Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
  • G01N33/5758—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
  • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
  • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
  • A61K51/1072—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants the tumor cell being from the reproductive system, e.g. ovaria, uterus, testes or prostate
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
  • G01N33/57555—Immunoassay; Biospecific binding assay; Materials therefor for cancer of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy

Definitions

• Prostate cancer is an entity that encompasses different types of tumors
• Adenocarcinomas and non-adenocarcinomas respond to, and therefore should be treated with, different treatments. Even within the adenocarcinomas, the lethality of the tumors is highly variable, from low
• PSMA is a Biomarker for Prostate Adenocarcinomas
• Prostate adenocarcinomas are AR + /PSMA + ; non-adenocarcinoma variants (e.g., small cell, neuroendocrine, sarcoma, etc.) make up a minority ( s 5%) of all prostate cancers and have a phenotype of AR-/PSMA-.
• non-adenocarcinomas derive from adenocarcinomas and these can manifest a mixed phenotype including both AR + /PSMA + and AR7PSMA * cells.
• the backbone of treatment of adenocarcinomas is hormonal therapy followed by taxane-based chemotherapy, non-adenocarcinomas do not respond to hormonal therapy and are treated instead with platinum-based chemotherapy.
• High PSMA is a Molecular Hallmark of Lethal Prostate Adenocarcinoma
• PC is the third most common cause of cancer deaths in American men. It is diagnosed in approximately 240,000 men annually in the U.S., with about 28,000 deaths yearly due to PC. However, the rate of diagnosis is far higher than the rate of death. It is well known that the substantial majority of patients diagnosed with prostate cancer will not die because of their PC. Since it has been impossible to distinguish those patients with "indolent" PC from those whose disease may be lethal, almost everyone undergoes treatment with radical surgery and/or radiation treatments. Those treatments, while intended to prevent metastasis and death due to PC, unfortunately also compromise quality of life. While this compromise may be acceptable in cases where it prevents death, it is not acceptable in cases when the patient was not at risk of death.
• Testing can be performed on tissue specimens ⁇ e.g., prostate biopsy, TURP, prostatectomy tissue), on bodily fluids (e.g., blood, urine, prostatic fluid, semen), or by imaging (e.g., by any agent capable of specific binding to PSMA such as: antibodies, antibody derivatives, PSMA ligands, small molecule PSMA binders, PSMA enzyme inhibitors, PSMA-binding peptides, PSMA-binding aptamers, etc).
• tissue specimens e.g., prostate biopsy, TURP, prostatectomy tissue
• bodily fluids e.g., blood, urine, prostatic fluid, semen
• imaging e.g., by any agent capable of specific binding to PSMA such as: antibodies, antibody derivatives, PSMA ligands, small molecule PSMA binders, PSMA enzyme inhibitors, PSMA-binding peptides, PSMA-binding aptamers, etc).
• PSMA binding agents can be labeled with any agent that allows detection (e.g., radioisotopes such as Zirconium-89, Technetium-99m, radioiodine, Indium- 1 1 1 , Copper-64, Iodine- 124, etc.; or dyes such as indocyanine green, cyanine dyes, fluorescent dyes, infrared dyes, enzymes, etc).
• detection e.g., radioisotopes such as Zirconium-89, Technetium-99m, radioiodine, Indium- 1 1 1 1 , Copper-64, Iodine- 124, etc.
• dyes such as indocyanine green, cyanine dyes, fluorescent dyes, infrared dyes, enzymes, etc.
• Imaging may be performed using positron emission tomography (PET), PET/Computed tomography (CT), PET/Magnetic resonance (MR), planar imaging, SPECT imaging, optical imaging, or dye imaging
• Such approaches have diagnostic and therapeutic uses and value. Diagnostically, one could (non-invasively) image a patient's prostate to determine if it harbored a lethal cancer and, if it did, pinpoint the location for a directed confirmatory biopsy (rather than the dozen or more rather random sampling biopsies currently utilized). If a lethal lesion is not identified on the imaging study, a biopsy can be omitted.
• a molecular biomarker capable of distinguishing prostate adenocarcinoma from a non-adenocarcinoma can guide therapy.
• the backbone of adenocarcinoma treatment is hormonal therapy with or without other treatments (e.g., taxane-based chemotherapy, immunotherapy, etc); non-adenocarcinomas would not be treated with hormonal therapy and use different chemotherapy agents (e.g., cisplatin, etoposide, etc.).
