WO2017066414A1 - Conjugués d'administration de médicaments destinés à être utilisés en multithérapie - Google Patents

Conjugués d'administration de médicaments destinés à être utilisés en multithérapie Download PDF

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Publication number
WO2017066414A1
WO2017066414A1 PCT/US2016/056787 US2016056787W WO2017066414A1 WO 2017066414 A1 WO2017066414 A1 WO 2017066414A1 US 2016056787 W US2016056787 W US 2016056787W WO 2017066414 A1 WO2017066414 A1 WO 2017066414A1
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cancer
disease
compound
formula
carcinoma
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PCT/US2016/056787
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English (en)
Inventor
Yingjuan J LU
II Leroy W. WHEELER
Christopher Paul Leamon
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Endocyte, Inc.
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Publication of WO2017066414A1 publication Critical patent/WO2017066414A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152

Definitions

  • the present disclosure pertains to the treatment of diseases with drug delivery conjugates in combination with antibodies.
  • the disclosure pertains to the treatment of diseases, such as cancer and viral diseases, with drug delivery conjugates in combination with PD-1 antibodies.
  • the mammalian immune system provides a means for the recognition and elimination of pathogenic cells, such as tumor cells, and other invading foreign pathogens. While the immune system normally provides a strong line of defense, there are many instances where pathogenic cells, such as cancer cells, and other infectious agents evade a host immune response and proliferate or persist with concomitant host pathogenicity.
  • Programmed death receptor 1 (PD-1) is an immunoinhibitory receptor that is primarily expressed on activated T and B cells.
  • PD-1 encoded by the gene Pdcdl
  • CTLA-4 is an immunoglobulin superfamily member related to CD28, and CTLA-4.
  • PD-1 has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-Ll and/or PD-L2).
  • the structure of murine PD-1 has been solved as well as the co-crystal structure of mouse PD-1 with human PD-Ll (Zhang, X. et al., Immunity 20: 337-347 (2004); Lin et al., Proc. Natl. Acad. Sci. USA 105: 3011-6 (2008)).
  • PD-1 and like family members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail that is responsible for the binding of signaling molecules.
  • the cytoplasmic tail of PD-1 contains two tyrosine-based signaling motifs, an ⁇ (immunoreceptor tyrosine-based inhibition motif) and an ITSM (immunoreceptor tyrosine-based switch motif). Interaction with its ligands has been shown to attenuate T-cell responses both in vitro and in vivo.
  • PD-1 on tumor infiltrating lymphocytes
  • PD-L1 on tumor cells
  • Such tissues include cancers of the lung, liver, ovary, cervix, skin, colon, glioma, bladder, breast, kidney, esophagus, stomach, oral squamous cell, urothelial cell, and pancreas as well as tumors of the head and neck (Brown J. A. et al., . Immunol. 170: 1257-1266 (2003); Dong H. et al., Nat. Med.
  • PD-1 has also been implicated in viral diseases.
  • the liver infection viruses, hepetitis B virus (HBV), and hepetitis C virus (HCV) induce overexpression of PD-1 ligands in hepatocytes and activate PD-1 signaling in T-effector cells, resulting in T-cell exhaustion and tolerance to the viral infection (Boni et al., Virol 81:4215-4225 (2007); Golden-Mason et al., Immunol 180:3637-3641 (2008)).
  • HIV infection frequently evades human immune system by similar mechanisms.
  • Therapeutic modulation of PD-1 signaling by antagonist molecules may revert immune cells from tolerance, and reactivated to eradicate cancer and chronic viral infection (Blank et al., Cancer Immunol Immunother 54:307-314 (2005); Okazaki et al., Int Immunol 19:813-824 (2007)).
  • B is a targeting ligand
  • L is a linker
  • D is a drug.
  • One such conjugate is a compound of the formula I
  • the disclosure provides a method for treating a disease in a patient comprising, administering to the patient a therapeutically effective amount of a folate-targeted chemotherapeutic, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of an anti-PD-1 antibody.
  • the disclosure provides a method for treating a disease in a patient comprising, administering to the patient a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, in combination with a
  • the disclosure provides a method of treating a disease in a patient comprising, administering to the patient a combination of a therapeutically effective amount of a folate-targeted chemotherapeutic, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an antibody that specifically binds to PD-1.
  • the disclosure provides a method of treating a disease in a patient comprising, administering to the patient a combination of a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a
  • the disclosure provides a. method of treating cancer in a patient previously identified as having a folate expressing cancer comprising, administering to the patient a therapeutically effective amount of a compound of the formula I, or a
  • the disclosure provides a method of treating cancer in a patient previously identified as having a folate expressing cancer comprising, administering to the patient a therapeutically effective amount of a folate-targeted chemotherapeutic, or a
  • the disclosure provides a method of treating cancer in a patient previously identified as having a folate expressing cancer comprising, administering to the patient a therapeutically effective amount of a compound of the formula I, or a
  • the disclosure provides a use of a folate-targeted chemotherapeutic, or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 antibody for treating a disease in a patient.
