WO2025207904A1 - Conjugué psma radiopharmaceutique et ses utilisations - Google Patents

Conjugué psma radiopharmaceutique et ses utilisations

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Publication number
WO2025207904A1
WO2025207904A1 PCT/US2025/021784 US2025021784W WO2025207904A1 WO 2025207904 A1 WO2025207904 A1 WO 2025207904A1 US 2025021784 W US2025021784 W US 2025021784W WO 2025207904 A1 WO2025207904 A1 WO 2025207904A1
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WIPO (PCT)
Prior art keywords
psma antibody
composition
psma
weight
dota
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Pending
Application number
PCT/US2025/021784
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English (en)
Inventor
Alex Brown
Shankar Vallabhajosula
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Convergent Therapeutics Inc
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Convergent Therapeutics Inc
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Publication date
Application filed by Convergent Therapeutics Inc filed Critical Convergent Therapeutics Inc
Publication of WO2025207904A1 publication Critical patent/WO2025207904A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • 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
    • A61K51/1093—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 conjugates with carriers being antibodies
    • 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
    • A61K51/1093—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 conjugates with carriers being antibodies
    • A61K51/1096—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 conjugates with carriers being antibodies radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications
    • 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
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/121—Solutions, i.e. homogeneous liquid formulation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3069—Reproductive system, e.g. ovaria, uterus, testes, prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • PC Prostate cancer
  • mCRPC metastatic castration-resistant prostate cancer
  • mCRPC metastatic castration-resistant prostate cancer
  • Chemotherapy compounds docetaxel and cabazitaxel, the androgen receptor signaling inhibitor enzalutamide, CYP-17-inhibitor abiraterone, autologous cellular immunotherapy with sipuleucel-T, and the bone-seeking a-emitter 223Ra have shown improved overall survival (OS) and most have demonstrated quality of life advantages as well.
  • OS overall survival
  • these agents have been tested in multiple disease states of mCRPC to determine if or when patients might benefit from each treatment.
  • these now established therapies become ineffective in controlling tumor progression over time.
  • Prostate-specific membrane antigen is a cell surface marker which can be overexpressed in malignant prostate tissues when compared to other organs in the human body such as kidney, proximal small intestine, and salivary glands, and is present and enriched in 75-95% of metastatic castration-resistant prostate cancer (mCRPC). PSMA is also expressed on the neovasculature within many non-prostate solid tumors, including lung cancer, colon cancer, breast cancer, renal cancer, liver cancer, pancreatic cancer, thyroid cancer, transitional cell carcinoma of the bladder, neuroendocrine carcinoma, glioblastoma multiforme, melanoma, and non-soft tissue sarcoma, but not on normal vasculature.
  • mCRPC metastatic castration-resistant prostate cancer
  • New therapies are urgently needed in order to treat cancers, including PSMA expressing cancers such as prostate cancer
  • radiotherapeutic compounds that accumulate to a greater degree in tumors without unacceptable uptake in normal organs, as absorbed dose is a function of the integral of cumulative activity.
  • the macrocycles currently in use e.g., DOTA
  • the macrocycles currently in use generally form complexes of insufficient stability with radionuclides, particularly for radionuclides of larger size, such as actinium, radium, bismuth, and lead isotopes.
  • additional therapies for treating PSMA expression cancers and the use of radiotherapeutic compounds for such specific cancers are thus a need for additional therapies for treating PSMA expression cancers and the use of radiotherapeutic compounds for such specific cancers.
  • compositions and pharmaceutical compositions of the present disclosure comprise anti -PSMA antibody conjugates which may be useful in treating various diseases and conditions as disclosed herein.
  • the composition comprises an anti-PSMA antibody or an anti-PSMA antibody fragment, conjugated to a 1,4, 7,10-tetraazacyclododecane- 1,4, 7,10- tetraacetic acid (DOTA) chelator, wherein the DOTA chelator is covalently linked to the anti- PSMA antibody in an average ratio range of about 2 DOTAs per anti-PSMA antibody to about 7 DOTAs per anti-PSMA antibody.
  • DOTA 1,4, 7,10-tetraazacyclododecane- 1,4, 7,10- tetraacetic acid
  • the composition comprises an anti-PSMA antibody conjugated to a 1,4, 7,10-tetraazacyclododecane- 1,4, 7, 10-tetraacetic acid (DOTA) chelator.
  • the anti-PSMA antibody is J591.
  • the average ratio range is about 3 DOTAs per anti-PSMA antibody to about 5 DOTAs per anti-PSMA antibody.
  • the anti-PSMA antibody or anti-PSMA antibody fragment comprises: (i) an immunoglobulin heavy chain variable region comprising SEQ ID NO: 1; and (ii) an immunoglobulin light chain variable region comprising SEQ ID NO: 2.
  • the DOTA is conjugated in a 3 arm or 4 arm configuration with the anti-PSMA antibody.
  • the conjugated anti-PSMA antibody or anti-PSMA antibody fragment is chelated or complexed to 225 Ac.
  • the DOTA is conjugated and chelated or complexed to 225 Ac, and the anti-PSMA antibody is J591, also known as 225 Ac labeled J591 tetraxetan.
  • At least 90% of the anti-PSMA antibody is in the form of a monomer. In another specific embodiment, at least 95% of the anti-PSMA antibody is in the form of a monomer. In another specific embodiment, at least 90% or at least 95% of the anti-PSMA antibody is in the form of a monomer as determined by HPLC-SEC.
  • compositions or pharmaceutical compositions described herein at least about 85%, 90%, or 95% of the 225 Ac activity in the composition is complexed or bound to conjugated anti-PSMA antibody. In another embodiment, at least 96% of the 225 Ac activity in the composition is complexed or bound to conjugated anti-PSMA antibody. In another embodiment, at least 99% of the 225 Ac activity in the composition is complexed or bound to conjugated anti-PSMA antibody. In another specific embodiment, the percentage of 225 Ac activity bound or complexed by the conjugated anti-PSMA antibody is determined by HPLC-SEC. In another specific embodiment, the composition is substantially free of, or contains less than 5% of unchelated, or free, 225 Ac.
  • the composition is a bulk composition and comprises a total of about 0.25 mCi to about 2.0 mCi from 225 Ac. In another specific embodiment, the composition comprises a total of about 0.5 mCi to about 1.0 mCi from 225 Ac.
  • the composition is a pharmaceutical composition and comprises a single unit dose of conjugated anti-PSMA antibody is chelated to 225 Ac and one or more pharmaceutically acceptable carriers or excipients.
  • the conjugated anti- PSMA antibody is chelated to 225 Ac.
  • the single unit dose of conjugated anti-PSMA antibody is 225 Ac-labeled J591 tetraxetan.
  • the composition of a single unit dose comprises a total of about 50 pCi to 350 pCi of 225 Ac per 20 mg of anti-PSMA antibody.
  • the composition comprises a single dose ranging from about 25 KBq/kg weight of a patient to about for about 100 KBq/kg weight of a patient.
  • the composition further comprises unconjugated or naked anti- PSMA antibody.
  • the unconjugated or naked anti-PSMA antibody is J591.
  • the unconjugated/naked anti-PSMA antibody has the same amino acid sequence as the conjugated anti-PSMA antibody.
  • the total anti-PSMA antibody in the composition (unconjugated and conjugated) is at a concentration of 0.8 mg/mL to 1.2 mg/ml.
  • the amount of the total anti-PSMA antibody in the composition (unconjugated and conjugated) is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, or about 40 mg.
  • the composition is a pharmaceutical composition and comprises a single unit dose of conjugated anti-PSMA antibody chelated to 225 Ac wherein the pharmaceutical composition is about 18 to 22 ml in a saline solution containing about l%-2% human serum albumin.
