An Update in the Use of Antibodies to Treat Glioblastoma Multiforme (original) (raw)
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Review Article An Update in the Use of Antibodies to Treat
2013
Copyright © 2013 Norma Y. Hernández-Pedro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Glioblastoma is a deadly brain disease and modest improvement in survival has been made. At initial diagnosis, treatment consists of maximum safe surgical resection, followed by temozolomide and chemoirradiation or adjuvant temozolomide alone. However, these treatments do not improve the prognosis and survival of patients. New treatment strategies are being sought according to the biology of tumors. The epidermal growth factor receptor has been considered as the hallmark in glioma tumors; thereby, some antibodies have been designed to bind to this receptor and block the downstream signaling pathways. Also, it is known that vascularization plays an important role in supplying new vessels to the tumor; therefore, new therapy...
Cancer Research
A mutant epidermal growth factor receptor (variously called ⌬EGFR, de2-7 EGFR, or EGFRvIII) containing a deletion of 267 amino acids of the extracellular domain is frequently highly expressed in human malignant gliomas and has been reported for cancers of the lung, breast, and prostate. We tested the efficacy of a novel monoclonal anti-⌬EGFR antibody, mAb 806, on the growth of intracranial xenografted gliomas in nude mice. Systemic treatment with mAb 806 significantly reduced the volume of tumors and increased the survival of mice bearing xenografts of U87 MG.⌬EGFR, LN-Z308.⌬EGFR, or A1207.⌬EGFR gliomas, each of which expresses high levels of ⌬EGFR. In contrast, mAb 806 treatment was ineffective with mice bearing the parental U87 MG tumors, which expressed low levels of endogenous wild-type EGFR, or U87 MG.DK tumors, which expressed high levels of kinase-deficient ⌬EGFR. A slight increase of survival of mice xenografted with a wild-type EGFR-overexpressing U87 MG glioma (U87 MG.wtEGFR) was effected by mAb 806 concordant with its weak cross-reactivity with such cells. Treatment of U87 MG.⌬EGFR tumors in mice with mAb 806 caused decreases in both tumor growth and angiogenesis, as well as increased apoptosis. Mechanistically, in vivo mAb 806 treatment resulted in reduced phosphorylation of the constitutively active ⌬EGFR and caused down-regulated expression of the apoptotic protector, Bcl-X L. These data provide preclinical evidence that mAb 806 treatment may be a useful biotherapeutic agent for those aggressive gliomas that express ⌬EGFR.
Cancer Research, 2001
A mutant epidermal growth factor receptor (variously called ⌬EGFR, de2-7 EGFR, or EGFRvIII) containing a deletion of 267 amino acids of the extracellular domain is frequently highly expressed in human malignant gliomas and has been reported for cancers of the lung, breast, and prostate. We tested the efficacy of a novel monoclonal anti-⌬EGFR antibody, mAb 806, on the growth of intracranial xenografted gliomas in nude mice. Systemic treatment with mAb 806 significantly reduced the volume of tumors and increased the survival of mice bearing xenografts of U87 MG.⌬EGFR, LN-Z308.⌬EGFR, or A1207.⌬EGFR gliomas, each of which expresses high levels of ⌬EGFR. In contrast, mAb 806 treatment was ineffective with mice bearing the parental U87 MG tumors, which expressed low levels of endogenous wild-type EGFR, or U87 MG.DK tumors, which expressed high levels of kinase-deficient ⌬EGFR. A slight increase of survival of mice xenografted with a wild-type EGFR-overexpressing U87 MG glioma (U87 MG.wtEGFR) was effected by mAb 806 concordant with its weak cross-reactivity with such cells. Treatment of U87 MG.⌬EGFR tumors in mice with mAb 806 caused decreases in both tumor growth and angiogenesis, as well as increased apoptosis. Mechanistically, in vivo mAb 806 treatment resulted in reduced phosphorylation of the constitutively active ⌬EGFR and caused down-regulated expression of the apoptotic protector, Bcl-X L. These data provide preclinical evidence that mAb 806 treatment may be a useful biotherapeutic agent for those aggressive gliomas that express ⌬EGFR.
2001
A mutant epidermal growth factor receptor (variously called ⌬EGFR, de2-7 EGFR, or EGFRvIII) containing a deletion of 267 amino acids of the extracellular domain is frequently highly expressed in human malignant gliomas and has been reported for cancers of the lung, breast, and prostate. We tested the efficacy of a novel monoclonal anti-⌬EGFR antibody, mAb 806, on the growth of intracranial xenografted gliomas in nude mice. Systemic treatment with mAb 806 significantly reduced the volume of tumors and increased the survival of mice bearing xenografts of U87 MG.⌬EGFR, LN-Z308.⌬EGFR, or A1207.⌬EGFR gliomas, each of which expresses high levels of ⌬EGFR. In contrast, mAb 806 treatment was ineffective with mice bearing the parental U87 MG tumors, which expressed low levels of endogenous wild-type EGFR, or U87 MG.DK tumors, which expressed high levels of kinase-deficient ⌬EGFR. A slight increase of survival of mice xenografted with a wild-type EGFR-overexpressing U87 MG glioma (U87 MG.wtEGFR) was effected by mAb 806 concordant with its weak cross-reactivity with such cells. Treatment of U87 MG.⌬EGFR tumors in mice with mAb 806 caused decreases in both tumor growth and angiogenesis, as well as increased apoptosis. Mechanistically, in vivo mAb 806 treatment resulted in reduced phosphorylation of the constitutively active ⌬EGFR and caused down-regulated expression of the apoptotic protector, Bcl-X L. These data provide preclinical evidence that mAb 806 treatment may be a useful biotherapeutic agent for those aggressive gliomas that express ⌬EGFR.
