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WO2025118126A1 - Utilisation d'un anticorps anti-il-17rb ou d'un fragment de liaison à l'antigène de celui-ci ou d'une composition - Google Patents

Utilisation d'un anticorps anti-il-17rb ou d'un fragment de liaison à l'antigène de celui-ci ou d'une composition Download PDF

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Publication number
WO2025118126A1
WO2025118126A1 PCT/CN2023/136312 CN2023136312W WO2025118126A1 WO 2025118126 A1 WO2025118126 A1 WO 2025118126A1 CN 2023136312 W CN2023136312 W CN 2023136312W WO 2025118126 A1 WO2025118126 A1 WO 2025118126A1
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seq
amino acid
acid sequence
antibody
use according
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English (en)
Chinese (zh)
Inventor
许展维
林坜桁
李伟民
胡玮聪
周启祥
梁瑞安
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Sinomab Bioscience Ltd
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Sinomab Bioscience Ltd
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Priority to PCT/CN2023/136312 priority Critical patent/WO2025118126A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • 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

Definitions

  • the present application belongs to the field of immunological drugs, and specifically, relates to the use of an anti-IL-17RB antibody or an antigen-binding fragment thereof, or a pharmaceutical composition comprising the same, in the preparation of a drug for treating FLG-related diseases.
  • the skin covers the entire human body and protects humans from various external stimuli. Damage to the barrier will lead to increased penetration of external antigens, which can easily induce skin inflammation. Persistent skin inflammation will in turn lead to further weakening of the skin barrier function. This will lead to a "vicious cycle" between the skin barrier and skin immunity.
  • Filaggrin (FLG) and its metabolites are key components for maintaining skin barrier function. For example, the lack of FLG is the main pathogenic factor of various skin diseases such as atopic dermatitis.
  • Atopic dermatitis is a chronic inflammatory skin disease that usually appears in childhood and can persist into adulthood. Over the past few decades, the prevalence and incidence of atopic dermatitis have continued to increase. Research data show that the prevalence in children is about 15% to 30%, and the prevalence in adults is as high as 10%, making atopic dermatitis the skin disease with the highest disease burden.
  • the pathogenesis of atopic dermatitis involves genetic susceptibility, immune and epidermal barrier dysfunction, and environmental factors. Itch is its primary symptom, and skin lesions can manifest as mild erythema or even severe lichenification of erythroderma.
  • glucocorticoids as the main treatment, can provide good relief, but they are not suitable for long-term use due to multiple side effects, and atopic dermatitis often recurs after cessation of use, so other treatments need to be combined to treat atopic dermatitis.
  • JAK inhibitors such as ruxolitinib, upadacitinib
  • calcineurin inhibitors PDE4 inhibitors
  • PDE4 inhibitors atopic dermatitis.
  • glucocorticoids as the main treatment, can provide good relief, but they are not suitable for long-term use due to multiple side effects, and atopic dermatitis often recurs after cessation of use, so other treatments need to be combined to treat atopic dermatitis.
  • the launch of upadacitinib sustained-release tablets provides more options for the treatment of patients with atopic dermatitis. After two weeks of application, the patient's skin lesions improved, and more patients achieved high levels of skin lesion clearance after 16
  • Dupixent TM is a fully human anti-IL-4/IL-13 monoclonal antibody. It was first approved by the FDA in March 2017 and was first approved for marketing in China in June 2020. It specifically binds to the IL-4R ⁇ subunit, thereby inhibiting the signal transduction of IL-4 and IL-13 and blocking the inflammatory response mediated by IL-4 and IL-13, thus it can be used to treat atopic dermatitis.
  • anti-IL-17RB antibodies can restore FLG expression in the skin of patients with allergic diseases or disorders (eg, dermatitis), thereby improving the skin barrier function and thereby achieving treatment of related diseases and disorders.
  • allergic diseases or disorders eg, dermatitis
  • the present application relates to a use of an isolated anti-IL-17RB antibody, or an antigen-binding fragment thereof, or a pharmaceutical composition comprising the same in the preparation of a drug for treating FLG-associated diseases, wherein the antibody comprises: HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, and HCDR3 shown in SEQ ID NO: 3; and/or, LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6.
  • the present application relates to an isolated anti-IL-17RB antibody, or an antigen-binding fragment thereof, or a pharmaceutical composition comprising the same for treating FLG-associated diseases, wherein the antibody comprises: HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2 and HCDR3 shown in SEQ ID NO: 3; and/or, LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5 and LCDR3 shown in SEQ ID NO: 6.
  • the present application relates to a method for treating FLG-associated diseases, comprising administering to a subject in need thereof an isolated anti-IL-17RB antibody, or an antigen-binding fragment thereof, or a pharmaceutical composition comprising the same, wherein the antibody comprises: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:2, and HCDR3 shown in SEQ ID NO:3; and/or, LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:6.
  • the present application relates to a drug for treating a FLG-associated disease, comprising an isolated anti-IL-17RB antibody, or an antigen-binding fragment thereof, or a pharmaceutical composition comprising the same, wherein the antibody comprises: HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, and HCDR3 shown in SEQ ID NO: 3; and/or, LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5 LCDR2 is shown and LCDR3 is shown as SEQ ID NO:6.