  • the disclosure provides a use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 antibody for treating a disease in a patient.
  • the disclosure provides a use of a folate-targeted chemotherapeutic, or a pharmaceutically acceptable salt thereof, in combination with an antibody that specifically binds to PD-1 for treating a disease in a patient.
  • the disclosure provides a use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, in combination with an antibody that specifically binds to PD-1 for treating a disease in a patient.
  • the disclosure provides a use of a folate-targeted chemotherapeutic, or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 for treating a cancer in a patient.
  • the disclosure provides a use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 for treating a cancer in a patient.
  • the disclosure provides a use of a folate-targeted chemotherapeutic, or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 for treating a cancer in a patient previously identified as having a folate expressing cancer.
  • the disclosure provides a use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 for treating a cancer in a patient previously identified as having a folate expressing cancer.
  • the disclosure provides a use of a folate-targeted chemotherapeutic, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disease in combination with an anti-PD-1 antibody.
  • the disclosure provides a use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disease in combination with an anti-PD-1 antibody,
  • the disclosure provides a use of a folate-targeted chemo therapeutic, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disease in combination with an antibody that specifically binds to PD-1.
  • the disclosure provides a use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disease in combination with an antibody that specifically binds to PD-1.
  • the disclosure provides a kit comprising a folate-targeted
  • chemotherapeutic or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody.
  • the disclosure provides a kit comprising a compound of the formula I, or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody.
  • kits comprising a folate-targeted
  • chemotherapeutic or a pharmaceutically acceptable salt thereof, an anti-PD-1 antibody
  • a set of instructions for administering a combination of a therapeutically effective amount of the folate-targeted chemotherapeutic and a therapeutically effective amount of the anti-PD-1 antibody.
  • the disclosure provides a kit comprising a compound of the formula I, or a pharmaceutically acceptable salt thereof, an anti-PD-1 antibody, and a set of instructions for administering a combination of a therapeutically effective amount of the compound of the formula I and a therapeutically effective amount of the anti-PD-1 antibody.
  • the disclosure provides a kit comprising a pharmaceutical
  • composition comprising a folate-targeted chemotherapeutic, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising an anti-PD-1 antibody.
  • the disclosure provides a kit comprising a pharmaceutical
  • composition compri sing a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising an anti-PD-1 antibody.
  • the disclosure provides a kit comprising a first pharmaceutical composition comprising a folate-targeted chemotherapeutic, or a pharmaceutically acceptable salt thereof, a second pharmaceutical composition comprising an anti-PD-1 antibody, and a set of instructions for administering a combination of a therapeutically effective amount of the first pharmaceutical composition and a therapeutically effective amount of the second
  • the disclosure provides a kit comprising a first pharmaceutical composition comprising a compound of the formula I, or a pharmaceutically acceptable salt thereof, a second pharmaceutical composition comprising an anti-PD-1 antibody, and a set of instructions for administering a combination of a therapeutically effective amount of the first pharmaceutical composition and a therapeutically effective amount of the second
  • the d sease is a viral disease or a cancer
  • the disease is a viral disease selected from the group consisting of HBV, HCV and HIV.
  • the disease is a cancer selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non- small cell lung cancer, small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma,
  • the disease is a cancer selected from the group consisting of triple-negative breast cancer, pleural mesothelioma, non- small cell lung cancer, small cell lung cancer, adenocarcinoma of the gastroesophageal junction, ovarian cancer, leiomyosarcoma and endometrial cancer, and a combination thereof.
  • the antibody is a monoclon al an ibod y ,
  • the antibody is selected from the group consisting of Nivolumab, Pidilizumab, Pembrolizumab, BMS936559,
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or the antibody is administered in a parenteral dosage form.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof is administered at the same time as the antibody. In some embodiments of any of the aspects described herein, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered prior to the antibody. In some embodiments of any of the aspects described herein, the antibody is administered prior to the compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the parenteral dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.
  • the therapeutically effective amount of the compound of the formula I is from about 0.5 mg/m to about 12.0 mg/m . In some embodiments of any of the aspects described herein, the
  • therapeutically effective amount is from about 0.5 mg/m to about 10.0 mg/m . In some embodiments of any of the aspects described herein, the therapeutically effective amount is
  • the therapeutically effective amount is from about 0.5 mg/m to about 6.0 mg/m . In some embodiments of any of the aspects described herein, the therapeutically
  • the therapeutically effective amount is from about 0.5 mg/m to about 4.0 mg/m . In some embodiments of any of the aspects described herein, the therapeutically effective amount is from about 0.5 mg/m to about 3.0 mg/m . In some embodiments of any of the aspects described herein, the
  • therapeutically effective amount is from about 0.5 mg/m to about 2.0 mg/m .
