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

Lorberboum-Galski, Haya; Barrett, Leslie V.; Kirkman, Robert L.; Ogata, Masato; Willingham, Mark C.; FitzGerald, David J.; Pastan, Ira

doi:10.1073/pnas.86.3.1008

Cited by 45 publications

(9 citation statements)

References 33 publications

(30 reference statements)

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“…Similarly, recombinant PE40 protein that lacks a TGFa domain was much less effective than TGFa-PE40cys at killing EGFR+ tumor cells in vitro (Table 1). This result is consistent with earlier experiments by Lorberboum-Galski et al (33) that purified PE40 was ineffective at killing target cells in vivo. Each of these studies suggests that a biologically active TGFa domain capable of binding to cellular EGFR is required for TGFa-PE408cys to effectively kill tumor cells that express EGFR.…”

Section: Discussionsupporting

confidence: 83%

Transforming growth factor alpha-Pseudomonas exotoxin fusion protein prolongs survival of nude mice bearing tumor xenografts.

Heimbrook

Stirdivant

Ahern

et al. 1990

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

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Section: Discussionsupporting

confidence: 83%

Transforming growth factor alpha-Pseudomonas exotoxin fusion protein prolongs survival of nude mice bearing tumor xenografts.

Heimbrook

Stirdivant

Ahern

et al. 1990

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

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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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“…IL-2-PE 40 also prevented experimental autoimmune encephalomyelitis in rat and murine models without toxicity and minimized the development of neutralizing anti-PE 40 antibodies [205][206][207][208][209]. In a lethal ascites tumor model, in which EL4J murine thymoma cells were transfected with the IL-2R -chain for high-affinity IL-2 binding, IL-2-PE 40 administered immediately or delayed 5 days after tumor infusion significantly inhibited tumor growth in 80% of treated animals to greater than 100 days.…”

Section: Il-2-pe 40 Fusionsmentioning

confidence: 91%

IL-2 Receptor Targeted Immunomodulatory Biologics: The Past, Present, and Future

Franke¹,

Shirwan²

2006

CIR

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The interleukin-2 (IL-2) and interleukin-2 receptor (IL-2R) system plays a central role in both the innate and adaptive arms of the immune response. Of major importance is the function of IL-2/IL-2R in the activation, differentiation, expansion, and maintenance of T cells that are critical to adaptive immunity. Clinically, the IL-2/IL-2R axis has been linked to the development and persistence of hematopoietic malignancies, autoimmune disorders, and allograft rejection. As such, the IL-2/IL-2R system has been extensively studied and exploited for T-cell directed immunotherapy. Several immunomodulatory approaches targeting this receptor system have been developed that include antibody-based ligands and radioisotopes, as well as immunoglobulin and cytokine chimeric biologics, which contain toxins and apoptosis-inducing proteins. While some of these biologics are already in clinical practice others are either in transition to the clinic or under development. We herein review the effectiveness and limitations of these biologics and discuss new strategies that could minimize the limitations and improve on the efficacy of IL-2R-targeted immunotherapy.

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

Cited by 45 publications

References 33 publications

Transforming growth factor alpha-Pseudomonas exotoxin fusion protein prolongs survival of nude mice bearing tumor xenografts.

Transforming growth factor alpha-Pseudomonas exotoxin fusion protein prolongs survival of nude mice bearing tumor xenografts.

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

IL-2 Receptor Targeted Immunomodulatory Biologics: The Past, Present, and Future

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