  • the anti-IL-17RB antibody described in the present application exhibits good affinity for IL-17RB (interleukin-17 receptor B), can reverse the downregulation of Th2-driven filaggrin expression, reduce the ILC2 population in the submental lymph nodes, weaken the secretion of IL-4, IL-5 and IL-13 by lymph node cells, significantly reduce epidermal hyperplasia, inhibit the infiltration of mast cells and eosinophils, and thereby restore the skin barrier to achieve the treatment of FLG-associated diseases.
  • IL-17RB interleukin-17 receptor B
  • the inventors also found through preclinical animal in vivo experiments that the anti-IL-17RB antibody described in the present application is more effective than upadacitinib in treating atopic dermatitis, especially in reducing itching and improving skin pathology.
  • Figure 1 Expression of filaggrin in terminally differentiated HaCaT cells after cytokine and anti-IL-17RB antibody hD9043 treatment.
  • A) Schematic representation of direct treatment of mature HaCaT cells with different agents; B) Schematic representation of co-culture between PBMC and mature HaCaT cells; C) Quantification of band intensity of filaggrin expression after direct treatment of mature HaCaT cells; D) Representative Western blot of filaggrin expression after co-culture; E) Quantification shows that 5 ⁇ g/mL anti-IL-17RB antibody hD9043 can significantly restore filaggrin levels in the presence of total alarmins. ***p ⁇ 0.001, **p ⁇ 0.01, *p ⁇ 0.05, analyzed by Student's t-test. N 3.
  • Figure 2 Development of an animal model of atopic dermatitis using DNFB.
  • ***p ⁇ 0.001 by two-way ANOVA with post hoc test. N 9.
  • FIG. 3 Anti-IL-17RB antibody hD9043 significantly reduced Th2 immunity in submental lymph nodes.
  • N 7-9.
  • By one-way ANOVA with post hoc test **p ⁇ 0.01, *p ⁇ 0.05 for C-E compared with IgG4+DNFB group.
  • N 6.
  • FIG. 4 Anti-IL-17RB antibody hD9043 significantly improves skin health by reducing epidermal thickness.
  • C-D Quantification showed that anti-IL-17RB antibody hD9043 could suppress DNFB-induced epidermal hyperplasia in dorsal skin and ears.
  • Student's t-test analysis ***p ⁇ 0.001 compared with saline control.
  • N 8-9.
  • FIG. 5 Under DNFB sensitization, anti-IL-17RB antibody hD9043 significantly inhibited the infiltration of eosinophils and mast cells into the dorsal skin and ear layers.
  • FIG. 6 Anti-IL-17RB antibody hD9043 attenuates Th2 inflammation in ear sections of DNFB-treated animals.
  • N 6.
  • FIG. 7 Anti-IL-17RB antibody hD9043 restores filaggrin expression in DNFB-treated animals.
  • B) Quantification confirmed that 5 mg/kg anti-IL-17RB antibody hD9043 can rescue filaggrin levels. *p ⁇ 0.05 compared with saline control by Student's t-test analysis. *p ⁇ 0.05 compared with IgG4+DNFB group by one-way ANOVA with post hoc test. N 5-6.
  • Figure 8 Summary of how anti-IL-17RB antibody (eg hD9043) administration rescues skin symptoms during AD progression.
  • anti-IL-17RB antibody eg hD9043
  • antibody herein refers to any protein or polypeptide that can specifically recognize and bind to an antigen, covering natural antibodies and artificial antibodies, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies, single-chain antibodies, single-domain antibodies, etc. that exhibit desired biological activity, and can be divided into 5 isotypes according to the heavy chain category, i.e., IgG, IgM, IgD, IgA and IgE.
  • isolated means that the target product (e.g., antibody, or antigen-binding fragment) has been separated from its natural environment.
  • an "antigen-binding fragment” or “antigen-binding portion” of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen.
  • antigen-binding fragments include, but are not limited to, Fab fragments, Fab' fragments, F(ab')2 fragments, Fd fragments, Fv fragments, dAb fragments, Isolated CDR regions, single-chain Fv molecules (scFv), etc.
  • isolated when referring to an antibody means that the antibody is substantially free of other cellular components with which it is naturally associated, for example, an isolated antibody can be one that is removed from its native or natural environment.
  • Humanized antibody refers to an antibody that contains complementarity determining regions (CDRs) derived from non-human animals and framework and constant regions derived from humans.
  • CDRs complementarity determining regions
  • variable region (V) refers to the region in which the amino acid sequence of the antibody light chain and heavy chain varies greatly, including the light chain variable region (VL) and the heavy chain variable region (VH).
  • constant region (C) refers to the region located at the carboxyl end of the antibody peptide segment and in which the amino acid sequence of the antibody light chain and heavy chain is relatively conserved, including the light chain constant region (CL) and the heavy chain constant region (CH).