• a molecular biomarker capable of distinguishing lethal from indolent PC could spare millions of men from interventions that unnecessarily compromise their quality of life and cost the health care system needless billions of dollars. It would allow treatment to be tailored to the underlying risk of the cancer. Those cancers that are indolent in nature could simply be monitored; those cancers with lethal risk could be treated more aggressively with surgery or radiation. Image mapping of the site/s of lesions could guide use of focal ablation therapies within the prostate.
• PSMA imaging of metastatic sites would aid in determining the location of where biopsies could be taken. This will improve the yield of biopsies, currently at only 25%. PSMA imaging would also provide a prostate cancer-specific imaging tool to evaluate response to drug therapy. Currently no such imaging modality exists. Computed tomography (CT) and magnetic resonance (MR) merely show masses, which may be either benign or malignant. Even in the case of a malignancy, such malignancy may be prostate cancer or another malignancy. Bone scans merely reflect bone metabolism and do not directly image the tumor. As a result, increased uptake on bone scan may be tumor or a benign process ⁇ e.g., inflammation, fracture).
• CT computed tomography
• MR magnetic resonance
• Bone scans merely reflect bone metabolism and do not directly image the tumor. As a result, increased uptake on bone scan may be tumor or a benign process ⁇ e.g., inflammation, fracture).
• FIG. 1 shows expression of PSMA and AR by cell lines. Equal amounts of cell lysates were loaded in each lane. PSMA was detected by monoclonal antibody (mAb) J591 ; AR was detected by mAb anti-AR (AR441). GAPDH was used as a loading control.
• mAb monoclonal antibody
• AR441 AR was detected by mAb anti-AR (AR441). GAPDH was used as a loading control.
• MDA-PCa-2b expresses a relatively low level of AR, just barely visible at this exposure.
• CWR22Rvl expresses a slightly larger AR protein (114 KD, versus 1 10 KD) due to duplication of exon 3).
• PC3 and another cell line, DU145 (not shown), were AR7PSMA " .
• PC3- PSMA is the PC3 line transfected with PSMA.
• Figure 2 shows two needle core biopsies from the same patient's prostate.
• the biopsy on left shows a Gleason pattern 3; on the right is an area of pattern 4 or 5. Both are immunohistochemically stained for PSMA.
• the low grade lesion barely expression PSMA; the high grade lesion is strongly PSMA-positive.
• Figure 3 also shows two needle core biopsies from another patient's prostate.
• the biopsy on left shows an area of Gleason pattern 3 ; on the right is an area of pattern 5. Both are immunohistochemically stained for PS A.
• the low grade lesion is PSMA-negative; the high grade lesion is strongly PSMA-positive.
• FIG. 4 shows that PSMA expression reveals tumor site, confirmed by pathology and immunohistochemistry.
• Panel (a) shows a 89 Zr-J591 pre-surgical PET scan with high intensity focal uptake in the right apex (white arrow).
• Panel (b) shows an H&E stained specimen, showing a Gleason 7 prostate cancer legion in the right apex (thin arrow)
• Panel (c) shows a high magnification
• Figure 5 shows PET and CT scans from a patient with metastatic prostate cancer.
• Figure 6 shows PET, CT, and bone scans from a patient with prostate carcinoma.
• the left panel show PET scans (with the upper panels showing 89 Zr-J591 imaging and the lower panels showing FDG imaging); the middle panel show CT scans (with the upper panels showing 89 Zr-J591 imaging and the lower panels showing FDG imaging); and the right panel shows bone scans.
• These data show that imaging using an anti-PSMA antibody, Zr-J591, shows more intense uptake into the lesion, as compared to the FDG PET scanning. Additionally, these data show involvement of the skeletal system with uptake in a number of lesions that were not clearly seen on bone scan and that were also non-FDG avid.
• Figures 7-9 show CT and PET/CT scan taken from the same patient as from
• the left panel shows CT scans (with the upper panels showing 89 Zr- J591 imaging and the lower panels showing FDG imaging) and the right panel shows PET/CT scans (with the upper panels showing 89 Zr-J591 imaging and the lower panels showing FDG imaging.
• CT scans with the upper panels showing 89 Zr- J591 imaging and the lower panels showing FDG imaging
• PET/CT scans with the upper panels showing 89 Zr-J591 imaging and the lower panels showing FDG imaging.
• FIG. 1 shows expression of PSMA and AR by cell lines. Equal amounts of cell lysates were loaded in each lane. PSMA was detected by monoclonal antibody (mAb) J591; AR was detected by mAb anti- AR (AR441). GAPDH was used as a loading control.
• mAb monoclonal antibody
• AR441 mAb anti- AR
• GAPDH was used as a loading control.
