WO2021202376A1 - Procédé de blocage d'absorption de radionucléides ciblés sur l'antigène membranaire spécifique de la prostate (psma) par des organes exocrines - Google Patents

Procédé de blocage d'absorption de radionucléides ciblés sur l'antigène membranaire spécifique de la prostate (psma) par des organes exocrines Download PDF

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WO2021202376A1
WO2021202376A1 PCT/US2021/024647 US2021024647W WO2021202376A1 WO 2021202376 A1 WO2021202376 A1 WO 2021202376A1 US 2021024647 W US2021024647 W US 2021024647W WO 2021202376 A1 WO2021202376 A1 WO 2021202376A1
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psma
mip
subject
radionuclide
psma ligand
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PCT/US2021/024647
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Jyoti ROY
Frank I. LIN
John A. Chiorini
Elaine Jagoda
Peter L. Choyke
Blake Matthew WARNER
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The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
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    • 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
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • 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
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • PSMA Prostate-specific membrane antigen
  • PCa prostate cancers
  • mCRPC metastatic castrate-resistant prostate cancer
  • PSMA has emerged as a promising target for targeted radionuclide therapy (TRT) (Rahbar et al., Mol Imaging 17: 1536012118776068, 2018; Chakravarty et al., Am J Nucl Med Mol Imaging 8: 247-267, 2018; Rahbar et al., Mol Imaging 17: 1536012118776068, 2018) due to its high expression in prostate cancer cells, but very limited physiologic expression in organs such as the kidneys, small intestines, neuroglia, lacrimal glands, and salivary glands (Gaertner et al., Oncotarget 8: 55094-55103, 2017).
  • TRT radionuclide therapy
  • Xerostomia is an abnormal dryness of the mouth due to insufficient saliva secretion.
  • the extent of xerostomia can depend upon several factors, such as the type of therapeutic radionuclide (beta or alpha emitter), administered dose, and the number of treatment cycles (Chakravarty et al. , Am J Nucl Med Mol Imaging 8: 247-267, 2018; Taieb et al, J Nucl Med 59: 747-748, 2018).
  • the submandibular, sublingual, and parotid glands are the three major salivary glands (SGs), and together with several minor salivary glands, are responsible for saliva production (de Paula et al, AnatRec 300: 1180-1188, 2017).
  • Acinar epithelium plays a role in the production and secretion of saliva, a complex fluid consisting of water, ions, and proteins (Langley, J Physiol 9: 55-64, 1888; Humphrey and Williamson, J Prosthet Dent 85: 162- 169, 2001).
  • the present disclosure describes methods to prevent or inhibit uptake of radionuclides into exocrine organs as a result of PSMA-targeted radiotherapy or radiodiagnostic procedures.
  • the methods include local administration of non-radiolab el ed PSMA ligand competitor prior to administration of a radionuclide-conjugated PSMA ligand.
  • the method includes locally administering to the at least one exocrine gland of the subject an effective amount of a non-radiolabel ed PSMA ligand competitor; and subsequently administering to the subject a therapeutically or diagnostically effective amount of a radionuclide-conjugated PSMA ligand.
  • the method includes locally administering to at least one exocrine gland of the subject an effective amount of a non-radiolabeled PSMA ligand competitor; and subsequently administering to the subject a therapeutically effective amount of a radionuclide-conjugated PSMA ligand.
  • the method includes locally administering to at least one salivary gland of the subject an effective amount of a non-radiolabeled PSMA ligand competitor; and subsequently administering to the subject a therapeutically effective amount of a radionuclide-conjugated PSMA ligand.
  • the exocrine gland is a salivary gland, such as a parotid gland or a submandibular gland, or the exocrine gland is a lacrimal gland.
  • local administration to the exocrine gland includes intraglandular administration, such as retrograde cannulation of a salivary gland or a lacrimal gland.
  • FIGS. 1A-1E provide an overview of the background, evidence, and proposed strategy to prevent PSMA targeted radioactive ligand from binding to PSMA expressed in the salivary glands by intraglandular infusion of non-radioactive PSMA ligand prior to systemic PSMA targeted radiotherapy.
  • FIG. 1A is a positron emission tomography (PET)-computed tomography (CT) scan of a patient who received intravenous 18 F-DCFPyL, which demonstrates uptake in the bladder, kidney, salivary (parotid, sublingual, submandibular, and minor/seromucous glands) and lacrimal glands.
  • PET positron emission tomography
  • CT computed tomography
  • FIG. 1B shows characteristic immunofluorescence staining of PSMA in representative human salivary glands (anti-PSMA staining is located on the apical lumen of acinar cells; nuclei are stained with DAP I).
  • FIG. 1C shows a representative human (upper) and mouse (lower) cannulated submandibular salivary glands to illustrate similarity in delivery of preventive therapy.
  • FIG. 1D is a scientific illustration to demonstrate the strategy to cannulate the main excretory duct of the salivary gland and deliver retrograde agents (“cold” DCFPyL, non-radioactive PSMA ligand) directly to the salivary gland expressing PSMA, thereby blocking systemically delivered “hot” radioligand uptake in the gland.
  • FIG. 1E shows the PSMA protein embedded in the apical membrane of the acinar salivary glands cells demonstrating the active site is the binding site for “cold” DCFPyL or other PSMA targeted ligands or inhibitors.
  • FIG. 2A is a table showing tissue:blood ratios of [ 18 F]DCFPyL in salivary glands (submandibular: SMG; sublingual :SLG; parotid:PRG) and kidneys at 1 hour after injection.
  • Mice in the systemic (SYS) saline control group were injected with [ 18 F]DCFPyL only, whereas mice in the SYS 1x, SYS 100x, SYS 500x, SYS 1000x groups were injected with [ 18 F]DCFPyL plus either 1- fold, 100-fold, 500-fold, or 1000-fold excess of unlabeled DCFPyL, respectively.
  • FIG. 2B is a table showing tissue:blood ratios of [ 18 F]DCFPyL in SMG, SLG, PRG, and kidneys at 1 hour after injection.
  • mice were cannulated (CAN) and infused with 50 ⁇ l of either saline (CAN saline control) or 1-fold, 10-fold, 100-fold, or 1000-fold excess of DCFPyL (CAN 1x, CAN 10x, CAN 100x,
  • mice were injected with [ 18 F]DCFPyL.
  • FIG. 3 is a table showing tissue:blood ratios of [ 18 F]DCFPyL in salivary glands (submandibular: SMG; sublingual: SLG; parotid:PRG) and kidneys at 1 hour after injection.
  • SMG were cannulated and either infused with saline (CAN saline control) or with 25 ⁇ l or 50 ⁇ l of 0.01- fold, 0.1-fold, or 1-fold excess of DCFPyL.
  • mice were injected with [ 18 F]DCFPyL.
  • FIGS. 4A-4C are graphs showing tissue:blood ratios of [ 18 F]DCFPyL in mice bearing 22RV1 prostate cancer tumors.
  • Mice in the SYS saline control (SYS CTRL) group were intravenously injected with [ 18 F]DCFPyL, whereas mice in the SYS 1x and SYS 0.1x groups were injected with [ 18 F]DCFPyL plus either 1-fold or 0.1-fold excess of DCFPyL.
  • FIG. 4A represents salivary gland:blood for various groups
  • FIG. 4B and FIG. 4C show 22RV1 tumonblood ratios and kidney:blood ratios, respectively.
  • FIGS. 5A-5C are graphs showing tissue:blood ratios of [ 18 F]DCFPyL in mice bearing 22RV1 prostate cancer tumors.
  • Right and left SMGs SMG-R, SMG-L were cannulated and infused with 50 ⁇ l of either saline (CAN saline control) or 1-fold or 0.1 -fold excess of DCFPyL (CAN 1x, CAN 0.1x, respectively).
  • CAN saline control CAN saline control
  • DCFPyL CAN 1x, CAN 0.1x, respectively.
  • FIG. 5 A represents salivary gland:blood ratios for various groups
  • FIG. 5B and FIG. 5C show 22RV1 tumonblood ratios and kidney :blood ratios, respectively.