  • CDR complementarity determining region
  • HVR hypervariable region
  • the CDRs of the heavy and light chains can be numbered starting from the N-terminus using a variety of numbering systems known in the art, for example, Kabat, Chothia, Aho, IMGT and Contact (see, Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition 1991, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Johnson et al., Nucleic Acids Res 2001, 29:205-206; Chothia & Lesk, J Mol Biol 1987, 196:901-917; Chothia et al., Nature 1989, 342:877-883).
  • the "percent identity" of an amino acid sequence refers to the percentage of the number of amino acid residues in the candidate sequence that are identical to the reference sequence as a percentage of the total number of amino acid residues in the candidate sequence, after the candidate sequence is aligned with the reference sequence and, if necessary, gaps are introduced to achieve the maximum percentage of sequence identity, and any conservative substitutions are not considered as part of the sequence identity.
  • Two or more sequences can be aligned to determine the percentage of sequence identity of the amino acid sequence by tools known in the art, such as BLASTp, ClustalW2 (see Higgins DG et al., Methods Enzymol 1996, 266: 383-402; Larkin MA et al., Bioinformatics 2007, 23: 2947-2948), ALIGN or Megalign (DNASTAR) software, etc.
  • tools known in the art such as BLASTp, ClustalW2 (see Higgins DG et al., Methods Enzymol 1996, 266: 383-402; Larkin MA et al., Bioinformatics 2007, 23: 2947-2948), ALIGN or Megalign (DNASTAR) software, etc.
  • X and Xaa are equivalent and refer to unspecified amino acids.
  • the scope of the term is specified by the definition in the relevant expression. In order to distinguish multiple "X"s in the same amino acid sequence, the multiple Xs that appear successively are numbered respectively (ie, written as Xn ) and the scope of the term is defined respectively.
  • subject and “individual” are used interchangeably herein and include mammals or non-mammalian vertebrates (e.g., chickens, emus, fish), including but not limited to domesticated animals (e.g., cows, sheep, cats, dogs, pigs, and horses), primates (e.g., humans, non-human primates such as monkeys), rabbits, and rodents (e.g., mice, rats, guinea pigs, hamsters), preferably humans.
  • mammals or non-mammalian vertebrates e.g., chickens, emus, fish
  • domesticated animals e.g., cows, sheep, cats, dogs, pigs, and horses
  • primates e.g., humans, non-human primates such as monkeys
  • rabbits e.g., mice, rats, guinea pigs, hamsters
  • rodents e.g., mice, rats, guinea pigs, hamsters
  • affinity refers to the intrinsic binding capacity of members of a binding pair to interact with each other.
  • affinity between one molecule of a binding pair and the other molecule can generally be expressed in terms of the equilibrium dissociation constant ( KD ).
  • treating means to alleviate, improve, relieve or delay a disease or its related symptoms, reduce or delay the onset or development of a disease or its related symptoms, reduce the risk of developing a disease or its related symptoms, maintain a disease or its related symptoms, produce a complete or partial reversal of a disease or its related symptoms, or cure a disease or its related symptoms.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the terms “comprise, comprises and comprising” or their equivalents are open-ended expressions, meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.
  • the anti-IL-17RB antibody of the present application can specifically recognize and bind to human IL-17RB, inhibit signal transduction downstream of the IL-17RB signaling pathway, and can reverse the downregulation of FLG expression driven by Th2, thereby reducing the ILC2 population in the lymph nodes.
  • the present application relates to the use of an isolated anti-IL-17RB antibody, or an antigen-binding fragment thereof, or a pharmaceutical composition comprising the same in the preparation of a medicament for treating FLG-associated diseases, wherein the antibody comprises: HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, and HCDR3 shown in SEQ ID NO: 3; and/or, LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6.
  • the present application relates to an isolated anti-IL-17RB antibody, or an antigen-binding fragment thereof, or a pharmaceutical composition comprising the same for treating FLG-associated diseases, wherein the antibody comprises: HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, and HCDR3 shown in SEQ ID NO: 3; and/or, LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6.
  • the present application relates to a drug for treating FLG-associated diseases, comprising an isolated anti-IL-17RB antibody, or an antigen-binding fragment thereof, or a pharmaceutical composition comprising the same, wherein the antibody comprises: HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, and HCDR3 shown in SEQ ID NO: 3; and/or, LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6.
  • the FLG-associated disease is at least one of atopic dermatitis, allergic rhinitis, eczema (e.g., eczema herpeticum), contact dermatitis (e.g., allergic contact dermatitis), urticaria, angioedema, psoriasis, dermatitis herpetiformis, bullous pemphigoid, pemphigus, epidermolysis bullosa, rosacea, ichthyosis, solar dermatitis, or symptoms related thereto.
  • atopic dermatitis e.g., allergic rhinitis, eczema (e.g., eczema herpeticum)
  • contact dermatitis e.g., allergic contact dermatitis
  • urticaria angioedema
  • psoriasis dermatitis herpetiformis
  • bullous pemphigoid pmphigu
  • the FLG-associated disease is atopic dermatitis or symptoms associated therewith.
  • the atopic dermatitis is infantile atopic dermatitis, childhood atopic dermatitis, or atopic dermatitis in youth and adulthood. In some specific embodiments, the atopic dermatitis is mild, moderate or severe atopic dermatitis.
