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JP-7855651-B2 - Multispecific antibodies and their use

JP7855651B2JP 7855651 B2JP7855651 B2JP 7855651B2JP-7855651-B2

Inventors

  • リタ ダイアン アゴスティネルリ
  • ファン ジン
  • マリオン テリーザ カサイアン
  • マシュー アリスター ランバート
  • キンバリー アン マルケット
  • ヴィルジニー マクメイナス
  • ジェシカ ヘーウォン ミン デバートロ
  • ニコール メリッサ ピチュ－ニコラス
  • リチャード トーマス シェルダン
  • リュドミラ チスティアコワ
  • シャオティアン ゾング
  • ジェームズ リザナー アプガー
  • アレクザンダー マイケル シュファード バロン
  • エリック マシュー ベネット
  • レアド ブルーム
  • ティン チェン
  • アーロン マイケル ダントナ
  • アーナブ ディー
  • リチャード リー ジーセック サード

Assignees

  • ファイザー・インク

Dates

Publication Date
20260508
Application Date
20240828
Priority Date
20230830

Claims (19)

  1. A pharmaceutical composition comprising an isolated antibody that specifically binds to IL-4, The antibody (i) contains the IL4-VH sequence of SEQ ID NO: 22 and the IL4-VL sequence of SEQ ID NO: 26 (ii) The IL4-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 200, and the IL4-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 201, (iii) A polypeptide sequence having IL4-VH encoded by the nucleic acid sequence of SEQ ID NO: 188, and a polypeptide sequence having IL4-VL encoded by the nucleic acid sequence of SEQ ID NO: 189, (iv) Sharing at least 90% amino acid sequence identity with an IL4-VH sequence encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127198, and an IL4-VL sequence encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127197, or (v) Sharing at least 90% amino acid sequence identity with a polypeptide sequence having IL4-VH encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127192, and a polypeptide sequence having IL4-VL encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127194, The antibody has an IC50 of less than 25 pM, as measured in a human monocyte assay for IL-4 induction neutralization of CD23. The antibody, in a buffer of 20 mM histidine, 8.5% sucrose, and 0.05 mg/mL EDTA pH 6.0, is at a concentration of at least 100 mg/mL and has a viscosity of less than 20 cP. The antibody comprises CDR-H1 containing the amino acid sequence of SEQ ID NO: 18, CDR-H2 containing the amino acid sequence of SEQ ID NO: 2, CDR-H3 containing the amino acid sequence of SEQ ID NO: 3, CDR-L1 containing the amino acid sequence of SEQ ID NO: 24, CDR-L2 containing the amino acid sequence of SEQ ID NO: 12, and CDR-L3 containing the amino acid sequence of SEQ ID NO: 25. Pharmaceutical composition.
  2. below: (i) The antibody binds to human IL-4 at a KD value less than a value selected from the group consisting of approximately 10 pM, 5 pM, 1 pM, and 800 fM. (ii) The antibody binds to cynomolgus monkey IL-4. (iii) The antibody does not bind to IL-4 derived from one or more species selected from the group consisting of dogs, sheep, rabbits, rats, and mice. (iv) The binding KD of the antibody to cynomolgus monkey IL-4 is within one order of magnitude of the binding KD of the antibody to human IL-4. (v) The antibody is characterized by an IC50 of less than 10 pM in a human monocyte assay for IL-4 induction neutralization of CD23. (vi) The antibody, at a concentration of 80 mg/mL in histidine-sucrose buffer at pH 5.8, has a viscosity of 20 cP or less at 25°C. (vii) The pharmaceutical composition according to claim 1, characterized by one or more of the following: the antibody contains lysine at residue 93 in its light chain.
  3. The pharmaceutical composition according to claim 1, further comprising an isolated antibody that specifically binds to IL-4 and an antibody that specifically binds to IL-13.
  4. The pharmaceutical composition according to claim 3, wherein the antibody comprises a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), CDR-H1 comprises the amino acid sequence of SEQ ID NO: 41, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 42, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 50, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 53, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 37, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 38.
  5. below: (i) the IL13-VH sequence of sequence number 51 and the IL13-VL sequence of sequence number 54; (ii) the IL13-VH sequence of sequence number 44 and the IL13-VL sequence of sequence number 46. (iii) IL13-VH sequence of sequence number 48, and IL13-VL sequence of sequence number 49, (iv) IL13-VH sequence of sequence number 48, and IL13-VL sequence of sequence number 58, (v) The IL13-VH sequence of sequence number 57 and the IL13-VL sequence of sequence number 59, (vi) The IL13-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 198, and the IL13-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 199, (vii) A polypeptide sequence having IL13-VH encoded by the nucleic acid sequence of SEQ ID NO: 187, and a polypeptide sequence having IL13-VL encoded by the nucleic acid sequence of SEQ ID NO: 188, (viiii) an IL13-VH sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127196, and an IL13-VL sequence deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127195, or (ix) a polypeptide sequence having IL13-VH, deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127193, and a polypeptide sequence having IL13-VL, deposited with ATCC and encoded by a plasmid having ATCC accession number PTA-127192, according to claim 3.
