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WO2025122660A1 - Protéines chimériques comprenant de l'il-2 masquée - Google Patents

Protéines chimériques comprenant de l'il-2 masquée Download PDF

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Publication number
WO2025122660A1
WO2025122660A1 PCT/US2024/058527 US2024058527W WO2025122660A1 WO 2025122660 A1 WO2025122660 A1 WO 2025122660A1 US 2024058527 W US2024058527 W US 2024058527W WO 2025122660 A1 WO2025122660 A1 WO 2025122660A1
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Prior art keywords
cancer
prodrug
seq
antibody
moiety
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English (en)
Inventor
Chunxiao YU
Yuefeng Lu
Kurt SHANEBECK
Jeanine RUIZ
Christine Tumanut
Xiaomin Fan
Donghui SHI
Jui Chang Chuang
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Askgene Pharma Inc
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Askgene Pharma Inc
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Priority claimed from PCT/US2023/082385 external-priority patent/WO2024119193A2/fr
Application filed by Askgene Pharma Inc filed Critical Askgene Pharma Inc
Priority to CN202480015930.6A priority Critical patent/CN120813378A/zh
Publication of WO2025122660A1 publication Critical patent/WO2025122660A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C07K16/246—IL-2
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction

Definitions

  • IL-2 exerts its activities by binding to IL-2 receptors (IL-2R), which consist of up to three individual subunits. Association of the ⁇ (CD25 or Tac antigen), ⁇ (CD122), and ⁇ ( ⁇ c, common ⁇ chain, or CD132) subunits results in a trimeric, high-affinity receptor for IL-2 (KD ⁇ 0.01 nM).
  • Dimeric IL-2 receptor consisting of the ⁇ and ⁇ subunits is termed intermediate-affinity IL-2R (KD ⁇ 1 nM).
  • the ⁇ subunit alone forms the monomeric low affinity IL-2 receptor (KD ⁇ 10 nM).
  • KD ⁇ 1 nM monomeric low affinity IL-2 receptor
  • KD ⁇ 10 nM monomeric low affinity IL-2 receptor
  • the dimeric intermediate-affinity IL-2 receptor binds IL-2 with approximately 100-fold lower affinity than the trimeric high-affinity receptor, both the dimeric and trimeric IL-2 receptors can transmit signal upon IL-2 binding (Minami et al., Annu Rev Immunol. (1993) 11:245-68).
  • the ⁇ subunit while conferring high-affinity binding of the receptor to IL-2, is not essential for IL-2 signaling.
  • the ⁇ and ⁇ subunits are essential for IL-2 signaling (Krieg et al., Proc Natl Acad Sci. (2010) 107:11906-11).
  • the trimeric IL-2 receptor is expressed by CD4+FoxP3+ regulatory T (Treg) cells. Treg cells consistently express the highest level of IL-2R ⁇ (CD25) in vivo (Fontenot et al., Nature Immunol. (2005) 6:1142-51).
  • the trimeric IL-2 receptor is also transiently induced on conventional activated T cells, whereas in the resting state these cells express only the dimeric IL-2 receptor.
  • Mutated versions of IL-2 have been developed to optimize treatment of cancer and autoimmune diseases.
  • IL-2 prodrugs have also been in development, which in general depends on protease cleavage for activation. There is a need to develop IL-2 prodrugs which does not need protease cleavage for activation to further increase efficacy of the prodrugs.
  • the present disclosure provides a prodrug comprising an IL-2 cytokine moiety, a masking moiety, and a carrier moiety, wherein the IL-2 cytokine moiety comprises SEQ ID NO:2, the masking moiety comprises an scFv specific for the IL-2 cytokine moiety, and the carrier moiety is an antibody against human PD-1, wherein the anti-PD-1 antibody comprises a heavy chain variable domain comprising amino acid residues 1-113 of SEQ ID NO:13 and a light chain variable domain comprising amino acid residues 1-107 of SEQ ID NO:15.
  • the scFv comprises a light chain variable domain comprising amino acid residues 452-560 of SEQ ID NO:13 and a heavy chain variable domain comprising amino acid residues 584-703 of SEEQ ID NO:13.