  • a method for treating a disease in a patient comprising, administering to the patient a therapeutically effective amount of a folate-targeted chemo therapeutic, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of an anti-PD- 1 antibody.
  • the disease is a cancer selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non-small cell lung cancer, small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma
  • HIV " .
  • the disease is a cancer selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non-small cell lung cancer, small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphom
  • the therapeutically effective amount of the compound of the formula I is an amount from about 0.5 mg/m 2 to about 12.0 mg/m 2 , or about 0.5 mg/m 2 to about 10.0 mg/m 2 , or about 0.5 mg/m 2 to about 8.0 mg/m 2 , or about 0.5 mg/m 2 to about 6.0 mg/m 2 , or about 0.5 mg/m 2 to about 4.0 mg/m 2 , or about 0.5 mg/m 2 to about
  • kits comprising a compound of the formula I, or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody.
  • kit of clause 27 further comprising a set of instructions for administering a combination of a therapeutically effective amount of the compound of the formula I and a therapeutically effective amount of the anti-PD-1 antibody.
  • FIG. 1 shows plots of the evaluation of Compound I against M109 tumor cells, 4T1-CI2 triple negative breast cancer cells, ID8-CI15 ovarian cancer cells, and Renca kidney cancer cells.
  • FIG. 1A Compound I showed a dose-dependent inhibition of cell proliferation in M109 cells with relative IC 50 values of -1.2 nM.
  • ⁇ Compound I;
  • ⁇ Compound I + folic acid.
  • FIG. IB Compound I showed a dose-dependent inhibition of cell proliferation in 4T1-CI2 cells with relative IC 50 values of -1.7 nM.
  • ( ⁇ ) Compound I; ( ⁇ ) Compound I + folic acid are examples of the evaluation of Compound I against M109 tumor cells, 4T1-CI2 triple negative breast cancer cells, ID8-CI15 ovarian cancer cells, and Renca kidney cancer cells.
  • FIG. 1A Compound I showed a dose-dependent inhibition of cell proliferation in M109 cells with relative IC 50 values of -1.2 nM.
  • ⁇
  • Compound I showed a dose-dependent inhibition of cell proliferation in ID8-CI15 cells with relative IC 50 values of -2.8 nM.
  • Compound I + folic acid Compound I showed a dose- dependent inhibition of cell proliferation in Renca cells with relative IC 50 values of -0.36 nM.
  • Compound I; ( ⁇ ) Compound I + folic acid Compound I + folic acid.
  • FIG. 2 shows studies related to PD-L1 expression in-vivo.
  • FIG. 2A and FIG. 2B show PD-L1 expression in M109, Renca, 4T1-CI2 and ID8-CI15 cells. Low levels of PD-L1 expression were also found on tumor-associated macrophages and other myeloid-derived noncancerous tumor cells (collectively referred as non-TAMs).
  • non-TAMs tumor-associated macrophages and other myeloid-derived noncancerous tumor cells
  • Fig. 2C shows CD8- CD4- double negative T cells were the majority of T cell populations in the M109 tumor (-7% total).
  • Both CD4+ and CD8+ T cells made up -1% each of the total tumor cell population.
  • FIG. 3. shows the antitumor effect of Compound I plus anti-PD-1 mAb in vivo.
  • FIG. 3 A shows Compound I treatment alone and produced 40% cures (2 out of 5 mice), while
  • FIG. 3B shows no gross toxicity or significant weight loss was observed during the course of treatment.
  • FIG. 4 shows the antitumor effect of Compound I plus anti-PD-1 mAb in vivo, upon tumor re-challenge.
  • FIG. 5A shows a chart of depletion of CD8+ T-cell population was accomplished by serial intraperitoneal injections of 200 ⁇ g of anti-CD8 (clone 2.43) mAb.
  • control A
  • Compound I Compound I + anti-CD8
  • T Anti-CD8.
  • FIG. 5B shows FACS staining of splenocytes which demonstrates the effectiveness of the depletion schedule.
  • folate-targeted chemotherapeutic refers to any compound known in the art that comprises a folate receptor binding ligand covalently attached to a chemotherapeutic agent by either a direct covalent bond or through a linker. It will be appreciated that "folate- targeted chemotherapeutic” include, but is not limited to those compounds described in Unites States Patent Number 7601332, PCT Publication Number WO2014/062697, and PCT
  • “folate-targeted chemotherapeutic” can include compounds of the formula B-L-D, wherein B is a folate binding ligand, L is an optional linker, and D is a drug or chemotherapeutic agent.
  • a "patient” can be administered the compound of the formula I and/or antibody described herein, and can be human or, in the case of veterinary applications, can be a laboratory, agricultural, domestic, or wild animal.
  • the patient can be a human, a laboratory animal such as a rodent (e.g.