  • a variety of methods for evaluating the severity of atopic dermatitis are known in the art, such as the Atopic Dermatitis Score (SCORAD), the Eczema Area and Severity Index Score (EASI), the Investigator's Global Scoring Method (IGA), the Itch Visual Analog Scale Score (VAS), etc., or simple and easy indicators can be used clinically to judge the severity of atopic dermatitis, such as: mild atopic dermatitis is a rash area of less than 5%; moderate atopic dermatitis is 5% to 10%, or the rash recurs; severe atopic dermatitis is skin lesions exceeding 10% of the body surface area, or the dermatitis is persistent, and the itching affects sleep violently.
  • SCORAD Atopic Dermatitis Score
  • EASI Eczema Area and Severity Index Score
  • IGA Investigator's Global Scoring Method
  • VAS Itch Visual Analog Scale Score
  • simple and easy indicators can be used clinically to judge the severity of
  • the associated symptoms of atopic dermatitis include dry skin, itchy skin, eczematous skin lesions (including erythema, papules, redness, swelling, blisters, skin erosions, and epidermal thickening), symptoms related to xeroderma, symptoms related to palmar dermatitis, white skin scratches, Hertoghe's sign, infraorbital wrinkles, periorbital halos (darkness around the eyes), pityriasis alba, low hairline, etc.
  • the anti-IL-17RB antibody comprises: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:12 or 13, and HCDR3 shown in SEQ ID NO:3; and/or, LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:6.
  • the anti-IL-17RB antibody comprises: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:12, and HCDR3 shown in SEQ ID NO:3; and/or, LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:6.
  • the anti-IL-17RB antibody comprises: a VH having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO:7 ( X1 VQLVQSGAEVKKPGASVKVSCKX2 SGYTFISYWMNWVRQAPGQGLEWMGRIDPYDSEIQYX3 QKFX4 X5 RVTX6 TRDTSISTAYMELSRLRSDDTAVYYCARSGGFDWFAYWGQGTLVTVSS); and/or a VH having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO:
  • the different amino acids in the amino acid sequence with at least 80% identity are mainly present (or all present) in the FR region (framework region).
  • the different amino acids in the amino acid sequence with at least 80% identity are mainly present (or all present) in the FR region (framework region).
  • the VH comprises an amino acid sequence shown in SEQ ID NO:7, optionally wherein the amino acid sequence has up to four (e.g., 1, 2, 3, 4) additional amino acid substitutions in the framework region.
  • the VH comprises the amino acid sequence shown in SEQ ID NO:7, wherein X3 is N. Further, X4 is K. Further, X5 is D. Further, X1 is Q. Further , X2 is A. Further, X6 is M.
  • the VH comprises the amino acid sequence shown in SEQ ID NO:7, wherein X1 is E. Further, X2 is T. Further, X6 is L.
  • the VH comprises the amino acid sequence shown in SEQ ID NO:7 , wherein X3 is A. Further, X4 is Q. Further, X5 is G. Further, X1 is E. Further, X2 is T. Further, X6 is L.
  • the anti-IL-17RB antibody comprises: a VH that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence shown in any one of SEQ ID NO: 8, 9 or 10; and/or a VL that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 11.
  • the different amino acids in the amino acid sequence with at least 80% identity are mainly present (or all present) in the FR region (framework region).
  • the anti-IL-17RB antibody comprises: a VH having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence set forth in SEQ ID NO: 8; and/or a VL having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence set forth in SEQ ID NO: 11.
  • the amino acids that differ in the amino acid sequence having at least 80% identity compared to the amino acid sequence set forth in SEQ ID NO: 8 or 11 are primarily present (or entirely present) in the FR region (framework region).
  • the anti-IL-17RB antibody comprises: a VH whose amino acid sequence is shown in SEQ ID NO:8, and a VL whose amino acid sequence is shown in SEQ ID NO:11.
  • the anti-IL-17RB antibody further comprises: a heavy chain constant region (CH) having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, 96%, 97%, 98%, 99% identity with the amino acid sequence shown in SEQ ID NO: 14 or 18.
  • the anti-IL-17RB antibody further comprises: a CH shown in SEQ ID NO: 14 or 18.
  • the anti-IL-17RB antibody further comprises a CH shown in SEQ ID NO: 18.
  • the anti-IL-17RB antibody further comprises a light chain constant region (CL), wherein the light chain constant region is selected from the constant region of a human ⁇ chain and a ⁇ chain, preferably a human ⁇ chain.
  • CL light chain constant region
  • the anti-IL-17RB antibody further comprises: a CL having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, 96%, 97%, 98%, 99% identity to the amino acid sequence shown in SEQ ID NO: 16.
  • the anti-IL-17RB antibody further comprises a CL shown in SEQ ID NO: 16.
  • the anti-IL-17RB antibody comprises a heavy chain that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, 96%, 97%, 98%, 99% identical to the amino acid sequence set forth in SEQ ID NO: 15, 19, 20, or 21.
  • the anti-IL-17RB antibody comprises a heavy chain set forth in SEQ ID NO: 15, 19, 20, or 21.
  • the anti-IL-17RB antibody comprises a heavy chain set forth in SEQ ID NO: 19.