Cancer research, 1987
Murine IgG2a monoclonal antibody (MAb) 425 specifically detects epidermal growth factor receptor, which is expressed on human gliomas and tumors of other tissue origin but rarely on normal brain tissues, and not at all on bone marrow and peripheral blood cells. 131I-labeled F(ab')2 fragments of this MAb injected into nude mice grafted with U-87 MG glioma cells preferentially localized in tumor tissue compared to normal mouse tissues, as determined by differential tissue counting of radioactivity. The mean tumor-to-tissue ratios of radioactivity ranged between 8.2 (blood) and 55.8 (muscle) at 2 days after the injection of 15 muCi of 131I-425 F(ab')2/mouse. Radiolabeled fragments of an anti-hepatitis virus IgG2a MAb did not localize in tumors. The localization index derived from the ratios of specific antibody to indifferent antibody in tumor tissue relative to blood was 9.94 at 2 days following the MAb injection. The labeled MAb did not localize in a xenograft of colorectal c...
Innovative Therapies against Human Glioblastoma Multiforme
ISRN Oncology, 2011
Glioblastoma multiforme is the most invasive and aggressive brain tumor in humans, and despite the latest chemical and radiative therapeutic approaches, it is still scarcely sensitive to these treatments and is generally considered an incurable disease. This paper will focus on the latest approaches to the treatment of this cancer, including the new chemicals such as proautophagic drugs and kinases inhibitors, and differentiating agents. In this field, there have been opening new perspectives as the discovery of possible specific targets such as the EGFRvIII, a truncated form of the EGF receptor. Antibodies against these targets can be used as proapoptotic agents and as possible carriers for chemicals, drugs, radioisotopes, and toxins. In this paper, we review the possible mechanism of action of these therapies, with particular attention to the combined use of toxic substances (for example, immunotoxins) and antiproliferative/differentiating compounds (i.e., ATRA, PPARγ agonists). All these aspects will be discussed in the view of progress clinical trials and of possible new approaches for directed drug formulations.
Hybridoma, 2001
, is a neutralizing murine monoclonal antibody (MAb) against EGF-R, and was generated at the Cuban Institute of Oncology. The antibody recognizes EGF-R with high affinity, inhibiting tyrosine kinase activation. A clinical trial was conducted in brain tumor patients to evaluate toxicity, immunogenicity, and clinical benefit of escalating doses of the antibody. Nine patients with histologically confirmed gliomas or meningiomas, who had active or recurrent disease after receiving conventional treatment, received four intravenous doses of ior egf/r3. Total dosages ranged from 160 to 480 mg. As inclusion criteria, radioimmunoscintigraphy with the same MAb labeled with 99m Technetium ( 99m Tc) was performed. Immune response against the murine antibody was also evaluated. After four doses of ior egf/r3 MAb, no significant toxicity was found, except in one patient who developed a grade 4 allergic adverse event. This reaction was probably related with previous sensitization to the same MAb and the development of human anti-mouse antibodies (HAMA) response. Despite no major objective antitumor responses, eight patients had stable disease on the 6-month evaluation, and two patients remain alive after four years of MAb therapy. 131
Utilization of125I monoclonal antibody in the management of primary glioblastoma multiforme
Radiation Oncology Investigations, 1995
The objective of this study was to assess the toxicity and potential efficacy of the adjuvant administration of an iodine 125 (125I)-labeled monoclonal antibody 425 for primary glioblastoma multiforme. From January 29, 1987, to October 1, 1993, 60 patients with a diagnosis of glioblastoma multiforme received an average of three intravenous or intraarterial injections of 125I-labeled antiepidermal growth factor receptor monoclonal antibody (1251425). All patients had biopsy or resection followed by postoperative radiation therapy. Patients were included who had either stereotactic irradiation or brachytherapy (5 patients), or who were not candidates for these treatments. Stratification was made by Karnofsky performance status (KPS) and age. Treatments were administered on an outpatient basis. The mean KPS was 78, and the total cumulative dose of 125I 425 was approximately 150 mCi. Among this entire group were 6 patients who received 10–80 mg of unlabeled “blocking” 425 to block binding sites on non-tumor cells prior to the second intravenous infusion of 125I 425. No patients were excluded from the statistical analysis. The median actuarial survival for all patients treated adjuvantly for glioblastoma multiforme was 13 months. Both age and KPS correlated positively with survival, as would be expected. The toxicity from the administration of repeated doses of 125I 425 was low. No patient had chronic toxicity attributed to the monoclonal antibody therapy. Acute toxicity was observed in 1 patient who received a single dose >60 mCi. We conclude that the repeated administration of 1251425 is safe and may have some benefit in the management of primary glioblastoma multiforme. This may be especially true for patients who do not qualify for other forms of more aggressive management. A prospective randomized trial should be performed. © 1995 Wiley-Liss, Inc.