  • mice, rats, hamsters, etc. mice, rats, hamsters, etc.
  • a rabbit, a monkey, a chimpanzee domestic animals such as dogs, cats, and rabbits, or agricultural animals such as cows, horses, pigs, sheep, goats, and wild animals in captivity such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins, and whales.
  • the cancers described herein can be a cancer cell population that is tumorigenic, including benign tumors and malignant tumors, or the cancer can be non- tumorigenic.
  • the cancer can arise spontaneously or by such processes as mutations present in the germline of the patient or somatic mutations, or the cancer can be chemically-, virally-, or radiation-induced.
  • Cancers applicable to the invention described herein include, but are not limited to, a carcinoma, a sarcoma, a lymphoma, a melanoma, a mesothelioma, a nasopharyngeal carcinoma, a leukemia, an adenocarcinoma, and a myeloma.
  • the cancers can be lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, leiomyosarcoma, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the
  • parathyroid gland non-small cell lung cancer, small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphomas, pleural mesothelioma, cancer of the bladder, Burkitt's lymphoma, cancer of the ureter, cancer of the kidney, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma,
  • CNS central nervous system
  • cholangiocarcinoma cholangiocarcinoma, Hurthle cell thyroid cancer or adenocarcinoma of the gastroesophageal junction.
  • the disease can be a viral disease.
  • the viral disease is HBV.
  • the viral disease is HCV.
  • the viral disease is HIV.
  • an antibody useful in connection with the present disclosure can be any antibody known to interact specifically with PD-1.
  • an antibody useful in connection with the present disclosure can be a polyclonal antibody.
  • an antibody useful in connection with the present disclosure can be a monoclonal antibody.
  • an antibody useful in connection with the present disclosure can be a mouse antibody (e.g. anti-murine antibody).
  • an antibody useful in connection with the present disclosure can be a monoclonal mouse antibody. See, for example, Kanai, T., et al., J. Immunology, v. 171: 4156-4163 (2003), which is incorporated herein by reference.
  • an antibody useful in connection with the present disclosure can be a humanized antibody. In some embodiments, an antibody useful in connection with the present disclosure can be a monoclonal humanized antibody.
  • Illustrative examples of antibodies useful in connection with the present disclosure include, but are not limited to, Nivolumab®, Pidilizumab®, Pembrolizuma®, BMS936559, MPDL3280A,
  • MEDI4736 and MSB0010718C See for example, Moreno, B.H., et al. Brit. J. Cancer, 112:
  • pharmaceutically acceptable salts of the compound of the formula I described herein are provided.
  • Pharmaceutically acceptable salts described herein include acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Illustrative examples include, but are not limited to, the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
  • Suitable base salts of the compound of the formula I are formed from bases which form non-toxic salts.
  • Illustrative examples include, but are not limited to, the arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • the compound of the formula I and/or antibody described herein may be administered as a formulation in association with one or more pharmaceutically acceptable carriers.
  • the carriers can be excipients.
  • the choice of carrier will to a large extent depend on factors such as the particular mode of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form.
  • Pharmaceutical compositions suitable for the delivery of the compound of the formula I and/or antibody described herein and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington: The Science & Practice of Pharmacy, 21th Edition (Lippincott Williams & Wilkins, 2005), incorporated herein by reference.
  • representative pharmaceutically acceptable carriers include, but are not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, and combinations thereof, that are physiologically compatible.
  • the carrier is suitable for parenteral administration.
  • Pharmaceutically acceptable carriers include, but are not limited to, sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Supplementary active compounds can also be incorporated into compositions of the invention.
  • liquid formulations may include suspensions and solutions.
  • Such formulations may comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • a carrier for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • Liquid formulations may also be prepared by the reconstitution of a solid.
  • an aqueous suspension may contain the active materials in admixture with appropriate excipients.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally-occurring phosphatide, for example, lecithin; a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example,
  • aqueous suspensions may also contain one or more preservatives, for example, ascorbic acid, ethyl, n-propyl, or p- hydroxybenzoate; or one or more coloring agents.
  • dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Additional excipients, for example, coloring agents, may also be present.
  • Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth; naturally-occurring phosphatides, for example, soybean lecithin; and esters including partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride can be included in the composition.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
  • Illustrative formats for oral administration include, but are not limited to, tablets, capsules, elixirs, syrups, and the like.
  • the route of administration and/or whether the compound of the formula I and/or antibody described herein is administered locally or systemically a wide range of permissible dosages are contemplated herein, including doses falling in the ranges described herein.
  • the dosages may be single or divided, and may administered according to a wide variety of protocols, including q.d., b.i.d., t.i.d., or even every other day, biweekly (b.i.w.), once a week, once a month, once a quarter, and the like.
  • the therapeutically effective amounts described herein correspond to the instance of administration, or alternatively to the total daily, weekly, month, or quarterly dose, as determined by the dosing protocol.
