Chimeric cytotoxin IL2-PE40 delays and mitigates adjuvant-induced arthritis in rats.

Case, John P.; Lorberboum-Galski, Haya; Lafyatis, Robert; FitzGerald, David J.; Wilder, Ronald L.; Pastan, Ira

doi:10.1073/pnas.86.1.287

Cited by 43 publications

(18 citation statements)

References 35 publications

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“…This hypothesis is further supported by the finding that IL-2-PE40, which is cytotoxic to IL-2 receptor-bearing T cells, prolongs allograft survival in mice and suppresses adjuvant arthritis in rats (39) as well as the observation that IL-2 diphtheria toxin is also active in vitro and in vivo (40,41,43). Chimeric toxins offer an alternative strategy in the treatment of autoimmune diseases and transplant rejection in humans.…”

Section: Resultssupporting

confidence: 61%

Cardiac allograft survival in mice treated with IL-2-PE40.

Lorberboum-Galski

Barrett

Kirkman

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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IL-2-PE40 is a chimeric protein composed of human interleukin 2 (IL-2) genetically fused to the amino terminus of a modified form of Pseudomonas exotoxin lacking its cell recognition domain. IL-2-PE40, which is extremely cytotoxic to IL-2 receptor-positive cells, was examined for its ability to prevent graft rejection in mice in which activation of T cells is prominent. We demonstrate that intraperitoneally administered IL-2-PE40 specifically and significantly prolongs the survival of vascularized heart allografts in mice. The chimeric toxin, IL-2-PE40, offers an alternative approach to the treatment of autoimmune diseases and transplant rejection in humans.

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Section: Resultssupporting

confidence: 61%

Cardiac allograft survival in mice treated with IL-2-PE40.

Lorberboum-Galski

Barrett

Kirkman

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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“…The injection of a suspension of heat-killed mycobacteria in mineral oil induces chronic, destructive peripheral arthritis in LEW/N rats, but not athymic LEW.rnu/rnu rats. Clinically apparent disease appears on or about day 10 after adjuvant injection (10,22). F344/N female rats develop equivocal or very low grade clinically-apparent arthritis (26).…”

Section: Resultsmentioning

confidence: 99%

“…AA was induced in female LEW/N rats and clinically scored as described (22 Purification of FGF-I antibody. Polyclonal antiserum against recombinant human FGF-l was prepared in a rabbit and affinity-purified on recombinant human FGF-1 coupled to cyanogen bromide-activated Sepharose 4B (Pharmacia Fine Chemical, Uppsala, Sweden) as described previously ( 1 1).…”

Section: Phosphotyrosine Proteins In Inflammatory Arthritis 553mentioning

confidence: 99%

Coexpression of phosphotyrosine-containing proteins, platelet-derived growth factor-B, and fibroblast growth factor-1 in situ in synovial tissues of patients with rheumatoid arthritis and Lewis rats with adjuvant or streptococcal cell wall arthritis.

Sano¹,

Engleka²,

Mathern³

et al. 1993

J. Clin. Invest.

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Fibroblast growth factor (FGF)-l and PDGF-B-like factors have been implicated in the pathobiology of RA and animal models of this disease. Since the receptors for FGF-1 and PDGF are tyrosine kinases, we examined the expression of tyrosine phosphorylated proteins (phosphotyrosine, P-Tyr) in synovial tissues from patients with RA and osteoarthritis (OA), and rats with streptococcal cell wall (SCW) and adjuvant arthritis (AA). Synovia from patients with RA and LEW/ N rats with SCW and AA arthritis, in contrast to controls, stained intensely with anti-P-Tyr antibody. The staining colocalized with PDGF-B and FGF-1 staining. Comparative immunoblot analysis showed markedly enhanced expression of a 45-kD P-Tyr protein in the inflamed synovia. Treatment with physiological concentrations of dexamethasone suppressed both arthritis and P-Tyr expression in AA. P-Tyr was only transiently expressed in athymic nude Lewis rats and was not detected in relatively arthritis-resistant F344/N rats. These data suggest that (a) FGF-1 and PDGF-B-like factors are upregulated and may induce tyrosine phosphorylation of proteins in vivo in inflammatory joint diseases, (b) persistent high level P-Tyr expression is T lymphocyte dependent, correlates with disease severity, and is strain dependent in rats, (c) corticosteroids, in physiological concentrations, downregulate P-Tyr expression in these lesions. (J. Clin. Invest. 1993. 91:553-565.)