  6. below: (i) The antibody binds to human IL-13 with a KD of less than a value selected from the group consisting of 10 nM, 5 nM, 2 nM, 1 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM, and 60 pM. (ii) The antibody binds to cynomolgus monkey IL-13 by arbitrary selection, within one order of magnitude of the KD ratio of the antibody to human IL-13. (iii) The IC50 of IL-13 in HT29 cells The concentration was measured by neutralization of pSTAT6 phosphorylation and was less than 100 pM. (iv) The IC50 of IL-13 is less than 20 pM as measured in a human monocyte assay for IL-13 induction of CD23. (v) The antibody has a terminal phase half-life of at least 14 days in cynomolgus monkeys. (vi) The antibody has a terminal phase half-life of at least 18 days in TG32 mice. (vii) The pharmaceutical composition according to claim 5, wherein the antibody is characterized by one or more non-binding antibodies derived from one or more species selected from the group consisting of dogs, rabbits, and mice.
  7. (i) The second and fifth polypeptide chains together form a first Fab domain containing the first antigen-binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain containing a second antigen-binding site, (iii) comprising first, second, third, fourth, and fifth polypeptide chains such that the first and third polypeptide chains together form a third Fab domain containing a third antigen-binding site, The first and second polypeptide chains associate together to form an antibody comprising two arms: a double Fab arm containing the first Fab domain and the second Fab domain, and a single Fab arm containing the third Fab domain. The antibody according to claim 3, (i') The first antigen-binding site specifically binds to IL-13, the second antibody-binding site specifically binds to IL-4, and the third antigen-binding site specifically binds to at least one additional target, (ii') The first antigen-binding site specifically binds to IL-4, the second antibody-binding site specifically binds to IL-13, and the third antigen-binding site specifically binds to at least one additional target, (iii') The first antigen-binding site specifically binds to IL-4, the second antibody-binding site specifically binds to at least one additional target, and the third antigen-binding site specifically binds to IL-13, (iv') The first antigen-binding site specifically binds to IL-13, the second antibody-binding site specifically binds to at least one additional target, and the third antigen-binding site specifically binds to IL-4, (v') The first antigen-binding site specifically binds to at least one additional target, the second antibody-binding site specifically binds to IL-13, and the third antigen-binding site specifically binds to IL-4, or (vi') The first antigen-binding site specifically binds to at least one additional target, the second antibody-binding site specifically binds to IL-4, and the third antigen-binding site specifically binds to IL-13. A pharmaceutical composition comprising the antibody described in claim 3.
  8. The antibody according to claim 3, further comprising an antibody that specifically binds to at least one additional target, comprising first, second, third, fourth, and fifth polypeptide chains, wherein the identity of the second, fourth, and fifth polypeptide chains is (i) The second polypeptide chain includes SEQ ID NO: 130, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO: 122. (ii) The second polypeptide chain includes SEQ ID NO: 133, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO: 122. (iii) The second polypeptide chain contains SEQ ID NO: 135, the fourth polypeptide chain contains SEQ ID NO: 136, and the fifth polypeptide chain contains SEQ ID NO: 122. (iv) The second polypeptide chain contains SEQ ID NO: 140, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122. (v) The second polypeptide chain contains SEQ ID NO: 149, the fourth polypeptide chain contains SEQ ID NO: 196, and the fifth polypeptide chain contains SEQ ID NO: 150. (vi) The second polypeptide chain contains SEQ ID NO: 154, the fourth polypeptide chain contains SEQ ID NO: 196, and the fifth polypeptide chain contains SEQ ID NO: 155. (vii) The second polypeptide chain contains SEQ ID NO: 152, the fourth polypeptide chain contains SEQ ID NO: 196, and the fifth polypeptide chain contains SEQ ID NO: 98. A pharmaceutical composition comprising an antibody, selected from the group consisting of (viiii) a second polypeptide chain comprising SEQ ID NO: 160, a fourth polypeptide chain comprising SEQ ID NO: 196, and a fifth polypeptide chain comprising SEQ ID NO: 158, and (ix) a second polypeptide chain comprising SEQ ID NO: 125, a fourth polypeptide chain comprising SEQ ID NO: 27, and a fifth polypeptide chain comprising SEQ ID NO: 122.