  • the compound of the formula I and/or antibody described herein may be administered directly into the blood stream, into muscle, and/or into an internal organ.
  • Suitable routes for such parenteral administration include, but are not limited to, intravenous, intraarterial, intraperitoneal, intrathecal, epidural, intracerebroventricular, intraurethral, intrasternal, intracranial, intratumoral, intramuscular and subcutaneous delivery.
  • Suitable means for parenteral administration include, but are not limited to, needle (including
  • microneedle injectors e.g., needle-free injectors, infusion techniques.
  • parenteral formulations are typically aqueous solutions which may contain carriers or excipients such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • a suitable vehicle such as sterile, pyrogen-free water.
  • any of the liquid formulations described herein may be adapted for parenteral administration of the compound of the formula I and/or antibody described herein.
  • the preparation of parenteral formulations under sterile conditions for example, by lyophilization under sterile conditions, may readily be
  • solubility of a compound of the formula I and/or antibody described herein used in the preparation of a parenteral formulation may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • formulations for parenteral administration may be formulated for immediate and/or modified release.
  • the I and/or antibody described herein may be administered in a time release formulation, for example in a composition which includes a slow release polymer.
  • the the compound of the formula I and/or antibody described herein can be prepared with carriers that will protect the compound of the formula I and/or antibody described herein against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate,
  • polyanhydrides polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PGLA).
  • Methods for the preparation of such formulations are generally known to those skilled in the art.
  • the compound of the formula I and/or antibody described herein or compositions comprising the compound of the formula I and/or antibody described herein may be continuously administered, where appropriate.
  • kits are provided. If a combination of the compound of the formula I and/or antibody described herein is to be administered, two or more pharmaceutical compositions may be combined in the form of a kit suitable for sequential administration or coadministration of the compositions.
  • a kit comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of the formula I described herein, and means for separately retaining the compositions, such as a container, divided bottle, or divided foil packet, and the other of which contains an antibody as described herein, and means for separately retaining the compositions, such as a container, divided bottle, or divided foil packet.
  • compositions comprising one or more of the compound of the formula I and/or antibody described herein, in containers having labels that provide instructions for use of the compound of the formula I and/or antibody described herein for patient treatment are provided.
  • Instructional materials provided with kits in accordance with the present teachings may be printed (e.g., on paper) and/or supplied in an electronic-readable medium (e.g., floppy disc, CD-ROM, DVD-ROM, zip disc, videotape, audio tape, etc.).
  • instructions may be provided by directing a user to an Internet web site (e.g., specified by the manufacturer or distributor of the kit) and/or via electronic mail, text message, social media, and/or the like, and combinations thereof.
  • sterile injectable solutions can be prepared by incorporating the compound of the formula I and/or antibody described herein in the required amount in an appropriate solvent with one or a combination of ingredients described above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the compound of the formula I and/or antibody described herein into a sterile vehicle which contains a dispersion medium and any additional ingredients of those described above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof, or the ingredients may be sterile-filtered together.
  • the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • any effective regimen for administering the compound of the formula I and/or antibody described herein can be used.
  • the compound of the formula I and/or antibody described herein can be administered as single doses, or the doses can be divided and administered as a multiple-dose daily regimen.
  • a staggered regimen for example, one to five days per week can be used as an alternative to daily treatment, and for the purpose of the methods described herein, such intermittent or staggered daily regimen is considered to be equivalent to every day treatment and is contemplated.
  • the patient is treated with multiple injections of the compound of the formula I and/or antibody described herein to treat the cancer. In one embodiment, the patient is injected multiple times
  • a patient may be administered a single dose of the antibody described herein, and multiple doses of the compound of the formula I, where the multiple doses of the compound of the formula I can be according to any of the dosing schedules and amounts described herein.
  • any suitable course of therapy with the compound of the formula I and/or antibody described herein can be used.
  • individual doses and dosage regimens are selected to provide a total dose administered during a month of about 15 mg.
  • the compound of the formula I and/or antibody described herein is administered in a single daily dose administered five days a week, in weeks 1, 2, and 3 of each 4 week cycle, with no dose administered in week 4.
  • the compound of the formula I and/or antibody described herein is administered in a single daily dose administered three days a week, of weeks 1, and 3 of each 4 week cycle, with no dose administered in weeks 2 and 4.
  • the compound of the formula I and/or antibody described herein is administered biweekly on weeks 1 and 2, i.e. on days 1, 4, 8, 11, of a 3-week cycle.
  • the compound of the formula I and/or antibody described herein is administered once weekly on weeks 1 and 2, i.e. days 1 and 8 of a 3 -week cycle.
  • the compound of the formula I and/or antibody described herein is administered once every 2 weeks on a cycle ranging from a 4-week cycle to a 30- week cycle.
