WO2022167052A1 - Utilisation d'acide ascorbique comme agent stabilisant pour des anticorps anti-b7-h3 - Google Patents

Utilisation d'acide ascorbique comme agent stabilisant pour des anticorps anti-b7-h3 Download PDF

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Publication number
WO2022167052A1
WO2022167052A1 PCT/DK2022/050018 DK2022050018W WO2022167052A1 WO 2022167052 A1 WO2022167052 A1 WO 2022167052A1 DK 2022050018 W DK2022050018 W DK 2022050018W WO 2022167052 A1 WO2022167052 A1 WO 2022167052A1
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WO
WIPO (PCT)
Prior art keywords
alternatively
pharmaceutical composition
antibody
antigen binding
binding fragment
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PCT/DK2022/050018
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English (en)
Inventor
Torben LUND-HANSEN
Johannes Nagel
Jon THOE FØRSTER
David Trump
Beth Kramer
Andreas Ingeman JENSEN
Original Assignee
Y-Mabs Therapeutics, Inc.
J. MØLLER SAN-PEDRO, Claus
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Application filed by Y-Mabs Therapeutics, Inc., J. MØLLER SAN-PEDRO, Claus filed Critical Y-Mabs Therapeutics, Inc.
Publication of WO2022167052A1 publication Critical patent/WO2022167052A1/fr

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    • 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
    • C07K16/2827—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 B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • A61K51/1096—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0085—Brain, e.g. brain implants; Spinal cord
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to pharmaceutical compositions comprising a radiolabeled B7H3 antibody or antigen binding fragment thereof and ascorbic acid, methods for stabilizing pharmaceutical compositions and use of ascorbic acid as a stabilizing agent and/or a scavenger agent.
  • radioimmune therapy has increased within the last years and decades. Of particular importance is the final stability of radiolabeled antibodies with regards to radiolysis by the emitted
  • Chakrabarti M. et al. 1996 relates to a method for protecting the murine monoclonal anti- CD5 antibody, T101, during the labeling procedure with 121 l or 90 Y by using various radioprotectants, such as human serum albumin, cysteamine, glycerol and ascorbic acid.
  • W00180884 with the title "Intrathecal administration of Rituximab for treatment of central nervous system lymphomas” discloses a radiolabeled anti-CD20 antibody, Rituximab, which might be administered intrathecally for treating central nervous system (CNS) lymphomas.
  • W003101495 with the title "Methods and compositions for radioimmunotherapy of brain and CNS tumors” discloses a method of treating a brain tumor administering a multispecific antibody with one targeting arm binding a cancer antigen and a capture arm that binds a radionuclide carrier.
  • the multispecific antibody can be administered intrathecally.
  • WO0232375 with the title "Uses of Monoclonal Antibody 8H9" discloses a composition comprising an effective amount of monoclonal antibody 8H9 or a derivative thereof and a suitable carrier.
  • Other antibodies comprising the complementary determining regions of monoclonal antibody 8H9 or a derivative thereof, capable of binding to the same antigen as the monoclonal antibody 8H9 are also disclosed.
  • Radiolabeled antibodies might be damaged during labeling, storage and/or in use. Thus, there is a need for providing methods for stabilizing pharmaceutical compositions comprising radiolabeled antibodies and processes for effectively producing such pharmaceutical compositions.
  • the invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the invention concerns a method of stabilizing a pharmaceutical composition comprising a radiolabeled B7H3 antibody or antigen binding fragment thereof, comprising: a. Producing said B7H3 antibody or antigen binding fragment thereof, b. Radiolabeling said B7H3 antibody or antigen binding fragment thereof, c. Formulating said radiolabeled B7H3 antibody or antigen binding fragment thereof into a pharmaceutical composition, d. Stabilizing said pharmaceutical composition by adding ascorbic acid.
  • the invention concerns a method of stabilizing a pharmaceutical composition comprising a radiolabeled B7H3 antibody or antigen binding fragment thereof, comprising: a. Producing said B7H3 antibody or antigen binding fragment thereof, b. Radiolabeling said B7H3 antibody or antigen binding fragment thereof, c. Providing a stabilized pharmaceutical composition by adding ascorbic acid and optionally additional excipients.
  • the invention concerns a process for producing a pharmaceutical composition comprising a radiolabeled B7H3 antibody or antigen binding fragment thereof, comprising: a. Producing said B7H3 antibody or antigen binding fragment thereof, b. Radiolabeling said B7H3 antibody or antigen binding fragment thereof, c. Formulating said radiolabeled B7H3 antibody or antigen binding fragment thereof into a pharmaceutical composition, d. Adding ascorbic acid to said pharmaceutical composition.
  • the invention concerns a process for producing a pharmaceutical composition comprising a radiolabeled B7H3 antibody or antigen binding fragment thereof, comprising: a. Producing said B7H3 antibody or antigen binding fragment thereof, b. Radiolabeling said B7H3 antibody or antigen binding fragment thereof, c. Providing a pharmaceutical composition by adding ascorbic acid and optionally additional excipients.
  • the invention concerns use of ascorbic acid as a stabilizing agent and/or a scavenger agent.
  • the invention concerns use of ascorbic acid as a stabilizing agent and/or a scavenger agent for a radiolabeled B7H3 antibody or antigen binding fragment thereof.
  • the invention concerns use of ascorbic acid as a stabilizing agent and/or a scavenger agent for a pharmaceutical composition comprising a radiolabeled B7H3 antibody or antigen binding fragment thereof.
  • the invention concerns use of ascorbic acid as a stabilizing agent and/or a scavenger agent for a pharmaceutical composition according to the invention.