  9. It comprises the first, second, third, fourth, and fifth polypeptide chains, (i) The second and fifth polypeptide chains together form a first Fab domain containing an IL-13 binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain containing an IL-4 binding site, (iii) The first and third polypeptide chains together form a third Fab domain containing at least one additional target binding site, The second polypeptide chain contains, in the direction from the N-terminus to the C-terminus, an optional linker including SEQ ID NO: 54, SEQ ID NO: 16, SEQ ID NO: 104, SEQ ID NO: 22, SEQ ID NO: 6, a CH2 domain, and a CH3 domain, the fourth polypeptide chain contains SEQ ID NO: 27, and the fifth polypeptide chain contains SEQ ID NO: 122. The pharmaceutical composition according to claim 8.
  10. The pharmaceutical composition according to claim 3, further comprising an antibody in which the antibody described in claim 3 specifically binds to TSLP.
  11. below: (i) A heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL) in which CDR-H1 contains the amino acid sequence of SEQ ID NO: 82, CDR-H2 contains the amino acid sequence of SEQ ID NO: 83, CDR-H3 contains the amino acid sequence of SEQ ID NO: 85, CDR-L1 contains the amino acid sequence of SEQ ID NO: 86, CDR-L2 contains the amino acid sequence of SEQ ID NO: 88, and CDR-L3 contains the amino acid sequence of SEQ ID NO: 90. (ii) CDR-H1 contains the amino acid sequence of SEQ ID NO: 82, CDR-H2 contains the amino acid sequence of SEQ ID NO: 83, CDR-H3 contains the amino acid sequence of SEQ ID NO: 85, CDR-L1 contains the amino acid sequence of SEQ ID NO: 86, CDR-L2 contains the amino acid sequence of SEQ ID NO: 88, and CDR-L3 contains the amino acid sequence of SEQ ID NO: 211, comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), (iii) CDR-H1 contains the amino acid sequence of SEQ ID NO: 82, CDR-H2 contains the amino acid sequence of SEQ ID NO: 83, CDR-H3 contains the amino acid sequence of SEQ ID NO: 85, CDR-L1 contains the amino acid sequence of SEQ ID NO: 86, CDR-L2 contains the amino acid sequence of SEQ ID NO: 88, and CDR-L3 contains the amino acid sequence of SEQ ID NO: 212, comprising a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL). The pharmaceutical composition according to claim 10, comprising one or more of the above.
  12. below: (i) the TSLP-VH sequence of sequence number 92 and the TSLP-VL sequence of sequence number 94, (ii) The TSLP-VH sequence of sequence number 92 and the TSLP-VL sequence of sequence number 93, (iii) The TSLP-VH sequence of sequence number 92 and the TSLP-VL sequence of sequence number 213, (iv) The TSLP-VH sequence of sequence number 92 and the TSLP-VL sequence of sequence number 214, (v) The TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204, and the TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 205, (vi) The TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204, and the TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 217, (vii) The TSLP-VH sequence encoded by the nucleic acid sequence of SEQ ID NO: 204, and the TSLP-VL sequence encoded by the nucleic acid sequence of SEQ ID NO: 218, (viiii) A polypeptide sequence having TSLP-VH encoded by the nucleic acid sequence of SEQ ID NO: 192, and a polypeptide sequence having TSLP-VL encoded by the nucleic acid sequence of SEQ ID NO: 193, (ix) A polypeptide sequence having TSLP-VH encoded by the nucleic acid sequence of SEQ ID NO: 192, and a polypeptide sequence having TSLP-VL encoded by the nucleic acid sequence of SEQ ID NO: 193, (x) A polypeptide sequence having TSLP-VH encoded by the nucleic acid sequence of SEQ ID NO: 192, and a polypeptide sequence having TSLP-VL encoded by the nucleic acid sequence of SEQ ID NO: 193, The pharmaceutical composition according to claim 10, comprising one or more of the following: (xi) a TSLP-VH sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127200; a TSLP-VL sequence deposited in ATCC and encoded by a plasmid having ATCC accession number PTA-127199; and (xi) a polypeptide sequence having TSLP-VH encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127202; and a polypeptide sequence having TSLP-VL encoded by a plasmid deposited in ATCC and having ATCC accession number PTA-127201.
