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WO2025113598A9 - Composition pharmaceutique stable d'anticorps mélangés - Google Patents

Composition pharmaceutique stable d'anticorps mélangés

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Publication number
WO2025113598A9
WO2025113598A9 PCT/CN2024/135436 CN2024135436W WO2025113598A9 WO 2025113598 A9 WO2025113598 A9 WO 2025113598A9 CN 2024135436 W CN2024135436 W CN 2024135436W WO 2025113598 A9 WO2025113598 A9 WO 2025113598A9
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
aqueous pharmaceutical
antibody
polysorbate
histidine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/135436
Other languages
English (en)
Chinese (zh)
Other versions
WO2025113598A1 (fr
Inventor
周兵兵
张乐
丛日圆
安振明
刘骏
孙丽霞
杨琛
张道星
于越
叶红燕
李道远
王庆民
孙波
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Qilu Pharmaceutical Co Ltd
Original Assignee
Qilu Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Qilu Pharmaceutical Co Ltd filed Critical Qilu Pharmaceutical Co Ltd
Publication of WO2025113598A1 publication Critical patent/WO2025113598A1/fr
Publication of WO2025113598A9 publication Critical patent/WO2025113598A9/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to a stable pharmaceutical composition containing mixed antibodies of anti-PD-1 and anti-CTLA-4 and uses thereof, belonging to the field of biotechnology.
  • Programmed death receptor-1 (PD1 or PD-1) is a 288-amino acid protein receptor expressed on activated T and B cells, natural killer cells, and monocytes. Binding to the PD-1 ligands PD-L1 or PD-L2 activates the PD-1 inhibitory signal, thereby suppressing T cell-mediated immune responses against tumor cells. To counteract this PD-1 pathway-mediated suppression of anti-tumor immune responses, several companies have developed monoclonal antibodies that bind to human PD-1 and block the interaction between PD-1 and its ligands. Immune checkpoint therapies targeting the programmed death receptor 1 (PD-1) axis have led to breakthrough improvements in clinical responses in a variety of human cancers.
  • Cytotoxic T lymphocyte-associated protein 4 (CTLA4 or CTLA-4) is a member of the immunoglobulin superfamily and consists of an extracellular V region, a transmembrane region, and a cytoplasmic region.
  • CTLA-4 shares homology with the co-stimulatory molecule receptor CD28 on the surface of T cells, and the two compete for binding to their ligands B7-1 (CD80) and B7-2 (CD86). These ligands are mainly expressed on the surface of antigen-presenting cells.
  • CTLA-4 is usually expressed on the surface of regulatory T cells (Treg) and conventional T cells in an activated state. After binding to B7 molecules, it inhibits the activation of T cells, participates in the negative regulation of immune responses, acts as an immune checkpoint, and downregulates immune responses. Therefore, CTLA-4 plays a very important role in immune regulation.
  • ZPML265 is a hybrid antibody drug formulation composed of a recombinant humanized IgG1 monoclonal antibody targeting human CTLA-4 and a recombinant humanized IgG4 monoclonal antibody targeting human PD-1. These two different antibodies are produced by a single host cell. This hybrid antibody can simultaneously and specifically bind to CTLA-4 and PD-1, thereby blocking the immune checkpoint signaling pathways between CTLA-4 and B7-1/B7-2, and between PD-1 and PD-L1. This relieves the inhibitory effects of these two pathways on T lymphocytes, restoring their functional activity and anti-tumor immune responses, thereby enabling the body to fight and kill tumors.
  • hybrid antibodies Compared to traditional monoclonal antibodies, hybrid antibodies offer improved safety and tolerability, are easy to administer, offer significant efficacy, and exhibit significantly superior efficacy compared to single antibodies. Furthermore, compared to bispecific antibodies, hybrid antibody combinations require less time to develop. Furthermore, the development of higher-concentration antibody formulations can shorten injection times and reduce injection volumes, increasing patient compliance. This can also reduce the frequency of antibody administration and improve production and storage efficiency. However, due to their large molecular weight and complex structure, antibody drugs are susceptible to degradation, aggregation, and undesirable chemical modifications, making them unstable. Hybrid antibodies, in particular, exist as a mixture of two antibodies at low concentrations. Developing high-concentration formulations presents the challenge of maintaining appropriate activity and delivery parameters at higher antibody or protein concentrations. Currently, there is an urgent need to develop stable pharmaceutical compositions at both low and high concentrations that are suitable for the production and administration of hybrid antibodies, maintain stability during storage and subsequent use, and achieve enhanced therapeutic efficacy.
  • the present disclosure aims to provide a pharmaceutical composition of mixed antibodies that is suitable for transportation and storage and has high long-term stability.
  • the present disclosure provides an aqueous pharmaceutical composition containing a mixed anti-CTLA-4 and anti-PD-1 antibody, wherein the pharmaceutical composition comprises the mixed antibody, a buffer, a stabilizer, and a surfactant.
  • the heavy chain amino acid sequence of the anti-CTLA-4 antibody is as shown in SEQ ID NO:1
  • the light chain amino acid sequence of the anti-CTLA-4 antibody is as shown in SEQ ID NO:2
  • the heavy chain amino acid sequence of the anti-PD-1 antibody is as shown in SEQ ID NO:3
  • the light chain amino acid sequence of the anti-PD-1 antibody is as shown in SEQ ID NO:4.
  • the molar ratio of anti-CTLA-4 antibody to anti-PD-1 antibody in the antibody cocktail is about 1:2.
  • the total concentration of the mixed antibodies in the pharmaceutical composition is about 20-200 mg/ml.
  • the mixed antibody is at a low concentration in the pharmaceutical composition, for example, about 20-30 mg/ml, including but not limited to the following concentrations: about 20 mg/ml, 21 mg/ml, 22 mg/ml, 23 mg/ml, 24 mg/ml, 25 mg/ml, 26 mg/ml, 27 mg/ml, 28 mg/ml, 29 mg/ml, 30 mg/ml or any value in between.