  • FIGS. 6A-6D are graphs showing the effect of administration of 10 nmol and 1 nmol of unlabeled DCFPyL in submandibular glands via cannulation at different time points on saliva flow (FIG. 6 A and FIG. 6C) and body weight (FIG. 6B and FIG. 6D).
  • FIGS. 6 A and 6C Each bar represents mean saliva volume ( ⁇ l) normalized to body weight (g) ⁇ SD.
  • FIG. 7A depicts the structure of [ 18 F]DCFPyL.
  • FIG. 7B is a graph showing HPLC analysis of [ 18 F]DCFPyL.
  • HPLC conditions Agilent Eclipse plus C18 column (4.6 x 150 mm, 3.5 pm), mobile phase: 10% acetonitrile in 0.1 M ammonium formate, with a flow rate of 1.0 mL/min.
  • Solid line in-line radio detector; dotted line: UV detector at 254 nm.
  • FIG. 8 is a graph showing biodistribution of [ 18 F]DCFPyL in selected organs at 1 hour post injection.
  • Mice in SYS saline control were i.v. injected with [ 18 F]DCFPyL only, whereas in the CAN saline group, mice were anesthetized and submandibular glands (SMG) were cannulated and infused with saline followed by i.v. injection of [ 18 F]DCFPyL 10 minutes after saline infusion.
  • SMG submandibular glands
  • FIG. 9 is a graph showing biodistribution of [ 18 F]DCFPyL in 22RV1 tumor bearing mice at
  • mice in the SYS saline control group were injected with [ 18 F]DCFPyL only, whereas in CAN saline group, mice were anesthetized and submandibular glands (SMG) were cannulated and infused with saline followed by intravenous injection of [ 18 F]DCFPyL 10 minutes after saline infusion.
  • SMG submandibular glands
  • R and L represents right and left, respectively.
  • FIG. 10 shows blood BUN, AST, ALT, albumin, creatinine, bilirubin, and amylase levels at
  • a salivary gland includes single or plural cells and can be considered equivalent to the phrase “at least one salivary gland.”
  • the term “comprises” means “includes.” It is further to be understood that any and all base sizes or amino acid sizes, and all molecular weight or molecular mass values, given for nucleic acids or polypeptides are approximate, and are provided for descriptive purposes, unless otherwise indicated. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some examples are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. All references cited herein, including patent applications and publications, are incorporated by reference in their entireties.
  • an agent such as a radiolabeled or unlabeled PSMA ligand, by any effective route.
  • routes of administration include, but are not limited to, injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal, intravenous, and intratumoral), intraglandular, oral, sublingual, rectal, transdermal, intranasal, vaginal and inhalation routes.
  • injection such as subcutaneous, intramuscular, intradermal, intraperitoneal, intravenous, and intratumoral
  • intraglandular administration means direct delivery of an agent to a gland, such as by cannulation of the gland.
  • Local administration refers to routes of administration that limit delivery of an agent to specific organs or tissues. Intraglandular administration is a type of local administration.
  • Systemic administration refers to routes of administration that permit an agent to enter the circulatory system, thereby delivering the agent to multiple organs and/or tissues.
  • routes of administration include intravenous, intraperitoneal, oral, and inhalation administration.
  • Cannulation Insertion of a cannula into a subject's body, such as into a vein, organ or gland (such as a salivary gland) of the subject. Retrograde cannulation refers to cannulation against the typical direction of flow, such as blood, tears, or saliva flow.
  • Conjugated refers to two molecules that are bonded together, for example by covalent bonds.
  • DCFPyL A small molecule PSMA ligand. When radiolabeled with a positron-emitting isotope, such as 18 F, DCFPyL can be used for positron emission tomography (PET). Upon administration of [ 18 F]DCFPyL, the DCFPyL moiety binds to PSMA expressed on tumor cells and the 18 F moiety facilitates PET imaging of PSMA-expressing tumor cells.
  • the chemical name of DCFPyL is 2-(3- ⁇ 1-carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl ⁇ -ureido)- pentanedioic acid.
  • an effective amount of a non-radiolab el ed PSMA ligand competitor can be the amount necessary to prevent or inhibit uptake of a PSMA-targeted radionuclide, such as the amount necessary to inhibit uptake by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or up to 100%.
  • a “therapeutically effective amount” is the quantity of an agent sufficient to achieve a desired effect in a subject being treated with the agent.
  • the therapeutically effective amount of a radionuclide-conjugated PSMA ligand can be the amount necessary to eliminate, reduce the size, or prevent metastasis of a tumor, such as reduce a tumor size and/or volume by at least 10%, at least 20%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, or even 100%, and/or reduce the number and/or size/volume of metastases by at least 10%, at least 20%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, or even 100%, for example as compared to a size/volume/number prior to treatment with the radionuclide-conjugated PSMA ligand.
  • the therapeutically effective amount of a non-radiolab el ed PSMA ligand competitor can be the amount necessary to prevent, reduce or eliminate xerostomia, for example by at least 10%, at least 15%, at least 20%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, or even 100%, for example as compared xerostomia observed without treatment with the non-radiolab el ed PSMA ligand competitor or prior to treatment with the non-radiolab el ed PSMA ligand competitor.
  • a dosage When administered to a subject, a dosage will generally be used that will achieve target tissue concentrations (for example, in tumors or salivary glands) that have been shown to achieve a desired in vitro effect.
  • a “diagnostically effective amount” is the quantity (e.g. of a radionuclide) necessary to enable diagnostic imaging, such as PET.
  • Exocrine gland A gland that secrete substances onto an epithelial surface by way of a duct. Examples of exocrine glands include sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, and mucous glands. By contrast, endocrine secrete their products directly into the bloodstream.
  • Lacrimal glands A pair of almond-shaped exocrine glands found in each eye, which secrete the aqueous layer of the tear film. They are located in the upper lateral region of each orbit, in the lacrimal fossa of the orbit formed by the frontal bone. The lacrimal glands produce tears that flow into canals that connect to the lacrimal sac. From that sac, the tears drain through the lacrimal duct into the nose.
  • Parotid glands A pair of salivary glands located on each side of the mouth, in front of each ear canal.
  • the parotid glands are one of three types of major salivary glands. They are the largest of the salivary glands and produce approximately 20% of the total saliva volume in the oral cavity. Saliva produced from the parotid glands is secreted into the mouth from a duct near the upper second molar.
  • Prostate cancer Any cancer originating from the male prostate.
  • Types of prostate cancer include, but are not limited to, prostate adenocarcinoma, prostate sarcoma and small cell prostate carcinoma.
  • PSMA-expressing cancer Any cancer that expresses or overexpresses prostate-specific membrane antigen (PSMS).
  • PSMS prostate-specific membrane antigen
  • examples of PSMA-expressing cancers include, but are not limited to, prostate cancer, liver cancer, lung cancer, renal cancer, glioblastoma, pancreatic cancer, melanoma, breast cancer, colon cancer, esophageal cancer and stomach cancer.
  • PSMA ligand Any natural or synthetic ligand that binds PSMA (such as human PSMA, e.g., OMIM 600934).
  • the PSMA ligand is a small molecule.
  • the PSMA ligand is selected from DCFPyL, MIP-1072, MIP-1379, MIP-1095, MIP-1404, MIP-1405, MIP-1427, MIP-1428, MIP-1519, MIP-1545, MIP-1555, MIP1558, 2- (phosphonomethyl)pentanedioic acid (PMPA), PSMA-11 (also known as “PSMA-HBED-CC”), PSMA-617, PSMA-1007, PSMA-I&T (“PSMA imaging & therapy”) and DCFBC.
  • the PSMA ligand inhibits the enzymatic activity of PSMA (e.g, a PSMA inhibitor).
  • PSMA interference agent Any agent or compound that reduces the mRNA or protein expression and/or stability and/or localization of PSMA for binding to PSMA ligands, thus reducing total exposure.
  • PSMA interference agents include, but are not limited to, RNA interference (e.g, antisense oligonucleotides, small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA)), CRISPR interference, protein interference (e.g, nucleic acid aptamers targeting PSMA protein, anti-PSMA antibodies, including anti-PSMA nanobodies and anti-PSMA antibody fragments.