  • the anti-IL-17RB antibody comprises a light chain that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, 96%, 97%, 98%, 99% identical to the amino acid sequence set forth in SEQ ID NO: 17.
  • the anti-IL-17RB antibody comprises a light chain set forth in SEQ ID NO: 17.
  • the anti-IL-17RB antibody is of IgG1, IgG2, IgG3 or IgG4 type, preferably IgG4 type.
  • the antigen-binding fragment of the isolated anti-IL-17RB antibody described herein is selected from a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fd fragment, a Fv fragment, a dAb fragment, an isolated CDR region, a scFv, and a nanobody.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
  • excipients described herein may be any pharmaceutically acceptable excipients, such as but not limited to solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, antioxidants, penetration enhancers, pH regulators, surfactants, diluents, etc.
  • pharmaceutically acceptable pharmaceutical excipients see, for example, Handbook of Pharmaceutical Excipients (4th edition), by R.C. Luo et al., translated by Zheng Junmin, 2005, Chemical Industry Press.
  • the pharmaceutical composition further comprises another therapeutic agent, including but not limited to antiallergic drugs, analgesics, anti-inflammatory drugs, anesthetic drugs, drugs for reducing body temperature, etc.
  • the pharmaceutical composition further comprises another therapeutic agent for specific dermatitis, such as glucocorticoids (such as hydrocortisone butyrate, mometasone furoate, econazole/triamcinolone acetonide), calcineurin inhibitors (such as tacrolimus, pimecrolimus), antibiotics (such as amoxicillin clavulanate potassium, levofloxacin hydrochloride), antipruritic drugs (such as doxepin hydrochloride, diclofenac diethylamine, ketoprofen), antihistamines (such as loratadine, cetirizine hydrochloride, ebastine, chlorpheniramine maleate), JAK inhibitors (such as ruxolitinib, upadacin
  • the anti-IL-17RB antibody, or antigen-binding fragment thereof, or pharmaceutical composition comprising the same as described herein may be in the form of a sterile aqueous solution, suspension, emulsion, liposome formulation or powder.
  • the anti-IL-17RB antibody, or antigen-binding fragment thereof, or pharmaceutical composition comprising the same as described herein may be in the form of a unit dose, which is convenient for administration to a patient according to the desired dose.
  • the dosage range of the anti-IL-17RB antibody, or antigen-binding fragment thereof, or pharmaceutical composition comprising the same described herein can be determined empirically by a clinician based on the mode of administration (including administration time, administration interval, administration route), the patient's age, weight, gender or pathological condition, diet, excretion rate and sensitivity to the drug, etc.
  • anti-IL-17RB antibodies, or antigen-binding fragments thereof, or pharmaceutical compositions comprising the same described herein can be prepared into any dosage form known in the art, such as injections, suspensions, solutions, powders, emulsions, sprays, tablets, pills, capsules, granules, ointments, suppositories, gels, etc.
  • anti-IL-17RB antibodies, or antigen-binding fragments thereof, or pharmaceutical compositions comprising the same described herein may be suitable for intravenous, intramuscular, intraarterial, intraarticular, subcapsular, subarachnoid, intraorbital, intracardiac, subcutaneous, parenteral, intraperitoneal, intraspinal, intranasal or epidermal administration, e.g., by injection or infusion.
  • the present application relates to a method for treating FLG-associated diseases, comprising administering an isolated anti-IL-17RB antibody, or an antigen-binding fragment thereof, or a pharmaceutical composition comprising the same to a subject in need thereof, wherein the antibody comprises: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:2, and HCDR3 shown in SEQ ID NO:3; and/or, LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:6.
  • a therapeutically effective amount or a prophylactic effective amount of an anti-IL-17RB antibody, or an antigen-binding fragment thereof, or a pharmaceutical composition comprising the same is administered to a subject in need.
  • the therapeutically effective amount or the prophylactic effective amount can be determined by a clinician according to the individual condition of the subject, the severity of the disease, gender, age, weight, mode of administration, etc. by conventional methods or experience.
  • the FLG-associated disease is atopic dermatitis, allergic rhinitis, eczema (e.g., herpetic eczema), contact dermatitis (e.g., allergic contact dermatitis), urticaria, angioedema, psoriasis, dermatitis herpetiformis, bullous pemphigoid, pemphigus, epidermolysis bullosa, rosacea, ichthyosis, solar dermatitis, or at least one of its related symptoms.
  • eczema e.g., herpetic eczema
  • contact dermatitis e.g., allergic contact dermatitis
  • urticaria edema
  • psoriasis dermatitis herpetiformis
  • bullous pemphigoid e.g., pemphigus
  • epidermolysis bullosa rosacea
  • the FLG-associated disease is atopic dermatitis or symptoms associated therewith.
  • the atopic dermatitis is infantile atopic dermatitis, childhood atopic dermatitis, or youth and adult atopic dermatitis. In some specific embodiments, the atopic dermatitis is mild, moderate or severe atopic dermatitis.
  • the associated symptoms of the atopic dermatitis include dry skin, itchy skin, eczematoid skin lesions (including erythema, papules, redness, blisters, skin erosions, epidermal thickening), dry skin disease related symptoms, palmar dermatitis related symptoms, white skin scratch disease, Hertoghe sign, infraorbital wrinkles, periorbital black halo (dark around the eyes), white pityriasis, low hairline, etc.
