BR96-DOX immunoconjugate targeting of chemotherapy in brain tumor models

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

An immunoconjugate of doxorubicin (adriamycin) and a tumor-specific monoclonal antibody, BR96-DOX (now SON-15) targets chemotherapy to cells that express the LewisY antigen. This immunoconjugate is internalized into lysosomes in antigen-expressing cells, with release of free doxorubicin after hydrolysis of the acid-labile linker. We review our studies using BR96-DOX in a human small-cell lung carcinoma intracerebral xenograft model in nude rats. We have found that the immunoconjugate is effective against intracerebral tumors when delivery is enhanced with osmotic disruption of the blood-brain barrier (BBB). Enhanced delivery of BR96-DOX with BBB opening can work together with radiotherapy to increase antitumor efficacy, which is maximally effective if immunoconjugate is administered prior to radiotherapy. In heterogeneous brain tumors, enhanced delivery of BR96-DOX significantly reduced tumor volumes, but local release of doxorubicin by targeting antigen expressing cells shows modest cytotoxicity against adjacent non-expressor cells. Although BR96-DOX is not effective against glioma cells tested, it does provide a model for drug-immunoconjugate therapy of gliomas. Our studies in a rat brain tumor model point out the importance of optimized delivery, antigenic heterogeneity, and bystander effect for brain tumor therapy. We review additional studies of drug-mAb immunoconjugates pertinent to the treatment of gliomas.

Original languageEnglish (US)
Pages (from-to)49-62
Number of pages14
JournalJournal of Neuro-Oncology
Volume65
Issue number1
DOIs
StatePublished - Oct 2003

Fingerprint

Immunoconjugates
Brain Neoplasms
Drug Therapy
Doxorubicin
Glioma
Blood-Brain Barrier
Antigens
Radiotherapy
Nude Rats
Bystander Effect
Small Cell Lung Carcinoma
Lysosomes
Tumor Burden
Heterografts
Neoplasms
Hydrolysis
Acids
Therapeutics
Pharmaceutical Preparations

Keywords

  • Blood-brain barrier
  • Brain tumor
  • Doxorubicin
  • Immunoconjugate
  • Targeted therapy

ASJC Scopus subject areas

  • Clinical Neurology
  • Cancer Research
  • Oncology
  • Neuroscience(all)

Cite this

BR96-DOX immunoconjugate targeting of chemotherapy in brain tumor models. / Muldoon, Leslie; Neuwelt, Edward.

In: Journal of Neuro-Oncology, Vol. 65, No. 1, 10.2003, p. 49-62.

Research output: Contribution to journalArticle

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