Free PSA antibodies as diagnostics, prognostics and therapeutics for prostate cancer
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.
1 . A method of monitoring fPSA levels in a subject with a prostate tumor, thereby monitoring a response to prostate cancer treatment, the method comprising:
administering an antibody polypeptide that binds to an epitope of fPSA to a subject who had previously received a prostate cancer treatment;
wherein the antibody polypeptide includes a detection entity;
detecting the administered antibody polypeptide in situ in the subject by identifying the detection entity, thereby determining a first post-treatment level of fPSA in the prostate tumor or tissue of the subject; and
comparing the first post-treatment level in the tumor or tissue with a pretreatment level of fPSA in the tumor or tissue of the subject, wherein a decrease in the first post-treatment level of fPSA when compared to the pretreatment level of fPSA is indicative that the treatment is effective;
wherein the antibody polypeptide is 5A10, 4G10, or an antigen-binding fragment thereof.
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 Fab, Fab′, F(ab′)2, scFv, Fv, dsFv diabody, or Fd fragment.
5 . The method of claim 1 , 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-211 ( 211 At), copper-67 ( 67 Cu), copper-64 ( 64 Cu), rhenium-186 ( 186 Re), rhenium-188 ( 188 Re), phosphorus-32 ( 32 P), samarium-153 ( 153 Sm), lutetium-177 ( 177 Lu), technetium-99m ( 99m Tc), gallium-67 ( 67 Ga), indium-111 ( 111 In), and thallium-201 ( 201 Tl).
6 . 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).
7 . The method of claim 1 , wherein the prostate cancer treatment previously administered to the subject is selected from a group comprising castration, RU58642, LG120907, LG105, RD162, MDV3100, BMS-641988, CH5137291, ataric acid, N-butylbenzenesulfonamide, cyproterone acetate, hydroxyflutamide, bicalutamide, nilutamide, TAK700, ARN-509, cabozantimib, ipilimumab, custirsen, BPX-101, alpharadin, denosumab, Prostvac-VF, and doxorubicin.
8 . 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.
9 . The method of claim 1 , wherein the method further comprises:
repeating the steps of administering and detecting so that a second post-treatment level of fPSA in the prostate tumor or tissue of the subject is determined;
continuing the prostate cancer treatment if the second post-treatment level is the same or lower than the first post-treatment level, and discontinuing or changing treatment if the second post-treatment level is higher than the first post-treatment level.