Targeting uPAR with antagonistic recombinant human antibodies in aggressive breast cancer

Aaron M. Le Beau, Sai Duriseti, Stephanie T. Murphy, Francois Pepin, Byron Hann, Joe Gray, Henry F. Van Brocklin, Charles S. Craik

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Components of the plasminogen activation system, which are overexpressed in aggressive breast cancer subtypes, offer appealing targets for development of new diagnostics and therapeutics. By comparing gene expression data in patient populations and cultured cell lines, we identified elevated levels of the urokinase plasminogen activation receptor (uPAR, PLAUR) in highly aggressive breast cancer subtypes and cell lines. Recombinant human anti-uPAR antagonistic antibodies exhibited potent binding in vitro to the surface of cancer cells expressing uPAR. In vivo these antibodies detected uPAR expression in triple negative breast cancer (TNBC) tumor xenografts using near infrared imaging and In single-photon emission computed tomography. Antibody-based uPAR imaging probes accurately detected small disseminated lesions in a tumor metastasis model, complementing the current clinical imaging standard F-fluorodeoxyglucose at detecting non-glucoseavid metastatic lesions. A monotherapy study using the antagonistic antibodies resulted in a significant decrease in tumor growth in a TNBC xenograft model. In addition, a radioimmunotherapy study, using the anti-uPAR antibodies conjugated to the therapeutic radioisotope 77Lu, found that they were effective at reducing tumor burden in vivo. Taken together, our results offer a preclinical proof of concept for uPAR targeting as a strategy for breast cancer diagnosis and therapy using this novel human antibody technology.

Original languageEnglish (US)
Pages (from-to)2070-2081
Number of pages12
JournalCancer Research
Volume73
Issue number7
DOIs
StatePublished - Apr 1 2013
Externally publishedYes

Fingerprint

Breast Neoplasms
Antibodies
Triple Negative Breast Neoplasms
Plasminogen
Heterografts
Radioimmunotherapy
Cell Line
Neoplasms
Urokinase-Type Plasminogen Activator
Single-Photon Emission-Computed Tomography
Tumor Burden
Radioisotopes
Anti-Idiotypic Antibodies
Cultured Cells
Therapeutics
Neoplasm Metastasis
Technology
Gene Expression
Growth
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Le Beau, A. M., Duriseti, S., Murphy, S. T., Pepin, F., Hann, B., Gray, J., ... Craik, C. S. (2013). Targeting uPAR with antagonistic recombinant human antibodies in aggressive breast cancer. Cancer Research, 73(7), 2070-2081. https://doi.org/10.1158/0008-5472.CAN-12-3526

Targeting uPAR with antagonistic recombinant human antibodies in aggressive breast cancer. / Le Beau, Aaron M.; Duriseti, Sai; Murphy, Stephanie T.; Pepin, Francois; Hann, Byron; Gray, Joe; Van Brocklin, Henry F.; Craik, Charles S.

In: Cancer Research, Vol. 73, No. 7, 01.04.2013, p. 2070-2081.

Research output: Contribution to journalArticle

Le Beau, AM, Duriseti, S, Murphy, ST, Pepin, F, Hann, B, Gray, J, Van Brocklin, HF & Craik, CS 2013, 'Targeting uPAR with antagonistic recombinant human antibodies in aggressive breast cancer', Cancer Research, vol. 73, no. 7, pp. 2070-2081. https://doi.org/10.1158/0008-5472.CAN-12-3526
Le Beau, Aaron M. ; Duriseti, Sai ; Murphy, Stephanie T. ; Pepin, Francois ; Hann, Byron ; Gray, Joe ; Van Brocklin, Henry F. ; Craik, Charles S. / Targeting uPAR with antagonistic recombinant human antibodies in aggressive breast cancer. In: Cancer Research. 2013 ; Vol. 73, No. 7. pp. 2070-2081.
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