  • the hybrid antibody is at a high concentration in the pharmaceutical composition, for example, about 100-200 mg/ml, including but not limited to the following concentrations: about 100 mg/ml, 105 mg/ml, 110 mg/ml, 115 mg/ml, 120 mg/ml, 125 mg/ml, 130 mg/ml, 135 mg/ml, 140 mg/ml, 145 mg/ml, 150 mg/ml, 155 mg/ml, 160 mg/ml, 165 mg/ml, 170 mg/ml, 175 mg/ml, 180 mg/ml, 185 mg/ml, 190 mg/ml, 195 mg/ml, 200 mg/ml or any value between any two numbers.
  • the buffer is selected from acetic acid-sodium hydroxide, histidine-hydrochloric acid, and histidine-acetic acid, and its concentration is about 5-50 mM, preferably about 10-20 mM, and more preferably about 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM or any value in between any two numbers.
  • the stabilizer is selected from sucrose or trehalose, and its concentration is about 50-100 mg/ml, preferably about 60-100 mg/ml, more preferably about 60 mg/ml, 65 mg/ml, 70 mg/ml, 75 mg/ml, 80 mg/ml, 85 mg/ml, 90 mg/ml, 95 mg/ml, 100 mg/ml or any value in between.
  • the surfactant is selected from polysorbate 20, polysorbate 80 and poloxamer 188, and its concentration is about 0.1-2 mg/ml, preferably about 0.1-1 mg/ml, more preferably about 0.1 mg/ml, 0.2 mg/ml, 0.3 mg/ml, 0.4 mg/ml, 0.5 mg/ml, 0.6 mg/ml, 0.7 mg/ml, 0.8 mg/ml, 0.9 mg/ml, 1 mg/ml or any value in between.
  • the pH of the pharmaceutical composition is in the range of about 4.0-6.0, preferably in the range of about 4.7-5.6, and more preferably in the range of about 5.0-5.4.
  • the pharmaceutical composition further comprises an antioxidant and/or a diffusing agent.
  • the antioxidant is selected from methionine and its concentration is about 0-50 mM, preferably about 5-50 mM, and more preferably about 10 mM.
  • the spreading agent is selected from hyaluronidase, and its concentration is about 0-4000 IU/ml, preferably about 500-4000 IU/ml, and more preferably about 2000 IU/ml.
  • the pharmaceutical composition may optionally further comprise arginine hydrochloride at a concentration of about 0-150 mM, preferably about 20-150 mM, and more preferably about 100 mM.
  • the low-concentration aqueous pharmaceutical composition disclosed herein comprises about 20-30 mg/ml of a mixed antibody; about 50-100 mg/ml of sucrose or about 50-100 mg/ml of trehalose; about 0.1-2 mg/ml of polysorbate 80 or about 0.1-2 mg/ml of polysorbate 20 or about 0.1-2 mg/ml of poloxamer 188; about 5-50 mM of acetic acid-sodium hydroxide or about 5-50 mM of histidine-hydrochloric acid or about 5-50 mM of histidine-acetic acid; wherein the pH of the aqueous pharmaceutical composition is about 4.0-6.0.
  • the low-concentration aqueous pharmaceutical composition described in the present disclosure comprises about 20-30 mg/ml of the mixed antibody; about 80-100 mg/ml of sucrose or about 80-100 mg/ml of trehalose; about 0.1-0.5 mg/ml of polysorbate 80 or about 0.1-0.5 mg/ml of polysorbate 20 or about 0.1-0.5 mg/ml of poloxamer 188; about 10-50 mM acetic acid-sodium hydroxide or about 10-50 mM histidine-hydrochloric acid or about 10-50 mM histidine-acetic acid; wherein the pH of the aqueous pharmaceutical composition is about 4.7-5.3.
  • the low-concentration aqueous pharmaceutical composition of the present disclosure comprises a component selected from the following:
  • Aqueous pharmaceutical composition A about 20 mg/ml of mixed antibody, about 50 mg/ml of sucrose, about 0.1 mg/ml of polysorbate 20, about 5 mM acetic acid-sodium hydroxide, pH about 4.0;
  • Aqueous pharmaceutical composition B about 20 mg/ml of mixed antibody, about 100 mg/ml of sucrose, about 2 mg/ml of polysorbate 20, about 50 mM acetic acid-sodium hydroxide, pH about 5.3;
  • Aqueous pharmaceutical composition C about 25 mg/ml of the mixed antibody, about 60 mg/ml of sucrose, about 0.3 mg/ml of polysorbate 20, about 10 mM acetic acid-sodium hydroxide, pH about 5.8;
  • Aqueous pharmaceutical composition D about 25 mg/ml of mixed antibody, about 70 mg/ml of sucrose, about 0.5 mg/ml of polysorbate 20, about 20 mM acetic acid-sodium hydroxide, pH about 5.2;
  • Aqueous pharmaceutical composition E about 25 mg/ml of the mixed antibody, about 90 mg/ml of sucrose, about 0.2 mg/ml of polysorbate 20, about 10 mM acetic acid-sodium hydroxide, pH about 5.0;
  • Aqueous pharmaceutical composition F about 25 mg/ml of the mixed antibody, about 100 mg/ml of sucrose, about 1 mg/ml of polysorbate 20, about 30 mM acetic acid-sodium hydroxide, pH about 6.0;
  • Aqueous pharmaceutical composition G about 30 mg/ml of mixed antibody, about 80 mg/ml of sucrose, about 0.6 mg/ml of polysorbate 20, about 20 mM acetic acid-sodium hydroxide, pH about 4.7;
  • Aqueous pharmaceutical composition H about 30 mg/ml of mixed antibody, about 100 mg/ml of sucrose, about 0.4 mg/ml of polysorbate 20, about 40 mM of acetic acid-sodium hydroxide, pH about 5.6.