  • RNA interference e.g, antisense oligonucleotides, small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA)
  • CRISPR interference e.g, CRISPR interference
  • protein interference e.g, nucleic acid aptamers targeting PSMA protein, anti-PSMA antibodies, including anti-PS
  • PSMA ligand competitor Any agent or compound that competes with a PSMA ligand for binding to PSMA (such as human PSMA, e.g., OMIM 600934).
  • the PSMA ligand is a small molecule.
  • the PSMA ligand is a PSMA-specific antibody or aptamer.
  • the PSMA ligand competitor is the same molecule as the PSMA ligand except that the competitor is not labelled with a radionuclide (i.e., it is a “cold” ligand).
  • the PSMA ligand competitor is non-labelled DCFPyL, MIP- 1072, MIP-1095, MIP-1379, MIP-1404, MIP-1405, MIP-1427, MIP-1428, MIP-1519, MIP-1545, MIP-1555, MIP1558, PMPA, PSMA-11, PSMA-617, PSMA-1007, PSMA-I&T or DCFBC.
  • Radionuclide An atom having excess nuclear energy that releases radiation as it breaks down and becomes more stable. Radionuclides can be naturally occurring or non-naturally occurring. Radionuclides are also known as radioisotopes, radioactive isotopes or radioactive nuclides. In some embodiments herein, the radionuclide is a radioactive isotope of gallium (Ga), iodine (I), yttrium (Y), lutetium (Lu), bismuth (Bi), actinium (Ac), bromine (Br), rhenium (Re), indium (In), thorium (Th) or technetium (Tc).
  • Non-limiting examples of radionuclides include 18 F, 123 I, 124 I, 125 I, 131 I, 211 At, 177 LU, 68 Ga, 99m Tc, 111 In, 90 Y, 213 Bi, 225 Ac, 75 Br, 77 Br, 228 Th, 229 Th, 229m Th, 230 Th, 231 Th, 232 Th, 233 Th, and 234 Th.
  • Salivary glands Exocrine glands that produce saliva through a system of ducts. Humans have three paired major salivary glands, the parotid, submandibular, and sublingual glands, as well as hundreds of minor salivary glands.
  • Subject Living multi-cellular vertebrate organisms, a category that includes both human and veterinary subjects, including human and non-human mammals.
  • Sublingual glands A pair of salivary glands found in the mouth, located on the floor of the oral cavity (under the tongue). The sublingual glands are one of the three types of major salivary glands. They are the smallest, most diffuse, and the only unencapsulated major salivary glands. The sublingual glands provide approximately 3-5% of the total salivary volume.
  • Submandibular glands A pair of salivary glands located below the jaw. The submandibular glands are one of the three types of major salivary glands in humans. They each weigh about 15 grams and produce approximately 65-70% of the total saliva in the oral cavity.
  • Uptake Absorption of a substance by living tissue.
  • uptake of a PSMA-targeted radionuclide in an exocrine gland refers to the incorporation or absorption of the radionuclide into an organ (such as a salivary gland) expressing PSMA.
  • uptake of the radionuclide by the exocrine gland is inhibited by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or up to 100%.
  • Xerostomia A condition characterized by dryness of the mouth, which can be caused by a change in the composition of the saliva or from reduced salivary flow. Xerostomia is a common side effect of many types of medications and medical treatments, such as PSMA-targeted radionuclide therapy. Xerostomia can lead to tooth decay, oral candidiasis, altered taste, halitosis, difficulty chewing and swallowing, and excessive thirst. Xerostomia is also known as “dry mouth.”
  • PSMA prostate-specific membrane antigen
  • TRT radionuclide therapy
  • the present disclosure describes a method of selectively reducing or blocking exocrine gland (such as salivary gland) PSMA uptake by directly applying a pre-infusion of non-radioactive (cold) PSMA ligand into the exocrine gland (see FIGS. 1 A-1E).
  • exocrine gland such as salivary gland
  • non-radiolab el ed PSMA ligand was administered via retrograde cannulation of the salivary ducts shortly prior to systemic injection of radiolabeled PSMA ligand.
  • Administration of cold PSMA ligand blocked salivary uptake of radiolabeled PSMA ligand via localized competitive inhibition.
  • a fluorine-18 labeled PSMA-targeted PET agent, [ 18 F]DCFPyL [ 18 F]DCFPyL
  • the method includes locally administering to the at least one exocrine gland of the subject an effective amount of a non- radiolabeled PSMA ligand competitor; and subsequently administering to the subject a therapeutically or diagnostically effective amount of a radionuclide-conjugated PSMA ligand.
  • the ligand of the non-radiolab el ed PSMA ligand competitor and the radionuclide- conjugated PSMA ligand are the same ligand ( e.g ., both DCFPyL or both DCFBC).
  • the ligand of the non-radiolab el ed PSMA ligand competitor and the radionuclide- conjugated PSMA ligand are a different ligand, wherein the PSMA ligand competitor binds with greater or equal affinity to PSMA as the radiolabeled PSMA ligand (e.g., one is DCFPyL and the other is DCFBC).
  • the at least one exocrine gland includes a salivary gland.
  • the salivary gland is one or more major salivary gland(s), such as one or both parotid glands, one or both submandibular glands, and/or one or both sublingual glands of the subject.
  • the at least one salivary gland is both parotid glands.
  • the at least one salivary gland is both submandibular glands.
  • the at least one salivary gland includes both parotid glands and both submandibular glands.
  • the at least one salivary gland can also include one or more minor salivary glands and/or one or both sublingual glands.
  • the at least one exocrine gland includes one or both lacrimal glands. In some examples, the at least one exocrine gland is both lacrimal glands of the subject.
  • the at least one exocrine gland includes one or more salivary glands, such as one or more major salivary glands, and one or both lacrimal glands. In some examples, the at least one exocrine gland includes both parotid glands and both lacrimal glands. In other examples, the at least one exocrine gland includes both submandibular glands and both lacrimal glands. In yet other examples, the at least one exocrine gland includes both parotid glands, both submandibular glands and both lacrimal glands of the subject. The at least one exocrine gland may also include one or more minor salivary glands and/or one or both sublingual glands.
  • local administration to the at least one exocrine gland includes intraglandular administration, such as retrograde cannulation of the at least one exocrine gland, such as retrograde cannulation of one or more salivary glands and/or lacrimal glands.
  • the radionuclide-conjugated PSMA ligand is administered systemically to the subject.
  • systemic administration is via intravenous or intraperitoneal administration.
  • the non-radiolab el ed PSMA ligand competitor is administered prior to administration of the radionuclide-conjugated PSMA ligand so that the unlabeled ligand can bind to available PSMA binding sites on the non-target exocrine glands, thereby preventing binding of the radionuclide-conjugated PSMA ligand.
  • the radionuclide- conjugated PSMA ligand is administered to the subject less than 90 minutes following administration of the non-radiolab el ed PSMA ligand competitor.
  • the radionuclide-conjugated PSMA ligand is administered to the subject less than 60 minutes following administration of the non-radiolab el ed PSMA ligand competitor. In other embodiments, the radionuclide-conjugated PSMA ligand is administered to the subject less than 30 minutes following administration of the non-radiolab el ed PSMA ligand competitor. In yet other embodiments, the radionuclide-conjugated PSMA ligand is administered to the subject less than 15 minutes following administration of the non-radiolab el ed PSMA ligand competitor.
  • the radionuclide-conjugated PSMA ligand is administered to the subject less than 90, less than 80, less than 70, less than 60, less than 50, less than 45, less than 40, less than 35, less than 30, less than 25, less than 20, less than 15, or less than 10 minutes following administration of the non-radiolab el ed PSMA ligand competitor.
  • the radionuclide- conjugated PSMA ligand is administered about 90, about 80, about 70, about 60, about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 15, about 10, or about 5 minutes after administration of the non-radiolab el ed PSMA ligand competitor.
  • the radionuclide-conjugated PSMA ligand is administered about 1 to 90, 5 to 90, 10 to 90, 15 to 90, 5 to 80, 5 to 70, 5 to 60, 5 to 50, 5 to 45, 5 to 40, 5 to 35, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 20, 10 to 30, or 10 to 15 minutes after administration of the non-radiolab el ed PSMA ligand competitor.
  • the PSMA ligand competitor can be any molecule capable of binding PSMA with the same or greater specificity than the selected radiolabeled PSMA ligand (i.e., any molecule that can compete for binding to PSMA).