• MDA-PCa-2b six of the cell lines (MDA-PCa-2b, LNCaP, LNCaP-AR, VCAP, CWR22Rvl and LAPC-4) expressed both AR and PSMA.
• MDA- PCa-2b expresses a relatively low level of AR, just barely visible at this exposure.
• PC3-PSMA is the PC3 line transfected with PSMA.
• FIG. 2 Two needle core biopsies were obtained from two different patients ( Figures 2 and 3). Each was stained immunohistochemically for PSMA expression.
• Figure 2 the biopsy on left shows a Gleason pattern 3; on the right is an area of pattern 4 or 5 and the low grade lesion barely expression PSMA; the high grade lesion is strongly PSMA-positive.
• Figure 3 the biopsy on left shows an area of Gleason pattern 3; on the right is an area of pattern 5 and the low grade lesion is PSMA-negative; the high grade lesion is strongly PSMA-positive.
• PSMA expression was assessed by PET, CT, and bone scanning ( Figures 4-9).
• FIG. 4 shows that PSMA expression reveals tumor site, confirmed by pathology and immunohistochemistry.
• Panel (a) shows a 89 Zr-J591 pre-surgical PET scan with high intensity focal uptake in the right apex (white arrow).
• Panel (b) shows an H&E stained specimen, showing a Gleason 7 prostate cancer legion in the right apex (thin arrow) corresponding to the focus shown in Panel (a); and a small focus of Gleason 6 (thick arrow), which was not shown in the PET scan.
• Panel (c) shows a high magnification immunohistochemical image of the right sided lesion in Panel (b), demonstrating positive staining for PSMA.
• an anti-PSMA antibody e.g., 89 Zr-J591
• 89 Zr-J591 for imaging, can be used to effectively visualize intraprostatic cancer foci and may preferentially identify lesions with Gleason sum > 7, while missing lesions with Gleason sum ⁇ 6.
• Figure 5 shows PET and CT scans from a patient with metastatic prostate cancer.
• Figure 6 shows PET, CT, and bone scans from a patient with prostate carcinoma.
• the left panel show PET scans (with the upper panels showing 89 Zr-J591 imaging and the lower panels showing FDG imaging); the middle panel show CT scans (with the upper panels showing 89 Zr-J591 imaging and the lower panels showing FDG imaging); and the right panel shows bone scans.
• These data show that imaging using an anti-PSMA antibody, 89 Zr-J591, shows more intense uptake into the lesion, as compared to the FDG PET scanning. Additionally, these data show involvement of the skeletal system with uptake in a number of lesions that were not clearly seen on bone scan and that were also non-FDG avid.
• Figures 7-9 show CT and PET/CT scan taken from the same patient as from
• the left panel shows CT scans (with the upper panels showing 89 Zr- J591 imaging and the lower panels showing FDG imaging) and the right panel shows PET/CT scans (with the upper panels showing 89 Zr-J591 imaging and the lower panels showing FDG imaging.
• CT scans with the upper panels showing 89 Zr- J591 imaging and the lower panels showing FDG imaging
• PET/CT scans with the upper panels showing 89 Zr-J591 imaging and the lower panels showing FDG imaging.
• Tissue Targeting Index a novel metric designed to semi-quantitatively score images was calculated using the ratio of lesion count density (corrected for background) to whole body count density, with maximum (TTI max ) and mean (TTI ave ) scores recorded.
• One aspect of the technology is a method of distinguishing between
• adenocarcinomas and non-adenocarcinomas in a prostate cancer patient comprising the steps of: (a) assaying a patient's prostate specific membrane antigen (PSMA) expression; and (b) determining, from the assay, if the patient's PSMA expression is indicative of prostate cancer adenocarcinoma or non-adenocarcinoma.
• PSMA expression is assayed on tissue specimen, such as a prostate biopsy, transurethral resection of the prostate, or prostatectomy tissue.
• the PSMA expression is assayed on bodily fluids, such as blood, urine, prostatic fluid, or semen.
• the PSMA expression is assayed by imaging.
• the imaging is conducted by employing any agent capable of specific binding to PSMA, such as an antibody, antibody derivative, PSMA ligand, small molecule PSMA binder, PSMA enzyme inhibitor, PSMA-binding peptide, or PSMA-binding aptamer.
• the agent is labeled with another agent that allows detection, such as Zirconium-89, Technetium-99m, radioiodine, Indium- 1 11 , Copper-64, Iodine- 124.
• the agent is a dye, such as indocyanine green, cyanine dyes, fluorescent dyes, infrared dyes, or enzymes.
