Other

Johns Hopkins University

Genspera, Inc.

Genbspera, Inc.

Hans Lilja

Samuel Ray Denmeade

John Tod Isaacs

S Brogger Christensen

Ulf-Hangkan Stenman

Ulf-Hakan Stenman

Janita Lovgren

ANGke Lundwall

The invention provides novel peptide prodrugs that contain cleavage sites specifically cleaved by human kallikrein 2 (hK2). These prodrugs are useful for substantially inhibiting the non-specific toxicity of a variety of therapeutic drugs. Upon cleavage of the prodrug by hK2, the therapeutic drugs are activated and exert their toxicity. Methods for treating cell proliferative disorders are also featured in the invention.

Activation of peptide prodrugs by hK2

The invention provides novel peptide prodrugs which contain cleavage sites specifically cleaved by prostate specific antigen (PSA). These prodrugs are useful for substantially inhibiting the non-specific toxicity of a variety of therapeutic drugs. PSA is secreted by prostatic glandular cells. Upon cleavage of the prodrug by PSA, the therapeutic drugs are activated and exert their toxicity. Novel sesquiterpene-&ggr;-lactones are also provided by the invention, and are designed to be linked to carrier moieties such as the peptides of the invention. Methods for treating cell proliferative disorders are also featured in the invention.

Tissue specific prodrug

According to the method of the invention, immunoassays are applied to measure free PSA as well as a proteinase inhibitor complex. Free PSA and PSA complex are according to the invention measured by a non-competitive immunoassay employing at least two different monoclonal antibodies. The invention is further characterized by that the PSA proteinase inhibitor complex of interest is formed either with .alpha..sub.1 -antichymotrypsin, .alpha..sub.1 -protease inhibitor (API) or .alpha..sub.2 -macroglobulin. Moreover, the invention is characterized by that free PSA, the PSA-proteinase inhibitor complex and their ratio are applied in the diagnosis of patients with prostate cancer.

Assay of free and complexed prostate-specific antigen (PSA)

Prostate specific antigen (PSA) is a protein that can form complexes with proteinase inhibitors such as .alpha..sub.1 -antichymotrypsin. The invention is characterized in that the measurement of the ratio of free PSA to PSA bound to proteinase inhibitors (free PSA:PSA-proteinase inhibitor complex) is useful in the diagnosis of patients with prostate cancer.

Prostate specific antigen (PSA)-proteinase inhibitor complexes

The invention relates to a bioaffinity assay of prostate-specific antigen (PSA) comprising the measurement of either the concentration of total PSA (PSA-T), the concentration of free form of PSA (PSA-F) or the concentration of PSA complexed to alpha-1-antichymotrypsin (PSA-ACT), PSA-T being the sum of PSA-F and PSA-ACT. According to the invention, additionally the concentration of human glandular kallikrein (hGK-1) is measured. The concentrations of PSA-T and hGK-1 can be measured in one single assay or in separate assays. The sum of the concentrations of PSA-T and hGK-1 is used to determine the ratio a) PSA-F/(PSA-T+hGK-1) and/or b) PSA-ACT/(PSA-T+hGK-1). Both of these ratios are shown to have clinical utility for the discrimination of prostate cancer and benign prostatic hyperplasia.

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Skanor, Sweden

Hans Lilja