  • the compound of the formula I and/or antibody described herein is administered once every 3 weeks on a cycle ranging from a 6-week cycle to a 36-week cycle.
  • the compound of the formula I and/or antibody described herein is administered once every 4 weeks on a cycle ranging from an 8-week cycle to a 52-week cycle.
  • the compound of the formula I and antibody described herein may be administered on schedules different from each another based on their dose level and mode of action.
  • the compound of the formula I can be administered in a single daily dose administered five days a week, in weeks 1, 2, and 3 of each 4 week cycle, with no dose administered in week 4, and the antibody described herein can be administered once, where the antibody can be administered at the same time as an administration of the compound of the formula I, prior to an administration of the compound of the formula I or after the administration of the compound of the formula I.
  • the compound of the formula I can be administered in a single daily dose administered five days a week, in weeks 1, 2, and 3 of each 4 week cycle, with no dose administered in week 4, and the antibody described herein can be administered once every 2 weeks on a cycle ranging from a 4-week cycle to a 30-week cycle, where the antibody can be administered at the same time as an administration of the compound of the formula I, prior to an administration of the compound of the formula I or after the administration of the compound of the formula I.
  • the compound of the formula I can be administered in a single daily dose administered five days a week, in weeks 1, 2, and 3 of each 4 week cycle, with no dose administered in week 4, and the antibody described herein can be administered once every 3 weeks on a cycle ranging from a 6- week cycle to a 36- week cycle, where the antibody can be administered at the same time as an administration of the compound of the formula I, prior to an administration of the compound of the formula I, or after the administration of the compound of the formula I.
  • the compound of the formula I can be administered biweekly on weeks 1 and 2, i.e. on days 1, 4, 8, 11, of a 3-week cycle, and the antibody described herein can be administered once, where the antibody can be administered at the same time as an administration of the compound of the formula I, prior to an administration of the compound of the formula I, or after the administration of the compound of the formula I.
  • the compound of the formula I can be administered biweekly on weeks 1 and 2, i.e.
  • the antibody described herein can be administered once every 2 weeks on a cycle ranging from a 4-week cycle to a 30- week cycle, where the antibody can be administered at the same time as an administration of the compound of the formula I, prior to an administration of the compound of the formula I or after the administration of the compound of the formula I.
  • the compound of the formula I can be administered biweekly on weeks 1 and 2, i.e.
  • the antibody described herein can be administered once every 3 weeks on a cycle ranging from a 6-week cycle to a 36-week cycle, where the antibody can be administered at the same time as an administration of the compound of the formula I, prior to an administration of the compound of the formula I, or after the administration of the compound of the formula I.
  • the unitary daily dosage of the compound of the formula I and/or the antibody described herein can vary significantly depending on the patient condition, the disease being treated (i.e., a cancer or a viral disease), or the route of administration of the compound of the formula I and/or the antibody described herein and tissue distribution.
  • the effective amount to be administered to a patient is based on body surface area, mass, and physician assessment of patient condition.
  • Therapeutically effective doses (also referred to herein as "therapeutically effective amount”) can range, for example, from about 0.5 mg/m 2 to about 12.0 mg/m 2.
  • the therapeutically effective doses described herein also include ranges of about 0.5 mg/m to about
  • the therapeutically effective dose may vary within the various ranges provided above based on the factors noted above.
  • the therapeutically effective dose for any particular patient or group of patients may be any number value between about 0.5 mg/m 2 and about 10.0 mg/m 2 , including but not limited to 1.0 mg/m 2 , 1.5, mg/m 2 , 2.0 mg/m 2 ,
  • the total dose may be administered in single dose or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
  • compositions and/or dosage forms for administration of the compound of the formula I and/or the antibody described herein are prepared from the compound of the formula I and/or the antibody described herein with a purity of at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5%.
  • compositions and or dosage forms for administration of the compound of the formula I and/or the antibody described herein are prepared from the compound of the formula I and/or the antibody described herein with a purity of at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99%, or at least about 99.5%.
  • purity determinations may be based on weight percentage, mole percentage, and the like. In addition, purity determinations may be based on the absence or substantial absence of certain predetermined components, such as, but not limited to, folic acid, disulfide containing components, oxidation products, disulfide components not containing a folate, and the like.
  • the purity of the compound of the formula I and/or the antibody described herein may be measured using any conventional technique, including various chromatography or spectroscopic techniques, such as high pressure or high performance liquid chromatography (HPLC), nuclear magnetic resonance spectroscopy, TLC, UV absorbance spectroscopy, fluorescence spectroscopy, and the like.
  • HPLC high pressure or high performance liquid chromatography
  • TLC nuclear magnetic resonance spectroscopy
  • UV absorbance spectroscopy fluorescence spectroscopy
  • the compound of the formula I and/or the antibody described herein is provided in a sterile container or package.
  • the methods described herein include the following examples.