  • the invention concerns a method of treating cancer in an individual, wherein the method comprises a step of administering a therapeutically effective amount of a pharmaceutical composition according to the invention.
  • the invention concerns a method for treating, preventing and/or alleviating the symptoms of a disorder affecting the central nervous system (CNS), such as a neurodegenerative condition and/or disease, an inflammatory disease or cancer, in particular a metastatic cancer, in a subject, wherein said method comprises a step of administration to said subject of a therapeutically effective amount of a pharmaceutical composition according to the invention, and wherein said pharmaceutical composition is delivered into CNS using a device allowing or adapted to provide intra-cerebroventricular administration.
  • CNS central nervous system
  • the invention concerns a method for treating, preventing and/or alleviating the symptoms of a condition in a subject, wherein said condition is characterized by B7H3 antigen or B7H3 antigen expression, and wherein said method comprises a step of administering a therapeutically effective amount of a pharmaceutical composition according to the invention and wherein said pharmaceutical composition is delivered into the central nervous system (CNS) using a device allowing or adapted to provide intra-cerebroventricular administration.
  • CNS central nervous system
  • the invention concerns a method for treating, preventing and/or alleviating the symptoms of a disorder affecting the central nervous system (CNS), such as a neurodegenerative condition and/or disease, an inflammatory disease or cancer, in particular a metastatic cancer, in a subject, wherein said method comprises a step of administration to said subject of a therapeutically effective amount of a pharmaceutical composition according to the invention, and wherein said pharmaceutical composition is delivered into CNS using convection-enhanced delivery (CED).
  • CNS central nervous system
  • CED convection-enhanced delivery
  • the invention concerns a method for treating, preventing and/or alleviating the symptoms of a condition in a subject, wherein said condition is characterized by B7H3 antigen or B7H3 antigen expression, and wherein said method comprises a step of administering a therapeutically effective amount of a pharmaceutical composition according to the invention, and wherein said pharmaceutical composition is delivered into the central nervous system (CNS) using convection-enhanced delivery (CED).
  • the invention concerns the pharmaceutical composition of the invention for use as a medicament.
  • the invention concerns the pharmaceutical composition of the invention for use in the treatment of cancer.
  • the invention concerns the pharmaceutical composition of the invention for use in a treatment comprising intracerebroventricular, intrathecal, intracerebral or intraventricular administration.
  • the invention concerns the pharmaceutical composition of the invention for use in a treatment comprising convection-enhanced delivery (CED).
  • CED convection-enhanced delivery
  • the invention concerns a kit of parts comprising a pharmaceutical composition comprising a radiolabeled B7H3 antibody or antigen binding fragment thereof and ascorbic acid.
  • the invention concerns a kit of parts comprising a pharmaceutical composition according to the invention and ascorbic acid.
  • the invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • B7H3 is in the present application and claims intended to mean a B7H3 antigen, and a B7H3 antibody is intended to mean an antibody capable of binding the B7H3 antigen.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is for delivery to the central nervous system (CNS).
  • CNS central nervous system
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is for intracerebroventricular (ICV), intrathecal, intracerebral or intraventricular administration.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is for convection-enhanced delivery (CED).
  • the invention concerns the pharmaceutical composition, wherein said ascorbic acid is a stabilizing agent and/or a scavenger agent.
  • the invention concerns the pharmaceutical composition, wherein the amount of said ascorbic acid is at least 0.001% (w/w), alternatively 0.005% (w/w), alternatively 0.01% (w/w), alternatively 0.02% (w/w), alternatively 0.03% (w/w), alternatively 0.04% (w/w), alternatively 0.05% (w/w), alternatively 0.06% (w/w), alternatively 0.07% (w/w), alternatively 0.08% (w/w), alternatively 0.09% (w/w), alternatively 0.1% (w/w).
  • the invention concerns the pharmaceutical composition, wherein the amount of said ascorbic acid is at most 10% (w/w), alternatively 9.5% (w/w), alternatively 9% (w/w), alternatively 8.5% (w/w), alternatively 8% (w/w), alternatively 7.5% (w/w), alternatively 7% (w/w), alternatively 6.5% (w/w), alternatively 6% (w/w), alternatively 5.5% (w/w), alternatively 5% (w/w).
  • the invention concerns the pharmaceutical composition, wherein the amount of said ascorbic acid is selected from 0.001-10% (w/w), 0.01-10% (w/w), 0.05-10% (w/w), 0.05-9% (w/w), 0.05-8% (w/w), 0.05-7% (w/w), 0.05-6% (w/w), 0.05-5% (w/w), 0.05-4% (w/w), 0.05-3% (w/w), 0.05-2% (w/w), 0.05-1.5% (w/w) and 0.05-1.3% (w/w).
  • the invention concerns the pharmaceutical composition, wherein the amount of said ascorbic acid is selected from 0.05-0.2% (w/w), 0.05-0.1% (w/w) and 1-1.5% (w/w).
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof comprises light chain CDR sequences according to SEQ ID NO: 1-3 and/or heavy chain CDR sequences according to SEQ ID NO: 4-6.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof comprises a VL sequence according to SEQ ID NO: 7 and/or a VH sequence according to SEQ ID NO: 8.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof comprises a light chain sequence according to SEQ ID NO: 9 and/or a heavy chain sequence according to SEQ ID NO: 10.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is Omburtamab or derived from Omburtamab.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof comprises or is an scFv.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof comprises or is a SADA (a self-assembly disassembly) construct.
  • SADA domains and techniques for using SADA compounds, comprising an antigen binding site in addition to a SADA domain is disclosed in WQ2018/204873, and the disclosure thereof may also be used according to the present invention.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof comprises or is linked to a chelating agent, such as a bifunctional chelating agent.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is, comprises or is linked to a functional group capable of binding radioisotopes, which exists as metallic ions.