  • the prodrug comprises a fusion polypeptide in which the scFv is fused to the C-terminus of a first heavy chain of the anti-PD-1 antibody through a first peptide linker comprising SEQ ID NO:16 and the IL-2 cytokine moiety is fused to the C- terminus of the scFv through a second peptide linker comprising SEQ ID NO:16.
  • the fusion polypeptide comprises SEQ ID NO:13 or an amino acid sequence at least 95% identical thereto
  • the second heavy chain of the anti-PD-1 antibody comprises SED ID NO:14 or an amino acid sequence at least 95% identical thereto
  • the light chains of the anti-PD-1 antibody each comprise SEQ ID NO:15 or an amino acid sequence at least 95% identical thereto.
  • the fusion polypeptide comprises SEQ ID NO:13
  • the second heavy chain of the anti-PD-1 antibody comprises SED ID NO:14
  • the light chains of the anti-PD-1 antibody each comprise SEQ ID NO:15.
  • a chimeric protein comprising a first heavy chain polypeptide chain, a second heavy chain polypeptide chain, and two identical light chains, wherein the first heavy chain polypeptide chain comprises SEQ ID NO:13 or an amino acid sequence at least 95% identical thereto, the second heavy chain polypeptide chain comprises SEQ ID NO:14 or an amino acid sequence at least 95% identical thereto, and two identical light chains each comprise SEQ ID NO:15 or an amino acid sequence at least 95% identical thereto.
  • the present disclosure provides pharmaceutical composition comprising the prodrug or chimeric protein herein and a pharmaceutically acceptable excipient.
  • the present disclosure provides polynucleotides encoding the present prodrug or chimeric protein, expression vectors comprising the polynucleotides, and host cells comprising the expression vector(s).
  • the present disclosure also provides a method of making a prodrug or chimeric protein, comprising culturing the present host cell under conditions that allow expression of the prodrug or chimeric protein, and isolating the expressed prodrug or chimeric protein from the culture.
  • the present disclosure provides a method of treating a cancer or an infectious disease or modulating the immune system in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the present prodrug, chimeric protein, or pharmaceutical composition.
  • prodrugs, chimeric proteins and pharmaceutical compositions for use in treating a cancer or an infectious disease or modulating the immune system in a patient in need thereof, and use of these prodrugs, chimeric proteins, and pharmaceutical compositions for the manufacture of a medicament for treating a cancer or an infectious disease or modulating the immune system in a patient in need thereof.
  • the patient has HIV infection; has a cancer selected from the group consisting of leukemia, lymphoma, kidney cancer, bladder cancer, urinary tract cancer, cervical cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, esophageal cancer, liver cancer, colorectal cancer, stomach cancer, squamous cell carcinoma, prostate cancer, pancreatic cancer, lung cancer such as non- small cell lung cancer, cholangiocarcinoma, breast cancer, and ovarian cancer, and medullary thyroid cancer; or an inflammatory or an autoimmune disease, optionally selected from asthma, Type I diabetes, rheumatoid arthritis, allergy, systemic lupus erythematosus, organ graft rejection, and graft-versus-host disease.
  • a cancer selected from the group consisting of leukemia, lymphoma, kidney cancer, bladder cancer, urinary tract cancer, cervical cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, e
  • FIGs. 1A-1E show schematic illustrations of the structures of antibody-cytokine fusion molecules and the sequences of the polypeptide chains, which form the fusion molecules.
  • FIG. 2 shows the results of the in vitro cell based activity assay (HEK Blue Reporter Assay).
  • FIG. 4 shows the results of the cell-based activity assay of IL-2 prodrugs ASKG812 EC DS and ASKG812N (also termed 812NW5-Mut4 or NW5-Mut4 herein) as compared to un-conjugated human IL-2.
  • FIG. 5 shows the activity of ASKG812N in an HEK blue reporter assay from the cynomolgus monkey PK study.
  • FIG. 6 shows the serum concentrations of ASKG812N and PK parameters in cynomolgus monkey.
  • FIG. 7 shows the expansion of immune cells induced by ASKG812N.