  • the anti-IL-17RB antibody comprises: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:12 or 13, and HCDR3 shown in SEQ ID NO:3; and/or, LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:6.
  • the anti-IL-17RB antibody comprises: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:12, and HCDR3 shown in SEQ ID NO:3; and/or, LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:6.
  • the anti-IL-17RB antibody comprises: an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, and/or a VL that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 11.
  • the different amino acids in the amino acid sequence with at least 80% identity are mainly present (or all present) in the FR region (framework region).
  • the different amino acids in the amino acid sequence with at least 80% identity are mainly present (or all present) in the FR region (framework region).
  • the VH comprises an amino acid sequence shown in SEQ ID NO:7, optionally wherein the amino acid sequence has up to four additional amino acid substitutions in the framework region.
  • the VH comprises the amino acid sequence shown in SEQ ID NO:7, wherein X3 is N. Further, X4 is K. Further, X5 is D. Further, X1 is Q. Further , X2 is A. Further, X6 is M.
  • the VH comprises the amino acid sequence shown in SEQ ID NO:7, wherein X1 is E. Further, X2 is T. Further, X6 is L.
  • the VH comprises the amino acid sequence shown in SEQ ID NO:7 , wherein X3 is A. Further, X4 is Q. Further, X5 is G. Further, X1 is E. Further, X2 is T. Further, X6 is L.
  • the anti-IL-17RB antibody comprises: a VH that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence shown in any one of SEQ ID NO: 8, 9 or 10; and/or a VL that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence shown in SEQ ID NO: 11.
  • the different amino acids in the amino acid sequence with at least 80% identity are mainly present (or all present) in the FR region (framework region).
  • the anti-IL-17RB antibody comprises: a VH having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence set forth in SEQ ID NO: 8; and/or a VL having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence set forth in SEQ ID NO: 11.
  • the amino acids that differ in the amino acid sequence having at least 80% identity compared to the amino acid sequence set forth in SEQ ID NO: 8 or 11 are primarily present (or entirely present) in the FR region (framework region).
  • the anti-IL-17RB antibody comprises: a VH whose amino acid sequence is shown in SEQ ID NO:8, and a VL whose amino acid sequence is shown in SEQ ID NO:11.
  • the anti-IL-17RB antibody further comprises: a heavy chain constant region (CH) having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity with the amino acid sequence shown in SEQ ID NO: 14 or 18.
  • the anti-IL-17RB antibody further comprises: a CH shown in SEQ ID NO: 14 or 18.
  • the anti-IL-17RB antibody further comprises a CH shown in SEQ ID NO: 18.
  • the anti-IL-17RB antibody further comprises a light chain constant region (CL), wherein the light chain constant region is selected from the constant region of a human ⁇ chain and a ⁇ chain, preferably a human ⁇ chain.
  • CL light chain constant region
  • the anti-IL-17RB antibody further comprises: a CL having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity to the amino acid sequence shown in SEQ ID NO: 16.
  • the anti-IL-17RB antibody further comprises a CL shown in SEQ ID NO: 16.
  • the anti-IL-17RB antibody comprises a heavy chain that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 15, 19, 20, or 21.
  • the anti-IL-17RB antibody comprises a heavy chain set forth in SEQ ID NO: 15, 19, 20, or 21.
  • the anti-IL-17RB antibody comprises a heavy chain set forth in SEQ ID NO: 19.
  • the anti-IL-17RB antibody comprises a light chain that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 17.
  • the anti-IL-17RB antibody comprises a light chain set forth in SEQ ID NO: 17.
  • the anti-IL-17RB antibody is of IgG1, IgG2, IgG3 or IgG4 type, preferably IgG4 type.
  • the antigen-binding fragment of the isolated anti-IL-17RB antibody described herein is selected from a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fd fragment, a Fv fragment, a dAb fragment, an isolated CDR region, a scFv, and a nanobody.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
  • excipients described herein may be any pharmaceutically acceptable excipients, such as but not limited to solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, antioxidants, penetration enhancers, pH regulators, surfactants, diluents, etc.
  • pharmaceutically acceptable pharmaceutical excipients see, for example, Handbook of Pharmaceutical Excipients (4th edition), by R.C. Luo et al., translated by Zheng Junmin, 2005, Chemical Industry Press.
  • the pharmaceutical composition further comprises another therapeutic agent, including but not limited to antiallergic drugs, analgesics, anti-inflammatory drugs, anesthetic drugs, drugs for reducing body temperature, etc.
  • the pharmaceutical composition further comprises another therapeutic agent for specific dermatitis, such as glucocorticoids (such as hydrocortisone butyrate, mometasone furoate, econazole/triamcinolone acetonide), calcineurin inhibitors (such as tacrolimus, pimecrolimus), antibiotics (such as amoxicillin clavulanate potassium, levofloxacin hydrochloride), antipruritic drugs (such as doxepin hydrochloride, diclofenac diethylamine, ketoprofen), antihistamines (such as loratadine, cetirizine hydrochloride, ebastine, chlorpheniramine maleate), JAK inhibitors (such as ruxolitinib, upadacin
  • the subject is selected from a human, a non-human primate or a murine, preferably a human.