  • the high-concentration aqueous pharmaceutical composition disclosed herein comprises about 100-200 mg/ml of a mixed antibody; about 50-100 mg/ml of sucrose or about 50-100 mg/ml of trehalose; about 0.1-2 mg/ml of polysorbate 80 or about 0.1-2 mg/ml of polysorbate 20 or about 0.1-2 mg/ml of poloxamer 188; about 5-50 mM of acetic acid-sodium hydroxide or about 5-50 mM of histidine-hydrochloric acid or about 5-50 mM of histidine-acetic acid; wherein the pH of the aqueous pharmaceutical composition is about 4.0-6.0; and optionally, further comprises about 0-50 mM of methionine, and/or, about 0-4000 IU/ml of hyaluronidase, and/or, about 0-150 mM of arginine hydrochloride.
  • the high-concentration aqueous pharmaceutical composition described in the present disclosure comprises about 100-200 mg/ml of the mixed antibody; about 50-100 mg/ml of sucrose or about 50-100 mg/ml of trehalose; about 0.1-2 mg/ml of polysorbate 80 or about 0.1-2 mg/ml of polysorbate 20 or about 0.1-2 mg/ml of poloxamer 188; about 5-50 mM of acetic acid-sodium hydroxide or about 5-50 mM of histidine-hydrochloric acid or about 5-50 mM of histidine-acetic acid; about 5-50 mM of methionine; about 500-4000 IU/ml of hyaluronidase; wherein the pH of the aqueous pharmaceutical composition is about 4.0-6.0; and optionally, further comprises about 20-150 mM of arginine hydrochloride.
  • the high-concentration aqueous pharmaceutical composition disclosed herein comprises about 100-200 mg/ml of the mixed antibody; about 60-90 mg/ml of sucrose or about 60-90 mg/ml of trehalose; about 0.2-1 mg/ml of polysorbate 80 or about 0.2-1 mg/ml of polysorbate 20 or about 0.2-1 mg/ml of poloxamer 188; about 10-20 mM acetic acid-sodium hydroxide or about 10-20 mM histidine-hydrochloric acid or about 10-20 mM histidine-acetic acid; about 10 mM methionine; about 2000 IU/ml of hyaluronidase; wherein the pH of the aqueous pharmaceutical composition is about 5.0-5.8; and optionally, further comprises about 100 mM arginine hydrochloride.
  • the high-concentration aqueous pharmaceutical composition of the present disclosure comprises a component selected from the following:
  • Aqueous pharmaceutical composition I about 100 mg/ml of mixed antibody, about 50 mg/ml of sucrose, about 0.2 mg/ml of polysorbate 20, about 10 mM histidine-hydrochloric acid, pH about 5.0;
  • Aqueous pharmaceutical composition J about 100 mg/ml of mixed antibody, about 82 mg/ml of sucrose, about 0.8 mg/ml of polysorbate 20, about 15 mM histidine-hydrochloric acid, pH about 5.4;
  • Aqueous pharmaceutical composition K about 100 mg/ml of mixed antibody, about 90 mg/ml of sucrose, about 1.5 mg/ml of polysorbate 20, about 40 mM histidine-hydrochloric acid, pH about 5.6;
  • Aqueous pharmaceutical composition L about 120 mg/ml of mixed antibody, about 80 mg/ml of sucrose, about 0.4 mg/ml of polysorbate 20, about 13 mM histidine-hydrochloric acid, pH about 5.0;
  • Aqueous pharmaceutical composition M about 120 mg/ml of the mixed antibody, about 70 mg/ml of sucrose, about 0.6 mg/ml of polysorbate 20, about 10 mM of histidine-HCl, about 10 mM of methionine, pH about 5.6;
  • Aqueous pharmaceutical composition N about 120 mg/ml of mixed antibody, about 63 mg/ml of sucrose, about 0.5 mg/ml of polysorbate 20, about 18 mM histidine-HCl, about 10 mM methionine, pH about 5.4;
  • Aqueous pharmaceutical composition O about 120 mg/ml of the mixed antibody, about 90 mg/ml of sucrose, about 1 mg/ml of polysorbate 20, about 20 mM histidine-HCl, about 10 mM methionine, pH about 5.0;
  • Aqueous pharmaceutical composition P about 150 mg/ml of the mixed antibody, about 100 mg/ml of sucrose, about 2 mg/ml of polysorbate 20, about 25 mM histidine-HCl, about 10 mM methionine, pH about 5.8;
  • Aqueous pharmaceutical composition Q about 150 mg/ml of the mixed antibody, about 60 mg/ml of sucrose, about 0.5 mg/ml of polysorbate 20, about 18 mM histidine-HCl, about 10 mM methionine, pH about 5.0;
  • Aqueous pharmaceutical composition R about 150 mg/ml of the mixed antibody, about 76 mg/ml of sucrose, about 0.8 mg/ml of polysorbate 20, about 30 mM histidine-HCl, about 10 mM methionine, pH about 5.4;
  • Aqueous pharmaceutical composition S about 200 mg/ml of mixed antibody, about 90 mg/ml of sucrose, about 0.7 mg/ml of polysorbate 20, about 50 mM histidine-HCl, about 10 mM methionine, pH about 5.2;
  • Aqueous pharmaceutical composition T about 200 mg/ml of mixed antibody, about 70 mg/ml of sucrose, about 1 mg/ml of polysorbate 20, about 15 mM histidine-HCl, about 10 mM methionine, pH about 5.4;
  • Aqueous pharmaceutical composition U about 200 mg/ml of mixed antibody, about 82 mg/ml of sucrose, about 0.5 mg/ml of polysorbate 20, about 10 mM of histidine-HCl, about 10 mM of methionine, about 2000 IU/ml of hyaluronidase, pH about 5.4;
  • Aqueous pharmaceutical composition V about 150 mg/ml of the mixed antibody, about 76 mg/ml of sucrose, about 0.8 mg/ml of polysorbate 20, about 18 mM of histidine-HCl, about 10 mM of methionine, and about 2000 IU/ml of hyaluronidase, with a pH of about 5.4;
  • Aqueous pharmaceutical composition W about 150 mg/ml of the mixed antibody, about 70 mg/ml of sucrose, about 0.6 mg/ml of polysorbate 20, about 15 mM of histidine-HCl, about 10 mM of methionine, and about 2000 IU/ml of hyaluronidase, with a pH of about 5.2;
  • Aqueous pharmaceutical composition X about 120 mg/ml of a mixed antibody, about 63 mg/ml of sucrose, about 0.5 mg/ml of polysorbate 20, about 13 mM of histidine-HCl, about 10 mM of methionine, and about 2000 IU/ml of hyaluronidase, with a pH of about 5.4;
  • Aqueous pharmaceutical composition Y about 120 mg/ml of the mixed antibody, about 70 mg/ml of sucrose, about 0.8 mg/ml of polysorbate 20, about 25 mM histidine-HCl, about 10 mM methionine, about 2000 IU/ml of hyaluronidase, pH about 5.2;
  • Aqueous pharmaceutical composition Z about 100 mg/ml of mixed antibody, about 60 mg/ml of sucrose, about 0.6 mg/ml of polysorbate 20, about 20 mM of histidine-HCl, about 10 mM of methionine, about 2000 IU/ml of hyaluronidase, and a pH of about 5.2.
