Free psa antibodies as diagnostics, prognostics and therapeutics for prostate cancer

Abstract

The present invention provides methods of monitoring and measuring tumor-associated free PSA (“fPSA”) with antibody polypeptides as an indication of androgen receptor signaling. In a particular embodiment, the methods may be used to assess the efficacy of anti-androgen and/or general anti-cancer treatments. The present invention also provides various methods and compositions relating to antibodies that are specific for tumor-associated or intratumoral fPSA. For example, the present invention provides compositions, including pharmaceutical compositions, comprising anti-fPSA antibodies, or fragments or characteristic portions thereof. The present invention further provides various therapeutic and/or diagnostic methods of using anti-fPSA antibodies and/or compositions.

What is claimed is: 
     
         1 . A method of monitoring in situ responses to prostate cancer treatment or therapy, the method comprising:
 administering an antibody polypeptide that binds to an epitope of fPSA;   determining a pretreatment level of expression or activity of fPSA in a tumor or tissue of the subject;   administering a prostate cancer treatment or therapy to the subject;   readministering the antibody polypeptide that binds to the epitope of fPSA;   determining a post-treatment level of expression or activity of fPSA in the tumor or tissue of the subject;   comparing the post-treatment level of expression or activity of fPSA in the tumor or tissue with the pretreatment level; and   based on the comparing, determining whether the therapy or treatment is effective as demonstrated by a decrease of in situ fPSA activity or expression.   
     
     
         2 . The method of  claim 1 , wherein the epitope of fPSA is within or adjacent to the catalytic cleft. 
     
     
         3 . The method of  claim 1 , wherein the prostate cancer treatment or therapy is an anti-androgen therapy. 
     
     
         4 . The method of  claim 1 , wherein the antibody polypeptide is a polyclonal antibody. 
     
     
         5 . The method of  claim 1 , further comprising, prior to the administration step, combining the antibody polypeptide with a detection entity. 
     
     
         6 . The method of  claim 5 , wherein the detection entity is selected from a group consisting of zirconium-89 ( 89 Zr), iodine-124 ( 124 I), iodine-131 ( 131 I), iodine-125 ( 125 I), bismuth-212 ( 212 Bi), bismuth-213 ( 213 Bi), astatine-221 ( 211 At), copper-67 ( 67 Cu), copper-64 ( 64 Cu), rhenium-186 ( 186 Re), rhenium-186 ( 188 Re), phosphorus-32 ( 32 P), samarium-153 ( 153 Sm), lutetium-177 ( 117 Lu), technetium-99m ( 99m Tc), gallium-67 ( 67 Ga), indium-111 ( 111 In) and thallium-201 (201Tl). 
     
     
         7 . The method of  claim 1 , wherein the determining step comprises detection by Single Photon Emission Computed Tomography (SPECT), Position Emission Tomography (PET), or Magnetic Resonance Imaging (MRI). 
     
     
         8 . The method of  claim 1 , wherein the prostate cancer treatment or therapy is selected from a group comprising castration, RU58642, LG120907, LG105, RD162, MDV3100, BMS-641988, CH5137291, ataric acid, N-butylbenzenesulfonamide, cyproterone acetate, hydroxyflutamide, bicalutamide, nilutamide, peptide antagonists, TAK700, ARN-509, cabozantimib, ipilimumab, custirsen, BPX-101, alpharadin, denosumab and Protsvac-VF. 
     
     
         9 . The method of  claim 1 , wherein an efficacious treatment is indicated by a reduction in the post-treatment level of expression or activity of fPSA relative to the pretreatment level of expression or activity of fPSA. 
     
     
         10 . A method of monitoring in situ androgen receptor signaling in a subject, the method comprising:
 administering an antibody polypeptide to the subject that binds to at least one epitope within or adjacent to a catalytic cleft of PSA, wherein the antibody polypeptide is complexed with a detection entity;   by an imaging protocol, detecting a presence of the detection entity in a prostatic tumor or metastatic cell thereof;   wherein the presence of the detection entity is correlated with androgen receptor signaling.   
     
     
         11 . The method of  claim 10 , wherein androgen receptor signaling is imaged in vitro. 
     
     
         12 . The method of  claim 10 , wherein androgen receptor signaling is imaged in vivo. 
     
     
         13 . The method of  claim 10 , further comprising quantifying the presence of the detection entity to determine a measure of fPSA expression or activity, wherein the measure of fPSA expression is quantitatively correlated with androgen receptor signaling. 
     
     
         14 . The method of  claim 10 , wherein the imaging protocol is selected from a group comprising Single Photon Emission Computed Tomography (SPECT), Position Emission Tomography (PET), or Magnetic Resonance Imaging (MRI). 
     
     
         15 . A method of treating prostate cancer or metastatic disease thereof in a subject, the method comprising administering to the subject an antibody polypeptide specific to fPSA conjugated to an anti-androgen therapy. 
     
     
         16 . A pharmaceutical composition comprising a monoclonal antibody or fragment thereof specific to fPSA. 
     
     
         17 . A kit for monitoring in situ androgen receptor signaling comprising:
 (a) an antibody polypeptide specific for fPSA;   (b) an agent capable of detecting the level of fPSA expression or activity;   (c) a control; and   (d) instructions to provide guidance for carrying out an assay embodied by the kit and for making a determination of androgen receptor signaling based upon that assay.   
     
     
         18 . Use of an antibody or antigen-binding fragment thereof specific for fPSA in the manufacture of a pharmaceutical treatment for prostate cancer, wherein the antibody or antigen-binding fragment thereof is combined with or conjugated to an anti-cancer agent. 
     
     
         19 . The use of  claim 18 , wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody. 
     
     
         20 . The use of  claim 18 , wherein the antibody or antigen-binding fragment thereof is a human monoclonal antibody. 
     
     
         21 . The use of  claim 18 , wherein the antibody or antigen-binding fragment thereof is a mouse monoclonal antibody. 
     
     
         22 . The use of  claim 21 , wherein the antibody is 5A10. 
     
     
         23 . The use of  claim 18 , wherein the anti-cancer agent is selected from the group comprising photosensitizers, nucleic acids, radiosensitizers, radioisotopes, superantigens, prodrugs, prodrug-activating enzymes, antiangiogenic agents and anti-androgen therapies. 
     
     
         24 . The use of  claim 23 , wherein the anti-cancer agent is selected from the group consisting of MDV3100, ARN-509 and doxorubicin. 
     
     
         25 . The use of  claim 18 , wherein the antibody or antigen-binding fragment thereof is specific for an epitope within or adjacent to the catalytic cleft of fPSA. 
     
     
         26 . The use of  claim 18 , wherein the fPSA is substantially intratumoral or associated with prostate cancer cells.