  • the composition of the pharmaceutical composition comprises unconjugated or naked anti-PSMA antibody and conjugated anti-PSMA antibody chelated to 225 Ac, wherein the ratio of the unconjugated or naked anti-PSMA antibody to conjugated anti- PSMA antibody chelated to 225 Ac is about 30: 1 by weight, about 29: 1 by weight, about 28:1 by weight, about 27: 1 by weight, about 26: 1 by weight, about 25: 1 by weight, about 24: 1 by weight, about 23: 1 by weight, about 22: 1 by weight, about 21: 1 by weight, about 20:1 by weight, about 19: 1 by weight, about 18: 1 by weight, about 17:1 by weight, about 16:1 by weight, about 15:1 by weight, about 14:1 by weight, about 13:1 by weight, about 12: 1 by weight, about 11: 1 by weight, about 10:1 by weight, about 9: 1 by weight, about 8:1 by weight, about 7: 1 by weight, about 6: 1 by weight, about 5:
  • the composition of the pharmaceutical composition comprises unconjugated or naked anti-PSMA antibody and conjugated anti-PSMA antibody chelated to 225 Ac, wherein the ratio of conjugated anti-PSMA antibody chelated to 225 Ac to unconjugated or naked anti-PSMA antibody is about 30:1 by weight, about 29:1 by weight, about 28:1 by weight, about 27: 1 by weight, about 26: 1 by weight, about 25: 1 by weight, about 24:1 by weight, about 23: 1 by weight, about 22: 1 by weight, about 21 :1 by weight, about 20: 1 by weight, about 19: 1 by weight, about 18:1 by weight, about 17:1 by weight, about 16: 1 by weight, about 15: 1 by weight, about 14: 1 by weight, about 13: 1 by weight, about 12: 1 by weight, about 11 :1 by weight, about 10: 1 by weight, about 9:1 by weight, about 8:1 by weight, about 7:1 by weight, about 6: 1 by weight, about 5
  • the composition of the pharmaceutical composition comprises unconjugated or naked J591 and 225 Ac labeled J591 tetraxetan, wherein the ratio of the unconjugated or naked J591 to 225 Ac labeled J591 tetraxetan is about 30:1 by weight, about 29:1 by weight, about 28:1 by weight, about 27: 1 by weight, about 26:1 by weight, about 25: 1 by weight, about 24: 1 by weight, about 23 : 1 by weight, about 22: 1 by weight, about 21: 1 by weight, about 20: 1 by weight, about 19: 1 by weight, about 18:1 by weight, about 17:1 by weight, about 16: 1 by weight, about 15: 1 by weight, about 14:1 by weight, about 13:1 by weight, about 12:1 by weight, about 11 :1 by weight, about 10:1 by weight, about 9: 1 by weight, about 8:1 by weight, about 7:1 by weight, about 6:1 by weight
  • the composition of the pharmaceutical composition comprises unconjugated or naked J591 and 225 Ac labeled J591 tetraxetan, wherein the ratio of the 225 Ac labeled J591 tetraxetan to unconjugated or naked J591 is about 30: 1 by weight, about 29:1 by weight, about 28:1 by weight, about 27:1 by weight, about 26: 1 by weight, about 25: 1 by weight, about 24: 1 by weight, about 23: 1 by weight, about 22: 1 by weight, about 21 :1 by weight, about 20: 1 by weight, about 19: 1 by weight, about 18:1 by weight, about 17: 1 by weight, about 16: 1 by weight, about 15:1 by weight, about 14:1 by weight, about 13: 1 by weight, about 12: 1 by weight, about 11: 1 by weight, about 10: 1 by weight, about 9: 1 by weight, about 8: 1 by weight, about 7:1 by weight, about 6:1 by weight,
  • the composition of the pharmaceutical composition comprises unconjugated or naked anti-PSMA antibody and conjugated anti-PSMA antibody chelated to 225 Ac, wherein the ratio of conjugated anti-PSMA antibody chelated to 225 Ac to unconjugated or naked anti-PSMA antibody ranges in the ratio of about 40: 1 to about 1:40 by weight, about 30:1 to about 1:30 by weight, about 20: 1 to about 1:20 by weight, about 10:1 to about 1:10 by weight, about 30:1 to about 1: 1 by weight, about 20:1 to about 1: 1 by weight, about 15: 1 to about 1:1 by weight, about 10: 1 to about 1 : 1 by weight, about 1 :30 to about 1 : 1 by weight, about 1 :20 to about 1 : 1 by weight, about 1 : 15 to about 1 : 1 by weight, or about 1 : 10 to about 1 : 1 by weight.
  • the composition or pharmaceutical composition comprises unconjugated or naked J591 and 225 Ac labeled J591 tetraxetan, wherein the ratio of the unconjugated or naked J591 to 225 Ac labeled J591 tetraxetan ranges in the ratio of about 40:1 to about 1:40 by weight, about 30: 1 to about 1 :30 by weight, about 20: 1 to about 1 :20 by weight, about 10:1 to about 1 : 10 by weight, about 30: 1 to about 1 : 1 by weight, about 20: 1 to about 1 : 1 by weight, about 15:1 to about 1:1 by weight, about 10:1 to about 1: 1 by weight, about 1:30 to about 1 : 1 by weight, about 1 : 20 to about 1 : 1 by weight, about 1 : 15 to about 1 : 1 by weight, or about 1 :10 to about 1 : 1 by weight.
  • the compositions or pharmaceutical compositions may have a specific immunoreactivity or immunoreactive fraction (IRF), thus establishing adequate stability and activity of the pharmaceutical composition.
  • IRF immunoreactivity or immunoreactive fraction
  • the IRF of 225 Ac labeled anti-PSMA antibody in the composition or pharmaceutical composition is at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or about 100%.
  • the immunoreactive fraction (IRF) of a composition or pharmaceutical composition comprising 225 Ac labeled J591 tetraxetan is at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or about 100%.
  • the IRF values are determined 10 days or less before administration to a patient.
  • the IRF value is determined by using PSMA-bound magnetic beads.
  • the IRF value is determined as, or substantially similar as, in Example 5, Example 6, or Example 7 described herein.
  • the IRF is determined from the bulk batch as described in Examples 3, 5-7 described herein, or in the sub-batches, which can include the drug product batches for administration directly to a patient.
  • the IRF is determined from the bulk batch and is used as the reliant IRF measure for determining the sub-batch and final drug product for administration to a patient.
  • the IRF is determined 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or on the day of administration to a patient.
  • this measurement is used as the representative measurement of the final drug product administered to a patient.
  • the pharmaceutical compositions described herein may also be administered to a patient or subject in need thereof for the treatment of cancer.
  • the cancer is prostate cancer.
  • the cancer is a PSMA expressing cancer.
  • the cancer is mCRPC.
  • the prostate cancer is castration-sensitive prostate cancer.
  • the methods include administering one or more doses to a patient, wherein the initial dose is a pharmaceutical composition described herein.
  • second or later dose administered to the patient is a pharmaceutical composition described herein.
  • the second dose is administered two to three weeks after the initial dose.
  • the present invention also includes methods or processes of conjugating DOTA to an anti- PSMA antibody.
  • the methods include conjugating DOTA to an anti- PSMA antibody by adding a 3 -arm DOTA-NHS to the anti -PSMA antibody at a ratio ranging from about 500: 1 to about 100: 1 DOTA-NHS to the anti -PSMA antibody, or about 400: 1 to about 200: 1 DOTA-NHS to the anti-PSMA antibody, or about 300: 1 DOTA-NHS to the anti-PSMA antibody, wherein the DOTA is covalently linked to the anti-PSMA antibody in an average ratio range of about 5 DOTAs per anti-PSMA antibody to about 3 DOTAs per anti-PSMA antibody.
  • the anti-PSMA antibody comprises: (i) an immunoglobulin heavy chain variable region comprising SEQ ID NO: 1; and (ii) an immunoglobulin light chain variable region comprising SEQ ID NO: 2.
  • at least 90% of the anti-PSMA antibody in the composition is conjugated with about 2-7 or about 3-5 DOTAs.
  • the present invention also includes methods or processes of making or chelating 225 Ac to a DOTA conjugated anti-PSMA antibody.
  • the method of chelating 225 Ac to a DOTA conjugated anti-PSMA antibody comprises adding 225 AcCh to a reaction vial comprising 2M tetramethyl ammonium acetate (TMAA) buffer, 0.85 M ascorbic acid.
  • the anti-PSMA antibody comprises: (i) an immunoglobulin heavy chain variable region comprising SEQ ID NO: 1; and (ii) an immunoglobulin light chain variable region comprising SEQ ID NO: 2.
  • Fig. 1 shows an HPLC-SEC Fraction Collection of a 225 Ac labeled J591 tetraxetan composition, which indicates that at least 96% of the J591 antibody is a monomer of 225 Ac labeled J591 tetraxetan and there are minimal high molecular weight species and low molecular weight species within the tested composition.