  • the present disclosure also provides a lyophilized preparation, which is obtained by lyophilizing the aqueous pharmaceutical composition of the present disclosure, or the aqueous pharmaceutical composition of the present disclosure is obtained by reconstitution of the lyophilized preparation.
  • the present disclosure also provides use of the aqueous pharmaceutical composition or lyophilized preparation in preparing a drug for treating tumors, wherein the tumor is selected from esophageal squamous cell carcinoma, melanoma, cervical cancer, small cell lung cancer, non-small cell lung cancer, colorectal cancer, liver cancer, and kidney cancer.
  • Figure 1 shows the changes in tumor volume after treatment with ZPML265, anti-PD-1 antibody, anti-CTLA-4 antibody, and IgG.
  • Figure 2 shows the changes in tumor volume of mice in different groups.
  • FIG3 shows the tumor weights of mice in different groups.
  • FIG4 shows the body weight changes of mice in different groups.
  • “About” includes and describes the value or parameter itself. For example, “about x” includes and describes “x” itself. As used herein, when used in conjunction with a measurement or to modify a value, unit, constant, or series of values, the term “about” includes, in addition to the value or parameter itself, a variation within ⁇ 20%, or in some cases within ⁇ 10%, or in some cases within ⁇ 5%, or in some cases within ⁇ 1%, or in some cases within ⁇ 0.1% of the specified value.
  • antibody typically refers to a Y-shaped tetrameric protein comprising two heavy (H) polypeptide chains and two light (L) polypeptide chains held together by covalent disulfide bonds and non-covalent interactions. Natural IgG antibodies have this structure. Each light chain comprises a variable domain (VL) and a constant domain (CL). Each heavy chain comprises a variable domain (VH) and a constant domain (CH).
  • IgA Five major classes of antibodies are known in the art: IgA, IgD, IgE, IgG, and IgM.
  • the corresponding heavy chain constant domains are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • IgG and IgA can be further divided into different subclasses, for example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4, and IgA can be divided into IgA1 and IgA2.
  • the light chains of antibodies from any vertebrate species can be assigned to one of two clearly distinct types, called ⁇ and ⁇ , based on the amino acid sequence of their constant domains.
  • antibodies in a broad sense may include polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies and primatized antibodies, CDR-grafted antibodies, human antibodies (including recombinantly produced human antibodies), recombinantly produced antibodies, intracellular antibodies, multispecific antibodies, bispecific antibodies, monovalent antibodies, multivalent antibodies, anti-idiotypic antibodies, synthetic antibodies (including mutant proteins and their variants), etc.
  • monoclonal antibody refers to a substantially homogeneous antibody produced by a single cell clone that is directed against a specific antigenic epitope.
  • Monoclonal antibodies can be prepared using a variety of techniques known in the art, including hybridoma technology, recombinant technology, phage display technology, transgenic animals, synthetic technology, or a combination of these techniques.
  • hybrid antibody refers to an antibody containing a limited number of primary antibody species, optionally no more than two, three, four, five, six, seven, eight, nine, or ten, produced from host cells (optionally cells from a single host cell line) that have been transfected with DNA encoding at least two different antibodies (optionally full-length primate IgG antibodies) with different binding specificities.
  • DNA encoding at least two different heavy chains (HCs) and at least two different light chains (LCs) can be introduced into the same host cell.
  • a host cell can be transfected with DNA encoding at least two but no more than four different antibodies with different binding specificities.
  • the sequences of all transfected DNA encoding HCs and LCs can be mutated to alter the amino acid sequence of the antibody, disfavoring non-homologous HC/LC pairing and strongly favoring homologous HC/LC pairing.
  • one or both of the two different HCs can be optionally altered to disfavor heterodimer formation.
  • only one heavy chain is altered to prevent heterodimer formation.
  • DNA encoding only two different antibodies is introduced into a host cell, only one of the antibodies encoded by the DNA comprises one or more partner-directed changes that favor cognate HC/LC pairing, while the other antibody does not comprise such changes.
  • the host cell produces only two major antibody species, wherein each HC predominantly pairs with its cognate LC, and most antibodies are tetramers containing two heavy chains having the same amino acid sequence and two light chains having the same amino acid sequence (see PCT/US2017/030676).
  • pharmaceutical preparation or “preparation” or “preparation formulation” are used interchangeably herein to refer to a preparation that is in a form that permits the effective presence of the pharmaceutically active ingredient and that contains no other components that are toxic to the subject to which the preparation is to be administered.
  • composition refers to a formulation or combination of formulations containing one, two, or more active ingredients, which allows the active ingredients contained therein to exist in a biologically effective form and does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered.
  • a “pharmaceutical composition” is present as a combination of separate formulations containing two or more different active ingredients, they can be administered simultaneously, sequentially, separately, or at intervals, with the goal of exerting the biological activities of the multiple active ingredients for combined treatment of a disease.
