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Clin Cancer Res. 2008 Oct 15;14(20):6515-24. doi: 10.1158/1078-0432.CCR-07-5041.

Antibody-mediated delivery of interleukin-2 to the stroma of breast cancer strongly enhances the potency of chemotherapy.

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1
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Switzerland.

Abstract

PURPOSE:

There is an interest in the discovery of biopharmaceuticals, which are well tolerated and which potentiate the action of anthracyclines and taxanes in breast cancer therapy.

EXPERIMENTAL DESIGN:

We have produced a recombinant fusion protein, composed of the human antibody fragment scFv(F16) fused to human interleukin-2 (F16-IL2), and tested its therapeutic performance in the MDA-MB-231 xenograft model of human breast cancer. The F16 antibody is specific to the alternatively spliced A1 domain of tenascin-C, which is virtually undetectable in normal tissues but is strongly expressed in the neovasculature and stroma of breast cancer.

RESULTS:

When used as monotherapy, F16-IL2 displayed a strikingly superior therapeutic benefit compared with unconjugated recombinant IL-2. The administration of doxorubicin either before (8 days, 24 h, or 2 h) or simultaneously with the injection of F16-IL2 did not decrease the accumulation of immunocytokine in the tumor as measured by quantitative biodistribution analysis. Therapy experiments, featuring five once per week coadministrations of 20 mug F16-IL2 and doxorubicin, showed a statistically significant reduction of tumor growth rate and prolongation of survival at a 4 mg/kg doxorubicin dose but not at a 1 mg/kg dose. By contrast, combination of F16-IL2 with paclitaxel (5 and 1 mg/kg) exhibited a significant therapeutic benefit compared with paclitaxel alone at both dose levels. F16-IL2, alone or in combination with doxorubicin, was well tolerated in cynomolgus monkeys at doses equivalent to the ones now used in clinical studies.

CONCLUSIONS:

F16-IL2 may represent a new useful biopharmaceutical for the treatment of breast cancer.

PMID:
18927291
DOI:
10.1158/1078-0432.CCR-07-5041
[Indexed for MEDLINE]
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