  13. (i) In a TARC production bioassay in human peripheral blood monocytes, IC50 < 10 pM, (ii) Melting point of 68°C, (iii) The pH 3.4 hold ΔHMMS% is less than 5, such that the pH 3.4 hold ΔHMMS% is defined as the difference between the percentage of high molecular weight species resulting from the degradation of the antibody at pH 3.4 at room temperature after 5 hours of incubation and the percentage of high molecular weight species resulting from the degradation of the antibody at pH 7.2 at room temperature after 5 hours of incubation. (iv) Anti-TSLP bioactivity with an IC50 of less than 10 pM, as measured by a TARC production bioassay in primary human PBMCs. (v) A score of less than 2% of high molecular weight species, as determined by analytical size exclusion chromatography (aSEC), (vi) A score of less than 12 in the affinity capture self-interacting nanoparticle spectroscopy (AC SINS) assay, (vii) IC50 <15 pM in human TSLP neutralization in a TARC production bioassay in human primary PBMCs, and (viiii) IC50 <35 pM in a cynomolgus monkey TSLP neutralization assay. The pharmaceutical composition according to claim 12, characterized by one or more of the above.
  14. (i) The IL-4 binding domain comprises a heavy chain variable region (IL4-VH) and a light chain variable region (IL4-VL), CDR-H1 comprises the amino acid sequence of SEQ ID NO: 18, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 3, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 24, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 12, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 25. (ii) The IL-13 binding domain includes a heavy chain variable region (IL13-VH) and a light chain variable region (IL13-VL), CDR-H1 includes the amino acid sequence of SEQ ID NO: 41, CDR-H2 includes the amino acid sequence of SEQ ID NO: 42, CDR-H3 includes the amino acid sequence of SEQ ID NO: 50, CDR-L1 includes the amino acid sequence of SEQ ID NO: 53, CDR-L2 includes the amino acid sequence of SEQ ID NO: 37, and CDR-L3 includes the amino acid sequence of SEQ ID NO: 38. (iii) The TSLP-binding domain includes a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), and CDR-H1 includes the amino acid sequence of SEQ ID NO: 82, CDR-H2 includes the amino acid sequence of SEQ ID NO: 83, CDR-H3 includes the amino acid sequence of SEQ ID NO: 85, CDR-L1 includes the amino acid sequence of SEQ ID NO: 86, CDR-L2 includes the amino acid sequence of SEQ ID NO: 88, and CDR-L3 includes the amino acid sequence of SEQ ID NO: 90. Or (iv) the TSLP-binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), where CDR-H1 contains the amino acid sequence of SEQ ID NO: 82, CDR-H2 contains the amino acid sequence of SEQ ID NO: 83, CDR-H3 contains the amino acid sequence of SEQ ID NO: 85, CDR-L1 contains the amino acid sequence of SEQ ID NO: 86, CDR-L2 contains the amino acid sequence of SEQ ID NO: 87, and CDR-L3 contains the amino acid sequence of SEQ ID NO: 211. , or (v) the TSLP-binding domain comprises a heavy chain variable region (TSLP-VH) and a light chain variable region (TSLP-VL), where CDR-H1 comprises the amino acid sequence of SEQ ID NO: 82, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 83, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 85, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 86, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 87, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 212. The pharmaceutical composition according to claim 10.
  15. The first, second, third, fourth, and fifth polypeptide chains are included such that the second and fifth polypeptide chains together form a first Fab domain containing a first antigen-binding site, the second and fourth polypeptide chains together form a second Fab domain containing a second antigen-binding site, and the first and third polypeptide chains together form a third Fab domain containing a third antigen-binding site, and the identity of the first, second, third, fourth, and fifth polypeptide chains is, (i) The first polypeptide chain includes SEQ ID NO: 165, the second polypeptide chain includes SEQ ID NO: 130, the third polypeptide chain includes SEQ ID NO: 99, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO: 122. (ii) The first polypeptide chain includes SEQ ID NO: 165, the second polypeptide chain includes SEQ ID NO: 130, the third polypeptide chain includes SEQ ID NO: 215, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO: 122. (iii) The first polypeptide chain includes SEQ ID NO: 165, the second