  • ZPML265" refers to a mixed antibody comprising an anti-CTLA-4 antibody and an anti-PD-1 antibody, wherein the heavy chain of the anti-CTLA-4 antibody is shown in SEQ ID NO:1, the light chain of the anti-CTLA-4 antibody is shown in SEQ ID NO:2, the heavy chain of the anti-PD-1 antibody is shown in SEQ ID NO:3, and the light chain of the anti-PD-1 antibody is shown in SEQ ID NO:4.
  • ZPML265 injection refers to a low-concentration formulation of ZPML265 for administration to a subject for the treatment of a disease.
  • ZPML265H injection refers to a high-concentration formulation of ZPML265 for administration to a subject for the treatment of a disease.
  • high concentration formulation refers to a formulation comprising the active pharmaceutical ingredient (API) at a concentration of about 100 mg/ml to 200 mg/ml.
  • the term "effective amount" refers to a dose of a pharmaceutical formulation comprising an active ingredient of the present disclosure that, after administration to a patient in a single or multiple doses, produces the desired effect in the patient being treated.
  • the effective amount can be readily determined by the attending physician, who is skilled in the art, by considering a variety of factors such as ethnic differences; weight, age, and health status; the specific disease involved; the severity of the disease; the response of the individual patient; the specific antibody being administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosing regimen; and the use of any concomitant therapy.
  • pharmaceutically acceptable excipient is a substance/agent that can be reasonably administered to a subject to provide an effective amount of an active pharmaceutical ingredient in a stable formulated form.
  • Suitable pharmaceutically acceptable excipients are well known in the art and include, but are not limited to, buffers, stabilizers, surfactants, and the like.
  • buffer refers to a pharmaceutically acceptable excipient that stabilizes the pH of a pharmaceutical formulation. Suitable buffers are well known in the art and can be found in the literature.
  • stabilizer is a pharmaceutically acceptable excipient used to protect the active pharmaceutical ingredient and/or formulation from chemical and/or physical degradation during production, storage, and use.
  • surfactant refers to a pharmaceutically acceptable excipient used to protect protein formulations from mechanical stresses such as agitation and shear.
  • antioxidant refers to a compound that prevents oxidation of the active ingredient under storage conditions.
  • the term "diffusing agent” refers to a compound used to increase the permeability of active substances into tissues (such as skin) and help the active substances diffuse effectively, such as hyaluronidase, which can hydrolyze hyaluronic acid, thereby reducing the viscosity of hyaluronic acid in the extracellular matrix and making the drug preparation easier to disperse in the tissue.
  • lyophilized preparation refers to a composition obtained or obtainable by a freeze-drying process of a liquid preparation. Preferably, it is a solid composition having a water content of less than 5%, preferably less than 3%.
  • treatment refers to clinical intervention intended to alter the disease process in an individual or cell, and can be either preventative or interventional in the clinical pathological process.
  • Therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the progression of the disease, improving or relieving the condition, and alleviating or improving the prognosis.
  • the term "individual” or “subject” or “patient” refers to any animal, such as a mammal or marsupial. Individuals of the present disclosure include, but are not limited to, humans, non-human primates (e.g., cynomolgus or rhesus monkeys or other types of macaques), mice, pigs, horses, donkeys, cattle, sheep, rats, and any type of poultry.
  • non-human primates e.g., cynomolgus or rhesus monkeys or other types of macaques
  • mice pigs, horses, donkeys, cattle, sheep, rats, and any type of poultry.
  • disease refers to any change or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • disease includes, but is not limited to, tumors, pathogen infection, autoimmune diseases, T-cell dysfunction, or immune tolerance deficiency (e.g., transplant rejection).
  • tumor refers to a disease characterized by the pathological proliferation of cells or tissues, and their subsequent migration or invasion into other tissues or organs. Tumor growth is typically uncontrolled and progressive, without inducing or inhibiting normal cell proliferation. Tumor includes “cancer” and refers broadly to all malignant tumors.
  • the term “combination” refers to a treatment regimen that provides at least two or more different therapies to achieve a specified therapeutic effect.
  • the therapies can be physical, such as radiotherapy, or chemical, such as administering a drug to a subject, and the drug also includes a combination drug.
  • “Combination drug” refers to a combination of two or more pharmaceutical preparations, each with an active ingredient, that need to be used in combination when administered to a subject.
  • the active ingredients can be mixed together to form a single administration unit, or they can be independently administered as administration units and used separately: when administered, the different pharmaceutical preparations can be administered essentially synchronously, simultaneously or sequentially.
  • Relapse-free survival was defined as the time from randomization to the first documented disease recurrence (local, regional, or distant) or death from any cause, whichever occurred first.
  • OS Overall survival
  • PFS Progression-free survival
  • ORR objective response rate
  • DCR Disease control rate
  • CR Complete remission
  • Partial response The sum of the target lesion diameters decreased by at least 30% compared with the baseline level.
  • PD Disease progression
  • the minimum value of the sum of all target lesion diameters measured during the entire experimental study is used as a reference, and the sum of diameters increases by at least 20% (if the baseline measurement value is the minimum, the baseline value is used as a reference): In addition, the absolute value of the sum of diameters must increase by at least 5 mm (the appearance of one or more new lesions is also considered as disease progression).
  • Stable disease The target lesion has not decreased to the level of PR, nor increased to the level of PD, but is somewhere in between.
  • the minimum sum of the diameters can be used as a reference for research.
  • Duration of response was defined as the time from the first tumor assessment as CR or PR (whichever was recorded first) to the first assessment as PD or death.
  • Treatment-emergent adverse events refer to adverse events that occur during treatment.
  • Treatment-related adverse events are adverse events related to study drugs that occur during treatment.
  • a serious adverse event refers to an adverse medical event (AE) such as death, life-threatening, permanent or severe disability or loss of function, the need for hospitalization or prolonged hospitalization, and congenital abnormalities or birth defects that occurs after the subject receives the investigational drug.
  • AE adverse medical event
  • Dose-limiting toxicity was defined as grade ⁇ 3 non-hematologic toxicity or grade ⁇ 4 hematologic toxicity occurring within 21 days (1 cycle) after the first dose.