  • Fig. 2 shows a double reciprocal plot of bead concentration and %Bound and the determination at infinite antigen excess of a composition comprising 225 Ac labeled J591 tetraxetan.
  • ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range “from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).
  • a cancer therapeutic refers to one or more cancer therapeutics or at least one cancer therapeutic.
  • the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein.
  • reference to “an inhibitor” by the indefinite article “a” or “an” does not exclude the possibility that more than one of the inhibitors is present, unless the context clearly requires that there is one and only one of the inhibitors.
  • salts includes both acid and base addition salts.
  • Pharmaceutically acceptable salts include those obtained by reacting an active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.
  • acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • treating means one or more of relieving, alleviating, delaying, reducing, improving, or managing at least one symptom of a condition in a subject.
  • the term “treating” may also mean one or more of arresting, delaying the onset (i.e., the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition.
  • terapéuticaally effective applied to dose or amount refers to that quantity of an antibody, compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.
  • a “subject” or “patient” can be a human, non- human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like.
  • ‘Mammal” includes humans and both domestic animals such as laboratory animals (e.g., mice, rats, monkeys, dogs, etc.) and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
  • laboratory animals e.g., mice, rats, monkeys, dogs, etc.
  • household pets e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits
  • non-domestic animals such as wildlife and the like.
  • substantially refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result.
  • an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed.
  • the exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking, the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained.
  • the use of “substantially” is equally applicable when used in a negative connotation to refer to the complete or near complete lack of action, characteristic, property, state, structure, item, or result.
  • compositions that is "substantially free of' other active agents would either completely lack other active agents, or so nearly completely lack other active agents that the effect would be the same as if it completely lacked other active agents.
  • a composition that is "substantially free of' an ingredient or element or another active agent may still contain such an item as long as there is no measurable effect thereof.
  • pharmaceutical combination refers to a single dosage form comprising at least two therapeutically active agents, or separate dosage forms comprising at least two therapeutically active agents together or separately for use in a combination therapy.
  • one therapeutically active agent may be formulated into one dosage form and the other therapeutically active agent may be formulated into a single or different dosage forms.
  • one therapeutically active agent may be formulated into a solid oral dosage form whereas the second therapeutically active agent may be formulated into a solution dosage form for parenteral administration, including as a kit, or from two kits.
  • a “fixed dosage form” as used herein means a dosage formulation in which one or more therapeutically active agents are combined in a single dosage formulation.
  • a “co-packaged form” as used herein means that the therapeutically active agents are taken together, more than one dosage forms wherein the therapeutically active agents are taken together, or more than one dosage forms wherein the therapeutically active agents are taken separately in two or more pharmaceutical compositions, i.e., such as two or more separate tablets, capsules, gel capsules, pellets, etc, but typically the separate compositions are as a single kit.
  • pharmaceutical composition refers to a formulation comprising at least one therapeutically active agent and a pharmaceutically acceptable excipient or carrier.
  • a non-limiting example of pharmaceutical compositions includes tablets, capsules, gel capsules, syrup, liquid, gel, suspension, solid dispersion, or combinations thereof.
  • complex refers to a complex of the compound of the invention, e.g. Formula (I) or Formula (II), complexed with a radionuclide or a metal ion, where at least one metal atom is chelated or sequestered.
  • a “conjugate” refers to a chelating agent, complexed or not complexed to at least one metal atom, that is covalently attached to a biological carrier, such as an antibody, including antibody that binds to PSMA.
  • a biological carrier such as an antibody, including antibody that binds to PSMA.
  • PSMA or “prostate-specific membrane antigen” protein refers to mammalian PSMA, preferably human PSMA protein.
  • the long transcript of PSMA encodes a protein product of about 100-120 kDa molecular weight characterized as a type II transmembrane receptor having sequence homology with the transferrin receptor and having NAALADase activity (Carter et al., “Prostate-Specific Membrane Antigen is a Hydrolase With Substrate and Pharmacologic Characteristics of a Neuropeptidase,” Proc. Natl. Acad. Set. USA 93:749-753 (1996), which is hereby incorporated by reference in its entirety).
  • An anti -PSMA antibody or PSMA receptor antibody is an antibody that interacts with (e.g., binds to) PSMA, preferably human PSMA protein.
  • the anti-PSMA antibody or PSMA receptor antibody interacts with, e.g., binds to, the extracellular domain of PSMA, e.g., the extracellular domain of human PSMA located at about amino acids 44-750 of human PSMA (amino acid residues correspond to the human PSMA sequence disclosed in U.S. Pat. No. 5,538,866, which is hereby incorporated by reference in its entirety).
  • Anti-PSMA antibodies or PSMA receptor antibodies are known in the art (Goldsmith et al., “Targeted Radionuclide Therapy for Prostate Cancer,” in Therapeutic Nuclear Medicine 617-628 (R. Baum ed. 2014), which is hereby incorporated by reference in its entirety).
  • Exemplary PSMA receptor antibodies or anti-PSMA antibodies include, but are not limited to, J591, J415, J533, and E99.
  • biological carrier refers to any biological targeting vector, such as a protein, an antibody, an antibody fragment, a hormone, a peptide, a growth factor, an antigen, a hapten or any other carrier, which functions in this invention to recognize a specific biological target site.
  • An antibody and an antibody fragment refers to any polyclonal, monoclonal, chimeric, human, mammalian, single chains, dimeric and tetrameric antibody or antibody fragment.
  • Such biological carrier when attached to a functionalized complex, serves to carry the attached ion to specific targeted tissues.
  • an antibody may comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding molecule thereof.
  • Each H chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • the heavy chain constant region comprises three constant domains, CHI, CH2 and CH3.
  • Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region comprises one constant domain, CL.
  • the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • Each VH and VL comprises three CDRs and four FRs, arranged from amino -terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the Abs may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • Naturally-produced antibodies are glycosylated, typically on the CH2 domain.
  • antibodies include monoclonal antibodies, monospecific antibodies, polyclonal antibodies, multispecific antibodies (including bispecific antibodies), engineered antibodies, recombinantly produced antibodies, wholly synthetic antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chainantibody heavy chain pairs, intrabodies, antibody fusions (sometimes referred to herein as “antibody conjugates”), heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain Fvs (scFv), camelized antibodies, affibodies, Fab fragments, Fab’ fragments, F(ab’)2 fragments, Fd’ fragments, Fd fragments, isolated CDRs, single chain Fvs, polypeptide-Fc fusions, single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); cameloid
  • Fc-silent antibody refers to an antibody comprising one or more mutations in the Fc domain that reduce, prevent, or eliminate binding of the Fc region of the antibody to Fc receptors, such as FcyR or FcR, which may result in decreased antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and/or complement-dependent cytotoxicity (CDC).
  • ADCC antibody-dependent cellular cytotoxicity
  • ADCP antibody-dependent cellular phagocytosis
  • CDC complement-dependent cytotoxicity
  • Exemplary mutations that may reduce, prevent, or eliminate antibody binding to an Fc receptor include, but are not limited to, S228P, E233P, L234A, L235A, L235E, L235F, G236R, G237A, D265A, N297A, L328R, P331S, and any combination thereof (Saunders, Conceptual Approaches to Modulate Antibody Effector Functions and Circulation Half-Life, Front. Immunol., 2019, doi.org/10.3389/fimmu.2019.01296).
  • substitution of any or all of positions 234, 235, 236 and/or 237 reduces affinity for Fey receptors, particularly FcyRl receptor (see, e.g., U.S. Pat. No. 6,624,821).
  • alanine is a preferred residue for substitution and L234A/L235A is a preferred dual mutation to reduce effector function.
  • other combinations of mutations with reduced effector functions include, but are not limited to, L234A/L235A/G237A, E233P/L234V/L235A/G236, A327G/A330S/P331S, K322A, L234A and L235A,
  • positions 234, 236 and/or 237 in human IgG2 are substituted with alanine and position 235 with glutamine, (see, e.g., U.S. Pat. No. 5,624,821).
  • Two amino acid substitutions in the complement Clq binding site at EU index positions 330 and 331 reduce complement fixation (see Tao et al., J. Exp. Med. 178:661 (1993) and Canfield and Morrison, J. Exp. Med. 173: 1483 (1991)).
