Improvement in the standard treatment for experimental glioma by fusing antibody Fc domain to endostatin

Laboratory investigation

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Object

Brain tumors pose many unique challenges to treatment. The authors hypothesized that Fc-endostatin may be beneficial. It is a newly synthesized recombinant human endostatin conjugated to the Fc domain of IgG with a long half-life (weeks) and unknown toxicity. The authors examined the efficacy of Fc-endostatin using various delivery methods.

Methods

Efficacy was assessed using the intracranial 9L gliosarcoma rat model treated with Fc-endostatin for use in rodents (mFc-endostatin), which was administered either systemically or locally via different delivery methods. Oral temozolomide (TMZ) was administered in combination with mFc-endostatin to determine if there was a beneficial synergistic effect.

Results

Intracranial delivery of mFc-endostatin via a polymer or convection-enhanced delivery 5 days after tumor implantation increased median survival, compared with the control group (p = 0.0048 and 0.003, respectively). Animals treated weekly with subcutaneous mFc-endostatin (started 5 days post–tumor implantation) also had statistically improved survival as compared with controls (p = 0.0008). However, there was no statistical difference in survival between the local and systemic delivery groups. Control animals had a median survival of 13 days. Animals treated either with subcutaneous mFc-endostatin weekly or with polymer had a median survival of 18 and 15 days, respectively, and those treated with oral TMZ for 5 days (Days 5–9) had a median survival of 21 days. Survival was further increased with a combination of oral TMZ and mFc-endostatin polymer, with a median survival of 28 days (p = 0.029, compared with TMZ alone). Subcutaneous mFc-endostatin administered every week starting 18 days before tumor implantation significantly increased median survival when compared with controls (p = 0.0007), with 12.5% of the animals ultimately becoming long-term survivors (that is, survival longer than 120 days). The addition of TMZ to either weekly or daily subcutaneous mFc-endostatin and its administration 18 days before tumor implantation significantly increased survival (p = 0.017 and 0.0001, respectively, compared with TMZ alone). Note that 12.5% of the animals treated with weekly subcutaneous mFc-endostatin and TMZ were long-term survivors.

Conclusions

Systemically or directly (local) delivered mFc-endostatin prolonged the survival of rats implanted with intracranial 9L gliosarcoma. This benefit was further enhanced when mFc-endostatin was combined with the oral chemotherapeutic agent TMZ.

Abbreviations used in this paper: CED = convection-enhanced delivery; FITC = fluorescein isothiocyanate; hFc- and mFc-endostatin = Fc-endostatin for use in humans and in rodents, respectively; p(CPP:SA) = polyanhydride poly(1,3-bis-[p-carboxyphenoxy] propane-co-sebacic anhydride) polymer; TMZ = temozolomide.

Article Information

Address correspondence to: Betty Tyler, Department of Neurosurgery, Johns Hopkins Medical Institution, 1550 Orleans Street/CRB2 Room 2M45, Baltimore, Maryland 21231. email: btyler@jhmi.edu.

Please include this information when citing this paper: published online September 16, 2011; DOI: 10.3171/2011.8.JNS11125.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Graph showing survival in rats bearing intracranial 9L gliosarcoma that were treated with mFc-endostatin 18 days before tumor implantation. Subcutaneous drug was administered either weekly or daily with and without TMZ. Those treated weekly with subcutaneous mFc-endostatin survived significantly longer, compared with controls (p = 0.0007). When combined with TMZ, subcutaneous mFc-endostatin administered both weekly and daily conferred survival benefits, as compared with TMZ alone (p = 0.0017 and 0.0001, respectively).

  • View in gallery

    Graphs showing survival of F344 rats after treatment with locally delivered mFc-endostatin. The treatment was started 5 days after intracranial 9L gliosarcoma tumor implantation. Animals treated with weekly subcutaneous endostatin had a median survival of 18 days (p = 0.0008), those treated with polymer or via CED had median survivals of 14 and 15 days, respectively (p = 0.003 and 0.0048, respectively, upper). Animals that received 5 days of oral gavage of TMZ had a median survival of 21 days. When mFc-endostatin polymer was given with oral TMZ, the median survival was increased to 28 days (p = 0.029, compared with TMZ alone, lower). po = oral delivery.

  • View in gallery

    Photomicrographs demonstrating immunohistochemical analysis of tissue from a rodent brain treated with subcutaneous mFc-endostatin (4.02 mg/kg) weekly (left) and an untreated control brain (right). The FITC-labeled polyclonal antibody against the mFc fragment reacted with the histological sections of tumors from rats treated with mFc-endostatin but not with the histological sections of the control group.

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