  • antigen-binding moiety refers to a polypeptide or a set of interacting polypeptides that specifically bind to an antigen, and includes, but is not limited to, an antibody (e.g., a monoclonal antibody, polyclonal antibody, a multi-specific antibody, a dual specific or bispecific antibody, an anti-idiotypic antibody, or a bifunctional hybrid antibody) or an antigen-binding fragment thereof (e.g., a Fab, a Fab’, a F(ab’)2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody (dAb), or a diabody), a single chain antibody, and an Fc-containing polypeptide such as an immunoadhesin or an scFv-Fc.
  • an antibody e.g., a monoclonal antibody, polyclonal antibody, a multi-specific antibody, a dual specific or bispecific antibody, an anti-idiotypic antibody
  • the antibody may be of any heavy chain isotype (e.g., IgG, IgA, IgM, IgE, or IgD) or subtype (e.g., IgG1, IgG2, IgG3, or IgG4).
  • the antibody may be of any light chain isotype (e.g., kappa or lambda).
  • the antibody may be human, non-human (e.g., from mouse, rat, rabbit, goat, or another non-human animal), chimeric (e.g., with a non-human variable region and a human constant region), or humanized (e.g., with non-human CDRs and human framework and constant regions).
  • the antibody is a derivatized antibody.
  • cytokine agonist polypeptide refers to a wildtype cytokine, or an analog thereof.
  • An analog of a wildtype cytokine has the same biological specificity (e.g., binding to the same receptor(s) and activating the same target cells) as the wildtype cytokine, although the activity level of the analog may be different from that of the wildtype cytokine.
  • the analog may be, for example, a mutein (i.e., mutated polypeptide) of the wildtype cytokine, and may comprise at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten mutations relative to the wildtype cytokine.
  • prodrug herein refers to a cytokine fusion protein that comprises a cytokine moiety bound by a masking moiety and has not yet been activated to remove the mask from the cytokine moiety.
  • cytokine antagonist refers to a moiety (e.g., a polypeptide) that binds to a cytokine and thereby inhibits the cytokine from binding to its receptor on the surface of a target cell and/or exerting its biological functions while being bound by the antagonist or mask.
  • cytokine antagonist or mask examples include, without limitations, a polypeptide derived from an extracellular domain of the cytokine’s natural receptor that makes contact with the cytokine and an antibody that binds to the cytokine or an antigen-binding fragment thereof (e.g., scFv).
  • effective amount or “therapeutically effective amount” refers to an amount of a compound or composition sufficient to treat a specified disorder, condition, or disease, such as ameliorate, palliate, lessen, and/or delay one or more of its symptoms.
  • an effective amount may be an amount sufficient to delay cancer development or progression (e.g., decrease tumor growth rate, and/or delay or prevent tumor angiogenesis, metastasis, or infiltration of cancer cells into peripheral organs), reduce the number of epithelioid cells, cause cancer regression (e.g., shrink or eradicate a tumor), and/or prevent or delay cancer occurrence or recurrence.
  • An effective amount can be administered in one or more administrations.
  • the term “functional analog” refers to a molecule that has the same biological specificity (e.g., binding to the same ligand) and/or activity (e.g., activating or inhibiting a target cell) as a reference molecule.
  • fused or “fusion” in reference to two polypeptide sequences refers to the joining of the two polypeptide sequences through a backbone peptide bond.
  • Two polypeptides may be fused directly or through a peptide linker that is one or more amino acids long.
  • a fusion polypeptide may be made by recombinant technology from a coding sequence containing the respective coding sequences for the two fusion partners, with or without a coding sequence for a peptide linker in between. In some embodiments, fusion encompasses chemical conjugation.
  • composition when used to refer to an ingredient in a composition means that the excipient is suitable for administration to a treatment subject, including a human subject, without undue deleterious side effects to the subject and without affecting the biological activity of the active pharmaceutical ingredient (API).
  • subject refers to a mammal and includes, but is not limited to, a human, a pet (e.g., a canine or a feline), a farm animal (e.g., cattle or horse), a rodent, or a primate.
  • treatment or “treating” is an approach for obtaining beneficial or desired clinical results.
  • Beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from a disease, diminishing the extent of a disease, ameliorating a disease state, stabilizing a disease (e.g., preventing or delaying the worsening or progression of the disease), preventing or delaying the spread (e.g., metastasis) of a disease, preventing or delaying the recurrence of a disease, providing partial or total remission of a disease, decreasing the dose of one or more other medications required to treat a disease, increasing the patient’s quality of life, and/or prolonging survival.
  • the methods of the present disclosure contemplate any one or more of these aspects of treatment.
  • the cytokine prodrugs have fewer side effects (including less immunogenicity risk from the cytokine as compared to the wildtype cytokine), better in vivo PK profiles (e.g., longer half-life) and better target specificity, and are more efficacious as compared to prior cytokine therapeutics.
  • the present prodrugs comprise a cytokine moiety comprising a cytokine agonist polypeptide linked to a carrier moiety and masked (bound) by a cytokine antagonist (masking moiety).
  • the cytokine antagonist may be, for example, an extracellular domain of a receptor for the cytokine, and is linked to the cytokine moiety or to the carrier moiety through a peptide linker (e.g., a cleavable or non-cleavable peptide linker).
  • a peptide linker e.g., a cleavable or non-cleavable peptide linker.
  • the prodrugs may be activated at a target site (e.g., at a tumor site or the surrounding environment) in the patient by cleavage of the linker and the consequent release of the cytokine mask from the prodrug, exposing the previously masked cytokine moiety and allowing the cytokine moiety to bind to its receptor on a target cell and exert its biological functions on the target cell.
  • a target site e.g., at a tumor site or the surrounding environment
  • the prodrugs disclosed herein can engage the target cell via “cis-binding” of a cytokine receptor and an antigen expressed on the cell surface, leading to increased activity of the prodrug without cleavage and removal of the masking moiety.
  • the cytokine moiety of the prodrugs may increase in activity at a target site (e.g., at a tumor site or the surrounding environment), where both the antigen targeted by the carrier and a receptor of the cytokine are expressed on the same cell.
  • the carriers for the prodrugs are antigen-binding moieties, such as antibodies or antigen-binding fragments thereof, that bind an antigen at the target site.
  • the present prodrugs are pro-inflammatory cytokine prodrugs that are metabolized to become pro-inflammatory cytokines at a target site in the body targeted by the carrier moiety.
  • the carrier moiety in the prodrug is an antibody or antigen-binding fragment thereof targeting a tumor antigen such that the prodrug is delivered to a tumor site in a patient and is metabolized locally (e.g., inside or in the vicinity of the tumor microenvironment) through cleavage of the linker linking the cytokine mask to the carrier moiety or the cytokine moiety, making the pro-inflammatory cytokine moiety available to interact with its receptor on a target cell and stimulating the target immune cells locally.
  • An IL-2 prodrug may comprise a cytokine moiety comprising an IL-2 agonist polypeptide, a carrier moiety, and a masking moiety (an IL-2 antagonist), wherein the cytokine moiety is fused to the carrier moiety directly or through a linker (e.g., cleavable or non-cleavable peptide linker), and the IL-2 antagonist is linked to the IL-2 agonist polypeptide or to the carrier moiety through a cleavable peptide linker.
  • the IL-2 agonist polypeptide may be an IL-2 mutein such as an IL-2 mutein described herein derived from a human IL-2.
  • the IL-2 mutein may have significantly reduced affinity for CD25 or the trimeric high-affinity IL-2R, as compared to wildtype IL-2.
  • the IL-2 mutein has binding affinity for the high-affinity IL-2R that is 100 times, 300 times, 500 times, 1,000 times, or 10,000 times lower as compared to wildtype IL-2.
  • all residue numbers in IL-2 and IL-2 muteins described herein are in accordance with the numbering in SEQ ID NO:1.
  • the IL- 2 agonist is an IL-2 mutein comprising SEQ ID NO:2.
  • the cytokine antagonist i.e., the masking moiety, in the present immunoconjugate may comprise a peptide, an antibody, or antibody fragment that binds to the cytokine moiety in the prodrug, thereby masking the cytokine moiety and inhibiting its biological functions.
