US20220233689A1 - Methods of treating tumors - Google Patents

Methods of treating tumors Download PDF

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Publication number
US20220233689A1
US20220233689A1 US17/562,958 US202117562958A US2022233689A1 US 20220233689 A1 US20220233689 A1 US 20220233689A1 US 202117562958 A US202117562958 A US 202117562958A US 2022233689 A1 US2022233689 A1 US 2022233689A1
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Prior art keywords
antibody
aspects
dose
administered
cancer
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US17/562,958
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Inventor
Masano Huang
Thomas Arthur HABY
Mehrnaz Khossravi
Scott Aaron HART
Rao Venkatramana MANTRI
Heather Elizabeth VEZINA
Amit Roy
Bindu Purnima MURTHY
Urvi Ashish ARAS
Kinjal Sanghavi
Xiaochen ZHAO
Akintunde BELLO
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Halozyme Inc
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Bristol Myers Squibb Co
Halozyme Inc
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Priority to US17/562,958 priority Critical patent/US20220233689A1/en
Assigned to HALOZYME, INC. reassignment HALOZYME, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRISTOL-MYERS SQUIBB COMPANY
Assigned to BRISTOL-MYERS SQUIBB COMPANY reassignment BRISTOL-MYERS SQUIBB COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MANTRI, RAO VENKATRAMANA, ROY, AMIT, ARAS, URVI ASHISH, SANGHAVI, Kinjal, HABY, THOMAS ARTHUR, MURTHY, BINDU PURNIMA, VEZINA, HEATHER ELIZABETH, KHOSSRAVI, MEHRNAZ, BELLO, Akintunde, ZHAO, Xiaochen, HUANG, Masano, HART, SCOTT AARON
Publication of US20220233689A1 publication Critical patent/US20220233689A1/en
Priority to US18/453,265 priority patent/US20240024471A1/en
Priority to US18/423,089 priority patent/US12582713B2/en
Priority to US18/736,323 priority patent/US20250057948A1/en
Priority to US19/347,548 priority patent/US20260158138A1/en
Priority to US19/358,181 priority patent/US20260034212A1/en
Abandoned legal-status Critical Current