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“…These fusion proteins selectively kill cells bearing appropriate growth factor receptors or antigens. Both chemically conjugated and recombinant products have been successfully used in animal models (13)(14)(15). Several of these are now being evaluated in animal models and in clinical trials (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

A recombinant single-chain immunotoxin composed of anti-Tac variable regions and a truncated diphtheria toxin.

Chaudhary

Gallo

FitzGerald

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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To kill human or primate cells expressing the p55 subunit of the interleukin 2 receptor, we have constructed a single-chain immunotoxin. DNA sequences encoding the first 388 amino acids of diphtheria toxin (DT) were fused to DNA elements encoding the antigen-binding portion (variable region or Fv) of the anti-Tac monoclonal antibody. The antigenbinding portion consists of 116 amino acids of the heavy-chain variable region connected by a 15-amino acid linker to 106 amino acids of the variable region of the light chain. The single-chain immunotoxin DT388-anti-Tac(Fv) was expressed in Escherichia coli and found in inclusion bodies. The monomeric form was then purified to near homogeneity with a high yield (3-5 mg/liter). Monomeric DT388-anti-Tac(Fv) was highly cytotoxic to cell lines bearing the p55 subunit of the human interleukin 2 receptor but not to cells without this subunit. DT388-anti-Tac(Fv) was also very effective in killing proliferating human T cells produced in a mixed leukocyte reaction.Both bacterial and plant toxins, including Pseudomonas exotoxin (PE) and diphtheria toxin (DT), have been employed in developing targeted toxins as reagents for the treatment of cancer, AIDS, and immunological disorders (see refs. 1-3 for review). Initially, chemical conjugation procedures were used to couple antibodies or growth factors to toxins (4-6). More recently, recombinant DNA techniques have been employed to synthesize chimeric toxins in Escherichia coli; these chimeric toxins are composed ofgrowth factors or lymphokines linked to modified forms of PE or DT (7-12). These fusion proteins selectively kill cells bearing appropriate growth factor receptors or antigens. Both chemically conjugated and recombinant products have been successfully used in animal models (13-15). Several of these are now being evaluated in animal models and in clinical trials (16-18).The immunogenic nature of these reagents currently prohibits their repeated and long-term or prophylactic use due to the production of antibodies to the chimeric toxin. Since the toxin portion is highly immunogenic, it is desirable to prepare reagents that have the same binding portion, but different toxin moieties, so that in the event of development of antibodies to one toxin a similar reagent with a different toxin can be used.Recently In anti-Tac(Fv)-PE40, the toxin is placed at the carboxyl end of the Fv. To determine if a toxin can be placed at the amino end of the single-chain antibody and also to try and circumvent the problem of high titer antibodies to PE40 that may arise upon repeated treatment with anti-Tac(Fv)-PE40, we have now constructed a recombinant immunotoxin [DT388-anti-Tac(Fv)] using a truncated form of DT that is devoid of its own receptor binding site. DT388-anti-Tac(Fv) was expressed in E. coli and was purified to near homogeneity. DT388-anti-Tac(Fv) was very cytotoxic to cell lines bearing the p55 subunit of the human IL-2 receptor. This fusion protein was also very effective in killing proliferating human T cells produced in ...

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Chimeric cytotoxin IL2-PE40 delays and mitigates adjuvant-induced arthritis in rats.

Cited by 43 publications

References 35 publications

Cardiac allograft survival in mice treated with IL-2-PE40.

Cardiac allograft survival in mice treated with IL-2-PE40.

Coexpression of phosphotyrosine-containing proteins, platelet-derived growth factor-B, and fibroblast growth factor-1 in situ in synovial tissues of patients with rheumatoid arthritis and Lewis rats with adjuvant or streptococcal cell wall arthritis.

A recombinant single-chain immunotoxin composed of anti-Tac variable regions and a truncated diphtheria toxin.

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