  • the PSMA ligand competitor is a small molecule.
  • the PSMA ligand competitor is DCFPyL, MIP-1072, MIP-1379, MIP-1095, MIP-1404, MIP-1405, MIP-1427, MIP- 1428, MIP-1519, MIP-1545, MIP-1555, MIP1558, PMPA, PSMA-11, PSMA-617, PSMA-1007, PSMA-I&T, or DCFBC.
  • the PSMA ligand competitor is DCFPyL.
  • the PSMA ligand competitor is a PSMA interference agent.
  • the PSMA interference agent is a PSMA-specific antibody, aptamer, antisense oligonucleotide, siRNA, shRNA, miRNA or CRISPR interference agent.
  • the PSMA ligand (to be radiolabeled) is a small molecule PSMA ligand (also referred to in the art as a “PSMA inhibitor”).
  • the PSMA ligand is DCFPyL, MIP-1072, MIP-1379, MIP-1095, MIP-1404, MIP-1405, MIP-1427, MIP-1428, MIP-1519, MIP-1545, MIP-1555, MIP1558, PMPA, PSMA-11, PSMA-617, PSMA-1007, PSMA- I&T, or DCFBC.
  • the labeled PSMA ligand includes DCFPyL.
  • the PSMA ligand is a PSMA interference agent.
  • the PSMA interference agent is a PSMA-specific antibody, aptamer, antisense oligonucleotide, siRNA, shRNA, miRNA or CRISPR interference agent.
  • the radionuclide of the radionuclide-conjugated PSMA ligand is a radioactive isotope of gallium (Ga), iodine (I), yttrium (Y), lutetium (Lu), bismuth (Bi), actinium (Ac), rhenium (Re), indium (In), thorium (Th) or technetium (Tc).
  • the radionuclide is 18 F, 123 I, 124 I, 125 I, 131 I, 211 At, 177 Lu, 68 Ga, 99m Tc, 111 ln, 90 Y, 213 Bi, 225 Ac, 75 Br, 77 Br,
  • the radionuclide-conjugated PSMA ligand is [ 18 F]DCFPyL
  • the subject has or is suspected of having a PSMA-expressing cancer.
  • the cancer can be any cancer or tumor that expresses or overexpresses PSMA.
  • the PSMA-expressing cancer is a prostate cancer, liver cancer, lung cancer, renal cancer, glioblastoma, pancreatic cancer, melanoma, breast cancer, colon cancer, esophageal cancer or stomach cancer.
  • the PSMA-expressing cancer is a prostate cancer, such as, but not limited to, prostate adenocarcinoma, prostate sarcoma or small cell prostate carcinoma.
  • the quantity of non-radiolab el ed PSMA ligand competitor administered to the subject may vary depending upon, for example, the cancer to be treated (or imaged), the weight and general health of the subject, the choice of PSMA ligand, and the radionuclide-conjugated PSMA ligand to be administered.
  • the effective amount of the non-radiolab el ed PSMA ligand competitor is an amount necessary to prevent or inhibit uptake of the radionuclide in at least one exocrine gland of a subject (such as a salivary gland) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or up to 100%, for example relative to an amount of uptake of the radionuclide in at least one exocrine gland of a subject (such as a salivary gland) without prior administration of the non-radiolab el ed PSMA ligand competitor.
  • the therapeutically effective or diagnostically effective amount of radionuclide- conjugated PSMA ligand administered to the subject will vary depending on a variety of factors, including the cancer to be treated (or imaged), the weight and general health of the subject, and the specific radionuclide and PSMA ligand selected.
  • the therapeutically effective amount of the radionuclide-conjugated PSMA ligand is the amount sufficient to reduce the tumor size and/or volume by at least 10%, at least 20%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, or even 100%, for example as compared to the size/volume prior to treatment.
  • the diagnostically effective amount of the radionuclide- conjugated PSMA ligand is the amount necessary to enable diagnostic imaging, such as PET.
  • the subject is administered no more than a 100-fold, 75-fold, 50-fold, 25- fold, 10-fold, 1-fold, 0.5-fold or 0.1 -fold excess of the non-radiolab el ed PSMA ligand competitor relative to the radionuclide-conjugated PSMA ligand.
  • the subject is administered about 0.001 -fold to 100-fold, 0.01-fold to 100-fold, 0.1-fold to 100-fold, 0.1-fold to 75-fold, 0.1-fold to 50-fold, 0.1-fold to 25-fold, 0.1-fold to 10-fold, 0.1-fold to 1-fold, 0.1-fold to 0.5-fold or 1-fold to 10-fold to excess of the non-radiolab el ed PSMA ligand competitor relative to the radionuclide-conjugated PSMA ligand.
  • the volume of non-radiolab el ed PSMA ligand administered locally to the exocrine gland of the subject is about 10 ⁇ L to about 250 ⁇ L, such as about 10 ⁇ L to about 200 ⁇ L, about 10 ⁇ L to about 100 ⁇ L, about 25 ⁇ L to about 100 ⁇ L, or about 25 ⁇ L to about 50 ⁇ L.
  • the concentration of non-radiolab el ed PSMA ligand administered is about 1 nM to about 10 nM, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nM.
  • the method further includes performing an assay to measure salivary flow and/or performing sialography on the subject.
  • the method includes locally administering to at least one exocrine gland of the subject an effective amount of a non-radiolabeled PSMA ligand competitor; and subsequently administering to the subject a therapeutically effective amount of a radionuclide-conjugated PSMA ligand.
  • the ligand of the non-radiolabeled PSMA ligand competitor and the radionuclide-conjugated PSMA ligand are the same ligand ( e.g ., both DCFPyL or both DCFBC).
  • the ligand of the non-radiolabeled PSMA ligand competitor and the radionuclide-conjugated PSMA ligand are different ligands, wherein the PSMA ligand competitor binds with greater or equal affinity to PSMA as the radiolabeled PSMA ligand (e.g., one is DCFPyL and the other is DCFBC).
  • the at least one exocrine gland includes a salivary gland.
  • the salivary gland is one or more major salivary gland(s), such as one or both parotid glands, one or both submandibular glands, and/or one or both sublingual glands of the subject.
  • the at least one salivary gland is both parotid glands.
  • the at least one salivary gland is both submandibular glands.
  • the at least one salivary gland includes both parotid glands and both submandibular glands.
  • the at least one salivary gland can also include one or more minor salivary glands and/or one or both sublingual glands.
  • the at least one exocrine gland includes one or both lacrimal glands. In some examples, the at least one exocrine gland is both lacrimal glands of the subject.
  • the at least one exocrine gland includes one or more salivary glands, such as one or more major salivary glands, and one or both lacrimal glands. In some examples, the at least one exocrine gland includes both parotid glands and both lacrimal glands. In other examples, the at least one exocrine gland includes both submandibular glands and both lacrimal glands. In yet other examples, the at least one exocrine gland includes both parotid glands, both submandibular glands and both lacrimal glands of the subject. The at least one exocrine gland may also include one or more minor salivary glands and/or one or both sublingual glands.
  • local administration to the at least one exocrine gland includes intraglandular administration, such as retrograde cannulation of the at least one exocrine gland, such as retrograde cannulation of one or more salivary glands and/or lacrimal glands.
  • the radionuclide-conjugated PSMA ligand is administered systemically to the subject.
  • systemic administration is via intravenous or intraperitoneal administration.
  • the non-radiolab el ed PSMA ligand competitor is administered prior to administration of the radionuclide-conjugated PSMA ligand so that the unlabeled ligand can bind to available PSMA binding sites on the non-target exocrine glands, thereby preventing binding of the radionuclide-conjugated PSMA ligand.
  • the radionuclide- conjugated PSMA ligand is administered to the subject less than 90 minutes following administration of the non-radiolab el ed PSMA ligand competitor.
  • the radionuclide-conjugated PSMA ligand is administered to the subject less than 60 minutes following administration of the non-radiolab el ed PSMA ligand competitor. In other embodiments, the radionuclide-conjugated PSMA ligand is administered to the subject less than 30 minutes following administration of the non-radiolab el ed PSMA ligand competitor. In yet other embodiments, the radionuclide-conjugated PSMA ligand is administered to the subject less than 15 minutes following administration of the non-radiolab el ed PSMA ligand competitor.