  • the prodrug comprises a masking moiety, wherein the masking moiety binds to a mutant IL-2 polypeptide disclosed herein and inhibits a biological activity of the mutant IL-2 polypeptide.
  • IL-2 antagonists may comprise peptides and antibodies that bind IL-2 and interfere with the binding of the IL-2 moiety to its receptors, leading to the reduced biological activities of the IL-2 moiety while masked.
  • the IL- 2 antagonist comprises an IL-2R ⁇ or IL-2R ⁇ extracellular domain or its functional analog such as one derived from human IL-2R ⁇ or IL-2R ⁇ .
  • the IL-2 antagonist comprises a peptide identified from the screening of a peptide library.
  • the masking moiety comprises an antibody or an antigen-binding fragment thereof.
  • the IL-2 antagonist comprises an antibody or fragment (e.g., scFv) thereof that blocks the binding of IL-2 or IL-2 muteins to an IL-2 receptor.
  • the scFv comprises a light chain variable domain comprising amino acid residues 452-560 of SEQ ID NO:13 and a heavy chain variable domain comprising amino acid residues 584-703 of SEEQ ID NO:13.
  • the prodrug further comprises a peptide linker, wherein the peptide linker links the masking moiety to the carrier. In some other embodiments, the peptide linker links the mutant IL-2 polypeptide to the carrier moiety.
  • the carrier moiety of the present prodrugs may be an antigen-binding moiety, or a moiety that does not bind an antigen.
  • the carrier moiety may improve the PK profiles such as serum half-life of the cytokine agonist polypeptide, and may also target the cytokine agonist polypeptide to a target site in the body, such as a tumor site.
  • the carrier moiety may be an antibody or an antigen-binding fragment thereof, or an immunoadhesin.
  • the antigen-binding moiety is a full-length antibody with two heavy chains and two light chains, a Fab fragment, a Fab’ fragment, a F(ab’)2 fragment, a Fv fragment, a disulfide linked Fv fragment, a single domain antibody, a nanobody, or a single-chain variable fragment (scFv).
  • the antigen- binding moiety is a bispecific antigen-binding moiety and can bind to two different antigens or two different epitopes on the same antigen. The antigen-binding moiety may provide additional and potentially synergetic therapeutic efficacy to the cytokine agonist polypeptide.
  • the cytokine agonist polypeptide and its mask may be fused to the N-terminus or C-terminus of the light chains and/or heavy chains of the antigen-binding moiety.
  • the cytokine agonist polypeptide and its mask may be fused to a heavy chain of an antibody or an antigen-binding fragment thereof.
  • the cytokine agonist polypeptide and its mask may be fused to the light chain of an antibody or an antigen-binding fragment thereof.
  • the cytokine agonist polypeptide is fused to the C- terminus of one or both of the heavy chains of an antibody, and the cytokine’s mask (masking moiety) is fused to the C-terminus of the cytokine agonist polypeptide through a cleavable or non-cleavable peptide linker.
  • the cytokine agonist polypeptide is fused to the C-terminus of one of the heavy chains of an antibody, and the cytokine’s mask is fused to the C-terminus of the other heavy chain of the antibody through a cleavable or non- cleavable peptide linker, wherein the two heavy chains contain mutations that allow their specific pairing.
  • the PD-1-binding moiety includes an antibody or fragment thereof known in the art that binds to PD-1 and disrupts the interaction between the PD-1 and its ligand (PD-L1) to stimulate an anti-tumor immune response.
  • the antibody or antigen-binding portion thereof binds specifically to PD-1.
  • the antigen-binding moiety is an anti-PD1 antibody.
  • the anti-PD-1 antibody is pembrolizumab or nivolumab.
  • the IL-2 agonist polypeptide may be fused to the carrier moiety with or without a peptide linker.
  • the peptide linker may be non-cleavable.
  • the peptide linker are G/S-rich linkers (i.e., 50% or more amino acids of the linker are glycine and/or serine (e.g., linkers comprising 1, 2, 3, 4, or 5 repeats of a motif having four consecutive glycine residues following by a serine).
