.11 to 5.5 ng/ml. Anti-Tac(Fv)-PE40KDEL, a derivative of anti-Tac(Fv)-PE40 which contains the KDEL carboxyl terminus, was more cytotoxic toward cells from all ATL patients and also killed CLL cells from 8 of 16 patients. DT388-anti-Tac(Fv), containing amino acids 1-388 of DT fused to the amino terminus of anti-Tac(Fv), was less cytotoxic than anti-Tac(Fv)-PE40 on ATL cells from 4 of 5 patients, but was cytotoxic toward CLL cells from 12 of 16 patients. DT388-IL2, where IL2 is substituted for anti-Tac(Fv), is similar to DAB389IL2, an IL2-toxin currently in clinical trials. DT388-IL2 and DAB389IL2 differ by only a few amino acids and have equal cytotoxic activity. DT388-IL2 was cytotoxic toward ATL cells from all patients tested, but usually required much higher concentrations than anti-Tac(Fv)-PE40 and was poorly active against CLL cells. Thus, recombinant toxins containing anti-Tac(Fv) are cytotoxic toward freshly isolated CLL and ATL cells and will be studied further as potential therapy for IL2R-related disorders.

• Authors: R J Kreitman, I Pastan
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 13 Issue 1-2 Pg. 1-10 (Mar 1994) ISSN: 1042-8194 [Print] United States
• PMID: 8025511 (Publication Type: Journal Article, Review)

Chemical References

• Antibodies, Monoclonal
• Bacterial Toxins
• Diphtheria Toxin
• Exotoxins
• Immunoglobulin Heavy Chains
• Immunoglobulin mu-Chains
• Immunotoxins
• Receptors, Interleukin-2
• Recombinant Proteins
• Virulence Factors
• ADP Ribose Transferases
• Pseudomonas aeruginosa exotoxin A

Topics

• ADP Ribose Transferases
• Amino Acid Sequence
• Antibodies, Monoclonal
• Bacterial Toxins (therapeutic use, toxicity)
• Cell Survival (drug effects)
• Diphtheria Toxin (therapeutic use, toxicity)
• Exotoxins (therapeutic use, toxicity)
• Humans
• Immunoglobulin Heavy Chains
• Immunoglobulin mu-Chains
• Immunotoxins (biosynthesis, therapeutic use, toxicity)
• Leukemia, B-Cell (therapy)
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, T-Cell (therapy)
• Leukemia-Lymphoma, Adult T-Cell
• Molecular Sequence Data
• Receptors, Interleukin-2 (immunology)
• Recombinant Proteins (biosynthesis, therapeutic use, toxicity)
• Tumor Cells, Cultured
• Virulence Factors