Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer

Abstract

Components of the plasminogen activation system (PAS) 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 (NIR) imaging and 111In single-photon emission computed tomography (SPECT). Antibody-based uPAR imaging probes accurately detected small disseminated lesions in a tumor metastasis model, complementing the current clinical imaging standard 18F-fluorodeoxyglucose (FDG) at detecting non-glucose-avid metastatic lesions. A monotherapy study using the antagonistic antibodies resulted in a significant decrease in tumor growth in a TNBC xenograft model. Additionally, a radioimmunotherapy (RIT) study, using the anti-uPAR antibodies conjugated to the therapeutic radioisotope 177Lu, 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.

Pro-migratory actions of the prostacyclin receptor in human breast cancer cells that over-express cyclooxygenase-2

“…In the present study insight was also obtained into the regulation of pro-migratory genes by prostanoids acting at the IP receptor. Silencing of the receptor decreased the expression of MMP7, MMP9, uPA and uPA-receptor mRNAs, but not MMP2 and IL8 mRNAs; these genes have been shown to promote tumor cell migration [29,31,32].…”

Stabilizing a Flexible Interdomain Hinge Region Harboring the SMB Binding Site Drives uPAR into Its Closed Conformation

“…In some cases, circulating uPAR DI shed by proteolysis is an even more powerful prognostic biomarker than intact uPAR [47,48]. Inline with these properties, uPAR is considered a relevant translational target for intervention therapy and huge efforts have accordingly been allocated, in recent years, to development and preclinical testing of various uPAR targeting strategies including uPA-activated prodrugs [49], small-molecule inhibitors [12,31,50], targeted radiotherapy [51], and mAbs [52,53].…”

In vivo anti-metastatic effects of uPAR retargeted measles virus in syngeneic and xenograft models of mammary cancer

“…As this receptor is predominantly expressed in cancer compared to non-cancer tissues, uPAR directed agents, like anti-uPAR antibodies or uPAR targeted nanoparticles have the potential to successfully target primary tumors and metastases in vivo, without affecting non-tumor bearing organs [27, 32]. Other uPAR directed strategies that have demonstrated in vivo antitumor efficacy include uPAR antisense oligonucleotides [33] and radiolabeled anti-uPAR antibodies [34]. …”