  • the peptide linker comprises a motif of G4S (SEQ ID NO:16).
  • the peptide linker comprises SEQ ID NO:17.
  • one or more expression vectors comprising the coding sequences for the polypeptide chains of the prodrugs may be transfected into mammalian host cells (e.g., CHO cells), and cells are cultured under conditions that allow the expression of the coding sequences and the assembly of the expressed polypeptides into the prodrug complex.
  • mammalian host cells e.g., CHO cells
  • Pharmaceutical compositions comprising the prodrugs and muteins (i.e., the active pharmaceutical ingredient or API) of the present disclosure may be prepared by mixing the API having the desired degree of purity with one or more optional pharmaceutically acceptable excipients (see, e.g., Remington's Pharmaceutical Sciences, 16th Edition., Osol, A. Ed.
  • compositions in the form of lyophilized formulations or aqueous solutions.
  • Pharmaceutically acceptable excipients are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers containing, for example, phosphate, citrate, succinate, histidine, acetate, or another inorganic or organic acid or salt thereof; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, ge
  • Buffers are used to control the pH in a range which optimizes the therapeutic effectiveness, especially if stability is pH dependent. Buffers are preferably present at concentrations ranging from about 50 mM to about 250 mM. Suitable buffering agents for use with the present invention include both organic and inorganic acids and salts thereof, such as citrate, phosphate, succinate, tartrate, fumarate, gluconate, oxalate, lactate, and acetate. Additionally, buffers may comprise histidine and trimethylamine salts such as Tris.
  • Preservatives are added to retard microbial growth, and are typically present in a range from 0.2% - 1.0% (w/v).
  • Suitable preservatives for use with the present invention include octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium halides (e.g., chloride, bromide, iodide), benzethonium chloride; thimerosal, phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol, 3-pentanol, and m-cresol.
  • Tonicity agents sometimes known as “stabilizers” are present to adjust or maintain the tonicity of liquid in a composition. When used with large, charged biomolecules such as proteins and antibodies, they are often termed “stabilizers” because they can interact with the charged groups of the amino acid side chains, thereby lessening the potential for inter- and intra-molecular interactions. Tonicity agents can be present in any amount between 0.1% to 25% by weight, or more preferably between 1% to 5% by weight, considering the relative amounts of the other ingredients.
  • Preferred tonicity agents include polyhydric sugar alcohols, preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol.
  • Non-ionic surfactants or detergents also known as “wetting agents” are present to help solubilize the therapeutic agent as well as to protect the therapeutic protein against agitation-induced aggregation, which also permits the formulation to be exposed to shear surface stress without causing denaturation of the active therapeutic protein or antibody.
  • Non-ionic surfactants are present in a range of about 0.05 mg/ml to about 1.0 mg/ml, preferably about 0.07 mg/ml to about 0.2 mg/ml.
  • Suitable non-ionic surfactants include polysorbates (20, 40, 60, 65, 80, etc.), polyoxamers (184, 188, etc.), PLURONIC ® polyols, TRITON ® , polyoxyethylene sorbitan monoethers (TWEEN ® -20, TWEEN ® -80, etc.), lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose.
  • Anionic detergents that can be used include sodium lauryl sulfate, dioctyle sodium sulfosuccinate and dioctyl sodium sulfonate.
  • Cationic detergents include benzalkonium chloride or benzethonium chloride.
  • the choice of pharmaceutical carrier, excipient or diluent may be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • Pharmaceutical compositions may additionally comprise any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s) or solubilizing agent(s).
  • compositions useful in the present invention may be formulated to be administered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestible solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route.
  • the pharmaceutical composition of the present disclosure is a lyophilized protein formulation.
  • the pharmaceutical composition may be an aqueous liquid formulation.
  • the prodrugs of the present invention can be used to treat a disease.
  • the prodrugs are used to treat cancer.
  • the prodrugs are used to treat an infection, for example, when the drug molecule is an antibacterial agent or an antiviral agent.
  • the method of treating a disease comprises administering to the subject an effective amount of the prodrugs disclosed herein.
  • the cancer is a solid cancer. In some embodiments, the cancer is a blood cancer or a solid tumor.