  • Humanized anti-IL-17RB antibodies hD9040, hD9041 and hD9042 were prepared according to the method disclosed in the "Experiments" section of WO2020115319A1, and IgG4 antibody hD9043 was prepared according to the method therein.
  • the humanized antibody has similar EC 50 values for binding to human IL-17RB by ELISA test, and has good binding affinity to human IL-17RB by Biacore test.
  • the humanized antibody also exhibits good high temperature thermal stability, no aggregation problem, low nonspecific interaction tendency and good solubility.
  • the anti-IL-17RB antibody used in the following examples is the humanized anti-IL-17RB antibody hD9043 prepared above.
  • Filaggrin is an important protein for the development and maintenance of the skin barrier to protect the host from pathogens, allergens, and UV-induced damage. Clinical studies have clearly shown that clinical severity is associated with barrier impairment in filaggrin-related eczema AD (Hasebe et al., J Invest Dermatol., 2009; 129(3): 682-9). Filaggrin levels are downregulated in both unaffected and lesional skin of AD (Howell et al., J Allergy Clin Immunol., 2007; 120(1): 150-155). In addition, null mutations in FLG (the gene encoding filaggrin) are strong genetic factors for AD. FLG null mutations have been shown to be associated with the severity and persistence of AD in adulthood (Moosbrugger-Martinz et al., Int J Mol Sci., 2022; 23(10): 5318).
  • Th2 cytokines are secreted by Th2-associated immune cells to suppress the expression of filaggrin in keratinocytes, as shown in vitro (Howell et al., J Allergy Clin Immunol., 2007; 120(1):150-155; Howell et al., J Invest Dermatol., 2008; 128(9):2248-58) and in vivo ( et al., J Invest Dermatol., 2016; 136(3): 631-639). Since anti-IL-17RB antibodies have been shown to exhibit anti-Th2 immune function in PBMC cultures, it is necessary to test the efficacy of anti-IL-17RB antibodies in reversing Th2-driven downregulation of filaggrin.
  • HaCaT cells are immortalized human keratinocytes used to test the above phenomena in vitro. HaCaT cells were first terminally differentiated into mature keratinocytes and maintained in a medium containing 1.8 mM calcium chloride.
  • POC proof-of-concept
  • IL-25 had no effect on filaggrin levels in mature HaCaT cells
  • a co-culture system with PBMCs was developed to investigate how anti-IL-17RB antibodies could modulate filaggrin expression in mature HaCaT cells. Placed on top of each 12-well plate coated with mature HaCaT cells. Total alarmins (IL-25+IL-33+TSLP, 20 ng/mL each) and the antibody were given to PBMC and co-cultured with the bottom HaCaT cells for 6 days. Protein was harvested from HaCaT cells for Western blot analysis.
  • DNFB 1-fluoro-2,4-dinitrobenzene
  • 0.15% DNFB was prepared in a 3:1 mixture of acetone and olive oil prior to topical application. After anesthesia, the dorsal skin of the mice was shaved and stripped with tape to disrupt the skin barrier. 0.15% DNFB was applied to the dorsal skin (1 cm ⁇ 1 cm) and ears of the mice once a week for 4 weeks, as shown in Figure 2A.
  • Antibodies (anti-IL-17RB antibodies or isotype IgG4 controls) were injected intraperitoneally into each group of mice in the same dosing mode as DNFB. Tissues were harvested from mice 24 hours after the last antibody treatment. At the same time, a healthy mouse control group (also called a non-disease saline group) was set up, and normal saline (100 ⁇ L) was injected intraperitoneally into the mice in the same administration mode as DNFB.
  • DNFB normal saline
  • Each mouse was scored for dermatitis based on the degree of erythema, edema, dryness/scarring, and abrasions/erosions observed on the back skin. Each symptom was scored as 0 (none), 1 (mild), 2 (moderate), or 3 (severe). The total dermatitis score was the sum of these individual scores (Feng et al., Front Med (Lausanne)., 2022:9:843230). The data showed that a peak of dermatitis was observed on day 14, and the mice recovered on day 21, showing reduced inflammation and erosion and increased hair regeneration (Figure 2B). Quantification of dermatitis scores confirmed that all doses of anti-IL-17RB antibodies significantly improved skin symptoms compared with the IgG4 control group ( Figure 2C). All mice in the non-disease saline group showed no signs of dermatitis.
  • the ILC2 population was gated as Lin-/CD45+/ST2+/ICOS+ cells.
  • the results showed that anti-IL-17RB antibody showed a clear trend in reducing the ILC2 population in submental lymph nodes (Figure 3B).
  • Figure 3C-3E Consistent with the results of ILC2, after 1 day of DNFB restimulation, the secretion of IL-4, IL-5, and IL-13 by lymph node cells in the anti-IL-17RB antibody-treated group was attenuated ( Figure 3C-3E ).