  • N297A, N297Q, or N297G (Eu numbering) mutations reduce glycosylation and thereby effector functions.
  • any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to Fc receptors.
  • any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcyR. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcyRIIIA. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcyRFV. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, eliminate or prevent ADCC, ADCP, and/or CDC.
  • mutations in the Fc region to reduce, prevent, or eliminate binding to Fc receptors occur at EU index positions 228, 233, 234, 235, 235, 235, 236, 237, 265, 297, 322, 327, 328, 330, 331, and any combination thereof.
  • mutations in the Fc region to reduce, prevent, or eliminate binding to Fc receptors include, but are not limited to, S228P, E233P, L234A, L235A, L235E, L235F, G236R, G237A, D265A, N297A, K322A, A327G, L328R, A330S, P331S, and any combination thereof.
  • Fc-enabled antibody As used herein, the terms “Fc-enabled antibody,” “Fc-enhanced antibody,” and “Fc- competent antibody” are used interchangeably and refer to an antibody comprising an FC domain that is capable of binding to Fc receptors, such as FcyR or FcR. These antibodies may further comprise one or more mutations to enhance or increase binding to Fc receptors, which may result in enhanced antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and/or complement-dependent cytotoxicity (CDC).
  • ADCC antibody-dependent cellular cytotoxicity
  • ADCP antibody-dependent cellular phagocytosis
  • CDC complement-dependent cytotoxicity
  • Exemplary mutations that may enhance ADCC include, but are not limited to, S298A, E333A, K334A, S239D, I332E, P247I, A339Q, and any combination thereof (van der Horst, et al., Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies, Cancers (Basel), 12(10):3041, 2020).
  • Exemplary mutations that may enhance ADCP include, but are not limited to, F234L, R292P, Y300L, V305I, P396L, A330L, G236A, and any combination thereof (van der Horst, et al., 2020).
  • any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enhance or enable binding to Fc receptors. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enhance or enable binding to FcyR. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enhance or enable binding to FcyRIIIA.
  • any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enhance or enable binding to FcyRIV. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enable or enhance ADCC, ADCP, and/or CDC. In some embodiments, one or more substitutions in the Fc region to enhance or enable binding to Fc receptors occur at EU index positions 234, 235, 236, 239, 243, 247, 267, 268, 292, 298, 300, 305, 324, 326, 330, 332, 333, 334, 339, 345, 396, 430, and any combination thereof.
  • mutations in the Fc region to enhance or enable binding to Fc receptors include, but are not limited to, F234L, L235V, G236A, S239D, F243L, P247I, S267E, H268E, R292P, S298A, Y300L, V305I, S324T, K326W, A330L, I332E, E333A, E333S, K334A, A339Q, E345G, P396L, E430G, and any combination thereof.
  • the Fc- enabled antibody comprises a modified IgGI domain characterized by substitutions at S239D, A330L, and I332E (Eu numbering).
  • glycoform perturbation can be used to enhance Fc-mediated therapeutic antibody function.
  • the N-linked Fc glycosylations on IgGI antibodies are important for effector function. Sialylation, galactosylation, bisecting sugars, and fucosylation can all affect binding and activity of IgG molecules. Controlling the glycosylation patterns on therapeutic antibodies can be done a number of different ways. The type of cell producing the recombinant antibody and its culture conditions can affect glycosylation and activity of therapeutic antibodies. Furthermore, bioreactor conditions and downstream processing can also affect the glycan microheterogenity. Low or afucosylated antibodies have been shown to enhance remediating properties.
  • amino acid engineered variants can have more broadly enhanced affinity for multiple FcyR, whereas glycoform engineered antibody can generally have more specific affinity for enhanced FcyRIIIa binding.
  • Glycoforms interact with proximal amino acids on the Fc portion and replacement of the amino acid that come in contact with Ig oligosaccharides can result in different glycoform structures. Additional mutations in the Fc region that enhance or enable binding to Fc receptors and alternative strategies for enhancing or enabling binding to Fc receptors are described in Saunders, 2019.
  • compositions including pharmaceutical compositions, comprising anti-PSMA antibody or an anti-PSMA antibody fragment conjugated to a chelator.
  • the chelator is a l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid (DOTA) chelator.
  • DOTA is conjugated in a 3 arm or 4 arm configuration with the anti-PSMA antibody or anti-PSMA antibody fragment.
  • the anti-PSMA antibody is J591.
  • J591 is as described in U.S. Patent No. 7,045,605, and PCT application publication WO2018/204477, which are hereby incorporated by reference in its entirety.
  • the chelator is one of the chelators in Table 2.
  • the chelator is DOTA, H2-MACROPA or PCTA.
  • the chelator is DOTA, which may be to form a three arm or four arm DOTA to an anti-PSMA antibody.
  • the chelator is DOTA conjugated to an anti-PSMA antibody, such as an anti-PSMA monoclonal antibody.
  • an anti-PSMA monoclonal antibody is J591.
  • the radionuclide is 225 Ac and the chelator is DOTA, H2- MACROPA or PCTA.
  • the chelator is DOTA, which may be 3 arm or 4 arm DOTA.
  • the conjugate is of Formula II wherein mAb is an anti-PSMA monoclonal antibody.
  • the chelator and antibody are linked with methods known in the art, including for example the use of NHS-ester or isothiocyanate linkage systems.
  • the linker conjugate binds to any amino acid of the antibody.
  • the conjugate is bound to a nucleophilic amino acid on the antibody.
  • the amino acid is at least a lysine.
  • the linker L is used to link the chelator and antibody with methods known in the art, including for example the use of NHS-ester or isothiocyanate linkage systems.
  • L is:
  • compositions or pharmaceutical compositions of the present application comprise various ratios of anti-PSMA antibody or an anti-PSMA antibody fragment to chelator from the conjugation process.
  • the anti-PSMA antibody or an anti-PSMA antibody fragment is conjugated to a chelator wherein the chelator is covalently linked to the anti-PSMA antibody in an average ratio range of about 1 chelator per anti-PSMA antibody or anti-PSMA antibody fragment to about 10 chelators per anti-PSMA antibody or anti-PSMA antibody fragment.
  • the anti-PSMA antibody or an anti-PSMA antibody fragment is conjugated to a chelator wherein the chelator is covalently linked to the anti-PSMA antibody in an average ratio range of about 2 chelators per anti-PSMA antibody or anti-PSMA antibody fragment to about 10 chelators per anti-PSMA antibody or anti-PSMA antibody fragment.
  • the anti-PSMA antibody or anti-PSMA antibody fragment is conjugated to a chelator wherein the chelator is covalently linked to the anti-PSMA antibody in an average ratio range of about 2 chelators per anti-PSMA antibody or anti-PSMA antibody fragment to about 9 chelators per anti-PSMA antibody or anti-PSMA antibody fragment.
  • the anti-PSMA antibody or anti-PSMA antibody fragment is conjugated to a chelator wherein the chelator is covalently linked to the anti-PSMA antibody in an average ratio range of about 2 chelators per anti-PSMA antibody or anti-PSMA antibody fragment to about 8 chelators per anti-PSMA antibody or anti-PSMA antibody fragment.
  • the anti- PSMA antibody or anti-PSMA antibody fragment is conjugated to a chelator wherein the chelator is covalently linked to the anti-PSMA antibody in an average ratio range of about 3 chelators per anti-PSMA antibody or anti-PSMA antibody fragment to about 7 chelators per anti-PSMA antibody or anti-PSMA antibody fragment.
  • the anti-PSMA antibody or anti-PSMA antibody fragment is conjugated to a chelator wherein the chelator is covalently linked to the anti-PSMA antibody in an average ratio range of about 3 chelators per anti-PSMA antibody or anti-PSMA antibody fragment to about 5 chelators per anti-PSMA antibody or anti-PSMA antibody fragment.
  • the anti-PSMA antibody is J591.
  • the chelator is DOTA.
  • the conjugate may be included in a pharmaceutical composition additionally comprising a pharmaceutically acceptable carrier or excipient.
  • the conjugated anti-PSMA antibody or anti-PSMA antibody fragment is chelated or complexed to a radionuclide.
  • the radionuclide is 225 Ac.
  • the composition or pharmaceutical composition is substantially free of unchelated, or free, 225 Ac.
