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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Animals
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / immunology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Doxorubicin / administration & dosage
  • Drug Synergism
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • Immunoenzyme Techniques
  • Immunoglobulin Fragments / immunology
  • Interleukin-2 / immunology
  • Interleukin-2 / pharmacokinetics
  • Interleukin-2 / therapeutic use*
  • Macaca fascicularis
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Paclitaxel / administration & dosage
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism
  • Stromal Cells / metabolism*
  • Tenascin / administration & dosage
  • Tenascin / immunology*
  • Tissue Distribution
  • Tumor Cells, Cultured


  • Antibodies, Monoclonal
  • Immunoglobulin Fragments
  • Interleukin-2
  • Recombinant Fusion Proteins
  • Tenascin
  • Doxorubicin
  • Paclitaxel