  • functional groups include DOTA-groups, DTPA-groups, and HEHA- groups, such as DOTA-hapten, DTPA-hapten, DOTA/HEHA-hapten and/or a HEHA-hapten.
  • DOTA or l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid, contains a central 12- membered tetraaza ring.
  • the DOTA ring structure may be substituted with different organic groups as known in the art and such substituted compounds comprising the DOTA ring structure may also be used according to the invention provided that the substituted compounds retain the ability of binding radioisotopes which exists as metallic ions.
  • One example of such a compound comprising a DOTA ring structure substituted with an organic group is p- aminobenzyl-DOTA (Bn-DOTA).
  • DTPA diethylenetriaminepentaacetic acid
  • DTPA consists of a diethylenetriamine backbone with five carboxymethyl groups, having the molecular formula C14H23N3O10.
  • the DTPA structure may be substituted with different organic groups as known in the art and such substituted compounds comprising the DTPA structure may also be used according to the invention provided that the substituted compounds retain the ability of binding radioisotopes which exists as metallic ions.
  • HEHA or l,4,7,10,13,16-hexaazacyclooctodecan-l,4,7,10,13,16-hexaacetic acid, contains a central 24 membered ring structure.
  • the HEHA structure may be substituted with different organic groups as known in the art and such substituted compounds comprising the HEHA ring structure may also be used according to the invention provided that the substituted compounds retain the ability of binding radioisotopes which exists as metallic ions.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is, comprises or is linked to a DOTA-hapten, DTPA-hapten, DOTA/HEHA-hapten and/or a HEHA-hapten.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof comprises an Fc part.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof does not comprise a Fc part or comprises an inactive or null Fc part.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is IgGl with inactive Fc or lgG4.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is an IgGl heterodimer with inactive Fc.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is labeled with a radioisotope.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is labeled with a radioisotope selected from the group consisting of 124 l, 131 l, 177 Lu, "mTc, 64 Cu, 86 Y, 90 Y, 225 Ac and 89 Zr.
  • the invention concerns the pharmaceutical composition, comprising at least one pharmaceutically acceptable excipient.
  • the invention concerns the pharmaceutical composition, wherein said pharmaceutically acceptable excipient is selected from the group consisting of diluents, carriers, preservatives, buffers and surfactants.
  • the invention concerns the pharmaceutical composition, wherein the pharmaceutically acceptable excipient is selected from the group consisting of sodium phosphate, human serum albumin, sodium chloride, sodium citrate dihydrate, sodium acetate, sodium ascorbate and hydrochloric acid.
  • the invention concerns the pharmaceutical composition comprising sodium phosphate solution, preferably in a concentration of 0.005-5 M, alternatively 0.01-1 M, alternatively 0.02-2 M, alternatively 0.05 M - 0.5 M, alternatively 0.05 M - 0.4 M, alternatively 0.1 M - 0.4 M, alternatively 0.1 M - 0.3 M, alternatively 0.15 M - 0.3 M, alternatively 0.15 M - 0.25 M, alternatively around 0.2 M.
  • the invention concerns the pharmaceutical composition, wherein the sodium phosphate solution is NaHzPC xHzO and/or NazHPC .
  • the invention concerns the pharmaceutical composition
  • the pharmaceutical composition comprising human serum albumin, preferably in a concentration of 0.001-10% w/w, alternatively 0.01-5% w/w, alternatively 0.05-5% w/w, alternatively 0.05-4% w/w, alternatively 0.1-4% w/w, alternatively 0.1-3.5% w/w, alternatively 0.1-3% w/w, alternatively 0.1-2.5% w/w, alternatively 0.2-2.5% w/w, alternatively 0.5-2.5% w/w.
  • the invention concerns the pharmaceutical composition
  • the pharmaceutical composition comprising an amount of human serum albumin selected from about 1% w/w, 1.1% w/w, 1.2% w/w, 1.3% w/w, 1.4% w/w, 1.5% w/w, 1.6% w/w, 1.7% w/w, 1.8% w/w, 1.9% w/w, 2.0% w/w, 2.1% w/w, 2.2% w/w, 2.3% w/w, 2.4% w/w, and 2.5% w/w.
  • the human serum albumin is recombinant human serum albumin.
  • the invention concerns the pharmaceutical composition
  • the pharmaceutical composition comprising sodium chloride, preferably in a concentration of 0.1-200 mM, alternatively 1- 100 mM, alternatively 5-95 mM, alternatively 10-90 mM, alternatively 15-85 mM, alternatively 20-80 mM, alternatively 25-75 mM, alternatively 30-70 mM, alternatively 35-65 mM, alternatively around 60 mM.
  • the invention concerns the pharmaceutical composition
  • the pharmaceutical composition comprising sodium citrate dihydrate, preferably in a concentration of 0.01-100 mM, alternatively 0.1-50 mM, 0.1-30 mM, alternatively 1-25 mM, alternatively 2-20 mM, alternatively 3-18 mM, alternatively 4-17 mM, alternatively 5-15 mM, alternatively 8-15 mM, alternatively 10-15 mM, alternatively 11-14 mM, alternatively around 12.5 mM.
  • the invention concerns the pharmaceutical composition
  • the pharmaceutical composition comprising sodium acetate, preferably in a concentration of 0.01-100 mM, alternatively 1-70 mM, alternatively 2-60 mM, alternatively 5-60 mM, alternatively 5-50 mM, alternatively 10- 50 mM, alternatively 15-45 mM, alternatively 20-40 mM, alternatively 25-35 mM, alternatively around 30 mM.