  • the maximum tolerated dose was defined as the highest dose level of the drug at which no more than one of six subjects experienced DLT during the 21-day treatment period (one cycle) after the first dose.
  • Protein content was determined using a Lunatic microspectrophotometer. Purified water was used for blank subtraction, and UV absorption at 280 nm was corrected by light scattering at 330 nm. Protein concentration was calculated according to Equation 1, where the extinction coefficient ⁇ was 1.64 (L/g ⁇ cm -1 ).
  • Size exclusion chromatography was used to quantify aggregates, monomers, and fragments. This method utilized a Waters Xbridge BEH SEC The HPLC system was run on a 7.8 ⁇ 300 mm column using a Waters E2695-2489 HPLC system. The mobile phase consisted of 100 mM sodium phosphate, 150 mM sodium chloride, pH 6.8. The sample was diluted to 1 mg/mL with the mobile phase, and the injection volume was 25 ⁇ L. Isocratic elution was performed at a flow rate of 0.5 mL/min for 30 min, with detection at 215 nm. Integration was performed using Empower 3 software, and the percentage of each component was calculated by area normalization.
  • an ampholyte carrier creates a uniform pH gradient from the anode to the cathode within the capillary under the influence of an electric field. Protein variants with different charges are focused and separated within the ampholyte pH gradient according to their isoelectric points. The focusing process is monitored in real time at a wavelength of 280 nm. A 100 ⁇ m inner diameter FC-coated fused silica capillary with an effective separation length of 5 cm was used. Samples were treated with a final concentration of 1% Cytiva Pharmalyte 3-10, 0.5% Cytiva Pharmalyte 8-10.5, 0.35% HPMC, and 1 M urea, for a final sample concentration of 0.5 mg/ml.
  • Focusing voltage and time were 1.5 kV for 1 min and 3 kV for 6 min, respectively.
  • Chromatograms were integrated using Empower 3 software. The contents of the acidic, main, and basic regions were calculated as peak area percentages, and the pI values of target peaks were calculated using marker pI values.
  • Hyaluronidase activity was assayed using a turbidimetric assay.
  • Hyaluronidase can enzymatically hydrolyze the hyaluronic acid substrate.
  • Excess hyaluronic acid solution can form a stable colloidal solution with acidified serum.
  • a standard curve was constructed by measuring the absorbance of different concentrations of standard samples and their corresponding values, thereby determining the activity of hyaluronidase.
  • a low-protein-adsorbed 96-well sample plate containing the test sample and standard sample and a 96-well substrate plate containing hyaluronic acid working solution were incubated at 37°C.
  • the test sample and standard sample were transferred from the sample plate to the substrate plate for reaction.
  • the serum working solution was then added to the substrate plate to terminate the reaction.
  • the absorbance of the plate was measured at 640 nm, and the activity of the test sample was calculated based on the standard curve.
  • a hybrid antibody produced by a single host cell line was prepared (see PCT/US2017/030676).
  • the hybrid antibody contains two active ingredients, namely a recombinant humanized IgG1 monoclonal antibody targeting human CTLA4 and a recombinant humanized IgG4 monoclonal antibody targeting human PD1.
  • the hybrid antibody can specifically bind to human CTLA4 and PD1 at the same time.
  • the amino acid sequences of the anti-CTLA4 antibody and the anti-PD1 antibody are shown in Table 1 below.
  • the molar ratio of the anti-PD-1 antibody to the anti-CTLA-4 antibody in ZPML265 is 2:1.
  • acetic acid-sodium hydroxide buffers were selected at concentrations of 10 mM, 20 mM, and 50 mM, respectively, to investigate the stability of the formulations. All formulations were sterile-filtered through a 0.22 ⁇ m low-protein-binding filter and aseptically filled into sterile 2 ml vials, sealed with film-coated rubber stoppers and aluminum-plastic combination caps. These formulations were stored at 40°C for 3 weeks to investigate sample stability. Table 4 provides information on the different formulations, and Table 5 presents the stability results for the different formulations.
  • polysorbate 20 and polysorbate 80 were selected as surfactants at concentrations of 0.2 mg/ml and 0.5 mg/ml, respectively, to investigate the stability of the formulations.
  • All formulations were sterile filtered through a 0.22 ⁇ m low protein binding filter and aseptically filled into sterile 2 ml vials, sealed with a film-coated rubber stopper and an aluminum-plastic combination cap. These formulations were placed under the following conditions: 40°C 3W and shaken (150 rpm, 25°C) for 24 hours to investigate sample stability.
  • Table 6 shows information on different formulations
  • Table 7 shows the stability results for different formulations.
  • Example 6 In vivo pharmacodynamics of anti-PD-1 component, anti-CTLA-4 component and ZPML265 in humanized NCG mouse HCC827 tumor model Research
  • NCG immunodeficient mice were used as experimental mice.
  • Human tumor cells were first inoculated, and then human PBMCs were injected intravenously to establish a tumor-bearing mouse model with a human immune system.
  • ZPML265, anti-human PD-1 antibody (the anti-PD-1 component of ZPML265), and anti-human CTLA-4 antibody (the anti-CTLA-4 component of ZPML265) were then administered.
  • the pharmacodynamic effects of anti-PD-1 antibody, anti-CTLA-4 antibody, and ZPML265 were investigated in the humanized NCG mouse HCC827 tumor model, and whether ZPML265 had a synergistic effect was explored.
  • PBMCs peripheral blood from healthy donors was centrifuged by density gradient to isolate PBMCs, which were resuspended in PBS to 1 ⁇ 108 cells/mL for inoculation.
  • HCC827 tumor cells were adjusted in PBS and inoculated subcutaneously in the right flank of NCG mice at a concentration of 5 ⁇ 106 cells /100 ⁇ L.
  • the day of tumor cell inoculation was designated as day 0.