  • ear and dorsal skin were isolated from animals after blood draw, fixed in 4% paraformaldehyde, dehydrated in increasing concentrations of ethanol, and embedded in paraffin. Five-micrometer sections were cut from tissue blocks by microtome and mounted on pre-coated slides.
  • Tissue sections were stained with hematoxylin-eosin to assess structural changes in the skin and ear layers after DNFB and anti-IL-17RB antibody treatment. Sections were dewaxed in two changes of xylene and rehydrated in decreasing concentrations of ethanol. After washing several times in water, sections were stained in hematoxylin solution for 1-2 minutes, washed in water to remove overstaining, and incubated in Scott tap water for 1 minute. Sections were dehydrated, stained in eosin solution for 1-2 minutes, and washed in 100% ethanol to remove overstaining. The stained sections were washed twice in xylene and then mounted with DPX mounting medium.
  • Impaired skin barrier function and epidermal thickening are often caused by Th2 inflammation and are used as indicators to assess the severity of AD (Kim et al., Allergy Asthma Proc., 2019; 40(2): 84-92).
  • Epidermal thickness was calculated in random areas in each image for quantification. Three to four images were analyzed for each animal. Representative images showed that 1 month of DNFB treatment altered the dorsal skin and ear layer in terms of increased epidermal and dorsal thickness, signs of perivasculitis, regular acanthosis, and spongiosis elongation of rete ridges, and anti-IL-17RB antibody could improve these symptoms (Figure 4A- Figure 4B). Quantification further confirmed that anti-IL-17RB antibody could significantly reduce DNFB-induced epidermal hyperplasia in the dorsal skin and ear layer ( Figure 4C- Figure 4D), indicating that disease severity was reduced during anti-IL-17RB antibody treatment.
  • Eosinophils and mast cells are two important cell types involved in the initiation and progression of AD (Kawakami et al., Curr Opin Immunol., 2009; 21(6): 666-678; Radonjic-Hoesli et al., Semin Immunopathol., 2021; 43(3): 393-409). Eosinophils and mast cells can form a positive loop, further enhancing the activation of Th2 and Th17, causing the transition of AD from the acute phase to the chronic phase. Therefore, it is necessary to clarify the role of anti-IL-17RB antibodies in mast cells and eosinophils.
  • mast cell infiltration To investigate mast cell infiltration, ear and dorsal skin sections were stained with 0.1% toluidine blue for 2-3 minutes to label mast cells and mounted in DPX mounting medium for microscopic analysis. Mast cells were labeled as light to dark purple cells under the microscope.
  • Th2 cytokines such as IL-4 and IL-13
  • filaggrin levels in the skin layer.
  • tissue sections were again stained by immunohistochemistry with anti-IL-4, anti-IL-13 and anti-filaggrin antisera.
  • DNFB could increase the secretion of IL-4 and IL-3, while anti-IL-17RB antibody could conversely suppress their expression in the ear (Fig. 6).
  • filaggrin in the epidermal and dorsal layers was also visualized and quantified. Consistent with the reduction of Th2 inflammation in the skin layer, anti-IL-17RB antibody could restore filaggrin levels and potentially improve the skin condition of DNFB-treated mice ( Figure 7).
  • Anti-IL-17RB antibodies can restore the skin barrier and reduce epidermal hyperplasia by suppressing Th2 immune responses, reducing eosinophil/mast cell infiltration, and restoring filaggrin expression in the skin layer.

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Abstract

Sont divulgués dans la présente demande un anticorps anti-IL-17RB isolé ou un fragment de liaison à l'antigène de celui-ci, ou une composition pharmaceutique le contenant, qui sont utilisés pour traiter des maladies associées à la FLG. L'anticorps anti-IL-17RB ou le fragment de liaison à l'antigène de celui-ci ou la composition pharmaceutique le contenant peut inverser la sous-expression de la filaggrine induite par les Th2, et peut ainsi traiter efficacement des maladies associées à la FLG.
PCT/CN2023/136312 2023-12-05 2023-12-05 Utilisation d'un anticorps anti-il-17rb ou d'un fragment de liaison à l'antigène de celui-ci ou d'une composition Pending WO2025118126A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120020985A1 (en) * 2009-04-06 2012-01-26 Medical Research Council Antibodies against il-17br
CN113260631A (zh) * 2018-12-07 2021-08-13 生命弧度公司 人源化的抗-il17br抗体
WO2023160610A1 (fr) * 2022-02-24 2023-08-31 Sinomab Bioscience Limited Protéines de liaison bispécifiques contre des alarmines et leurs utilisations
CN116802210A (zh) * 2020-11-16 2023-09-22 英国研究与创新署 用于治疗肠癌的组合物和方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120020985A1 (en) * 2009-04-06 2012-01-26 Medical Research Council Antibodies against il-17br
CN113260631A (zh) * 2018-12-07 2021-08-13 生命弧度公司 人源化的抗-il17br抗体
CN116802210A (zh) * 2020-11-16 2023-09-22 英国研究与创新署 用于治疗肠癌的组合物和方法
WO2023160610A1 (fr) * 2022-02-24 2023-08-31 Sinomab Bioscience Limited Protéines de liaison bispécifiques contre des alarmines et leurs utilisations

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