  • the invention concerns the pharmaceutical composition
  • the pharmaceutical composition comprising sodium ascorbate, preferably in a concentration of 0.1-200 mM, alternatively 1- 100 mM, alternatively 5-95 mM, alternatively 10-90 mM, alternatively 15-85 mM, alternatively 20-80 mM, alternatively 25-75 mM, alternatively 30-70 mM, alternatively 35-65 mM, alternatively around 60 mM.
  • the invention concerns the pharmaceutical composition comprising hydrochloric acid.
  • Hydrochloric acid may be added for adjusting pH.
  • the invention concerns the pharmaceutical composition having a pH between 3-9, alternatively 4-8, alternatively 4.5-8.5, alternatively 5-7, alternatively 5-8, alternatively 5.5-7.5, alternatively 5.5-7, alternatively 6-7, alternatively 6.5- 7, alternatively 6.5-6.8.
  • the invention concerns the pharmaceutical composition, wherein said pharmaceutical composition has an increased stability compared to a pharmaceutical composition not comprising ascorbic acid.
  • the invention concerns the pharmaceutical composition, wherein said stability is increased during labeling, during storage and/or in use.
  • the invention concerns the pharmaceutical composition, wherein the amount of high molecular weight aggregates (HMW) and/or low molecular weight fragments (LMW) is reduced compared to a pharmaceutical composition not comprising ascorbic acid.
  • HMW high molecular weight aggregates
  • LMW low molecular weight fragments
  • the invention concerns the pharmaceutical composition, wherein the amount of HMW and/or LMW is reduced at least by a factor 1.5 compared to a pharmaceutical composition not comprising ascorbic acid.
  • the invention concerns the pharmaceutical composition, wherein the amount of HMW is below 10%, alternatively 9%, alternatively 8%, alternatively 7%.
  • the invention concerns the pharmaceutical composition, wherein the amount of LMW is below 10%, alternatively 9%, alternatively 8%, alternatively 7%, alternatively 6%, alternatively 5%.
  • the invention concerns the pharmaceutical composition, wherein the amount of HMW and/or LMW is measured after a storage period of 96 hours at -80 °C or after a storage period of 120 h at 2 - 8 °C.
  • the invention concerns the pharmaceutical composition, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is the sole active ingredient.
  • the invention concerns the pharmaceutical composition, which is a pharmaceutically acceptable composition.
  • the invention concerns a method of stabilizing a pharmaceutical composition comprising a radiolabeled B7H3 antibody or antigen binding fragment thereof, comprising: a. Producing said B7H3 antibody or antigen binding fragment thereof, b. Radiolabeling said B7H3 antibody or antigen binding fragment thereof, c. Formulating said radiolabeled B7H3 antibody or antigen binding fragment thereof into a pharmaceutical composition, d. Stabilizing said pharmaceutical composition by adding ascorbic acid.
  • the invention concerns a method of stabilizing a pharmaceutical composition comprising a radiolabeled B7H3 antibody or antigen binding fragment thereof, comprising: a. Producing said B7H3 antibody or antigen binding fragment thereof, b. Radiolabeling said B7H3 antibody or antigen binding fragment thereof, c. Providing a stabilized pharmaceutical composition by adding ascorbic acid and optionally additional excipients.
  • the invention concerns the method, wherein the stabilized pharmaceutical composition is a pharmaceutical composition according to the invention.
  • the invention concerns a process for producing a pharmaceutical composition comprising a radiolabeled B7H3 antibody or antigen binding fragment thereof, comprising: a. Producing said B7H3 antibody or antigen binding fragment thereof, b. Radiolabeling said B7H3 antibody or antigen binding fragment thereof, c. Formulating said radiolabeled B7H3 antibody or antigen binding fragment thereof into a pharmaceutical composition, d. Adding ascorbic acid to said pharmaceutical composition.
  • the invention concerns a process for producing a pharmaceutical composition comprising a radiolabeled B7H3 antibody or antigen binding fragment thereof, comprising: a. Producing said B7H3 antibody or antigen binding fragment thereof, b. Radiolabeling said B7H3 antibody or antigen binding fragment thereof, c. Providing a pharmaceutical composition by adding ascorbic acid and optionally additional excipients.
  • the invention concerns the process, wherein the pharmaceutical composition is a pharmaceutical composition according to the invention.
  • the invention concerns the method or the process, wherein the amount of said ascorbic acid is at least 0.001% (w/w), alternatively 0.005% (w/w), alternatively 0.01% (w/w), alternatively 0.02% (w/w), alternatively 0.03% (w/w), alternatively 0.04% (w/w), alternatively 0.05% (w/w), alternatively 0.06% (w/w), alternatively 0.07% (w/w), alternatively 0.08% (w/w), alternatively 0.09% (w/w), alternatively 0.1% (w/w).
  • the invention concerns the method or the process, wherein the amount of said ascorbic acid is at most 10% (w/w), alternatively 9.5% (w/w), alternatively 9% (w/w), alternatively 8.5% (w/w), alternatively 8% (w/w), alternatively 7.5% (w/w), alternatively 7% (w/w), alternatively 6.5% (w/w), alternatively 6% (w/w), alternatively 5.5% (w/w), alternatively 5% (w/w).
  • the invention concerns the method or the process, wherein the amount of said ascorbic acid is selected from 0.001-10% (w/w), 0.01-10% (w/w), 0.05- 10% (w/w), 0.05-9% (w/w), 0.05-8% (w/w), 0.05-7% (w/w), 0.05-6% (w/w), 0.05-5% (w/w), 0.05-4% (w/w), 0.05-3% (w/w), 0.05-2% (w/w), 0.05-1.5% (w/w) and 0.05-1.3% (w/w).