  • the composition or pharmaceutical composition contains less than about 10% of unchelated, or free, 225 Ac.
  • the composition or pharmaceutical composition contains less than about 9% of unchelated, or free, 225 Ac.
  • the composition or pharmaceutical composition contains less than about 8% of unchelated, or free, 225 Ac.
  • the composition or pharmaceutical composition contains less than about 7% of unchelated, or free, 225 Ac.
  • the composition or pharmaceutical composition contains less than about 6% of unchelated, or free, 225 Ac. In another embodiment, the composition or pharmaceutical composition contains less than about 5% of unchelated, or free, 225 Ac. In another embodiment, the composition or pharmaceutical composition contains less than about 4% of unchelated, or free, 225 Ac. In another embodiment, the composition or pharmaceutical composition contains less than about 3% of unchelated, or free, 225 Ac. In another embodiment, the composition or pharmaceutical composition contains less than about 2% of unchelated, or free, 225 Ac. In another embodiment, the composition or pharmaceutical composition contains less than about 1% of unchelated, or free, 225 Ac.
  • a substantial amount or majority of the 225 Ac activity in the composition or pharmaceutical composition is complexed or bound to conjugated anti-PSMA antibody such as a J591-DOTA conjugate.
  • conjugated anti-PSMA antibody such as a J591-DOTA conjugate.
  • at least about 80% of the 225 Ac activity in the composition or pharmaceutical composition is complexed or bound to conjugated anti-PSMA antibody.
  • at least about 90% of the 225 Ac activity in the composition or pharmaceutical composition is complexed or bound to conjugated anti- PSMA antibody.
  • at least about 91% of the 225 Ac activity in the composition or pharmaceutical composition is complexed or bound to conjugated anti-PSMA antibody.
  • At least about 92% of the 225 Ac activity in the composition or pharmaceutical composition is complexed or bound to conjugated anti-PSMA antibody.
  • at least about 93% of the 225 Ac activity in the composition or pharmaceutical composition is complexed or bound to conjugated anti-PSMA antibody.
  • at least about 94% of the 225 Ac activity in the composition or pharmaceutical composition is complexed or bound to conjugated anti-PSMA antibody.
  • at least about 95% of the 225 Ac activity in the composition or pharmaceutical composition is complexed or bound to conjugated anti-PSMA antibody.
  • at least about 96% of the 225 Ac activity in the composition or pharmaceutical composition is complexed or bound to conjugated anti-PSMA antibody.
  • the anti-PSMA antibody is J591.
  • J591 is conjugated to DOTA and chelated or complexed to 225 Ac, also known as 225 Ac labeled J591 tetraxetan.
  • composition or pharmaceutical composition comprising 225 Ac activity complexed or bound to conjugated anti-PSMA antibody can be further purified.
  • postradiolabeling purification can be applied with techniques known in the art, for example, using column chromatography purification such as with a protein A column, HIC column, size exclusion column, an ion exchange column, columns to specifically bind to a tag on the antibody (ex, His-tag), and other known affinity chromatography techniques.
  • the composition may be a bulk composition or a composition comprising more than one dose to a patient.
  • the composition may comprise at least 2 doses, at least 3 doses, at least 4 doses, at least 5 doses, at least 6 doses, at least 7 doses, at least 8 doses, at least 9 doses at least 10 doses, at least 11 doses, at least 12 doses, at least 13 doses, at least 14 doses, at least 15 doses, at least 16 doses, at least 17 doses, at least 18 doses, at least 19 doses, or at least 20 doses for one or more patients.
  • the bulk composition comprises 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses 10 doses, 11 doses, 12 doses, 13 doses, 14 doses, 15 doses, 16 doses, 17 doses, 18 doses, 19 doses, or 20 doses for one or more patients.
  • the composition comprises a total of about 0. 1 mCi to about 3.0 mCi from 225 Ac. In another embodiment, the composition comprises a total of about 0.25 mCi to about 2.5 mCi from 225 Ac. In another embodiment, the composition comprises a total of about 0.5 mCi to about 2.0 mCi from 225 Ac. In another embodiment, the composition comprises a total of about 0.25 mCi to about 2.5 mCi from 225 Ac. In another embodiment, the composition comprises a total of about 0.5 mCi to about 1.5 mCi from 225 Ac. In another embodiment, the composition comprises a total of about 0.5 mCi to about 1.0 mCi from 225 Ac.
  • the composition comprises a total of about 0. 1 mCi to about 5.0 mCi from 225 Ac. In another embodiment, the composition comprises a total of about 0.25 mCi to about 3.5 mCi from 225 Ac. In another embodiment, the composition comprises a total of about 0.5 mCi to about 2.5 mCi from 225 Ac. In another embodiment, the composition comprises a total of about 0.25 mCi to about 2.5 mCi from 225 Ac. In another embodiment, the composition comprises a total of about 0.5 mCi to about 2 mCi from 225 Ac. In another embodiment, the composition comprises a total of about 0.5 mCi to about 1.5 mCi from 225 Ac. In another embodiment, the composition comprises a total of about 0.5 mCi to about 1.0 mCi from 225 Ac.
  • compositions of the present invention include pharmaceutical compositions and non-pharmaceutical compositions comprising an anti-PSMA antibody or an anti-PSMA antibody fragment conjugated to a chelator, wherein the conjugated anti-PSMA antibody or anti-PSMA antibody fragment are substantially in the form of a monomer.
  • pharmaceutical compositions or non-pharmaceutical compositions of the present invention comprise 225 Ac labeled anti-PSMA antibody conjugate substantially in the form of a monomer.
  • at least about 60%, or at least about 70%, or at least about 80% of the 225 Ac labeled anti-PSMA antibody conjugate in the composition is in the form of a monomer.
  • At least about 94% of the 225 Ac labeled anti-PSMA antibody conjugate in the composition is in the form of a monomer. In another specific embodiment, at least about 95% of the 225 Ac labeled anti-PSMA antibody conjugate in the composition is in the form of a monomer. In another specific embodiment, at least about 96% of the 225 Ac labeled anti-PSMA antibody conjugate in the composition is in the form of a monomer. In another specific embodiment, at least about 97% of the 225 Ac labeled anti-PSMA antibody conjugate is in the composition in the form of a monomer. In another specific embodiment, at least about 98% of the 225 Ac labeled anti-PSMA antibody conjugate in the composition is in the form of a monomer.
  • At least about 99% of the 225 Ac labeled anti-PSMA antibody conjugate in the composition is in the form of a monomer.
  • the anti-PSMA antibody conjugate is conjugated to DOTA.
  • the anti-PSMA antibody is J591.
  • at least about 60%, or about 70%, or about 80%, or about 90% of the 225 Ac labeled J591 tetraxetan in the composition is in the form of a monomer.
  • at least about 91% of the 225 AC labeled J591 tetraxetan is in the composition in the form of a monomer.
  • At least about 92% of 225 Ac labeled J591 tetraxetan is in the composition in the form of a monomer. In another specific embodiment, at least about 93% of the 225 Ac labeled J591 tetraxetan in the composition is in the form of a monomer. In another specific embodiment, at least about 94% of the 225 Ac labeled J591 tetraxetan in the composition is in the form of a monomer. In another specific embodiment, at least about 95% of the 225 Ac labeled J591 tetraxetan in the composition is in the form of a monomer.
  • At least about 96% of the 225 Ac labeled J591 tetraxetan in the composition is in the form of a monomer. In another specific embodiment, at least about 97% of 225 Ac labeled J591 tetraxetan in the composition is in the form of a monomer. In another specific embodiment, at least about 98% of the 225 Ac labeled J591 tetraxetan in the composition is in the form of a monomer. In another specific embodiment, at least about 99% of the 225 Ac labeled J591 tetraxetan in the composition is in the form of a monomer.
  • the composition or pharmaceutical composition may have a particular immunoreactivity.
  • the conjugation of chelating agents to an antibody as well as labeling procedure or radiolysis during mAb storage may adversely alter the antibody and affect the immunoreactivity.
  • Unfavorable in vivo behavior of radioimmunopharmaceuticals such as reduced tumor uptake, increased nonspecific localization and radiation exposure of nontarget tissues, can be result. Therefore, the determination of immunoreactive fraction (IRF) is essential to ensure the efficacy and stability of radiolabeled antibodies, including the drug product.