  • the radionuclide-conjugated PSMA ligand is administered to the subject less than 90, less than 80, less than 70, less than 60, less than 50, less than 45, less than 40, less than 35, less than 30, less than 25, less than 20, less than 15, or less than 10 minutes following administration of the non-radiolab el ed PSMA ligand competitor.
  • the radionuclide- conjugated PSMA ligand is administered about 90, about 80, about 70, about 60, about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 15, about 10, or about 5 minutes after administration of the non-radiolab el ed PSMA ligand competitor.
  • the radionuclide-conjugated PSMA ligand is administered about 1 to 90, 5 to 90, 10 to 90, 15 to 90, 5 to 80, 5 to 70, 5 to 60, 5 to 50, 5 to 45, 5 to 40, 5 to 35, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 20, 10 to 30, or 10 to 15 minutes after administration of the non-radiolab el ed PSMA ligand competitor.
  • the PSMA ligand competitor can be any molecule capable of binding PSMA with the same or greater specificity than the selected radiolabeled PSMA ligand (i.e. any molecule that can compete for binding to PSMA).
  • the PSMA ligand competitor is a small molecule.
  • the PSMA ligand competitor is DCFPyL, MIP-1072, MIP-1379, MIP-1095, MIP-1404, MIP-1405, MIP-1427, MIP- 1428, MIP-1519, MIP-1545, MIP-1555, MIP1558, PMPA, PSMA-11, PSMA-617, PSMA-1007, PSMA-I&T, or DCFBC.
  • the PSMA ligand competitor is DCFPyL.
  • the PSMA ligand competitor is a PSMA interference agent.
  • the PSMA interference agent is a PSMA-specific antibody, aptamer, antisense oligonucleotide, siRNA, shRNA, miRNA or CRISPR interference agent.
  • the PSMA ligand (to be radiolabeled) is a small molecule PSMA ligand.
  • the PSMA ligand is DCFPyL, MIP-1072, MIP-1379, MIP-1095, MIP-1404, MIP-1405, MIP-1427, MIP-1428, MIP-1519, MIP-1545, MIP-1555, MIP1558, PMPA, PSMA-11, PSMA-617, PSMA-1007, PSMA-I&T, or DCFBC.
  • the labeled PSMA ligand includes DCFPyL.
  • the PSMA ligand is a PSMA interference agent.
  • the PSMA interference agent is a PSMA- specific antibody, aptamer, antisense oligonucleotide, siRNA, shRNA, miRNA or CRISPR interference agent.
  • the radionuclide of the radionuclide-conjugated PSMA ligand is a radioactive isotope of gallium (Ga), iodine (I), yttrium (Y), lutetium (Lu), bismuth (Bi), actinium (Ac), rhenium (Re), indium (In), thorium (Th) or technetium (Tc).
  • the radionuclide is 18 F, 123 I, 124 I, 125 I, 131 I, 211 At, 177 Lu, 68 Ga, 99m Tc, 111 ln, 90 Y, 213 Bi, 225 Ac, 75 Br, 77 Br,
  • the radionuclide-conjugated PSMA ligand is [ 18 F]DCFPyL
  • the cancer to be treated can be any cancer or tumor that expresses or overexpresses PSMA.
  • the PSMA-expressing cancer is a prostate cancer, liver cancer, lung cancer, renal cancer, glioblastoma, pancreatic cancer, melanoma, breast cancer, colon cancer, esophageal cancer or stomach cancer.
  • the PSMA-expressing cancer is a prostate cancer, such as, but not limited to, prostate adenocarcinoma, prostate sarcoma or small cell prostate carcinoma.
  • the quantity of non-radiolab el ed PSMA ligand competitor administered to the subject may vary depending upon, for example, the cancer to be treated, the weight and general health of the subject, the choice of PSMA ligand, and the radionuclide-conjugated PSMA ligand to be administered.
  • the effective amount of the non-radiolab el ed PSMA ligand competitor is an amount necessary to prevent or inhibit uptake of the radionuclide in at least one exocrine gland of a subject (such as a salivary gland) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or up to 100%, for example relative to an amount of uptake of the radionuclide in at least one exocrine gland of a subject (such as a salivary gland) without prior administration of the non-radiolab el ed PSMA ligand competitor.
  • the therapeutically effective amount of radionuclide-conjugated PSMA ligand administered to the subject will vary depending on a variety of factors, including the cancer to be treated, the weight and general health of the subject, and the specific radionuclide and PSMA ligand selected.
  • the therapeutically effective amount of the radionuclide- conjugated PSMA ligand is the amount sufficient to reduce the tumor size and/or volume by at least 10%, at least 20%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, or even 100%, for example as compared to the size/volume prior to treatment.
  • the subject is administered no more than a 100-fold, 75-fold, 50-fold, 25- fold, 10-fold, 1-fold, 0.5-fold or 0.1 -fold excess of the non-radiolab el ed PSMA ligand competitor relative to the radionuclide-conjugated PSMA ligand.
  • the subject is administered about 0.001 -fold to 100-fold, 0.01-fold to 100-fold, 0.1-fold to 100-fold, 0.1-fold to 75-fold, 0.1-fold to 50-fold, 0.1-fold to 25-fold, 0.1-fold to 10-fold, 0.1-fold to 1-fold, 0.1-fold to 0.5-fold or 1-fold to 10-fold to excess of the non-radiolab el ed PSMA ligand competitor relative to the radionuclide-conjugated PSMA ligand.
  • the volume of non-radiolab el ed PSMA ligand administered locally to the exocrine gland of the subject is about 10 ⁇ L to about 250 ⁇ L, such as about 10 ⁇ L to about 200 ⁇ L, about 10 ⁇ L to about 100 ⁇ L, about 25 ⁇ L to about 100 ⁇ L, or about 25 ⁇ L to about 50 ⁇ L.
  • the concentration of non-radiolab el ed PSMA ligand administered is about 1 nM to about 10 nM, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nM.
  • the method further includes performing an assay to measure salivary flow and/or performing sialography on the subject.
  • C Method of Preventing or Reducing the Severity of Xerostomia
  • the method includes locally administering to at least one salivary gland of the subject an effective amount of a non-radiolab el ed PSMA ligand competitor; and subsequently administering to the subject a therapeutically or diagnostically effective amount of a radionuclide-conjugated PSMA ligand.
  • the ligand of the non-radiolab el ed PSMA ligand competitor and the radionuclide- conjugated PSMA ligand are the same ligand ( e.g ., both DCFPyL or both DCFBC).
  • the ligand of the non-radiolab el ed PSMA ligand competitor and the radionuclide- conjugated PSMA ligand are different ligands, wherein the PSMA ligand competitor binds with greater or equal affinity to PSMA as the radiolabeled PSMA ligand (e.g., one is DCFPyL and the other is DCFBC).
  • the disclosed treatment reduces the severity of xerostomia by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, for example relative to the severity of xerostomia without prior administration of the non-radiolab el ed PSMA ligand competitor.
  • the disclosed treatment prevents xerostomia in at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or up to 100% of subjects, for example relative to an amount of xerostomia observed without prior administration of the non- radiolabeled PSMA ligand competitor.
  • the disclosed treatment reduces the number of mouth sores by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, for example relative to the number of mouth sores without prior administration of the non-radiolab el ed PSMA ligand competitor.
  • the disclosed treatment increases the flow rate of a salivary gland by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, or at least 500%, for example relative to the flow rate without prior administration of the non-radiolab el ed PSMA ligand competitor.
  • the normal salivary flow rate for unstimulated saliva from the parotid gland is 0.4 to 1.5 mL/min/gland.
  • the normal flow rate for unstimulated, “resting” whole saliva is 0.3 to 0.5 mL/min; for stimulated saliva, 1 to 2 mL/min.
  • the disclosed treatment reduces tooth decay, tooth loss, or cavities by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, for example relative to amount of tooth decay, number of lost teeth, or number of cavities without prior administration of the non-radiolab el ed PSMA ligand competitor.
  • the disclosed treatment reduces oral candidiasis by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, for example relative to the amount of oral candidiasis without prior administration of the non- radiolabeled PSMA ligand competitor.
