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RU-2861706-C2 - MULTISPECIFIC ANTIBODIES AND USE THEREOF

RU2861706C2RU 2861706 C2RU2861706 C2RU 2861706C2RU-2861706-C2

Abstract

FIELD: biotechnology. SUBSTANCE: invention relates to an isolated antibody that specifically binds to IL-33, an isolated antibody that specifically binds to IL-33, specifically binds to IL-4 and specifically binds to IL-13, to methods for producing same, and also to a pharmaceutical composition containing such an antibody. Also disclosed are an isolated polynucleotide encoding an antibody that specifically binds to IL-33, an isolated polynucleotide encoding an antibody that specifically binds to IL-33, that specifically binds to IL-4 and that specifically binds to IL-13, as well as vectors and cells containing the above polynucleotides. EFFECT: treating a disease mediated by or associated with the activity of IL-4, IL-13, IL-33, TSLP and p40. 36 cl, 49 dwg, 87 tbl, 89 ex

Inventors

  • AGOSTINELLI, Rita Diane
  • JIN, FANG
  • KASAIAN, Marion Teresa
  • LAMBERT, MATTHEW ALLISTER
  • MARQUETTE, KIMBERLY ANN
  • MCMANUS, Virginie
  • MIN DEBARTOLO, Jessica Haewon
  • PICHE-NICHOLAS, NICOLE MELISSA
  • SHELDON, Richard Thomas
  • TCHISTIAKOVA, LIOUDMILA
  • ZHONG, XIAOTIAN
  • APGAR, James Reasoner
  • BARRON, Alexander Michael Shuford
  • BENNETT, ERIC MATTHEW
  • BLOOM, LAIRD
  • CHEN, TING
  • D'ANTONA, AARON MICHAEL
  • DE, ARNAB
  • GIESECK III, Richard Lee

Dates

Publication Date
20260508
Application Date
20230228
Priority Date
20220303

Claims (20)

  1. 1. An isolated antibody that specifically binds to IL-33, comprising the variable region of the heavy chain (IL33-VH) and the variable region of the light chain (IL33-VL) containing
  2. (i) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:73 and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:78;
  3. (ii) the CDR-H1, CDR-H2, and CDR-H3 sequences of SEQ ID NO:63 and the CDR-L1, CDR-L2, and CDR-L3 sequences of SEQ ID NO:71; or
  4. (iii) the CDR-H1, CDR-H2 and CDR-H3 sequences of SEQ ID NO:80 and the CDR-L1, CDR-L2 and CDR-L3 sequences of SEQ ID NO:81.
  5. 2. An isolated antibody that specifically binds to IL-33, comprising the variable region of the heavy chain (IL33-VH) and the variable region of the light chain (IL33-VL), wherein
  6. CDR-H1 contains the amino acid sequence SEQ ID NO:60;
  7. CDR-H2 contains the amino acid sequence SEQ ID NO:61;
  8. CDR-H3 contains the amino acid sequence SEQ ID NO:72;
  9. CDR-L1 contains the amino acid sequence SEQ ID NO:75;
  10. CDR-L2 comprises the amino acid sequence of SEQ ID NO:76, and
  11. CDR-L3 contains the amino acid sequence SEQ ID NO:77.
  12. 3. The antibody of claim 1 or 2, comprising an IL33-VH framework sequence derived from a human germline VH sequence selected from the group consisting of DP47, DP48, DP50, DP51, DP54 and DP77, and,
  13. optionally further comprising an IL33-VL framework sequence derived from a human germline VL sequence selected from the group consisting of DPK1, DPK3, DPK4, DPK5, DPK7, DPK8 and DPK9.
  14. 4. An antibody according to any one of claims 1-3, comprising
  15. (i) IL33-VH with the sequence of SEQ ID NO: 73 and IL33-VL with the sequence of SEQ ID NO: 78; or
  16. (ii) IL33-VH with the sequence of SEQ ID NO:63 and IL33-VL with the sequence of SEQ ID NO:71; or
  17. (iii) IL33-VH with the sequence of SEQ ID NO: 80 and IL33-VL with the sequence of SEQ ID NO: 81; or
  18. (iv) IL33-VH with a sequence encoded by the nucleic acid sequence of SEQ ID NO:202, and
  19. IL33-VL with a sequence encoded by the nucleic acid sequence SEQ ID NO:203;
  20. (v) a polypeptide sequence carrying IL33-VH encoded by the nucleic acid sequence of SEQ ID NO:190, and