  • IRF immunoreactive fraction
  • the composition or pharmaceutical composition comprises 225 Ac labeled anti-PSMA antibody conjugate (such as 225 Ac labeled J591 tetraxetan), wherein the immunoreactive fraction (IRF) of 225 Ac labeled anti-PSMA antibody conjugate (such as 225 Ac labeled J591 tetraxetan) is at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%.
  • the IRF is determined using PSMA-bound magnetic beads.
  • the IRF is determined as in m ' Nucl Med Biol. 2019 Apr; 71: 32-38.
  • the immunoreactive fraction (IRF) of a composition or pharmaceutical composition comprising 225 Ac labeled J591 tetraxetan is at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or about 100%.
  • the IRF values are determined 7 days or less before administration to a patient.
  • the IRF value is determined by using PSMA-bound magnetic beads.
  • the IRF value is determined as or substantially similar as in Example 5 or Example 6.
  • the compositions or pharmaceutical compositions may have a specific immunoreactivity or immunoreactive fraction (IRF), thus establishing adequate stability and activity of the pharmaceutical composition.
  • IRF immunoreactivity or immunoreactive fraction
  • the IRF of 225 Ac labeled anti-PSMA antibody in the composition or pharmaceutical composition is at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or about 100%.
  • the immunoreactive fraction (IRF) of a composition or pharmaceutical composition comprising 225 Ac labeled J591 tetraxetan is at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or about 100%.
  • the IRF values are determined 10 days or less before administration to a patient.
  • the IRF value is determined by using PSMA-bound magnetic beads.
  • the IRF value is determined as, or substantially similar as, in Example 5, Example 6, or Example 7 described herein.
  • the IRF is determined on the bulk batch as described in Examples 3, 5- 7 described herein. In another embodiment, the IRF determined on the bulk batch and is used as the reliant IRF measure for determining the sub-batch and final drug product for administration to a patient. In a specific embodiment, the IRF is determined, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or on the day of administration to a patient. In a specific embodiment, this measurement is used as the representative measurement of the final drug product administered to a patient.
  • the amount of anti- PSMA antibody in a single unit dose is about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg.
  • the composition of a single unit dose comprises a total of about 1 pCi to 1000 pCi of 225 Ac per 20 mg of anti-PSMA antibody. In another embodiment, the composition of a single unit dose comprises a total of about 10 pCi to 500 pCi of 225 Ac per 20 mg of anti-PSMA antibody. In another embodiment, the composition of a single unit dose comprises a total of about 25 pCi to 400 pCi of 225 Ac per 20 mg of anti-PSMA antibody.
  • composition of a single unit dose comprises a total of about 30 pCi to 350 pCi of 225 Ac per 20 mg of anti-PSMA antibody. In another embodiment, the composition of a single unit dose comprises a total of about 50 pCi to 250 pCi of 225 Ac per 20 mg of anti-PSMA antibody. In another embodiment, the composition of a single unit dose comprises a total of aboutlOO pCi to 200 pCi of 225 Ac per 20 mg of anti-PSMA antibody.
  • the amount of anti-PSMA antibody in a single unit dose is about 15 mg to about 25 mg per 20 ml volume. In another specific embodiment, the amount of anti-PSMA antibody in a single unit dose is about 20 mg per 20 ml volume.
  • the composition of a single unit dose comprises a total of about 1 pCi to 1000 pCi of 225 AC per 20 mg of anti-PSMA antibody per 20 ml volume. In another embodiment, the composition of a single unit dose comprises a total of about 10 pCi to 500 pCi of 225 AC per 20 mg of anti-PSMA antibody per 20 ml volume. In another embodiment, the composition of a single unit dose comprises a total of about 25 pCi to 400 pCi of 225 Ac per 20 mg of anti-PSMA antibody per 20 ml volume.
  • the composition of a single unit dose comprises a total of about 30 pCi to 350 pCi of 225 Ac per 20 mg of anti-PSMA antibody per 20 ml volume. In another embodiment, the composition of a single unit dose comprises a total of about 50 pCi to 250 pCi of 225 Ac per 20 mg of anti-PSMA antibody per 20 ml volume. In another embodiment, the composition of a single unit dose comprises a total of about 100 pCi to 200 pCi of 225 Ac per 20 mg of anti-PSMA antibody per 20 ml volume.
  • the composition and dose may be determined and vary based on the weight of the patient or subject.
  • the composition comprises a single dose ranging from about 10 KBq/kg weight of a patient to about 150 KBq/kg weight of a patient.
  • the composition comprises a single dose ranging from about 15 KBq/kg weight of a patient to about 100 KBq/kg weight of a patient.
  • the composition comprises a single dose ranging from about 25 KBq/kg weight of a patient to about 65 KBq/kg weight of a patient.
  • the composition additionally comprises unconjugated (or naked) anti-PSMA antibody.
  • the unconjugated (or naked) anti-PSMA antibody has the same amino acid sequence as the conjugated anti-PSMA antibody or antibody fragment.
  • the anti-PSMA antibody is J591.
  • the anti-PSMA antibody or anti-PSMA antibody fragment comprises: (i) an immunoglobulin heavy chain variable region comprising SEQ ID NO: 1; and (ii) an immunoglobulin light chain variable region comprising SEQ ID NO: 2.
  • the total anti-PSMA, antibody i.e., the total of the conjugated and unconjugated antibody is at a concentration of about 0.1 mg/ml to about 5 mg/ml in the composition. In another embodiment, the total anti-PSMA antibody is at a concentration of about 0.2 mg/ml to about 3 mg/ml in the composition. In another embodiment, the total anti-PSMA antibody is at a concentration of about 0.4 mg/ml to about 2 mg/ml in the composition. In another embodiment, the total anti-PSMA antibody is at a concentration of about 0.6 mg/ml to about 1.5 mg/ml in the composition. In another embodiment, the total anti-PSMA antibody is at a concentration of about 0.7 mg/ml to about 1.2 mg/ml in the composition.
  • the overall weight of the total anti-PSMA antibody in the composition (unconjugated and conjugated) is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, or about 40 mg.