  • the invention concerns the method or the process, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof comprises light chain CDR sequences according to SEQ ID NO: 1-3 and/or heavy chain CDR sequences according to SEQ ID NO: 4-6.
  • the invention concerns the method or the process, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof comprises a VL sequence according to SEQ ID NO: 7 and/or a VH sequence according to SEQ ID NO: 8.
  • the invention concerns the method or the process, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof comprises a light chain sequence according to SEQ ID NO: 9 and/or a heavy chain sequence according to SEQ ID NO: 10.
  • the invention concerns the method or the process, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is Omburtamab or derived from Omburtamab.
  • the invention concerns the method or the process, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof comprises or is an scFv.
  • the invention concerns the method or the process, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof comprises or is a SADA construct.
  • the invention concerns the method or the process, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof comprises or is linked to a chelating agent, such as a bifunctional chelating agent.
  • a chelating agent such as a bifunctional chelating agent.
  • the invention concerns the method or the process, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is, comprises or is linked to a DOTA-group, DTPA-group, DOTA/HEHA-group and/or a HEHA-group, such as DOTA-hapten, DTPA-hapten, DOTA/HEHA-hapten and/or a HEHA-hapten.
  • the invention concerns the method or the process, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is labeled with a radioisotope.
  • the invention concerns the method or the process, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is labeled with a radioisotope selected from the group consisting of 124 l, 131 l, 177 Lu, "mTc, 64 Cu, 86 Y, 90 Y, 225 Ac and 89 Zr.
  • the invention concerns the method or the process, wherein said pharmaceutical composition comprises at least one pharmaceutically acceptable excipient.
  • the invention concerns the method or the process, wherein said pharmaceutical composition comprises a pharmaceutically acceptable excipient selected from the group consisting of diluents, carriers, preservatives, buffers and surfactants.
  • the invention concerns the method or the process, wherein said pharmaceutical composition has an increased stability compared to a pharmaceutical composition not comprising ascorbic acid.
  • the invention concerns the method or the process, wherein the stability of said pharmaceutical composition is increased during labeling, during storage and/or in use.
  • the invention concerns the method or the process, wherein the amount of HMW and/or LMW in said pharmaceutical composition is reduced compared to a pharmaceutical composition not comprising ascorbic acid.
  • the invention concerns the method or the process, wherein the amount of HMW and/or LMW in said pharmaceutical composition is reduced at least by a factor 1.5 compared to a pharmaceutical composition not comprising ascorbic acid. According to an embodiment, the invention concerns the method or the process, wherein the amount of HMW in said pharmaceutical composition is below 10%, alternatively 9%, alternatively 8%, alternatively 7%.
  • the invention concerns the method or the process, wherein the amount of LMW in said pharmaceutical composition is below 10%, alternatively 9%, alternatively 8%, alternatively 7%, alternatively 6%, alternatively 5%.
  • the invention concerns the method or the process, wherein the amount of HMW and/or LMW in said pharmaceutical composition is measured after a storage period of 96 hours at -80 °C or after a storage period of 120 h at 2 - 8 °C.
  • the invention concerns the method or the process, wherein said radiolabeled B7H3 antibody or antigen binding fragment thereof is the sole active ingredient in said pharmaceutical composition.
  • the invention concerns the method or the process, wherein in said pharmaceutical composition is a pharmaceutically acceptable composition.
  • the invention concerns use of ascorbic acid as a stabilizing agent and/or a scavenger agent.
  • the invention concerns use of ascorbic acid as a stabilizing agent and/or a scavenger agent for a radiolabeled B7H3 antibody or antigen binding fragment thereof.
  • the invention concerns use of ascorbic acid as a stabilizing agent and/or a scavenger agent for a pharmaceutical composition comprising a radiolabeled B7H3 antibody or antigen binding fragment thereof.
  • the invention concerns use of ascorbic acid as a stabilizing agent and/or a scavenger agent for a pharmaceutical composition according to the invention.
  • the invention concerns a method of treating cancer in an individual, wherein the method comprises a step of administering a therapeutically effective amount of a pharmaceutical composition according to the invention.
  • the invention concerns a method for treating, preventing and/or alleviating the symptoms of a disorder affecting the central nervous system (CNS), such as a neurodegenerative condition and/or disease, an inflammatory disease or cancer, in particular a metastatic cancer, in a subject, wherein said method comprises a step of administration to said subject of a therapeutically effective amount of a pharmaceutical composition according to the invention, and wherein said pharmaceutical composition is delivered into CNS using a device allowing or adapted to provide intra-cerebroventricular administration.
  • CNS central nervous system
  • the invention concerns a method for treating, preventing and/or alleviating the symptoms of a condition in a subject, wherein said condition is characterized by B7H3 antigen or B7H3 antigen expression, and wherein said method comprises a step of administering a therapeutically effective amount of a pharmaceutical composition according to the invention and wherein said pharmaceutical composition is delivered into the central nervous system (CNS) using a device allowing or adapted to provide intra-cerebroventricular administration.
  • CNS central nervous system
  • the invention concerns a method for treating, preventing and/or alleviating the symptoms of a disorder affecting the central nervous system (CNS), such as a neurodegenerative condition and/or disease, an inflammatory disease or cancer, in particular a metastatic cancer, in a subject, wherein said method comprises a step of administration to said subject of a therapeutically effective amount of a pharmaceutical composition according to the invention, and wherein said pharmaceutical composition is delivered into CNS using convection-enhanced delivery (CED).