polypeptide chain includes SEQ ID NO: 130, the third polypeptide chain includes SEQ ID NO: 216, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO: 122. (iv) The first polypeptide chain includes a sequence encoded by the nucleic acid described in SEQ ID NO: 192, the second polypeptide chain includes a sequence encoded by the nucleic acid described in SEQ ID NO: 188, the third polypeptide chain includes a sequence encoded by the nucleic acid described in SEQ ID NO: 193, the fourth polypeptide chain includes a sequence encoded by the nucleic acid described in SEQ ID NO: 189, and the fifth polypeptide chain includes a sequence encoded by the nucleic acid described in SEQ ID NO: 187; and (v) The first polypeptide chain corresponds to ATCC deposit PTA-127202. The pharmaceutical composition according to claim 10, comprising a sequence encoded by a nucleic acid, wherein the second polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127192, the third polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127201, the fourth polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127194, and the fifth polypeptide chain comprises a sequence encoded by a nucleic acid corresponding to ATCC deposit PTA-127193, selected from the group.
  16. (i) The TSLP junction includes TSLP-VH of SEQ ID NO: 92 and TSLP-VL of SEQ ID NO: 94 (ii) The IL-4 binding portion includes IL4-VH of SEQ ID NO: 22 and IL4-VL of SEQ ID NO: 26, (iii) The IL-13 binding portion includes IL13-VH of SEQ ID NO: 51 and IL13-VL of SEQ ID NO: 54 The pharmaceutical composition according to claim 10.
  17. It comprises the first, second, third, fourth, and fifth polypeptide chains, (i) The second and fifth polypeptide chains together form a first Fab domain containing an IL-13 binding site, (ii) The second and fourth polypeptide chains together form a second Fab domain containing an IL-4 binding site, (iii) The first and third polypeptide chains together form a third Fab domain containing a TSLP binding site, The first polypeptide chain includes SEQ ID NO: 165, the second polypeptide chain includes SEQ ID NO: 130, the third polypeptide chain includes SEQ ID NO: 99, the fourth polypeptide chain includes SEQ ID NO: 27, and the fifth polypeptide chain includes SEQ ID NO: 122. The pharmaceutical composition according to claim 10.
  18. (i) In a buffer solution of 20 mM histidine, 8.5% sucrose, and 0.05 mg/mL EDTA at pH 6.0, at a concentration of at least 100 mg/mL, with a viscosity of less than 20 cP. (ii) In a buffer solution of 20 mM histidine, 8.5% sucrose, and 0.05 mg/mL EDTA at pH 6.0, at a concentration of at least 50 mg/mL, with a viscosity of less than 12 cP. (iii) In cynomolgus monkeys, the terminal phase half-life is at least 12 days. (iv) In TG-32 mice, the terminal phase half-life is at least 18 days. (v) To bind to human IL-4 with an affinity constant of less than 220 pM, as measured by SPR. (vi) To bind to human IL-13 with an affinity constant of less than 220 pM, as measured by SPR. (vii) Binding to human IL-4 with an affinity constant of less than 1 pM, as measured by KinExA in a fixed antigen assay in PBS. (viiii) In a fixed antigen assay in PBS, the affinity constant measured by KinExA is less than 2 pM, and the cynomolgus monkey IL-13 binds to this substance. (ix) An IC50 of less than 12 pM, as measured in a human monocyte assay for IL-4 induction of CD23 in cynomolgus monkeys. (x) IC50 < 12 pM as measured in a human monocyte assay for IL-13 induction of CD23 in cynomolgus monkeys. The pharmaceutical composition according to claim 5, characterized by one or more of the above.
  19. Atopic dermatitis, asthma, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, nodular prurigo, keloids, bullous pemphigoid, chronic urticaria, IPF, scleroderma, systemic sclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), cancer, bladder cancer, breast cancer, clear cell kidney cancer, squamous cell carcinoma of the head/neck, squamous cell carcinoma of the lung, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer (SCLC), triple-negative breast cancer, urothelial carcinoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B cell carcinoma Follicular lymphoma (DLBCL), follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myelocellular leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL), heme malignancy, acute lymphoblastic leukemia (ALL), acute bone marrow A pharmaceutical composition according to any one of claims 1 to 18 for use in one or more treatments selected from the group consisting of leukemia malformation (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma , follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), and small lymphocytic lymphoma (SLL).

