Classifications

• • 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
  • A61K51/0402—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
  • 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
  • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present application relates to methods and compositions for synergistic uptake and retention of small molecule ligands.
• Combination therapy is a common, accepted treatment approach for virtually all types of cancers and has been the standard therapeutic approach for several decades.
• the basis for the adoption of combination therapy was the early chemotherapy- experience where it was determined that the high mutational rate of cancers allowed rapid development of resistant strains of tumor cells when only a single agent was employed.
• the goal of combination therapies is to increase efficacy and minimize the development of tumor resistance or escape. This is generally achieved by employing 2 or more anti-cancer agents each of which has a different mechanism of action, making the development of resistant tumor cells more difficult and less likely.
• the additive or synergistic effects of combining two or more agents can be the difference between successful and unsuccessful treatment of the patient.
• a first aspect of the present application relates to a method of treating a subject for cancer.
• the method involves providing a first agent comprising a first targeting component coupled to a first cancer therapeutic component and providing a second agent comprising a second targeting component coupled to a second cancer therapeutic component.
• the first and second targeting components have different biodistributions and/or pharmacokinetics in the subject.
• the first and second agents are administered no more than eight hours apart from each other, to the subject to treat cancer.
• the amount of first and second cancer therapeutic component internalized and retained within a tumor is greater than the sum of first and second cancer therapeutic component internalized and retained in a tumor if each of the first and second agents were administered individually.
• Combined targeting using two different targeting agents each with different biodistributions and/pharmacokinetics is novel; it has never before been considered or utilized as described herein.
• Previous attempts, for example in the field of targeted radiopharmaceuticals have been limited to use of a single targeting agent (e.g., a somatostatin receptor type 2 (SSTR- 2) ligand) administered either (1) in alternating cycles carrying 2 different therapeutic moieties with a minimum of 6 weeks between cycles (Villard et al., “Cohort Study of Somatostatin-Based
• This benefit also allows, for the first time, to overcome the prior inability to co-administer two radiopharmaceuticals where either or, especially, both are at their maximum tolerated dose/s.
• FIG. 2 shows that, when measured via autopsy 72 hours post-treatment, mice treated with both 617-Lu 177 plus J591-Lu 177 have the greatest number of radioactive counts which exceeds the sum of the counts in the tumors that got either agent alone.
• a first aspect of the present application relates to a method of treating a subject for cancer.
• the method involves providing a first agent comprising a first targeting component coupled to a first cancer therapeutic component and providing a second agent comprising a second targeting component coupled to a second cancer therapeutic component.
• the first and second targeting components have different biodistributions and/or pharmacokinetics in the subject.
• the first and second agents are administered no more than eight hours apart from each other, to the subject to treat cancer.
• the amount of first and second cancer therapeutic component internalized and retained within a tumor is greater than the sum of first and second cancer therapeutic component internalized and retained in a tumor if each of the first and second agents were administered individually.
• the term “subject” is intended to include human and non-human animals.
• Non-human animals include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dog, cow, chickens, amphibians, reptiles, etc.
• the first and second agents are administered no more than 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour apart from each other. In one embodiment, the first and second agents are administered simultaneously.
• the timing should result in the amount of first and second cancer therapeutic component internalized and retained within a tumor being greater than the sum of first and second cancer therapeutic components internalized and retained in a tumor if each of the first and second agents were administered individually.
• the cancer is prostate cancer, neuroendocrine cancer, breast cancer, non-Hodgkin’s lymphoma, or Hodgkin’s lymphoma.
• the cancer is a primary tumor, while in other embodiments, the cancer is a secondary or metastatic tumor.
• the first and second agent may be “target-specific.”
• the therapeutic component that is coupled to the first and second targeting components may exert its anti-cancer effect without the need for release from the first and second targeting components.
• the therapeutic component may be released from the first and second agents and allowed to interact locally at the particular targeting site.
• contemplated targeting components may include a nucleic acid, peptide, polypeptide, protein, glycoprotein, carbohydrate, or lipid.
• a targeting component may be a naturally occurring or synthetic ligand for a cell surface receptor, e.g., a growth factor, hormone, LDL, transferrin, etc.
• a targeting component can be an antibody, which term is intended to include antibody fragments and/or derivatives, characteristic portions of antibodies, single chain targeting moieties which can be identified, for example, using procedures such as phage display.