  • the disclosed treatment reduces dysgeusia by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, for example relative to the amount of dysgeusia without prior administration of the non-radiolab el ed PSMA ligand competitor.
  • the disclosed treatment reduces glossodynia by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, for example relative to the amount of glossodynia without prior administration of the non-radiolab el ed PSMA ligand competitor. In some examples, combinations of these affects are achieved.
  • the at least one salivary gland is one or more major salivary glands, such as one or both parotid glands, one or both submandibular glands and/or one or both sublingual glands.
  • the at least one salivary gland is both parotid glands.
  • the at least one salivary gland is both submandibular glands.
  • the at least one salivary gland is both parotid glands and both submandibular glands of the subject.
  • the at least one salivary gland may also include one or more minor salivary glands and/or one or both sublingual glands.
  • local administration to the at least one salivary gland includes intraglandular administration, such as retrograde cannulation of the at least one salivary gland.
  • the radionuclide-conjugated PSMA ligand is administered systemically to the subject.
  • systemic administration is via intravenous or intraperitoneal administration.
  • the non-radiolab el ed PSMA ligand competitor is administered prior to administration of the radionuclide-conjugated PSMA ligand so that the unlabeled ligand can bind to available PSMA binding sites on the non-target exocrine glands, thereby preventing binding of the radionuclide-conjugated PSMA ligand.
  • the radionuclide- conjugated PSMA ligand is administered to the subject less than 90 minutes following administration of the non-radiolab el ed PSMA ligand competitor.
  • the radionuclide-conjugated PSMA ligand is administered to the subject less than 60 minutes following administration of the non-radiolab el ed PSMA ligand competitor. In other embodiments, the radionuclide-conjugated PSMA ligand is administered to the subject less than 30 minutes following administration of the non-radiolab el ed PSMA ligand competitor. In yet other embodiments, the radionuclide-conjugated PSMA ligand is administered to the subject less than 15 minutes following administration of the non-radiolab el ed PSMA ligand competitor.
  • the radionuclide-conjugated PSMA ligand is administered to the subject less than 90, less than 80, less than 70, less than 60, less than 50, less than 45, less than 40, less than 35, less than 30, less than 25, less than 20, less than 15, or less than 10 minutes following administration of the non-radiolab el ed PSMA ligand competitor.
  • the radionuclide- conjugated PSMA ligand is administered about 90, about 80, about 70, about 60, about 50, about 45, about 40, about 35, about 30, about 25, about 20, about 15, about 10, or about 5 minutes after administration of the non-radiolab el ed PSMA ligand competitor.
  • the radionuclide-conjugated PSMA ligand is administered about 1 to 90, 5 to 90, 10 to 90, 15 to 90, 5 to 80, 5 to 70, 5 to 60, 5 to 50, 5 to 45, 5 to 40, 5 to 35, 5 to 30, 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 20, 10 to 30, or 10 to 15 minutes after administration of the non-radiolab el ed PSMA ligand competitor.
  • the PSMA ligand competitor can be any molecule capable of binding PSMA with the same or greater specificity than the selected radiolabeled PSMA ligand (i.e. any molecule that can compete for binding to PSMA).
  • the PSMA ligand competitor is a small molecule.
  • the PSMA ligand competitor is DCFPyL, MIP-1072, MIP-1379, MIP-1095, MIP-1404, MIP-1405, MIP-1427, MIP- 1428, MIP-1519, MIP-1545, MIP-1555, MIP1558, PMPA, PSMA-11, PSMA-617, PSMA-1007, PSMA-I&T, or DCFBC.
  • the PSMA ligand competitor is DCFPyL.
  • the PSMA ligand competitor is a PSMA interference agent.
  • the PSMA interference agent is a PSMA-specific antibody, aptamer, antisense oligonucleotide, siRNA, shRNA, miRNA or CRISPR interference agent.
  • the PSMA ligand (to be radiolabeled) is a small molecule PSMA ligand (also referred to in the art as a “PSMA inhibitor”).
  • the PSMA ligand is DCFPyL, MIP-1072, MIP-1379, MIP-1095, MIP-1404, MIP-1405, MIP-1427, MIP-1428, MIP-1519, MIP-1545, MIP-1555, MIP1558, PMPA, PSMA-11, PSMA-617, PSMA-1007, PSMA- I&T, or DCFBC.
  • the labeled PSMA ligand includes DCFPyL.
  • the PSMA ligand is a PSMA interference agent.
  • the PSMA interference agent is a PSMA-specific antibody, aptamer, antisense oligonucleotide, siRNA, shRNA, miRNA or CRISPR interference agent.
  • the radionuclide of the radionuclide-conjugated PSMA ligand is a radioactive isotope of gallium (Ga), iodine (I), yttrium (Y), lutetium (Lu), bismuth (Bi), actinium (Ac), rhenium (Re), indium (In), thorium (Th) or technetium (Tc).
  • the radionuclide is 18 F, 123 I, 124 I, 125 I, 131 I, 211 At, 177 Lu, 68 Ga, 99m Tc, 111 ln, 90 Y, 213 Bi, 225 Ac, 75 Br, 77 Br,
  • the radionuclide-conjugated PSMA ligand is [ 18 F]DCFPyL
  • the subject has or is suspected of having a PSMA-expressing cancer.
  • the cancer can be any cancer or tumor that expresses or overexpresses PSMA.
  • the PSMA-expressing cancer is a prostate cancer, liver cancer, lung cancer, renal cancer, glioblastoma, pancreatic cancer, melanoma, breast cancer, colon cancer, esophageal cancer or stomach cancer.
  • the PSMA-expressing cancer is a prostate cancer, such as, but not limited to, prostate adenocarcinoma, prostate sarcoma or small cell prostate carcinoma.
  • the quantity of non-radiolab el ed PSMA ligand competitor administered to the subject may vary depending upon, for example, the cancer to be treated (or imaged), the weight and general health of the subject, the choice of PSMA ligand, and the radionuclide-conjugated PSMA ligand to be administered.
  • the effective amount of the non-radiolab el ed PSMA ligand competitor is an amount necessary to prevent or inhibit uptake of the radionuclide in at least one exocrine gland of a subject (such as a salivary gland) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or up to 100%, for example relative to an amount of uptake of the radionuclide in at least one exocrine gland of a subject (such as a salivary gland) without prior administration of the non-radiolab el ed PSMA ligand competitor.
  • the therapeutically effective or diagnostically effective amount of radionuclide- conjugated PSMA ligand administered to the subject will vary depending on a variety of factors, including the cancer to be treated (or imaged), the weight and general health of the subject, and the specific radionuclide and PSMA ligand selected.
  • the therapeutically effective amount of the radionuclide-conjugated PSMA ligand is the amount sufficient to reduce the tumor size and/or volume by at least 10%, at least 20%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, or even 100%, for example as compared to the size/volume prior to treatment.
  • the diagnostically effective amount of the radionuclide- conjugated PSMA ligand is the amount necessary to enable diagnostic imaging, such as PET.
  • the subject is administered no more than a 100-fold, 75-fold, 50-fold, 25- fold, 10-fold, 1-fold, 0.5-fold or 0.1 -fold excess of the non-radiolab el ed PSMA ligand competitor relative to the radionuclide-conjugated PSMA ligand.
  • the subject is administered about 0.001 -fold to 100-fold, 0.01-fold to 100-fold, 0.1-fold to 100-fold, 0.1-fold to 75-fold, 0.1-fold to 50-fold, 0.1-fold to 25-fold, 0.1-fold to 10-fold, 0.1-fold to 1-fold, 0.1-fold to 0.5-fold or 1-fold to 10-fold to excess of the non-radiolab el ed PSMA ligand competitor relative to the radionuclide-conjugated PSMA ligand.
  • the volume of non-radiolab el ed PSMA ligand administered locally to the salivary gland of the subject is about 10 ⁇ L to about 250 ⁇ L, such as about 10 ⁇ L to about 200 ⁇ L, about 10 ⁇ L to about 100 ⁇ L, about 25 ⁇ L to about 100 ⁇ L, or about 25 ⁇ L to about 50 ⁇ L.
  • the concentration of non-radiolab el ed PSMA ligand administered is about 1 nM to about 10 nM, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nM.