  • CNS central nervous system
  • CED convection-enhanced delivery
  • the invention concerns a method for treating, preventing and/or alleviating the symptoms of a condition in a subject, wherein said condition is characterized by B7H3 antigen or B7H3 antigen expression, and wherein said method comprises a step of administering a therapeutically effective amount of a pharmaceutical composition according to the invention and wherein said pharmaceutical composition is delivered into the central nervous system (CNS) using convection-enhanced delivery (CED).
  • CNS central nervous system
  • CED convection-enhanced delivery
  • the invention concerns the method, wherein said device comprises a catheter.
  • the invention concerns the method, wherein said device comprises a reservoir, such as an Ommaya reservoir.
  • the invention concerns the method, wherein said cancer is a brain cancer, a central nervous system (CNS) lymphoma or a CNS cancer.
  • said cancer is a brain cancer, a central nervous system (CNS) lymphoma or a CNS cancer.
  • the invention concerns the method, wherein said cancer is selected among a carcinoma, a sarcoma, a lymphoma and a leukemia.
  • the invention concerns the method, wherein said cancer is selected among neuroblastoma, medulloblastoma, glioblastoma, small cell lung cancer, nonsmall cell carcinoma, a pediatric sarcoma, an adult sarcoma, breast cancer, liver cancer, melanoma, non-small cell lung carcinoma, lung adenocarcinoma or a gastrointestinal cancer.
  • said cancer is selected among neuroblastoma, medulloblastoma, glioblastoma, small cell lung cancer, nonsmall cell carcinoma, a pediatric sarcoma, an adult sarcoma, breast cancer, liver cancer, melanoma, non-small cell lung carcinoma, lung adenocarcinoma or a gastrointestinal cancer.
  • the invention concerns the method, wherein said cancer is an ovarian cancer or gastric cancer.
  • the invention concerns the method, wherein said pharmaceutical composition is administered intracerebroventricularly, intrathecally, intracerebrally or intraventricularly.
  • the invention concerns the method, wherein said condition or cancer is characterized by overexpression of B7H3.
  • the invention concerns the pharmaceutical composition for use as a medicament.
  • the invention concerns the pharmaceutical composition for use in the treatment of cancer.
  • the invention concerns the pharmaceutical composition for use in a method of treating according to the invention.
  • the invention concerns the pharmaceutical composition for use according to the invention, wherein said cancer is a brain cancer, a central nervous system (CNS) lymphoma or a CNS cancer.
  • said cancer is a brain cancer, a central nervous system (CNS) lymphoma or a CNS cancer.
  • the invention concerns the pharmaceutical composition for use according to the invention, wherein said cancer is selected among a carcinoma, a sarcoma, a lymphoma and a leukemia.
  • the invention concerns the pharmaceutical composition for use according to the invention, wherein said cancer is selected among neuroblastoma, medulloblastoma, glioblastoma, small cell lung cancer, non-small cell carcinoma, a pediatric sarcoma, an adult sarcoma, breast cancer, liver cancer, melanoma, non-small cell lung carcinoma, lung adenocarcinoma or a gastrointestinal cancer.
  • the invention concerns the pharmaceutical composition for use according to the invention, wherein said cancer is an ovarian cancer or gastric cancer.
  • the invention concerns the pharmaceutical composition for use according to the invention, wherein said pharmaceutical composition is administered intracerebroventricularly, intrathecally, intracerebrally or intraventricularly.
  • the invention concerns the pharmaceutical composition for use in a treatment comprising intracerebroventricular, intrathecal, intracerebral or intraventricular administration.
  • the invention concerns the pharmaceutical composition for use according to the invention, wherein said pharmaceutical composition is administered using convection-enhanced delivery (CED).
  • CED convection-enhanced delivery
  • the invention concerns the pharmaceutical composition for use in a treatment comprising convection-enhanced delivery (CED).
  • CED convection-enhanced delivery
  • the invention concerns a kit of parts comprising a pharmaceutical composition comprising a radiolabeled B7H3 antibody or antigen binding fragment thereof and ascorbic acid.
  • the invention concerns a kit of parts comprising a pharmaceutical composition according to the invention and ascorbic acid.
  • the invention concerns the kit of parts, further comprising instructions for use.
  • Ascorbic acid is an organic acid with a ring structure similar to glucose. It may exist in two forms in humans, L-ascorbate (reduced form) and Dehydroascorbate (oxidized form). Ascorbic acid might be provided in mineral ascorbate form, such as sodium ascorbate, calcium ascorbate or other mineral ascorbates.
  • mineral ascorbate form such as sodium ascorbate, calcium ascorbate or other mineral ascorbates.
  • a potential antibody used in clinical trials for brain cancer treatment in children is the radiolabeled omburtamab ( 131 l-omburtamab) targeting the B7-H3 antigen.
  • the application of the radiolabeled compound may be performed via intracerebral injection into the cerebrospinal fluid (CSF).
  • the 131 l-omburtamab apparently distributes via the CSF and accumulates in the tumor tissue leading to a precise radiation damage of the tumor tissue.
  • the antibody may be used for further studies with the radiometal 177 Lu and the antibody conjugate DTPA-omburtamab.
  • antigen binding fragments encompassed within the term "antigen binding fragment thereof" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VH, VL, CHI and CL domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VH and VL domains of a single arm of an antibody, (v) a dAb fragment, which comprises a single variable domain; and (vi) an isolated complementarity determining region (CDR).
  • a Fab fragment a monovalent fragment consisting of the VH, VL, CHI and CL domains
  • F(ab')2 fragment a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region
  • an "antigen binding fragment”, as described herein, is or comprises such a single chain antibody. In some embodiments, an "antigen binding fragment" is or comprises a diabody.
  • Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites.
  • an antigen binding fragment is or comprises a single chain "linear antibody” comprising a pair of tandem Fv segments (VH-CHT -VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen binding regions.