• the imaging is done by positron emission tomography (PET), PET/Computed tomography (CT), PET/Magnetic resonance (MR), planar imaging, SPECT imaging, optical imaging, or dye imaging.
• One aspect of the technology is a method of distinguishing between lethal and indolent prostate cancer in a patient comprising the steps of: (a) assaying a patient's prostate specific membrane antigen (PSMA) expression; and (b) determining, from the assay, if the patient's PSMA expression is indicative of lethal or indolent prostate cancer.
• PSMA expression is assayed on tissue specimen, such as a prostate biopsy, transurethral resection of the prostate, or prostatectomy tissue.
• the PSMA expression is assayed on bodily fluids, such as blood, urine, prostatic fluid, or semen.
• the PSMA expression is assayed by imaging.
• the imaging is conducted by employing any agent capable of specific binding to PSMA, such as an antibody, antibody derivative, PSMA ligand, small molecule PSMA binder, PSMA enzyme inhibitor, PSMA-binding peptide, or PSMA-binding aptamer.
• the agent is labeled with another agent that allows detection, such as Zirconium-89, Technetium-99m, radioiodine, Indium- 1 11 , Copper-64, Iodine- 124.
• the agent is a dye, such as indocyanine green, cyanine dyes, fluorescent dyes, infrared dyes, or enzymes.
• the imaging is done by positron emission tomography (PET), PET/Computed tomography (CT), PET/Magnetic resonance (MR), planar imaging, SPECT imaging, optical imaging, or dye imaging.
• Another aspect of the technology is a method of distinguishing between adenocarcinomas and non-adenocarcinomas in a prostate cancer patient comprising the steps of: (a) assaying a patient's prostate specific membrane antigen (PSMA) expression; (b) determining, from the assay, if the patient's PSMA expression is indicative of prostate cancer adenocarcinoma or non-adenocarcinoma; and (c) administering to the patient: (i) an anti-androgen therapy if the PSMA is indicative of an adenocarcinoma; or (ii) a chemotherapeutic therapy if the PSMA expression is indicative of a non-adenocarcinoma.
• PSMA prostate specific membrane antigen
• the PSMA expression is assayed on tissue specimen, such as a prostate biopsy, transurethral resection of the prostate, or prostatectomy tissue.
• the PSMA expression is assayed on cells present in bodily fluids, such as blood, urine, prostatic fluid, or semen.
• the PSMA expression is assayed by imaging.
• the imaging is conducted by employing any agent capable of specific binding to PSMA, including an antibody, antibody derivative, PSMA ligand, small molecule PSMA binder, PSMA enzyme inhibitor, PSMA-binding peptide, or PSMA-binding aptamer.
• the agent is labeled with another agent that allows detection.
• the agent that allows detection is Zirconium-89,
• the agent that allows detection is a dye, such as indocyanine green, cyanine dyes, fluorescent dyes, infrared dyes, or enzymes.
• the imaging is done by positron emission tomography (PET), PET/Computed tomography (CT), PET/Magnetic resonance (MR), planar imaging, SPECT imaging, optical imaging, or dye imaging.
• One aspect of the technology is a method of distinguishing between lethal versus indolent cancer in a prostate cancer patient comprising the steps of: (a) assaying a patient's prostate specific membrane antigen (PSMA) expression; (b) determining, from the assay, if the patient's PSMA expression is indicative of lethal or indolent prostate cancer; and (c)
• PSMA prostate specific membrane antigen
• the PSMA expression is assayed on tissue specimen, such as a prostate biopsy, transurethral resection of the prostate, or prostatectomy tissue.
• the PSMA expression is assayed on cells present in bodily fluids, such as blood, urine, prostatic fluid, or semen.
• the PSMA expression is assayed by imaging.
• the imaging is conducted by employing any agent capable of specific binding to PSMA, such as an antibody, antibody derivative, PSMA ligand, small molecule PSMA binder, PSMA enzyme inhibitor, PSMA- binding peptide, or PSMA-binding aptamer.
• the agent is labeled with another agent that allows detection, such as Zirconium-89, Technetium-99m, radioiodine, Indium- 1 11, Copper-64, Iodine- 124.
• the agent that allows detection is a dye, such as indocyanine green, cyanine dyes, fluorescent dyes, infrared dyes, or enzymes.
• the imaging is done by positron emission tomography (PET), PET/Computed tomography (CT), PET/Magnetic resonance (MR), planar imaging, SPECT imaging, optical imaging, or dye imaging.
• PET positron emission tomography
• CT PET/Computed tomography
• MR PET/Magnetic resonance
• planar imaging SPECT imaging
• SPECT imaging optical imaging
• dye imaging or dye imaging.

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