  • the composition of pharmaceutical composition comprises unconjugated or naked anti-PSMA antibody and conjugated anti-PSMA antibody chelated to 225 Ac, wherein the ratio of the unconjugated or naked anti-PSMA antibody to conjugated anti- PSMA antibody chelated to 225 Ac is about 30: 1 by weight, about 29: 1 by weight, about 28:1 by weight, about 27: 1 by weight, about 26: 1 by weight, about 25: 1 by weight, about 24: 1 by weight, about 23: 1 by weight, about 22: 1 by weight, about 21: 1 by weight, about 20:1 by weight, about 19: 1 by weight, about 18: 1 by weight, about 17:1 by weight, about 16:1 by weight, about 15:1 by weight, about 14:1 by weight, about 13:1 by weight, about 12: 1 by weight, about 11: 1 by weight, about 10:1 by weight, about 9: 1 by weight, about 8:1 by weight, about 7: 1 by weight, about 6: 1 by weight, about 5: 1
  • the composition of pharmaceutical composition comprises unconjugated or naked anti-PSMA antibody and conjugated anti-PSMA antibody chelated to 225 Ac, wherein the ratio of conjugated anti-PSMA antibody chelated to 225 Ac to unconjugated or naked anti-PSMA antibody is about 30:1 by weight, about 29:1 by weight, about 28:1 by weight, about 27: 1 by weight, about 26: 1 by weight, about 25: 1 by weight, about 24:1 by weight, about 23: 1 by weight, about 22: 1 by weight, about 21 :1 by weight, about 20: 1 by weight, about 19: 1 by weight, about 18:1 by weight, about 17:1 by weight, about 16: 1 by weight, about 15: 1 by weight, about 14: 1 by weight, about 13: 1 by weight, about 12: 1 by weight, about 11 :1 by weight, about 10: 1 by weight, about 9:1 by weight, about 8: 1 by weight, about 7: 1 by weight, about 6:1 by weight, about 5:
  • the composition of pharmaceutical composition comprises unconjugated or naked J591 and 225 Ac labeled J591 tetraxetan, wherein the ratio of the unconjugated or naked J591 to 225 Ac labeled J591 tetraxetan is about 30:1 by weight, about 29:1 by weight, about 28:1 by weight, about 27:1 by weight, about 26: 1 by weight, about 25:1 by weight, about 24: 1 by weight, about 23 : 1 by weight, about 22: 1 by weight, about 21: 1 by weight, about 20: 1 by weight, about 19: 1 by weight, about 18: 1 by weight, about 17:1 by weight, about 16: 1 by weight, about 15: 1 by weight, about 14:1 by weight, about 13:1 by weight, about 12:1 by weight, about 11 :1 by weight, about 10:1 by weight, about 9: 1 by weight, about 8:1 by weight, about 7: 1 by weight, about 6: 1 by weight,
  • the composition of pharmaceutical composition comprises unconjugated or naked J591 and 225 Ac labeled J591 tetraxetan, wherein the ratio of the 225 Ac labeled J591 tetraxetan to unconjugated or naked J591 is about 30: 1 by weight, about 29:1 by weight, about 28:1 by weight, about 27:1 by weight, about 26: 1 by weight, about 25: 1 by weight, about 24: 1 by weight, about 23: 1 by weight, about 22: 1 by weight, about 21 :1 by weight, about 20: 1 by weight, about 19: 1 by weight, about 18:1 by weight, about 17:1 by weight, about 16: 1 by weight, about 15:1 by weight, about 14:1 by weight, about 13: 1 by weight, about 12: 1 by weight, about 11: 1 by weight, about 10: 1 by weight, about 9: 1 by weight, about 8: 1 by weight, about 7:1 by weight, about 6:1 by weight, about
  • the composition of pharmaceutical composition comprises unconjugated or naked anti-PSMA antibody and conjugated anti-PSMA antibody chelated to 225 Ac, wherein the ratio of conjugated anti-PSMA antibody chelated to 225 Ac to unconjugated or naked anti-PSMA antibody ranges in the ratio of about 40: 1 to about 1:40 by weight, about 30:1 to about 1:30 by weight, about 20: 1 to about 1:20 by weight, about 10:1 to about 1:10 by weight, about 30:1 to about 1: 1 by weight, about 20:1 to about 1 :1 by weight, about 15: 1 to about 1:1 by weight, about 10: 1 to about 1 : 1 by weight, about 1 :30 to about 1 : 1 by weight, about 1 :20 to about 1 : 1 by weight, about 1 : 15 to about 1 : 1 by weight, or about 1 : 10 to about 1 : 1 by weight.
  • the composition of pharmaceutical composition comprises unconjugated or naked J591 and 225 Ac labeled J591 tetraxetan, wherein the ratio of the unconjugated or naked J591 to 225 Ac labeled J591 tetraxetan ranges in the ratio of about 40:1 to about 1:40 by weight, about 30: 1 to about 1 :30 by weight, about 20: 1 to about 1 :20 by weight, about 10:1 to about 1 : 10 by weight, about 30: 1 to about 1 : 1 by weight, about 20: 1 to about 1 : 1 by weight, about 15:1 to about 1:1 by weight, about 10:1 to about 1: 1 by weight, about 1:30 to about 1 : 1 by weight, about 1 : 20 to about 1 : 1 by weight, about 1 : 15 to about 1 : 1 by weight, or about 1 :10 to about 1 : 1 by weight.
  • the composition or pharmaceutical composition may have a particular immunoreactivity.
  • the conjugation of chelating agents to an antibody as well as labeling procedure or radiolysis during antibody storage may adversely alter the antibody and affect the immunoreactivity.
  • Unfavorable in vivo behavior of radioimmunopharmaceuticals such as reduced tumor uptake, increased nonspecific localization and radiation exposure of nontarget tissues, can be result. Therefore, the determination of immunoreactive fraction (IRF) is essential to ensure the efficacy and stability of radiolabeled antibodies, including the drug product.
  • IRF immunoreactive fraction
  • the immunoreactivity or IRF of 225 Ac labeled anti-PSMA antibody conjugate is tested as described in J. Immunol. Methods 1984, 72 (1), 77- 89.
  • the immunoreactivity or IRF of 225 Ac labeled anti-PSMA antibody conjugate is tested as described in NuclMed Biol. 2019 Apr; 71 : 32-38 by using PSMA-bound magnetic beads.
  • the composition or pharmaceutical composition comprises 225 Ac labeled anti-PSMA antibody conjugate (such as 225 Ac labeled J591 tetraxetan), wherein the immunoreactive fraction (IRF) of 225 Ac labeled anti-PSMA antibody conjugate (such as 225 Ac labeled J591 tetraxetan) is at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%.
  • the IRF is determined using PSMA-bound magnetic beads.
  • the IRF is determined as in in Nucl Med Biol. 2019 Apr; 71 : 32-38.
  • the immunoreactive fraction (IRF) of a composition or pharmaceutical composition comprising 225 Ac labeled J591 tetraxetan is at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or about 100%.
  • the IRF values are determined 7 days or less before administration to a patient.
  • the IRF value is determined by using PSMA-bound magnetic beads.
  • the IRF value is determined as or substantially similar as in Example 5, Example 6, or Example 7 described herein.
  • compositions or pharmaceutical compositions comprising a 225 Ac labeled anti-PSMA antibody conjugate (such as 225 Ac labeled J591 tetraxetan) and a pharmaceutically acceptable excipient or carrier is provided.
  • the compositions or pharmaceutically acceptable compositions may include bulk compositions or single use compositions, or single unit dose formulations as describe herein, and include a pharmaceutically acceptable carrier which may include a pharmaceutically acceptable excipient, binder, and/or diluent.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
  • suitable formulations or pharmaceuticals for various methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, inert diluents and sterile aqueous or organic solutions.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05M phosphate buffer or saline.
  • Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions.
  • non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • the pharmaceutical composition is in PlasmaLyte® which contains 0.8- 8% sucrose, 0.002% Polysorbate 80 (PS80), and 0.001- 1% glycerol.
  • Liquid carriers suitable for use in the present application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • water partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols
  • oils e.g. fractionated coconut oil and arachis oil
  • Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition and/or combination an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions and/or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
  • compositions or pharmaceutical compositions described herein include antimicrobial agents, which may include antibiotics, antifungals, antivirals, and/or bacteriostatic agents.
  • the antimicrobial agent is ethylenediaminetetraacetic acid disodium salt.
  • a liquid composition can also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate, or sodium acetate.
  • a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
  • a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
  • injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.
  • Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules, vials, or in multi-dose containers.
  • composition of the present disclosure are administered by the intravenous route.
  • parenteral administration may be provided in a bolus or by infusion.
  • the pharmaceutical compositions comprising the 225 Ac to a DOTA conjugated anti-PSMA antibody is 225 Ac labeled J591 tetraxetan described herein and is administered to a patient or subject in need thereof for the treatment of cancer.
  • the cancer is prostate cancer.
  • the cancer is a PSMA expressing cancer.
  • the cancer is mCRPC.
  • the prostate cancer is castration-sensitive prostate cancer.
  • the methods include administering one or more doses to a patient, wherein the initial dose is a pharmaceutical composition described herein.
  • second or later dose administered to the patient is a pharmaceutical composition described herein.
  • the second dose is administered two to three weeks after the initial dose.
  • TMAA tetramethyl ammonium acetate
  • 2M pH 8.5 ⁇ 0.3
  • 225 Ac chloride 0.4-0.5 or 0.7-1.0 mCi
  • the contents were then gently mixed, followed by the addition of 0.3 or 0.6 mL (or 3 or 6 mg) of the conjugated J591 tetraxetan antibody (10 mg/mL).
  • the contents were gently mixed.
  • the pH of the reaction mixture was measured and adjusted with 0.1 M HC1 to 5.5 - 6.2.
  • the labeling reaction was quenched by adding 0.1 mL of diethylenetriamine pentaacetate (DTP A) solution (10 mM), and incubated for 10 min.
  • DTP A diethylenetriamine pentaacetate
  • the 225 Ac labeled J591 tetraxetan was then purified from free 225 Ac-DTPA using a gel filtration method with 10 DG desalting column and sterile saline with 2% human serum albumin (saline-HSA) as an eluent.
  • the 225 Ac labeled J591 tetraxetan was collected using 3.5 mL of eluent.
  • the volume of purified labeled product was adjusted to 5 or 10 mL using saline-HSA solution.