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    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • 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
    • C07K16/2803—Immunoglobulins [IG], 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
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    • C07K16/2803—Immunoglobulins [IG], 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
    • C07K16/2827—Immunoglobulins [IG], 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 B7 molecules, e.g. CD80, CD86
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    • C12N9/14—Hydrolases (3)
    • C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
    • C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
    • C12N9/2474—Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • cancer immunotherapy had focused substantial effort on approaches that enhance anti-tumor immune responses by adoptive-transfer of activated effector cells, immunization against relevant antigens, or providing non-specific immune-stimulatory agents such as cytokines.
  • intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including the development of antibodies such as nivolumab and pembrolizumab (formerly lambrolizumab; USAN Council Statement, 2013) that bind specifically to the Programmed Death-1 (PD-1) receptor and block the inhibitory PD-1/PD-1 ligand pathway (Topalian et al., 2012a, b; Topalian et al., 2014; Hamid et al., 2013; Hamid and Carvajal, 2013; McDermott and Atkins, 2013).
  • PD-1 Programmed Death-1
  • the dose of the antibody is about 300 mg to about 900 mg administered about every two weeks. In some aspects, the dose of the antibody is about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, or about 900 mg administered about every
  • the pharmaceutical composition comprises: (a) about 120 mg/mL of the anti-PD-1 antibody; (b) about 20 mM L-histidine; (c) about 250 mM sucrose; (d) about 0.05% w/v polysorbate 80; (e) about 50 ⁇ M pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U/mL rHuPH20.
  • a “humanized antibody” refers to an antibody in which some, most or all of the amino acids outside the CDRs of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. In one aspect of a humanized form of an antibody, some, most or all of the amino acids outside the CDRs have been replaced with amino acids from human immunoglobulins, whereas some, most or all amino acids within one or more CDRs are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abrogate the ability of the antibody to bind to a particular antigen.
  • a “humanized antibody” retains an antigenic specificity similar to that of the original antibody.
  • an “anti-cancer agent” promotes cancer regression in a subject.
  • a therapeutically effective amount of the drug promotes cancer regression to the point of eliminating the cancer.
  • “Promoting cancer regression” means that administering a therapeutically effective amount of the drug, alone or in combination with an anti-neoplastic agent, results in a reduction in tumor growth or size, necrosis of the tumor, a decrease in severity of at least one disease symptom, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • the terms “effective” and “effectiveness” with regard to a treatment includes both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the drug to promote cancer regression in the patient.
  • Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.
  • stable in reference to a formulation or drug product, is one in which an antibody, antibodies, or molecules therein essentially retain their physical and chemical stability and integrity upon storage. Stability of a formulation herein can be measured at selected temperatures after selected time periods. For example, an increase in aggregate formation or low molecular weight species are indicators of instability. Retention of original clarity and/or color throughout shelf-life are also indicators utilized to monitor stability.
  • a “stable” drug product is one wherein an increase in aggregation, as measured by an increase in the percentage of high molecular weight species (% HMW), is less than about 5%, and preferably less than about 3%, when the formulation is stored at 2-8° C. for at least about one year.
  • the dose of the antibody e.g., the anti-PD-1 antibody (e.g., nivolumab)
  • the dose of the antibody is about 250 mg to about 400 mg of the antibody administered about every week.
  • the dose of the antibody, e.g., the anti-PD-1 antibody (e.g., nivolumab) is about 250 mg to about 350 mg of the antibody administered about every week.
  • the dose of the antibody, e.g., the anti-PD-1 antibody (e.g., nivolumab) is about 275 mg to about 325 mg of the antibody administered about every week.
  • At least one of the two subcutaneous unit doses comprises about 150 mg of the antibody in a total volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL).
  • the two subcutaneous unit doses are administered to the subject at two different bodily locations.
  • the first subcutaneous unit dose is administered at a first bodily location
  • the second subcutaneous unit dose is administered at a second bodily location
  • the third subcutaneous unit dose is administered at a third bodily location
  • the fourth subcutaneous unit dose is administered at a fourth bodily location.
  • the dose of about 1200 mg of the antibody comprises at least eight subcutaneous unit doses. In some aspects, at least one of the eight subcutaneous unit doses comprises about 150 mg of the antibody. In some aspects, at least one of the eight subcutaneous unit doses comprises about 150 mg of the antibody in a total volume of about 2 mL. In some aspects, at least one of the eight subcutaneous unit doses comprises about 150 mg of the antibody in a total volume of greater than about 2 mL. In some aspects, at least one of the eight subcutaneous unit doses comprises about 150 mg of the antibody in a total volume of greater than about 5 mL.
  • At least one of the two subcutaneous unit doses comprises about 1200 mg of the antibody in a total volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In certain aspects, at least one of the two subcutaneous unit doses comprises about 1200 mg of the antibody in a total volume of less than about 2 mL. In some aspects, the two subcutaneous unit doses are administered to the subject at a single bodily location. In some aspects, the two subcutaneous unit doses are administered to the subject at two different bodily locations.
  • the dose of about 2400 mg of the antibody comprises three subcutaneous unit doses. In some aspects, at least one of the three subcutaneous unit doses comprises about 800 mg of the antibody. In some aspects, each of the three subcutaneous unit doses comprises about 800 mg of the antibody. In some aspects, at least one of the three subcutaneous unit doses comprises about 800 mg of the antibody in a total volume of about 2 mL. In some aspects, at least one of the three subcutaneous unit doses comprises about 800 mg of the antibody in a total volume of greater than about 2 mL. In some aspects, at least one of the three subcutaneous unit doses comprises about 800 mg of the antibody in a total volume of greater than about 5 mL.
  • the first subcutaneous unit dose is administered at a first bodily location
  • the second subcutaneous unit dose is administered at a second bodily location
  • the third subcutaneous unit dose is administered at a third bodily location
  • the fourth subcutaneous unit dose is administered at a fourth bodily location.
  • the dose comprises at least about 5000 units to at least about 100,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some aspects, the dose comprises at least about 5000 units, at least about 10,000 units, at least about 15,000 units, at least about 20,000 units, at least about 25,000 units, at least about 30,000 units, at least about 35,000 units, at least about 40,000 units, at least about 45,000 units, at least about 50,000 units, at least about 55,000 units, at least about 60,000 units, at least about 65,000 units, at least about 70,000 units, at least about 75,000 units, at least about 80,000 units, at least about 85,000 units, at least about 90,000 units, at least about 95,000 units, or at least about 100,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20).
  • an endoglycosidase hydrolase enzyme e.g., rHuPH20.
  • the dose comprises at least about 20,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some aspects, the dose comprises at least about 30,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some aspects, the dose comprises at least about 40,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some aspects, the dose comprises at least about 50,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20).
  • the amount of the endoglycosidase hydrolase enzyme can be expressed in terms of units or the amount of the endoglycosidase hydrolase enzyme (e.g., rHuPH20) can be expressed in terms mg (or in other weight-based units).
  • the dose comprises an amount of an endoglycosidase hydrolase enzyme (e.g., rHuPH20) expressed as at least about 500 U or at least about 0.00455 mg.
  • the dose comprises an amount of an endoglycosidase hydrolase enzyme (e.g., rHuPH20) expressed as at least about 2000 U or at least about 0.0182 mg.
  • the vial is a pen injector.
  • Standard pen injectors require the patient to activate a push-button, which actuates the needle into the targeted injection site.
  • some aspects of the present disclosure are directed to an injection pen comprising (a) about 150 mg/mL of the anti-PD-1 antibody; (b) about 20 mM L-histidine; (c) about 250 mM sucrose; (d) about 0.05% w/v polysorbate 80; (e) about 50 ⁇ M pentetic acid; (f) about 5 mM methionine; and (g) about 0.0182 mg/mL rHuPH20.
  • the pharmaceutical composition comprises: (a) about 150 mg/mL of the anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w/v polysorbate 80; (e) about 50 ⁇ M pentetic acid; (f) about 5 mM methionine; (g) an anti-OX40 antibody; and (h) about 2000 U/mL rHuPH20.
  • the second antibody comprises an anti-TIGIT antibody.
  • the anti-TIGIT antibody comprises BMS-986207.
  • the anti-TIGIT antibody comprises clone 22G2, as described in WO 2016/106302.
  • the anti-TIGIT antibody comprises MTIG7192A/RG6058/RO7092284, or clone 4.1D3, as described in WO 2017/053748.
  • the anti-TIGIT antibody comprises selected from the anti-TIGIT antibodies described in, for example, WO 2016/106302 (Bristol-Myers Squibb Company) and WO 2017/053748 (Genentech).
  • the pharmaceutical composition comprises: (a) about 150 mg/mL of the anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w/v polysorbate 80; (e) about 50 ⁇ M pentetic acid; (f) about 5 mM methionine; (g) an anti-TIGIT antibody; and (h) about 2000 U/mL rHuPH20.
  • an anti-CD47 antibody can be formulated together with an anti-PD-1 antibody in any one of formulations disclosed herein as a single formulation.
  • the pharmaceutical composition comprises: (a) about 150 mg/mL of the anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w/v polysorbate 80; (e) about 50 ⁇ M pentetic acid; (f) about 5 mM methionine; and (g) an anti-CD47 antibody.
  • the actual amount of rHuPH20 drug substance added during manufacture of the drug product is determined based on the protein concentration and the enzyme activity of the rHuPH20 drug substance, which can range from 8.5 to 12.5 mg/mL and 80 to 140 kU/mg, respectively.
  • Formulation A No pentetic acid, no methionine; 2.
  • Formulation B 50 ⁇ M pentetic acid, no methionine; 3.
  • Formulation C No pentetic acid, 5 mM methionine; and 4.
  • Formulation D 50 ⁇ M pentetic acid, 5 mM methionine.
  • SC nivolumab was supplied at 154.57 mg/mL and was administered by SC injection at doses of 0 mg/kg (vehicle), 50 mg/kg (no rHuPH20), or 50 mg/kg (with rHuPH20, 2000 U/mL), twice (Days 1 and 22/20 [males/females]), to groups of 3 monkeys per sex.
  • Example 3 Subcutaneous Nivolumab in Combination with Recombinant Human Hyaluronidase in Previously Treated Advanced, Recurrent, or Metastatic Non-Small Cell Lung Cancer
  • NSCLC neurostystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystysysysystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystystysty

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US17/562,958 2020-12-28 2021-12-27 Methods of treating tumors Abandoned US20220233689A1 (en)

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Application Number Priority Date Filing Date Title
US17/562,958 US20220233689A1 (en) 2020-12-28 2021-12-27 Methods of treating tumors
US18/453,265 US20240024471A1 (en) 2020-12-28 2023-08-21 Methods of treating tumors
US18/423,089 US12582713B2 (en) 2020-12-28 2024-01-25 Methods of treating tumors
US18/736,323 US20250057948A1 (en) 2020-12-28 2024-06-06 Methods of treating tumors
US19/347,548 US20260158138A1 (en) 2020-12-28 2025-10-01 Methods of treating tumors
US19/358,181 US20260034212A1 (en) 2020-12-28 2025-10-14 Methods of treating tumors

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US202063131240P 2020-12-28 2020-12-28
US202163150420P 2021-02-17 2021-02-17
US202163184082P 2021-05-04 2021-05-04
US17/562,958 US20220233689A1 (en) 2020-12-28 2021-12-27 Methods of treating tumors

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US18/453,265 Continuation US20240024471A1 (en) 2020-12-28 2023-08-21 Methods of treating tumors
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US18/736,323 Continuation US20250057948A1 (en) 2020-12-28 2024-06-06 Methods of treating tumors
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