• Targeting components may also be a targeting peptide, targeting peptidomimetic, or a small molecule, whether naturally-occurring or artificially created (e.g., via chemical synthesis).
• Antibodies against molecular targets on tumors are known.
• antibodies and antibody fragments which specifically bind markers produced by or associated with tumors have been disclosed, inter alia, in U.S. Patent No. 3,927,193 to Hansen, and U.S. Patent Nos. 4,331,647, 4,348,376, 4,361,544, 4,468,457, 4,444,744, 4,818,709 and 4,624,846 to Goldenberg, the contents of all of which are incorporated herein by reference in their entirety.
• antibodies against an antigen e.g., a gastrointestinal, lung, liver, breast, prostate, kidney, bladder, ovarian, testicular, brain, hematopoietic or lymphatic tumor, a sarcoma or a melanoma, are advantageously used.
• an antigen e.g., a gastrointestinal, lung, liver, breast, prostate, kidney, bladder, ovarian, testicular, brain, hematopoietic or lymphatic tumor, a sarcoma or a melanoma.
• the antibodies of the present application may exist in a variety of forms including, for example, polyclonal antibodies, monoclonal antibodies, intracellular antibodies (“intrabodies”), antibody fragments (e.g. Fv, Fab and F(ab)2), half-antibodies, hybrid derivatives, as well as single chain antibodies (scFv), chimeric antibodies and humanized antibodies (Ed Harlow and David Lane, USING ANTIBODIES: A LABORATORY MANUAL (Cold Spring Harbor Laboratory Press, 1999); Houston et al., “Protein Engineering of Antibody Binding Sites: Recovery of Specific Activity in an Anti-Digoxin Single-Chain Fv Analogue Produced in Escherichia coliJ'Proc.
• Antibodies of the present application may also be synthetic antibodies.
• a synthetic antibody is an antibody which is generated using recombinant DNA technology, such as, far example, an antibody expressed by a bacteriophage.
• the synthetic antibody is generated by the synthesis of a DNA molecule encoding and expressing the antibody of the present application or the synthesis of an amino acid sequence specifying the antibody, where the DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence technology which is available and well known in the art.
• Methods for monoclonal antibody production may be carried out using the techniques described herein or are well-known in the art (MONOCLONAL ANTIBODIES - PRODUCTION, ENGINEERING AND CLINICAL APPLICATIONS (Mary A. Ritter and Heather M. Ladyman eds., 1995), which is hereby incorporated by reference in its entirety).
• the process involves obtaining immune cells (lymphocytes) from the spleen of a mammal which has been previously immunized with the antigen of interest either in vivo or in vitro.
• monoclonal antibodies can be made using recombinant DNA methods as described in U.S . Patent No. 4,816,567 to Cabilly et al, which is hereby incorporated by reference in its entirety.
• the polynucleotides encoding a monoclonal antibody are isolated from mature B-cells or hybridoma cells, for example, by RT-PCR using oligonucleotide primers that specifically amplify the genes encoding the heavy and light chains of the antibody.
• the isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors, which when transfected into host cells such as E.
• coli cells simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein
• monoclonal antibodies are generated by the host cells.
• recombinant monoclonal antibodies or fragments thereof of the desired species can be isolated from phage display libraries (McCafferty et al., “Phage Antibodies: Filamentous Phage Displaying Antibody Variable Domains,” Nature 348:552-554 (1990); Clackson et al., “Making Antibody Fragments using Phage Display Libraries,” Nature 352:624-628 (1991); and Marks et al., “By-Passing Immunization.
• the monoclonal antibody of the present application can be a humanized antibody.
• Humanized antibodies are antibodies that contain minimal sequences from non-human (e.g., murine) antibodies within the variable regions. Such antibodies are used therapeutically to reduce antigenicity and human anti-mouse antibody responses when administered to a human subject.
• humanized antibodies are typically human antibodies with minimal to no non-human sequences.
• a human antibody is an antibody produced by a human or an antibody having an amino acid sequence corresponding to an antibody produced by a human.
• binding portions of such antibodies include the monovalent Fab fragments, Fv fragments (e.g., single-chain antibody, scFv), and single variable VH and VL domains, and the bivalentF(ab’) 2 fragments, Bis-scFv, diabodies, triabodies, minibodies, etc.
• antibody fragments can be made by conventional procedures, such as proteolytic fragmentation procedures, as described in James Coding, MONOCLONAL ANTIBODIES:PRINCIPLES AND PRACTICE 98-118 (Academic Press, 1983) and Ed Harlow and David Lane, ANTIBODIES: A LABORATORY MANUAL (Cold Spring Harbor Laboratory, 1988), which are hereby incorporated by reference in their entirety, or other methods known in the art.
• modifications would include modification of any of the amino acids to include the D-stereoisomer, substitution in the aromatic side chain of an aromatic amino acid, derivitization of the amino or carboxyl groups in the side chains of an amino acid containing such a group in a side chain, substitutions in the amino or carboxy terminus of the peptide, linkage of the peptide to a second peptide or biologically active moiety, and cyclization of tire peptide (G. Van Binst and D. Tourwe, “Backbone Modifications in Somatostatin Analogues: Relation Between Conformation and Activity,” Peptide Research 5:8-13 (1992), which is hereby incorporated by reference in its entirety).
• the first and second cancer therapeutic components are independently selected from the group consisting of a radionuclide and a cytotoxic agent.