  • This Bulk-batch vial was stored at 2-8°C for 6-24 hours to allow 225 Ac to reach secular equilibrium with its daughters. Once equilibrium was reached, the amount of 225 Ac activity was measured in a dose calibrator and activity was confirmed. Individual batches may then be drawn from this bulk batch.
  • the Bulk-batch was used to prepare 1-3 subbatches.
  • a patient specific 225 Ac dose of intermediate from Bulk-batch (90-220 pCi in 1-3 mL) was estimated and corrected for decay; QC and retain samples were taken.
  • the volume of the intermediate is then mixed (in a 30 ml sterile syringe) with naked unconjugated J591 to bring the total antibody mass to 22 mg.
  • the volume is then adjusted to 22 mL with sterile saline-HSA solution.
  • each sub-batch solution was sterile filtered directly into a 30 mL sterile and pyrogen-free vial (container-closure system) using 0.2p sterile membrane filter.
  • the 225 Ac activity in each of the sub-batches was measured and documented. After testing for appearance (visual inspection), QC and retain samples (1.2 mL) were withdrawn from each of the sub-batch vials. The vials with patient-specific unit-doses were again measured for total 225 Ac activity and documented as the calibration or reference time.
  • the washed beads are resuspended in 390 pL of PBS-T and the beads in all tubes except the control arm are incubated with 1 pg (10 pL) of His-tagged or biotinylated PSMA antigen for 15 min on a rotating mixer at room temperature. Subsequently, the beads are washed once with 400 pL of PBS-T before adding 1 ng of the 225 Ac labeled J591 tetraxetan resuspended in 1% BSA-PBS or PBS-T. The 225 Ac labeled J591 tetraxetan is incubated with PSMA antigen-coated beads for 30 min on a rotating mixer at room temperature.
  • a large excess (1-5 pg) of the unlabeled J591 is added a few seconds prior to adding 1 ng of the 225 Ac labeled J591 tetraxetan to PSMA antigen-coated beads in the blocking arm. Thereafter, the beads are isolated using a magnet, and the supernatant containing unbound radioligand was aspirated with a pipette and collected in separate tubes. To remove non-specifically-bound 225 Ac labeled J591 tetraxetan, the beads are washed twice with 400 pL of PBS-T. Finally, the beads, supernatant and washes are measured for radioactivity on a gamma counter.
  • the 225 Ac labeled J591 tetraxetan IRF or TBF is determined from the percentage of total activity bound to PSMA antigen-coated magnetic beads minus the percentage of non-specific binding in the control arm.
  • the assay indicates that the 225 Ac labeled J591 tetraxetan from Example 3 and 4 is immunoreactive and has an IRF of at least 60%.
  • the 225 Ac labeled J591 tetraxetan from the bulk batch of Example 3 was tested for immunoreactivity, i.e., the immunoreactive fraction (IRF).
  • IRF immunoreactive fraction
  • 10 pl was taken from the bulk batch composition (diluted 1:500 in 1% HSA ) and added to 5.0 ml of PBS containing 1% HSA.
  • 5 different volumes of PSMA-bound magnetic beads i.e., 1.0, 0.75, 0.5, 0.25, 0.125 mL
  • PSMA-bound magnetic beads i.e., 1.0, 0.75, 0.5, 0.25, 0.125 mL
  • the tubes were then kept in a magnetic stand for 5 min to allow for separation of the antibody bound PSMA magnetic beads from the unbound antibody.
  • the solution with the unbound antibody (unbound 225 Ac labeled J591 tetraxetan) was then removed.
  • the antibody bound magnetic beads were then washing two or more times with PBS containing 1% HSA.
  • the radioactivity of the beads from each tube was then tested in the gamma counter.
  • a determination of %bound of each concentration of PSMA-beads was determined.
  • a double reciprocal plot of bead concentration and %Bound is performed and the IRF at infinite antigen excess was determined. As shown in Fig. 2, the IRF at infinite antigen excess was 112%.
  • the bulk batch is first diluted 1:500 in 1% HSA in phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the diluted bulk is added to 5 point-dilution series of PSMA bound magnetic beads as in Example 6) and to a set of standards.
  • the various dilutions (test articles) and standards are first measured in the Gamma Counter and then incubated at 37°C for 2 hrs. with agitation.
  • the test articles are then washed twice with 1% HSA in PBS and then suspended in 1 mL of 1% HSA in PBS. All test articles and standards are then measured in the Gamma Counter.
  • the test articles and standards are then stored at 2-8°C overnight to allow the 225 Ac to reach secular equilibrium (> 6 hrs).
  • Example 8 Purity of Prior art 225 Ac labeled J591 DOTA Conjugate
  • 225 Ac labeled J591 DOTA conjugate from Example 1 tested to confirm purity and immunoreactivity.
  • the monomer purity, high molecular weight and low molecular weight impurities are analyzed by high performance liquid chromatography-size exclusion chromatography-(HPLC-SEC). Only about 65% of 225 Ac labeled J591 tetraxetan is determined to be in the monomer form, and about 25-30% of 225 Ac labeled J591 is in a high molecular form, indicating an unstable composition comprising 225 Ac labeled J591.
  • the IRF is determined as in the protocol of Example 5, and indicates that the 225 Ac labeled J591 DOTA conjugate from Example 1 has a significantly lower IRF, i.e., less than 60%.

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Abstract

La présente invention concerne des compositions comprenant un conjugué d'anticorps anti-PSMA marqué à l'225Ac et leurs procédés de fabrication et d'utilisation. Les compositions de la présente invention sont utiles pour le traitement des cancers, y compris du cancer de la prostate.
PCT/US2025/021784 2024-03-27 2025-03-27 Conjugué psma radiopharmaceutique et ses utilisations Pending WO2025207904A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040213791A1 (en) * 2001-06-01 2004-10-28 Neil Bander Modified antibodies to prostate-specific membrane antigen and uses thereof
US8772459B2 (en) * 2009-12-02 2014-07-08 Imaginab, Inc. J591 minibodies and Cys-diabodies for targeting human prostate specific membrane antigen (PSMA) and methods for their use

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
US20040213791A1 (en) * 2001-06-01 2004-10-28 Neil Bander Modified antibodies to prostate-specific membrane antigen and uses thereof
US8772459B2 (en) * 2009-12-02 2014-07-08 Imaginab, Inc. J591 minibodies and Cys-diabodies for targeting human prostate specific membrane antigen (PSMA) and methods for their use

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Title
KARCZMARCZYK URSZULA, WOJDOWSKA WIOLETTA, MIKOŁAJCZAK RENATA, MAURIN MICHAŁ, LASZUK EWA, GARNUSZEK PIOTR: "Influence of DOTA Chelators on Radiochemical Purity and Biodistribution of 177 Lu- and 90 Y-Rituximab in Xenografted Mice", IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH, SHAHEED BEHESHTI MEDICAL UNIVERSITY - SCHOOL OF PHARMACY, IR, vol. 17, no. 4, 1 January 2018 (2018-01-01), IR , pages 1201, XP093362794, ISSN: 1735-0328 *
NAWAZ ET AL.: "Simple, mild, one-step labelling of proteins with gallium-68 using a tris(hydroxypridinine) bifunctional chelator: a 68Ga-THP-scFv targeting the prostate-specific membrane antigen", EJNMMI RESEARCH, vol. 7, 15 October 2017 (2017-10-15), pages 1 - 9, XP021250169, Retrieved from the Internet <URL:https://link.springer.com/content/pdf/10.1186/s13550-017-0336-6.pdf> [retrieved on 20250508], DOI: 10.1186/s13550-017-0336-6 *
SUBRAMANIAN KRITIKA, STANGL-KREMSER JUDITH, SAWOSZCZYK LADY, AVLONITIS VASILIOS, GERNERD ANDREW, NIXON KYLA, ZGALJARDIC MICHAEL, T: "α-Labeling of J591, an Antibody Targeting Prostate-Specific Membrane Antigen: The Technique and Considerations from the First Dedicated Production Lab at an Academic Institution in the United States", JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY., SOCIETY OF NUCLEAR MEDICINE, NEW YORK, NY., US, vol. 51, no. 3, 1 September 2023 (2023-09-01), US , pages 215 - 219, XP093362792, ISSN: 0091-4916, DOI: 10.2967/jnmt.122.265166 *
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