  • Exemplary cancers that may be treated include, but are not limited to, leukemia, lymphoma, kidney cancer, bladder cancer, urinary tract cancer, cervical cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, esophageal cancer, liver cancer, colorectal cancer, stomach cancer, squamous cell carcinoma, prostate cancer, pancreatic cancer, lung cancer such as non-small cell lung cancer, cholangiocarcinoma, breast cancer, and ovarian cancer, and medullary thyroid cancer.
  • the prodrugs are used to treat a bacterial infection such as sepsis.
  • the bacteria causing the bacterial infection are drug-resistant bacteria.
  • the antigen-binding moiety (carrier moiety) disclosed herein binds to a bacterial antigen.
  • the prodrugs are used to treat a viral infection.
  • the virus causing the viral infection is hepatitis C (HCV), hepatitis B (HBV), human immunodeficiency virus (HIV), a human papilloma virus (HPV).
  • the antigen-binding moiety disclosed herein binds to a viral antigen.
  • dosages and routes of administration of the present pharmaceutical compositions are determined according to the weight and conditions of the subject, according to standard pharmaceutical practice.
  • the pharmaceutical composition is administered to a subject through any route, including orally, transdermally, by inhalation, intravenously, intra-arterially, intramuscularly, direct application to a wound site, application to a surgical site, intraperitoneally, by suppository, subcutaneously, intradermally, transcutaneously, by nebulization, intrapleurally, intraventricularly, intra-articularly, intraocularly, intracranially, or intraspinally.
  • the composition is administered to a subject intravenously.
  • the dosage of the pharmaceutical composition is a single dose or a repeated dose.
  • the doses are given to a subject once per day, twice per day, three times per day, or four or more times per day. In some embodiments, about 1 or more (such as about 2, 3, 4, 5, 6, or 7 or more) doses are given in a week. In some embodiments, the pharmaceutical composition is administered weekly, once every 2 weeks, once every 3 weeks, once every 4 weeks, weekly for two weeks out of 3 weeks, or weekly for 3 weeks out of 4 weeks. In some embodiments, multiple doses are given over the course of days, weeks, months, or years. In some embodiments, a course of treatment is about 1 or more doses (such as about 2, 3, 4, 5, 7, 10, 15, or 20 or more doses).
  • the term “approximately” or “about” as applied to one or more values of interest refers to a value that is similar to a stated reference value. In certain embodiments, the term refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context.
  • Ref3 is an anti-PD-1 antibody-IL-2 mutein fusion molecule, which has a structure as illustrated in FIG.1C. It is a mouse analog of eciskafusp alfa which is currently in clinical development. [0069] All three molecules have the same anti-PD-1 antibody as that of mPD-1 molecule. 812mN-mut4 comprises two copies of the masked IL-2 mutein.
  • the human version (i.e., with anti-human PD-1 antibody, 812KN-mut4) of the fusion molecule 812mN-mut4 showed stronger in vitro cell-based biological activity than that of the human version (812KW5- mut4) of 812mW5-mut4, which comprises only one copy of the same masked IL-2 mutein (FIG.2).
  • the IL-2 mutein in Ref3 is not masked. It has the strongest in vitro cell-based IL-2 activity among the three molecules (FIG.2).
  • 812KW5-mut4 has weaker activity than 812KN-mut4 and the reference molecule Ref3.
  • the IL-2 moieties are the same between the human versions and the mouse versions.
  • FIG.3A and FIG.3B The in vivo efficacy and safety results of the two chimeric molecules, Ref3, and the anti-mouse PD-1 antibody are shown in FIG.3A and FIG.3B.
  • 812mW5- mut4 has similar anti-tumor efficacy as that of Ref3 (FIG.3A), yet 812mW5-mut4 is safer than Ref3 as there was no body weight drop for 812mW5-mut4, but significant body weight loss was observed with Ref3 (FIG.3B). It was also surprising that 812mW5-mut4 was observed to have stronger in vivo efficacy than that of 812mN-mut4, as the latter was expected to have stronger in vitro cell-based activity.