  • the examples further illustrate additional features of the various embodiments of the invention described herein.
  • the examples are illustrative and are not to be construed as limiting other embodiments of the invention described herein.
  • other variations of the examples are included in the various embodiments of the invention described herein.
  • Compound I was prepared according to the methods described in International Patent Publication No. WO2014062697, incorporated herein by reference for the example on pages 76 to 91.
  • Anti-mouse PD-1 (clone RMP1-14; cat# BE0146) and anti-CD8a+ T-cell (clone 2.43, cat# BE0061) used for in-vivo studies were purchased from BioXCell.
  • the flow cytometry antibodies used for surface marker staining were purchased from eBioscience: PD-L1 (clone MIH5; cat# 25-5982), F4/80 (clone BM8; cat# 12-4801), CDl lb (clone Ml/70; cat# 48-0112), CD38 (clone 145-2C11; cat# 25-0031), CD4 (clone GK1.5; cat# 46-0041), and CD8p (clone H3517.2; cat# 11-0083).
  • the FR-a expressing mouse cell lines utilized to evaluate Compound I activity in invito) and in-vivo studies were (1) a subclone of M109 Madison lung carcinoma, (2) 4T1-C12, a breast carcinoma cell line transfected with the murine FR-a (3) ID8-C115, an ovarian carcinoma cell line transfected with the murine FR-a, and (4) Renca, a kidney carcinoma cell line. All cells were grown in a folate-free RPMI1640 medium (Gibco BRL) (FFRPMI) containing 10% heat-inactivated fetal calf serum (HIFCS) and antibiotics, and maintained under a 5% C0 2 atmosphere using standard cell culture techniques.
  • FFRPMI1640 medium Gibco BRL
  • HFCS heat-inactivated fetal calf serum
  • M109 tumor cells, 4T1-CI2 triple negative breast cancer cells, ID8-C115 ovarian carcinoma cell line, and Renca kindey cancer cells in 96-well plates (20,000 cells/well) were treated with 10-fold serial dilutions of Compound I ( ⁇ 1 ⁇ ) in FFRPMI medium without and with 100-fold molar excess of FA. After a 2 h exposure, the drug-containing media were replaced and the cells were washed and allowed to incubate further for 72 h.
  • the cell viability was assessed by adding XTT (2,3-bis(2-methoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5- carboxanilide) to the culture medium for 2 h following the manufacturer's instructions. All results were expressed as % absorbance (minus background) relative to the untreated control cells.
  • mice Female Balb/c mice were purchased from Harlan Sprague Dawley (Indianapolis, IN) and used when they reached 6-8 weeks of age. The mice were fed a folate-deficient diet (Harlan Teklad) on the day of tumor implantation.
  • Harlan Teklad a folate-deficient diet
  • M109 tumors were maintained in Balb/c mice by subcutaneous passages. Tumors were harvested when desired and regenerated according to a pre-established procedure. For subcutaneous tumor implants, 1 x 10 6 viable tumor cells at an early passage (PI) were suspended in 100 ⁇ of folate-deficient RPMI1640 supplemented with 1% syngeneic mouse serum (antibiotic-free) and injected into the shoulder region. 4T1-C12 and Renca tumors were generated by subcutaneous implantation of cultured cells at 2 x 10 6 and 7.5 x 10 6 , respectively. ID8-C115 ascites tumors were generated by intra-peritoneal implantation of 5 x 10 6 cells per animal.
  • Solid tumors (100-1000 mm ) were harvested, weighed, and minced into small pieces then transferred into 50 mL tubes containing 20 mL of a tumor digestion cocktail.
  • the enzymatic tumor digestion cocktail consisted of 0.5 mg/mL Collagenase IV (Sigma-Aldrich, Catalog* C5138), 0.5 mg/mL Hyaluronidase (Sigma-Aldrich, Catalog* H3506) and 0.1 mg/mL DNase I (Sigma-Aldrich, Catalog* DN25) in serum- free and folate-deficient RPMI1640 medium supplemented with antibiotics.
  • the tumor fragments were digested for one hour at 37°C at 300 rpm on a horizontal shaker.
  • the tumor digest was centrifuged at 400 x g for 5 minutes and tumor cell pellet underwent a red blood cell lysis step, was then washed with cold phosphate-buffered saline (PBS, pH 7.4) and finally filtered through a 40 ⁇ nylon cell strainer.
  • PBS cold phosphate-buffered saline
  • Ascites was collected via an LP. injection of 5 mL of cold PBS containing 5 mM EDTA then removal of the intra-peritoneal fluid containing ascitic tumor cells. The cells were then collected by a 5 minute 400 x g centrifugation, followed by an RBC lysis step, then a cold PBS wash and finally a 40 ⁇ nylon filtration to remove tissue and large cellular aggregates.