  • an antigen binding fragment may have structural elements characteristic of chimeric or humanized antibodies. In general, humanized antibodies are human.
  • a SADA construct may be defined as a polypeptide conjugate comprising: (i) a self-assembly disassembly (SADA) domain or SADA polypeptide and
  • the SADA construct further comprises a second binding domain that binds to a second target, which is different from or identical to the first target.
  • the first and/or second binding domain is or comprises an antibody, antibody component, or antigen binding fragment.
  • the first and second binding domains are part of a bispecific antibody agent.
  • the bispecific antibody agent comprises a first binding domain that binds a tumor target and a second binding domain that binds a metal-Bn-DOTA.
  • the SADA construct may be characterized by one or more multimerization dissociation constants (KD).
  • KD multimerization dissociation constants
  • the SADA construct may be constructed and arranged so that it adopts a first multimerization state and one or more higher-order multimerization states, wherein: the first multimerization state is less than about 70 kDa in size, at least one of the higher-order multimerization states is a homo-tetramer or higher-order homo-multimer greater than 150 kDa in size, wherein the higher-order homo-multimerized conjugate is stable in aqueous solution when the conjugate is present at a concentration above the SADA polypeptide KD, and the conjugate transitions from the higher-order multimerization state(s) to the first multimerization state under physiological conditions when the concentration of the conjugate is below the SADA polypeptide KD.
  • a SADA domain is composed of multimerization domains which are each composed of helical bundles that associate in a parallel or anti-parallel orientation.
  • a SADA domain is selected from the group of one of the following human proteins: p53, p63, p73, heterogeneous nuclear Ribonucleoprotein (hnRNPC) C, or N- terminal domain of Synaptosomal-associated protein 23 (SNAP-23), Stefin B (Cystatin B), Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4), Cyclin-D-related protein (CBFA2T1), or variants or fragments thereof.
  • human proteins p53, p63, p73, heterogeneous nuclear Ribonucleoprotein (hnRNPC) C, or N- terminal domain of Synaptosomal-associated protein 23 (SNAP-23), Stefin B (Cystatin B), Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4), Cyclin
  • a SADA polypeptide is or comprises a tetramerization domain of p53, p63, p73, hnRNPC, SNAP-23, Stefin B, KCNQ4, or CBFA2T1.
  • a SADA polypeptide is or comprises a sequence that is at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a sequence of p53, p63, p73, hnRNPC, SNAP-23, Stefin B, KCNQ4, or CBFA2T1.
  • the present disclosure provides various conjugates comprising a SADA domain linked to one or more binding domains.
  • such conjugates are characterized in that they multimerize to form a complex of a desired size under relevant conditions (e.g., in a solution in which the conjugate is present above a threshold concentration or pH and/or when present at a target site characterized by a relevant level or density of receptors for the payload), and disassemble to a smaller form under other conditions (e.g., absent the relevant environmental multimerization trigger).
  • SADA constructs, SADA domains and SADA polypeptides are further described and exemplified in WO2018204873.
  • the antibody or antigen binding fragment thereof comprises a chelating agent, such as a bifunctional chelating agent.
  • the antibody or antigen binding fragment thereof is or comprises a DOTA-group, DTPA-group, DOTA/HEHA-group and/or a HEHA-group, such as DOTA-hapten, DTPA-hapten, DOTA/HEHA- hapten and/or a HEHA-hapten.
  • the antibody or antigen binding fragment thereof is linked to a chelating agent, such as a bifunctional chelating agent.
  • the antibody or antigen binding fragment thereof is linked to a DOTA- group, DTPA-group, DOTA/HEHA-group and/or a HEHA-group, such as DOTA-hapten, hapten, DOTA/HEHA-hapten and/or a HEHA-hapten.
  • DOTA- group DTPA-group
  • DOTA/HEHA-group a HEHA-group
  • DOTA-hapten hapten
  • hapten DOTA/HEHA-hapten
  • HEHA-hapten e.g., HEHA-hapten
  • suitable chelating agents, groups and haptens are described in W02019010299, W00059896 and WO0168618.
  • Convection-enhanced delivery is a form of direct delivery that bypasses the bloodbrain barrier, producing high local drug concentrations with limited systemic exposure. Convection-enhanced delivery (CED) generates a pressure gradient at the tip of an infusion catheter to deliver therapeutics directly through the interstitial spaces of the central nervous system.
  • Intracerebroventricular (ICV) administration is an injection technique of substances directly into the cerebrospinal fluid in cerebral ventricles in order to bypass the blood brain barrier.
  • Intracerebroventricular (ICV) administration helps bypass the blood-brain barrier by permitting high concentrations of a drug to directly reach the central compartment of the brain.
  • ICV administration an external drug reservoir may be used or a drug reservoir may be implanted subcutaneously in the scalp.
  • a catheter may be used to connect the reservoir to the ventricular space in the brain.
  • Fig. 1 shows high molecular weight aggregates (HMW) and low molecular weight fragments (LMW) content in compositions comprising 131 l-omburtamab, rHSA and no ascorbic acid stored at -80 °C at time 0 hours.
  • HMW high molecular weight aggregates
  • LMW low molecular weight fragments
  • Fig. 2 shows HMW and LMW content in compositions comprising 131 l-omburtamab, rHSA and no ascorbic acid stored at -80 °C at time 96 hours.
  • Fig. 3 shows HMW and LMW content in compositions comprising 131 l-omburtamab, rHSA and 0.1% ascorbic acid stored at -80 °C at time 0 hours.
  • Fig. 4 shows HMW and LMW content in compositions comprising 131 l-omburtamab, rHSA and 0.1% ascorbic acid stored at -80 °C at time 96 hours.