  • the average tumor volume reached 60-80 mm3 approximately day 5 after tumor cell inoculation
  • 1 ⁇ 107 PBMCs/100 ⁇ L/mouse were injected intravenously. Intraperitoneal administration began 1 hour after PBMC inoculation.
  • Tumor volume inhibition (TGI) and tumor volume were used as biological indicators of pharmacodynamics (PD) in this study.
  • ZPML265 was buffer-exchanged with the intended excipient solution and concentrated by ultrafiltration to the desired antibody concentration. After ultrafiltration and concentration, the desired excipients were added to the antibody solution as a stock solution. Finally, the protein concentration was adjusted to the desired concentrations, such as approximately 100 mg/ml, 120 mg/ml, 150 mg/ml, and 200 mg/ml, using buffer. All formulations were sterile-filtered through a 0.22 ⁇ m low-protein-binding filter and aseptically filled into sterile 2 ml vials, sealed with a film-coated rubber stopper and an aluminum-plastic combination cap. These formulations were placed under the following conditions: 25°C for 2 minutes and 40°C for 1 minute to investigate sample stability. Table 10 shows information for different formulations, and Table 11 shows the stability results for different formulations.
  • the surfactant and arginine hydrochloride content were further optimized, and polysorbate 20 at concentrations of 0.5 mg/ml and 1 mg/ml, poloxamer 188 at concentrations of 0.2 mg/ml and 0.5 mg/ml, and arginine hydrochloride at concentrations of 0 mg/ml and 100 mg/ml were selected, respectively, to investigate the stability of the formulation. All formulations were sterile filtered through a 0.22 ⁇ m low protein binding filter and aseptically filled into sterile 2 ml vials, sealed with a film-coated rubber stopper and an aluminum-plastic combination cap.
  • hyaluronidase was introduced into the formulation, and the pH value of the formulation was further optimized.
  • the stability of the formulation was investigated at pH 5.0, 5.2, 5.4, 5.6, and 5.8, with an enzyme activity of 2000 IU/ml. All prepared formulations were sterile filtered through a 0.22 ⁇ m low protein binding filter and aseptically filled into sterile 2 ml vials, sealed with a film-coated rubber stopper and an aluminum-plastic combination cap. These formulations were placed under the following conditions: 40°C 1M, 2-8°C 3M, and 25°C 1M to investigate sample stability. Table 15 shows the information of different formulations, and Table 16 shows the stability results of different formulations.
  • the buffer was further optimized in the high-concentration formulation, and 10mM and 20mM acetic acid-sodium hydroxide and 10mM and 20mM histidine-hydrochloric acid were selected as buffers, respectively, to investigate the stability of the formulation.
  • All formulations were sterile filtered through a 0.22 ⁇ m low protein binding filter and aseptically filled into sterile 2ml vials, sealed with a film-coated rubber stopper and an aluminum-plastic combination cap. These formulations were placed under the following conditions: 40°C 1M, 2-8°C 3M, 25°C 3M and 30°C 3M to investigate the stability of the samples.
  • Table 17 shows the information of different formulations
  • Table 18 shows the stability results of different formulations.
  • Enzyme activity stability was further investigated in high-concentration formulations. All formulations were sterile filtered through a 0.22 ⁇ m low protein binding filter and aseptically filled into sterile 2 ml vials, sealed with a film-coated rubber stopper and an aluminum-plastic combination cap. These formulations were placed under the following conditions: 40°C for 7 days, 2-8°C for 3 M, 6 M, and 9 M, and 25°C for 1 M, 3 M, and 6 M to investigate sample stability. Table 19 shows information on different formulations, Table 20 shows the stability results for different formulations, and Table 21 shows the enzyme activity results for formulation R1.
  • Example 12 Anti-tumor effects of ZPML265H injection and ZPML265 injection in the subcutaneous transplantation model of MC38-hPDL1 in B6-hPD1hCTLA4 mice Tumor effect evaluation
  • MC38-hPDL1 tumor cells were inoculated subcutaneously in the right flank of B6-hPD1/hCTLA4 humanized mice (Jiangsu Jicui Pharmaceutical Kang Biotechnology Co., Ltd.) at a concentration of 1 ⁇ 106 cells/100 ⁇ l.
  • mice When the average tumor volume reached 86.72 mm ⁇ , 56 mice were randomly divided into seven groups of eight based on body weight and tumor volume. Mice in group G1 were given NaCl plus the adjuvant of ZPML265H injection (with hyaluronidase rHuPH20) as a control.
  • mice in groups G2-G4 were given different doses of ZPML265 injection (0.1 mg/kg in G2, 0.3 mg/kg in G3, and 1 mg/kg in G4).
  • Mice in groups G5-G7 were given different doses of ZPML265H injection (0.1 mg/kg in G5, 0.3 mg/kg in G6, and 1 mg/kg in G7). Dosing was twice weekly for a total of eight doses. NaCl was administered via the tail vein in mice in group G1, and the excipient for ZPML265H injection (with added hyaluronidase rHuPH20) was administered subcutaneously. Mice in groups G2-G4 received the drug via the tail vein, and mice in groups G5-G7 received the drug subcutaneously.
  • the day of grouping was defined as D0, and the dosing period lasted from D0 to D28, with dosing dates being D0, D3, D7, D10, D14, D17, D21, and D24, with the experiment ending on D28.
  • tumor size was measured and mice were weighed on D0, D3, D7, D10, D14, D17, D21, D24, and D28.
  • animals were euthanized, and changes in tumor volume (TGITV), tumor weight (TGITW), and body weight were analyzed.
  • Experimental results are presented as mean ⁇ standard error (SEM). Data were analyzed using SPSS 24. Comparisons between two groups were performed using the independent sample T-test (T-test), with P ⁇ 0.05 considered significant.
  • Graphing software was Graphpad Prism 9.
  • the tumor volume inhibition rates (TGITV) in the ZPML265-treated groups at doses of 0.1, 0.3, and 1 mg/kg were 56.42%, 66.36%, and 89.44%, respectively, and in the ZPML265H-treated groups at doses of 0.1, 0.3, and 1 mg/kg, were 66.85%, 80.35%, and 99.78%, respectively.