  • HEK-BlueTM IL-2 cells were generated by stable transfection of HEK 293 cells with the human CD25 (IL-2R ⁇ ), CD122 (IL-2R ⁇ ), and CD132 (IL-2R ⁇ ) genes, along with the human JAK3 and STAT5 genes.
  • STAT5-inducible secreted embryonic alkaline phosphatase (SEAP) reporter gene was also introduced.
  • SEAP embryonic alkaline phosphatase
  • the HEK Blue IL-2 reporter cell line was maintained at sub-confluent density in assay medium containing 1:250 dilution of HEK-Blue CLR selection and 1 ⁇ g/mL puromycin. Cells were harvested when reaching adherence, using CellstripperTM (Corning) to detach.
  • test articles Serial dilutions of test articles were performed in 96-well tissue culture plates in 50 ⁇ L/well assay medium. Cells were counted and adjusted to a concentration to 600,000 cells/mL. 50 ⁇ L/well (30,000 cells/well) were dispensed into assay plates containing sample dilutions. The assay plates were incubated overnight at 37 o C in a CO 2 incubator. 20 ⁇ L of supernatant was transferred then from the assay plates to ELISA plates. 180 ⁇ L QUANTI-BlueTM reagent (InvivoGen) was added to the plates and the plates were incubated at 37 o C for 1 hour. OD650 was measured using a microplate spectrophotometer.
  • ASKG812 EC comprises a first heavy chain polypeptide chain of SEQ ID NO:18, a second heavy chain polypeptide chain of SEQ ID NO:19, and two identical light chains of SEQ ID NO:20.
  • Example 3 Cynomolgus Monkey PK and PD Study [0073] One male cynomolgus monkey was dosed intravenously with test article ASKG812N at 5 mg/kg at Day 1 and Day 15, and 10 mg/kg at Day 40. Blood was sampled at pre-dose, 0, 5 min, 2 h, 8 h, 24 h, 48 h, 72 h, 120 h, 168 h, 240 h, and 336 h post-dose.
  • PK analysis serum samples were assayed for test article by ELISA. Briefly, ELISA plates were coated with 100 ⁇ L/well PD -1 (ACRO, Cat. #PD1-H5221) at 1 ⁇ g/mL in PBS. Plates were blocked with 100 ⁇ l/well of 3% BSA. After 2 hours of incubation and subsequent wash (four times with PBST), 100 ⁇ L of serum samples diluted in 1% BSA or standard was added to each well (1:100).
  • FIG. 5 shows the PK of ASKG812N in cynomolgus monkey
  • FIG. 6 shows the PK parameters and serum concentrations of ASKG812N in cynomolgus monkey.
  • FIG. 7 shows that ASKG812N significantly expanded CD4+ and CD8+ T cells, and Treg cells in cynomolgus monkey. It also expanded NK cells, though to a lesser extent. Those results demonstrate that ASKG812N was active in stimulating the immune system and preferentially expanded the T cells over NK cells.

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Abstract

L'invention concerne des promédicaments d'IL-2, ainsi que des méthodes d'utilisation de ceux-ci pour moduler le système immunitaire chez un sujet.
PCT/US2024/058527 2023-12-04 2024-12-04 Protéines chimériques comprenant de l'il-2 masquée Pending WO2025122660A1 (fr)

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Citations (4)

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WO2019173832A2 (fr) * 2018-03-09 2019-09-12 AskGene Pharma, Inc. Nouveaux promédicaments à base de cytokine
WO2020242884A1 (fr) * 2019-05-24 2020-12-03 Proviva Therapeutics (Hong Kong) Limited Compositions d'il-2 et leurs méthodes d'utilisation
WO2024119193A2 (fr) * 2022-12-02 2024-06-06 AskGene Pharma, Inc. Polypeptides d'il-2 mutants et promédicaments d'il-2

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WO2019173832A2 (fr) * 2018-03-09 2019-09-12 AskGene Pharma, Inc. Nouveaux promédicaments à base de cytokine
WO2020242884A1 (fr) * 2019-05-24 2020-12-03 Proviva Therapeutics (Hong Kong) Limited Compositions d'il-2 et leurs méthodes d'utilisation
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