Description

This invention relates to antibodies that specifically bind to one or more of IL-4, IL-13, IL-33, TSLP, and p40. The invention further relates to antibodies that bind to one of IL-4, IL-13, IL-33, or TSLP. The invention further relates to multispecific antibodies that specifically bind to IL-4 and IL-13, and at least one other target. The invention relates to multispecific antibodies that bind to one of IL-4, IL-13, IL-33, TSLP, or p40. The invention also relates to related molecules, e.g., nucleic acids encoding such antibodies or multispecific antibodies, compositions, and related methods, e.g., methods for producing and purifying such antibodies and multispecific antibodies, as well as their use in diagnostic and therapeutic methods. Background: 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 treatment and prevention of one or more symptoms associated with individual diseases or conditions, such as atopic dermatitis, asthma, cancer, COPD, food allergies, allergic rhinitis, eosinophilic esophagitis, chronic rhinosinusitis with nasal polyps, alopecia areata, nodular prurigo, keloids, bullous pemphigoid, chronic urticaria, IPF, and scleroderma. This includes the use of the antibodies of this disclosure to treat one or more diseases or conditions selected from the group consisting of systemic sclerosis, diabetic nephropathy, Behçet's disease, gout, Alzheimer's disease, atherosclerosis, fungal keratitis, non-alcoholic steatohepatitis (NASH), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, allergies, alopecia, idiopathic pulmonary fibrosis, systemic sclerosis, keloids, systemic lupus erythematosus (SLE), primary biliary cirrhosis, and hidradenitis suppurativa. IL-4 and IL-13 are key drivers of immune activation, leading to inflammation, edema, fibrosis, and pruritus in atopic disorders (48, 49). IL-4 and IL-13 interact with cells via a common receptor consisting of IL-4Rα and IL-13Rα1 (type II receptor), expressed in monocytes, fibroblasts, keratinocytes, epithelial cells, smooth muscle cells, and other non-lymphoid cell types (29). IL-4 can also activate cells via the common IL-4Rα/IL-2Rγ (type I receptor), expressed in T cells, B cells, and monocytes. Association of IL-4Rα via either receptor activates STAT6, inducing atopic-related genes (29). While IL-4 and IL-13 may be involved in common receptors and signaling pathways, differences in cytokine availability, localization, and receptor binding affinity result in distinct response profiles (49, 50). Further differentiation may arise from type I receptors (IL-4Rα/γc) (51) that drive Th2 differentiation via IL-4 rather than IL-13, and from cell surface "decoy" IL-13Rα2 (52, 53) that mediate the neutralization and depletion of IL-13 rather than IL-4. The roles of IL-4 and IL-13 in atopic diseases are supported by genetic associations, extensive validation in preclinical models, and the clinical efficacy of IL-4 and IL-13 neutralization 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, demonstrating the activity of IL-4 and IL-13 in these indications (54-56). The anti-IL-13 mAbs leburikizumab (Lilly) (57) and tralokinumab (Adbry®, Leo Pharma) (58, 59) have also demonstrated efficacy in AD, albeit with more limited activity in asthma (60, 61). The efficacy of anti-IL-13 mAbs in AD suggests a major role for IL-13 neutralization in the efficacy of Dupixent®. Nevertheless, available meta-analyses (62, 63) suggest that Dupixent® has superior activity to leburikizumab and tralokinumab, in line with the additional benefit of IL-4 blockade. IL-33 is passively released during cell necrosis or when tissue is damaged, suggesting that it may function as an alarmin that modifies the immune system after damage to endothelial or epithelial cells during infection, physical stress, or trauma. IL-33 plays a crucial role in type 2 innate immunity through the activation of eosinophils, basophils, mast cells, macrophages, and group 2 innate lymphoid cells (ILC2) associated with allergic inflammation via its receptor ST2 (96). Thymic interstitial lymphocyte necrosis factor (TSLP) is an important epithelial cytokine in the initiation and persistence of inflammation. Tezspire® (tezeperumab, Amgen) is a TSLP antibody approved for the treatment of asthma. IL-4 and IL-13 are primarily associated with type 2 effector responses. In contrast, IL-12 and IL-23 are involved in type 1 and type 3 (Th17) responses, respectively (77). IL-12 drives helper T1 (Th1) cell differentiation and interferon-γ (IFN-γ) production, while IL-23 promotes the maintenance of Th17 cells that produce IL-17 and other type 3 cytokines. Type 1 and