  • the single-cell suspensions prepared from solid tumors and ascites were blocked in a FACS stain solution on ice for 20 minutes prior to staining for flow cytometry.
  • the FACS stain solution consisted of 1% bovine serum albumin fraction V (Fisher scientific, cat* BP1600), 0.5 mg/mL human immunoglobulin (Equitech-Bio, cat* SLH66) and 0.05% sodium azide in PBS.
  • PD-L1, F4/80, CD1 lb, CD3, CD4, CD8 the tumor cells were stained in the FACS stain solution containing various fluorophore conjugated antibodies purchased from eBioscience at optimized concentrations (0.4 - 2.5 ⁇ g/mL).
  • the tumor cells were washed with PBS and re-suspended in PBS containing 3 ⁇ propidium iodide for dead cell exclusion. Data was collected on the Gallios flow cytometer (Beckman Coulter) and analyzed using the Kaluza vl.2 software (Beckman Coulter).
  • Compound I was administered intravenously at 2000 nmol/kg on days 0, 3, 6, and 9.
  • Anti-PD-1 mAb was administered intraperitoneally at 250 ⁇ g/dose on days 1, 4, 7, and 10. Mice were weighed and measured for tumor size 3 times per week.
  • the animals were euthanized when the tumor volume reached -1500 mm . Individual mice lacking measurable tumors for > 60 days after first treatment will be classified as cures.
  • Compound I was evaluated for its in- vitro activity against Ml 09 tumor cells, 4T1-CI2 triple negative breast cancer cells, ID8-C115 ovarian carcinoma cell line, and Renca kindey cancer cells. The cells were exposed for 2 h to 10-fold serial dilutions of Compound 1 (1 pM - 1 ⁇ ) without or with 100-fold excess FA and followed by a 72 h chase in drug-free medium.
  • Compound I showed a dose-dependent inhibition of cell proliferation with relative IC 50 values of -1.2 nM in M109 cells, -1.7 nM in 4T1-CI2 cells, -2.8 nM in ID8-CI15 cells, and -0.36 nM in Renca cells. Importantly, the observed antiproliferative activity was competable in the presence of excess FA, indicating a FR-specific mode of action. Results are shown in FIGs. 1A - ID.
  • M109 tumor cells expressed the highest level of PD-Ll followed by Renca, 4T1-C12, and then ID8-C115. Moreover, low levels of PD-Ll expression were also found on tumor-associated macrophages and other myeloid-derived non-cancerous tumor cells (collectively referred as non-TAMs). In the M109 tumor, other myeloid-derived non- macrophage cell populations (F4/80- CDl lb+) had a lower PD-Ll expression than TAMs (Fig. 2C). Since PD-Ll high M109 tumors are syngeneic to Balb/c mice, CD3+ T cell subsets were further analyzed. As shown in Fig. 2D, CD8- CD4- double negative T cells were the majority of T cell populations in the M109 tumor (-7% total). Both CD4+ and CD8+ T cells made up -1% each of the total tumor cell population.

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Abstract

La présente invention concerne le traitement de maladies par des conjugués d'administration de médicaments associés à des anticorps. L'invention concerne en particulier le traitement de maladies telles que le cancer et des maladies virales par des conjugués d'administration de médicaments associés à des anticorps PD-1.
PCT/US2016/056787 2015-10-14 2016-10-13 Conjugués d'administration de médicaments destinés à être utilisés en multithérapie WO2017066414A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090217401A1 (en) * 2005-05-09 2009-08-27 Medarex, Inc Human Monoclonal Antibodies To Programmed Death 1(PD-1) And Methods For Treating Cancer Using Anti-PD-1 Antibodies Alone or in Combination with Other Immunotherapeutics
US20130116195A1 (en) * 2009-12-04 2013-05-09 Christopher Paul Leamon Binding ligand linked drug delivery conjugates of tubulysins
US20140045919A1 (en) * 2007-12-04 2014-02-13 Alnylam Pharmaceuticals, Inc. Folate Conjugates
US20140107316A1 (en) * 2012-10-16 2014-04-17 Endocyte, Inc. Drug delivery conjugates containing unnatural amino acids and methods for using

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090217401A1 (en) * 2005-05-09 2009-08-27 Medarex, Inc Human Monoclonal Antibodies To Programmed Death 1(PD-1) And Methods For Treating Cancer Using Anti-PD-1 Antibodies Alone or in Combination with Other Immunotherapeutics
US20140045919A1 (en) * 2007-12-04 2014-02-13 Alnylam Pharmaceuticals, Inc. Folate Conjugates
US20130116195A1 (en) * 2009-12-04 2013-05-09 Christopher Paul Leamon Binding ligand linked drug delivery conjugates of tubulysins
US20140107316A1 (en) * 2012-10-16 2014-04-17 Endocyte, Inc. Drug delivery conjugates containing unnatural amino acids and methods for using

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