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES The present invention relates to antibodies that specifically bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40. The present invention also relates to antibodies that bind to one of IL-4, IL-13, IL-33, or TSLP. The invention also relates to multispecific antibodies that specifically bind to IL-4 and IL-13 and at least one other target. The present invention relates to multispecific antibodies that bind to IL-4, IL-13, and one of IL-33, TSLP, or p40. The present invention also relates to related molecules, such as nucleic acids, encoding such antibodies or multispecific antibodies, compositions, and related methods, such as methods for producing and purifying such antibodies and multispecific antibodies, and their use in diagnostics and therapy. LINK TO THE SEQUENCE LIST "This application contains a sequence listing, which is provided electronically in .xml format and is incorporated herein by reference in its entirety. This .xml file, created on February 9, 2023, is named PC072799 Sequence Listing.xml and is 252 KB in size." LEVEL OF TECHNOLOGY The present invention relates to antibodies that specifically bind to one or more of IL-4, IL-13, IL-33, TSLP and p40, as well as compositions, methods and uses thereof, including the use of the antibodies of the present invention for the treatment of one or more diseases or conditions selected from the group consisting of atopic dermatitis, atopic dermatitis, asthma, cancer, COPD, food allergy, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, prurigo nodularis, keloids, bullous pemphigoid, chronic urticaria, IPE, scleroderma and systemic sclerosis, diabetic kidney disease, Behcet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergy, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis and hidradenitis suppurativa, including the treatment and prevention of one or more symptoms associated with the relevant disease or condition. IL-4 and IL-13 are key drivers of immune system activation, leading to inflammation, edema, fibrosis, and itch in atopic disorders (48, 49). IL-4 and IL-13 interact with cells through a common receptor consisting of IL-4Rα and IL-13Rα1 (type II receptor), expressed on monocytes, fibroblasts, keratinocytes, epithelial cells, smooth muscle cells, and other non-lymphoid cell types (29). IL-4 can also activate cells through IL-4Rα/IL-2Rγ (type I receptor), expressed on T cells, B cells, and monocytes. Engagement of IL-4Rα through either receptor activates STAT6, causing the induction of atopy-related genes (29). Although IL-4 and IL-13 may engage a common receptor and signaling pathway, differences in cytokine availability, localization, and receptor binding affinity result in distinct response profiles (49, 50). Further differentiation may result from the type I receptor (IL-4Rα/γc), which drives Th2 differentiation through IL-4 but not IL-13 (51), and the cell surface “decoy” IL-13Rα2, which mediates neutralization and depletion of IL-13 but not IL-4 (52, 53). The role of IL-4 and IL-13 in atopic disease is supported by genetic associations, extensive validation studies in preclinical models, and the clinical efficacy of neutralizing IL-4 and IL-13 in a range of atopic indications (48). The anti-IL-4Rα drug Dupixent® (dupilumab; Sanofi/Regeneron) blocks responses to both cytokines and is approved for the treatment of moderate-to-severe atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps, suggesting activity of IL-4 and IL-13 in these indications (54–56). Anti-IL-13 mAbs lebrikizumab (Lilly) (57) and tralokinumab (AdbryT M ; Leo Pharma) (58, 59) have also demonstrated efficacy in AD, with more limited activity in asthma (60, 61). The efficacy of anti-IL-13 mAbs in AD suggests that IL-13 neutralization plays a major role in the efficacy of Dupixent®. However, available meta-analyses (62, 63) indicate that Dupixent® has greater activity than lebrikizumab and tralokinumab, consistent with the additional benefit of IL-4 blockade. IL-33 is passively released during cell necrosis or tissue injury, suggesting that it may function as an alarmin that alerts the immune system after damage to endothelial or epithelial cells during infection, physical stress, or injury. IL-33 plays an important role in type 2 innate immunity by activating allergic inflammation-associated eosinophils, basophils, mast cells, macrophages, and innate lymphoid cells type 2 (ILC2) via its receptor ST2 (96). Thymic stromal lymphoprotein (TSLP) is an epithelial cytokine critical for the initiation and maintenance of inflammation. Tezspire® (tezepelumab, Amgen) is a TSLP antibody approved for the treatment of asthma. IL-4 and IL-13 are ass