• the first and/or second cancer therapeutic component is a radionuclide selected from the group consisting of “Re, 90 Y, 67 Cu, 169 Er, 121 Sn, 127 Te, 142 Pr, 143 Pr, 198 Au, 199 Au, 161 Tb, 109 Pd, 188 Rd, 166 Dy, 166 Ho, 149 Pm, 131 Pm, 133 Sm, 139 Gd, 172 Tm, 169 Yb, 173 Yb, 177 Lu, 105 Rh, m Ag, 131 1, 177 mSn, 225 Ac, 227 Th, 212 Pb, 211 At, and combinations thereof.
• Procedures for labeling agents with radioactive isotopes are generally known in the art.
• the chelating ligand can be a derivative of 1,4,7, 10-tetraazacyclododecanetetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), and 1-p- Isothiocyanato-benzyl-methyl-diethylenetriaminepentaacetic acid (ITC-MX).
• DOTA 1,4,7, 10-tetraazacyclododecanetetraacetic acid
• EDTA ethylenediaminetetraacetic acid
• DTPA diethylenetriaminepentaacetic acid
• ITC-MX 1-p- Isothiocyanato-benzyl-methyl-diethylenetriaminepentaacetic acid
• cytotoxic agents such as chemotherapeutic agents
• chemotherapeutic agents are well known in the art.
• Most of the chemotherapeutic agents currently in use in treating cancer possess functional groups that are amenable to chemical crosslinking directly with an amine or carboxyl group of the first targeting component of the present application.
• free amino groups are available on methotrexate, doxorubicin, daunorubicin, cytosinarabinoside, cisplatin, vindesine, mitomycin, and bleomycin while free carboxylic acid groups are available on methotrexate, melphalan, and chlorambucil.
• the exact dosage of the first and second agents of the application is chosen by the individual physician in view of the patient to be treated. In general, dosage and administration are adjusted to provide an effective amount of the agent to the patient being treated.
• the “effective amount” of an agent refers to the amount necessary to elicit the desired biological response.
• the effective amount of agent may vary depending on such factors as the desired biological endpoint, the drug to be delivered, the target tissue, the route of administration, etc.
• the effective amount of agent containing an anti-cancer drug might be the amount that results in a reduction in tumor size by a desired amount over a desired period of time. Additional factors which may be taken into account include tire severity of the disease state; age, weight and gender of the patient being treated; diet, time and frequency of administration; drug combinations; reaction sensitivities; and tolerance/response to therapy.
• doses can range from about 25% to about 100% of the MTD of the targeted agent when given as a single agent.
• the dose can be delivered once, continuously, such as by continuous pump, or at periodic intervals. Dosage maybe adjusted appropriately to achieve desired drug levels, locally, or systemically. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous IV dosing over, for example, 24 hours or multiple doses per day also are contemplated to achieve appropriate systemic levels of compounds.
• the administering step is carried out to treat cancer in a subject.
• a subject having cancer is selected prior to the administering step.
• Such administration can be carried out systemically or via direct or local administration to the tumor site.
• suitable modes of systemic administration include, without limitation, orally, topically, transdermally, parenterally, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, or by intranasal instillation, by intracavitary or intravesical instillation, intraoculariy, intraarterialy, intralesionally, or by application to mucous membranes.
• Suitable modes of local administration include, without limitation, catheterization, implantation, direct injection, dermal/transdermal application, or portal vein administration to relevant tissues, or by any other local administration technique, method or procedure generally known in the art.
• the mode of affecting delivery of agent will vary depending on the type of therapeutic agent (e.g., an antibody or an inhibitory nucleic acid molecule) and the disease to be treated.
• solutions or suspensions of the agent can be prepared in water suitably mixed with a surfoctant such as hydroxypropylcellulose.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
• oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
• water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• the agents may also be formulated as a depot preparation.
• Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt
• the cancer is prostate cancer.
• the first targeting component is a PSMA receptor antibody or antigen binding portion thereof and the second targeting component is a PSMA receptor binding peptide or PSMA receptor inhibitor.
• a PSMA receptor antibody is an antibody that interacts with (e.g., binds to)
• PSMA preferably human PSMA protein.
• the 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. Patent No. 5,538,866, which is hereby incorporated by reference in its entirety)- 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).

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Optics & Photonics (AREA)
• Physics & Mathematics (AREA)
• Immunology (AREA)
• Oncology (AREA)
• Cell Biology (AREA)
• Reproductive Health (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)
• Detergent Compositions (AREA)
• Medicinal Preparation (AREA)

Priority Applications (6)

Applications Claiming Priority (2)

Publications (2)

Family

ID=80950778

Family Applications (1)

Country Status (7)

Cited By (3)

Families Citing this family (1)

Family Cites Families (3)

• 2021
  • 2021-09-28 US US18/247,427 patent/US20240000979A1/en active Pending
  • 2021-09-28 WO PCT/US2021/052271 patent/WO2022072293A2/en not_active Ceased
  • 2021-09-28 JP JP2023520041A patent/JP2023547999A/ja active Pending
  • 2021-09-28 EP EP21876268.0A patent/EP4221764A4/en active Pending
  • 2021-09-28 CA CA3194600A patent/CA3194600A1/en active Pending
  • 2021-09-28 AU AU2021352378A patent/AU2021352378A1/en active Pending
  • 2021-09-28 IL IL301842A patent/IL301842A/en unknown

Also Published As

Similar Documents

Legal Events