  • Fig. 5 shows LMW content in a composition comprising 177 Lu-DTPA-omburtamab, HSA and 0.8% ascorbic acid stored at 2 - 8°C at time 0 hours.
  • Fig. 6 shows LMW content in a composition comprising 177 Lu-DTPA-omburtamab, HSA and 0.8% ascorbic acid stored at 2 - 8°C at time 120 hours.
  • Fig. 7 shows HMW and LMW content in a composition comprising 177 Lu-DTPA-omburtamab and 1.2% ascorbic acid stored at -80°C at time 0 hours.
  • Fig. 8 shows HMW and LMW content in a composition comprising 177 Lu-DTPA-omburtamab and 1.2% ascorbic acid stored at -80°C at time 124 hours.
  • Example 1 131 l-omburtamab for intracerebroventricular (ICV) administration
  • composition comprising 131 l-omburtamab drug product with and without ascorbic acid was measured and compared. Content of 131 l-omburtamab drug product is shown in Table 1.
  • Table 1 Content of 131 l-omburtamab drug product for ICV administration.
  • compositions comprising 131 l-omburtamab ICV drug product were prepared.
  • Composition 1 comprised 131 l-omburtamab drug product with 2% (w/w) recombinant human serum albumin (rHSA) as stabilizing agent.
  • Composition 2 comprised 131 l-omburtamab drug product with 2% (w/w) rHSA as stabilizing agent and 0.1% (w/w) ascorbic acid. The stability of these compositions was compared and analyzed after a storage time of 96 h at -80°C. The results are summarized in Table 2 and Figures 1-4.
  • Table 2 Summary of stability studies of 131 l-omburtamab including ascorbic acid in final drug product formulation.
  • EOS End of Synthesis
  • HMW High molecular weight aggregates
  • LMW Low molecular weight fragments.
  • Addition of ascorbic acid shows a clear effect regarding the evolution of by-products.
  • the evolving by-products are high molecular weight aggregates (HMW) as well as low molecular weight fragments (LMW).
  • HMW high molecular weight aggregates
  • LMW low molecular weight fragments
  • the increase of HMW for Composition 1 (no ascorbic acid) was 7.1% and the increase of LMW was 4.3%.
  • Composition 2 When adding ascorbic acid to the composition (Composition 2) the in-growth of by-products after 96 h could be reduced.
  • the development of both HMW and the LMW were reduced.
  • the increase was reduced to 0.8% for HMW and 2.9% for LMW, respectively.
  • Example 2 131 l-omburtamab for convection enhanced delivery (CED)
  • compositions comprising 131 l-omburtamab drug product with and without ascorbic acid was measured and compared.
  • Content of 131 l-omburtamab CED drug product is shown in Table 3.
  • compositions comprising 177 Lu-DTPA-omburtamab drug product and different amounts of ascorbic acid was measured and compared. Content of 177 Lu-DTPA-omburtamab drug product is shown in Table 4.
  • Composition A comprising 177 Lu-DTPA-omburtamab was prepared.
  • Composition A comprised 177 Lu-DTPA-omburtamab drug product with 5% (w/w) human serum albumin (HSA) as stabilizing agent and 0.8% (w/w) ascorbic acid.
  • HSA human serum albumin
  • the stability of the product was evaluated over a storage period of 120 h at 2 - 8°C. The results are summarized in Table 5 and Figures 5-6.
  • Table 5 Summary of stabi ity studies of 177 Lu-DTPA-omburtamab including HSA and ascorbic acid in final drug product formulation. EOS: End of Synthesis; LMW: Low molecular weight fragments.
  • Composition B comprising 177 Lu-DTPA-omburtamab was prepared.
  • Composition B comprised 177 Lu-DTPA-omburtamab drug product with 1.2% (w/w) ascorbic acid.
  • the stability of the product was evaluated over a storage period of 124 h at -80°C. The results are summarized in Table 6 and Figures 7-8.
  • Table 6 Summary of stability studies of 177 Lu-DTPA-omburtamab including ascorbic acid in final drug product formulation.
  • EOS End of Synthesis; HMW: High molecular weight aggregates; LMW: Low molecular weight fragments
  • the stabilizing/scavenging effect of ascorbic acid seem to be present for compositions comprising 177 Lu-DTPA-omburtamab as well. Addition of ascorbic acid leads to a low evolution of HMWs and LMWs in the tested compositions. The amount of HMWs and LMWs does not reaches the upper value of the specification limits (10% LMW/HMW).
  • SEQ ID NO. 1 Anti-B7H3 Light chain CDR-1
  • SEQ ID NO. 2 Anti-B7H3 Light chain CDR-2
  • SEQ ID NO. 3 Anti-B7H3 Light chain CDR-3
  • SEQ ID NO. 4 Anti-B7H3 Heavy chain CDR-1
  • SEQ ID NO. 8 Anti-B7H3 VH

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Abstract

La présente invention concerne des compositions pharmaceutiques comprenant un anticorps B7H3 radiomarqué ou un fragment de liaison à l'antigène de celui-ci et de l'acide ascorbique, des méthodes de stabilisation de compositions pharmaceutiques et l'utilisation de l'acide ascorbique en tant qu'agent stabilisant et/ou agent de piégeage.
PCT/DK2022/050018 2021-02-08 2022-02-07 Utilisation d'acide ascorbique comme agent stabilisant pour des anticorps anti-b7-h3 WO2022167052A1 (fr)

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WO2023110044A1 (fr) * 2021-12-15 2023-06-22 Y-Mabs Therapeutics, Inc. Formulations comprenant un complexe sada

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