  • the method further includes performing an assay to measure salivary flow and/or performing sialography on the subject.
  • the disclosed methods utilize both a radiolabeled PSMA ligand and a non-radiolab el ed (cold) competitor PSMA ligand.
  • the radiolabeled and cold PSMA ligands can either be the same ligand, or they can be different ligands so long as the cold PSMA ligand is capable of competing with the radiolabeled ligand for binding to PSMA on target cells. This means that the PSMA ligand competitor must bind with greater or equal affinity to PSMA as the radiolabeled PSMA ligand.
  • the PSMA ligand is a small molecule PSMA ligand, which are generally classified into three groups: (1) urea-based glutamate heterodimers; (2) phosphoramidates; and (3) and 2-(phosphinylmethyl) pentanedioic acids (Lüitje etal, Theranostics 5(12): 1388-1401, 2015).
  • the small molecule PSMA ligand is based on a glutamate-urea-lysine heterodimer, or a glutamate-urea-glutamate based dimer, that binds specifically to an enzymatic site on PSMA.
  • the radionuclide-conjugated PSMA ligand includes a glutamate-urea-amino acid based small molecule ligand conjugated to a radionuclide through an intervening linker.
  • the PSMA ligand is DCFPyL, MIP-1072, MIP-1379, MIP-1095, MIP-1404, MIP-1405, MIP-1427, MIP-1428, MIP- 1519, MIP-1545, MIP-1555, MIP1558, PMPA, PSMA-11, PSMA-617, PSMA-1007, PSMA-I&T or DCFBC.
  • PSMA ligands for use in imaging (such as PET, CT or SPECT) and/or radiotherapy are described in, for example, Czamiecki et al. ( Transl Androl Urol 7(5): 831-843, 2018); Lüitje etal. (Theranostics 5(12): 1388-1401, 2015); Schwarzenboeck et al. (, J NuclMed 58: 1545-1552, 2017); U.S. Patent Application Publication Nos. 2019/0008988, 2018/0207299 and 20150110814; U.S. Patent Nos. 8,465,725 and 8,487,129; and PCT Publication No. WO 2020/028323, each of which is herein incorporated by reference.
  • DCFPyL ((((S)-1-carboxy-5-(6-fluoronicotinamido)pentyl)carbamoyl)-L-glutamic acid): MIP-1072 ((S)-2-(3-((S)-1-Carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedioic acid):
  • MIP-1095 ((S)-2-(3-((S)-1-Carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedioicacid): MIP-1379: MIP-1404: MIP-1405:
  • MIP-1427 MIP-1428: MIP-1519: MIP-1545:
  • PSMA-11 PSMA-617: PSMA-1007 (labeled with 18 F):
  • DCFBC N-( ⁇ (1r)- 1-Carboxy-2-[(4-Fluorobenzyl)sulfanyl]ethyl ⁇ carbamoyl)-L-Glutamic Acid
  • the PSMA ligand is an aptamer that specifically binds PSMA.
  • Exemplary PSMA aptamers are disclosed in U.S. Patent Application Nos. 2019/0177730, 2014/0148503, 2013/0209514 and 2016/0291023, which are herein incorporated by reference in their entireties.
  • the PSMA ligand is an antibody, such as a monoclonal antibody, that specifically binds PSMA.
  • the PSMA antibody is a human antibody, a chimeric antibody or a synthetic antibody. Exemplary PSMA-specific monoclonal antibodies are described in, for example, U.S. Patent Application Publication Nos.
  • [ 18 F]DCFPyL (FIG. 7A) was synthesized according to a previously described procedure with 32-43% radiochemical yield and >98% purity (FIG. 7B) (Basuli etal. , J Labelled Comp Radiopharm 2017; 60: 168-175, 2017). The molar activity was 1200-2600 Ci/mmol (4.4 x 10 13 - 9.62 x 10 13 Bq; end of synthesis).
  • 22RV1 prostate cancer cells were from ATCC and cultured as a monolayer using RPMI 1640 medium supplemented with 10% fetal bovine serum, 1% 2 mM glutamine, 1% penicillin- streptomycin at 37°C in a 5% CO2 and 95% humidified atmosphere.
  • RPMI 1640 medium supplemented with 10% fetal bovine serum, 1% 2 mM glutamine, 1% penicillin- streptomycin at 37°C in a 5% CO2 and 95% humidified atmosphere.
  • mice submandibular gland was cannulated according to previously described procedures (Adesanya etal. , Hum Gene Ther 7: 1085-1093, 1996). Briefly, healthy or 22RV1 tumor-bearing male athymic nude mice were anesthetized by intramuscularly injecting a mixture of ketamine chloride (60 mg/kg) and xylazine (5 mg/kg). To decrease the saliva flow, mice were also intramuscularly injected with atropine (0.5 mg/kg). DCFPyL or saline was delivered to the SMGby retrograde infusion via a cannula (5 mm) inserted into the orifice of the SMG duct (FIG. 1C).
  • mice 5- to 6-week-old healthy male athymic nude mice (Charles River, 490) were randomly divided into systemic (SYS) and cannulation (CAN) groups. SYS mice were further randomized into systemic saline control (SYS saline control) and systemic blocking groups. Mice in SYS saline control group were administered (intravenously, tail vein) with 100 ⁇ Ci of [ 18 F]DCFPyL alone whereas mice in systemic blocking were administered with the same dose of radioactivity in the presence of either 1000-, 500-, 100-, or 10-fold excess of unlabeled DCFPyL (SYS 1000x, SYS 500x, SYS 100x, SYS 10x).
  • mice in the CAN group were further subdivided into CAN saline control and CAN blocking groups (CAN 1000x, CAN 100x, CAN 10x, CAN 1x).
  • CAN saline control group right and left SMG (SMG-R, SMG-L) of mice were cannulated and infused with 50 ⁇ l of saline.
  • SMG-R and SMG-L were cannulated and infused with 1000-, 100-, 10-, or 1-fold excess of DCFPyL (50 ⁇ l).
  • the systemic dose of [ 18 F]DCFPyL (100 ⁇ Ci, i.v.) was administered 10 minutes after the infusion of the respective agents in the SMG.
  • %ID/g ⁇ [CPM tissue / CPM total injected dose] / [tissue weight (g)] ⁇ X 100
  • mice Healthy male athymic nude mice (5 -6-week-old, Charles River, 490) were randomly grouped into various CAN groups (saline control and blocking group).
  • SMG-R and SMG-L of mice in CAN saline control group were cannulated and infused with either 50 ⁇ l or 25 ⁇ l of saline.
  • SMG-R was cannulated and infused with 50 ⁇ l or 25 ⁇ l of either 1-fold (CAN 1x) or 0.1-fold excess (CAN 0.1x) of DCFPyL whereas, SMG-L were infused with either 50 ⁇ l or 25 ⁇ l of saline.
  • mice were intravenously (tail vein) administered [ 18 F]DCFPyL (100 ⁇ Ci). After 1 hour, mice were euthanized, followed by biodistribution analysis. Radioactive content in the blood and each tissue was counted using a gamma counter and expressed as %ID/g of tissue and T:Bs.
  • 22RV1 cells [2 x 10 6 cells per mouse; RPMI 1640:matrigel (50:50)] were subcutaneously injected by the right shoulder of athymic nude mice (male, 5-6-week-old, Charles River, 490).
  • mice were randomized into SYS (SYS saline control, SYS 1x, SYS 0.1x) and CAN (CAN saline control, CAN 1x, CAN 0.1x) groups.
  • Mice in SYS groups were injected with [ 18 F]DCFPyL (100 ⁇ Ci, i.v.) either in the presence [(SYS 1x: 1-fold excess); (SYS 0.1x: 0.1-fold excess)] or absence (SYS saline control) of an excess of DCFPyL.
  • mice in CAN groups were cannulated and infused with 50 ⁇ l of either saline (CAN saline control) or 1-fold or 0.1-fold excess of DCFPyL (CAN 1x, CAN 0.1x).
  • SMG-L of mice in the CAN group was cannulated and infused with 50 ⁇ l of saline.
  • mice in the CAN groups were intravenously injected with 100 ⁇ Ci of [ 18 F]DCFPyL.