  • the tumor volumes in the ZPML265 and ZPML265H-treated groups showed significant differences, indicating that different doses of ZPML265 and ZPML265H had a significant inhibitory effect on tumor volume in a dose-dependent manner.
  • the tumor weight results showed a consistent trend with the tumor volume results.
  • the tumor weight inhibition rates (TGITW) in the ZPML265-treated groups at doses of 0.1, 0.3, and 1 mg/kg were 52.46%, 68.02%, and 85.54%, respectively.
  • the tumor weight inhibition rates in the ZPML265H-treated groups at doses of 0.1, 0.3, and 1 mg/kg were 71.14%, 79.83%, and 99.66%, respectively.
  • both the ZPML265 and ZPML265H-treated groups significantly reduced tumor weight in a dose-dependent manner.
  • Example 13 A Phase II clinical trial evaluating the safety and efficacy of ZPML265 injection combined with paclitaxel-cisplatin/carboplatin in patients with recurrent or metastatic cervical cancer. Clinical Research
  • AST Alanine aminotransferase
  • ALT aspartate aminotransferase
  • Dosage regimen The dose of ZPML265 injection is 5 mg/kg, once every three weeks, administered by intravenous infusion.
  • the medications used in this study are as follows: The following drugs are administered once every 3 weeks, with each cycle consisting of 21 days (3 weeks). Paclitaxel and cisplatin/carboplatin are administered for a maximum of 6 cycles. After 6 cycles, subjects receive ZPML265 injection for maintenance treatment. ZPML265 injection is administered until disease progression, intolerable toxicity, initiation of other anti-cancer treatments, loss to follow-up, death, or study withdrawal (whichever occurs first).
  • the dosing window is the planned dosing date (calculated from the date of the first dose) ⁇ 3 days. Exceeding the dosing window is considered early or delayed dosing, and subsequent dosing dates must be recalculated based on the actual date of the last dose.
  • ZPML265 injection 5 mg/kg, intravenous infusion (IV), D1, Q3W; the intravenous infusion time is more than 30 minutes. After the infusion is completed, 20 ml of the same solvent is used to flush the tube. The entire infusion time including the flushing is 60 minutes ( ⁇ 5 minutes); ZPML265 injection must not be injected by intravenous push.
  • Chemotherapy drug regimen
  • paclitaxel is administered at 175 mg/m 2 D1 and cisplatin is administered at 70 mg/m 2 D2, both with a dosing frequency of Q3W.
  • paclitaxel was administered at 135 mg/m 2 D1 and cisplatin was administered at 50 mg/m 2 D2, with a dosing frequency of Q3W.
  • paclitaxel is administered at 135mg/ m2D1 and cisplatin is administered at 60mg/ m2D2 , both at a frequency of Q3W.
  • paclitaxel is administered at 175 mg/m 2 D1 and carboplatin is administered at AUC 6 D1, both with a dosing frequency of Q3W.
  • paclitaxel was administered at 135 mg/m 2 D1 and carboplatin was administered at AUC 5 D1, with a dosing frequency of Q3W.
  • paclitaxel was administered at 135mg/ m2D1 and carboplatin was administered at AUC 5-6D1, with a dosing frequency of Q3W.
  • efficacy data for evaluable cases showed an objective response rate (ORR) of 78.6% (22/28), a disease control rate (DCR) of 100.0% (28/28), and a median progression-free survival (mPFS) of 12.5 months.
  • ORR objective response rate
  • DCR disease control rate
  • mPFS median progression-free survival
  • ZPML265 injection combined with paclitaxel-cisplatin/carboplatin showed a significant efficacy trend in patients with recurrent or metastatic cervical cancer, with controllable overall safety and good tolerability.
  • Example 14 Evaluation of the safety of ZPML265 injection combined with paclitaxel-cisplatin/carboplatin and bevacizumab for first-line treatment of patients with recurrent or metastatic cervical cancer Phase II clinical study of safety and efficacy
  • AST Alanine aminotransferase
  • ALT aspartate aminotransferase
  • Cisplatin 50 mg/m 2 , intravenous infusion, D1 or D2, Q3W;
  • Bevacizumab 15 mg/kg, intravenous infusion, D1, Q3W.
  • ZPML265 injection combined with paclitaxel-cisplatin/carboplatin and bevacizumab was used until disease progression, intolerable toxicity, initiation of new anti-tumor treatment, loss to follow-up, death, withdrawal from the study, or other withdrawal criteria (whichever occurred first).
  • the subject should receive 6 cycles of chemotherapy if tolerated. Subsequently, chemotherapy can be stopped and treatment with ZPML265 and bevacizumab can be continued according to the investigator's decision and/or the subject's wishes until disease progression or other exit criteria are met.
  • Evaluation indicators The endpoints of this study are safety and efficacy indicators and other indicators.
  • DCR disease control rate
  • PFS progression-free survival
  • efficacy data for evaluable cases showed an objective response rate (ORR) of 83.3% (25/30), a disease control rate (DCR) of 96.7% (29/30), and a median progression-free survival (mPFS) of 16.4 months.
  • ORR objective response rate
  • DCR disease control rate
  • mPFS median progression-free survival
  • ZPML265 injection combined with paclitaxel-cisplatin/carboplatin and bevacizumab showed a significant efficacy trend in patients with recurrent or metastatic cervical cancer, with controllable overall safety and good tolerability.

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Abstract

L'invention concerne une composition pharmaceutique contenant des anticorps mélangés anti-CTLA-4 et anti-PD-1, qui présente un excellent effet en termes de stabilité, de sécurité et d'efficacité thérapeutique, ce qui permet de résoudre efficacement les problèmes de mauvaise stabilité et de toxicité élevée d'une composition pharmaceutique contenant des anticorps mélangés anti-CTLA-4 et anti-PD-1.
PCT/CN2024/135436 2023-12-01 2024-11-29 Composition pharmaceutique stable d'anticorps mélangés Pending WO2025113598A1 (fr)

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