  • mice in the CAN groups were intravenously injected with 100 ⁇ Ci of [ 18 F]DCFPyL.
  • mice in the CAN groups were intravenously injected with 100 ⁇ Ci of [ 18 F]DCFPyL.
  • mice in the CAN groups were intravenously injected with 100 ⁇ Ci of [ 18 F]DCFPyL.
  • mice in the CAN groups were intravenously injected with 100 ⁇ Ci of [ 18 F]DCFPyL.
  • mice in the CAN groups were intravenously injected with
  • mice healthy male athymic nu/nu mice (5 -6-week-old, Charles River, 490) were divided into three groups: CAN saline control, CAN-10, and CAN-1. Right and left SMG of mice in all the groups were cannulated. Both SMGs of mice in the CAN saline control were infused with 50 ⁇ l of sterile saline whereas SMGs of mice in the CAN-10 and CAN-1 groups were infused with 50 ⁇ l of 10 nmol and 1 nmol of DCFPyL, respectively.
  • One week prior (baseline) to performing cannulation saline was collected from mice in all the groups, followed by the collection of saliva at 1 -month and 2-month time-points.
  • mice were monitored for the duration of 1 month; to examine chronic toxicity, a different set of mice were monitored for 2 months. During the study period, mice were weekly weighed. At the end of the study period, mice were euthanized, and blood samples were collected to examine functional biomarkers such as BUN, blood albumin, ALT, AST, creatinine, amylase, and blood bilirubin for kidney and liver functions. H&E staining was performed in SMGs of mice collected at the end of 2 months to compare SMG anatomy between saline control and CAN- 10 groups.
  • functional biomarkers such as BUN, blood albumin, ALT, AST, creatinine, amylase, and blood bilirubin for kidney and liver functions.
  • H&E staining was performed in SMGs of mice collected at the end of 2 months to compare SMG anatomy between saline control and CAN- 10 groups.
  • Example 2 Prevention of PSMA-TRT mediated xerostomia via retrograde cannulation of salivary glands
  • This example describes the finding that local administration of cold (i.e., non-radiolab el ed) PSMA ligand to the salivary gland prior to systemic administration of PSMA-targeted radionuclide significantly inhibits uptake of the radionuclide in the salivary gland.
  • cold i.e., non-radiolab el ed
  • PSMA expression and its localization in parotid and submandibular salivary glands of humans were determined by immunofluorescence staining.
  • PSMA immunofluorescence demonstrated strong, apical membrane staining exclusively in the acini of the SGs.
  • mice in the SYS 1x, 100x, 500x, and 1000x groups respectively exhibited 12%, 34%, 24%, and 40% decreased uptake of [ 18 F]DCFPyL in SMG compared to the SYS saline control group.
  • Reduced uptakes were also observed in PRG (1x:4.4%, 100x:20%, 500x:17%,1000x:26%) and SLG (1x: 11%, 100x:23%, 500x:53%, 1000x:50%). Since these experiments were performed in non-tumor bearing mice and PSMA is known to be expressed in mouse kidneys, renal uptake of [ 18 F]DCFPyL was considered as a surrogate for tumor uptake.
  • mice in the CAN 1x group exhibited 53%, 36%, and 28% reduced uptake (T:B) in SMG, PRG, and SLG, respectively, compared to CAN saline control (FIG. 2B).
  • mice in the CAN 10x, 100x, and 1000x groups showed a 42-53% reduction in SMG T:B, a 42-47% reduction in PRG T:B, and a28- 34% reduction in SLG T:B compared to mice in the control group (FIG. 2B).
  • CAN 1x Compared to the CAN saline control, CAN 1x exhibited a 7.4% reduction in renal uptake (T:B) of [ 18 F]DCFPyL, whereas 70-86% radioactivity was blocked in the CAN 10x, CAN 100x, and CAN 1000x groups. Compared to the higher blocking dose of DCFPyL, the 1x dose showed relatively similar blocking of [ 18 F]DCFPyL in the SGs with the least blocking in the kidney.
  • Kidney T:B for CAN saline control was calculated as 37.89, whereas kidney T:B in CAN 1x, CAN 0.1x and CAN 0.01x group was found to be 35.06, 35.16, and 37.36, respectively.
  • the CAN 1x and CAN 0.1x doses resulted in significantly higher SMG blocking of [ 18 F]DCFPyL than CAN 0.01x, with only a marginal difference in renal uptake between the groups.
  • Contralateral blocking of SGs was achieved by the SG cannulation approach. Since only the right SMG was cannulated and infused with DCFPyL, reduced uptake of [ 18 F]DCFPyL was expected only in the right SMG. However, bilateral blocking was noted in all three major SGs. While the exact mechanism is unknown, one possible explanation is that the major salivary glands in mice are interconnected via ducts. In contrast to mice, sialography of human SG performed with fluoroscopy does not demonstrate any bilateral uptake of the contrast agent (Gadodia et al., Acta Radiologica 51: 156-163, 2010). Another possible explanation is that there could be leakage or absorption of the unlabeled DCFPyL into the blood circulation in the mouse model, which may also account for the observed blocking of [ 18 F]DCFPyL in distant sites such as the kidneys.
  • Sialendoscopy is commonly used in the clinic to diagnose and treat several conditions of salivary glands (Strychowsky et al., Arch Otolaryngol Head Neck Surg 138: 541-547). Sialendoscopy has been evaluated in patients undergoing 225 Ac-PSMA-617 therapy to prevent xerostomia, and in one study, the SMG and PRG were cannulated and irrigated with sterile saline and prednisolone injections (Rathke etal, lair .1 Nucl Med Mol Imaging 46: 139-147, 2019). Although some initial improvement was observed, it was unclear if the effect was due to saline irrigation or administration of the steroids.
  • Radioprotectors such as short-acting anticholinergic drugs, amifostine, and local anesthetic have also been evaluated to protect the salivary gland against ionizing radiation (Langbein et al. , JNucl Med 59: 1172-1173, 2018; Hakim et al. , Ini .1 Radiat Oncol Biol Phys 82: E623-E630, 2012; Utley et al, Radiat Res 68: 284-291, 1976; Grundmann et al, J Dent Res 88: 894-903, 2009; Hosono, Int J Radiat Biol 95: 1427-1430, 2019).
  • PSMA-based TRT therapies are predominantly being investigated in patients who have exhausted all other forms of PCa therapy (Malcolm et al, Cancers 11(2): E268, 2019). Accumulating clinical evidence suggests that the SG toxicity of PSMA-TRT needs to be balanced against the therapeutic benefits of these agents.
  • An effective method to prevent xerostomia will permit the administration of higher therapeutic doses in mCRPC patients and may result in a better clinical outcomes.
  • Effective management of SG toxicity may permit the introduction of effective PSMA-TRT early in the course of the treatment paradigm. Even though continuous efforts are being made to prevent PSMA-TRT mediated xerostomia, better strategies are needed to address this problem.
  • the study disclosed herein provides data demonstrating that cannulating the salivary glands followed by direct infusion of unlabeled PSMA inhibitor in the SG selectively blocks the uptake of PSMA-targeted radionuclides in the SG without interfering with the uptake of the radioactive agent in the tumor. Since SG cannulation or sialendoscopy is a wel1-established procedure that is being successfully practiced in the clinic, this approach can be easily translated into the clinic to benefit mCRPC patients (Strychowsky etal, Arch Otolaryngol Head Neck Surg 138: 541-547).

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Abstract

L'invention concerne un procédé de protection d'organes exocrines des effets hors cible de la thérapie par radionucléides ciblés sur l'antigène membranaire spécifique de la prostate (PSMA). Le procédé comprend l'administration locale d'un compétiteur de ligand PSMA non marqué avant l'administration systémique d'un ligand PSMA conjugué à un radionucléide. Les procédés décrits peuvent être utilisés dans le traitement du cancer de la prostate et d'autres cancers exprimant le PSMA, ainsi que pour réduire la xérostomie chez des sujets recevant une radiothérapie ciblée par le PSMA.
PCT/US2021/024647 2020-03-30 2021-03-29 Procédé de blocage d'absorption de radionucléides ciblés sur l'antigène membranaire spécifique de la prostate (psma) par des organes exocrines WO2021202376A1 (fr)

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