WO2024130541A1

WO2024130541A1 - IL-1α-TARGETING ANTIBODY OR ANTIGEN-BINDING FRAGMENT THEREOF AND USE THEREOF

Info

Publication number: WO2024130541A1
Application number: PCT/CN2022/140312
Authority: WO
Inventors: 李竹石; 朱燕; 邓涛; 赵真虎; 龙杨洋; 陈洪; 王颖
Original assignee: 成都优洛生物科技有限公司
Priority date: 2022-12-20
Filing date: 2022-12-20
Publication date: 2024-06-27
Also published as: CN117957250A

Abstract

An isolated anti-IL-1α antibody or an antigen-binding fragment thereof, a nucleic acid encoding same and a pharmaceutical composition comprising same, and the use of the antibody or the antigen-binding fragment thereof, the nucleic acid and the pharmaceutical composition for treating IL-1α-associated diseases.

Description

An antibody or antigen-binding fragment targeting IL-1α and its application

Technical Field

The present application relates to the field of antibody drug development, and in particular, to anti-IL-1α antibodies or antigen-binding fragments thereof, nucleic acids encoding the same, pharmaceutical compositions containing the same, and their uses in treating IL-1α-related diseases.

Background technique

Interleukin-1 (IL-1) is a cytokine belonging to the chemokine family, which can be synthesized and secreted by monocytes, macrophages, etc., including IL-1α and IL-1β. Among them, IL-1α is composed of 159 amino acids, encoded by the IL-1A gene, and can play an immunomodulatory role, such as activating CD4+T cells, promoting the formation of antibodies, improving antigen presentation by antigen presenting cells (APCs), and enhancing NK cell activity.

It has been reported that IL-1α can induce the activation of key transcription factors associated with inflammation and immune responses, such as nuclear factor κB (NF-κB), activator protein-1 (AP-1), c-Jun N-terminal kinase (JNK), p38 and other mitogen-associated protein kinases (MAPK), extracellular signal-regulated kinases (ERK) and interferon-regulated genes. Once activated, these signaling cascades promote the development of immune responses (Charles A. Dinarello, Annual Review of Immunology, Immunological and Inflammatory Functions of the Interleukin-1 Family, Vol. 27: 519-550). In the extracellular space, released or membrane-bound IL-1α binds to IL-1R1 on the cell surface and triggers a pro-inflammatory cascade. IL-1α is involved in autoimmune diseases, inflammatory diseases and cancer. For example, IL-1α is involved in diseases characterized by tissue or organ inflammation (such as pericarditis, myositis), destruction of barrier epithelium (such as skin diseases, respiratory diseases, colitis), and endothelial damage or thromboembolic activation (such as Behcet's syndrome, vasculitis) (Giulio Cavalli, Autoimmunity Reviews, Interleukin 1α: a comprehensive review on the role of IL-1α in the pathogenesis and treatment of autoimmune and inflammatory diseases, Vol. 20(3):102763); moreover, IL- IL-1α is a highly proinflammatory cytokine in the tumor microenvironment that often increases tumor growth and invasiveness and has been reported as a candidate target for anti-cancer therapy (Peleg Rider et al., Seminars in Immunology, Interleukin-1α, Vol. 25 (2013): 430-438; Kim Jun Cheng et al., Critical Reviews in Oncology/Hematology, IL-1α and colorectal cancer pathogenesis: Enthralling candidate for anti-cancer therapy, Vol. 163: 103-398).

In the art, a variety of antibodies have been developed against IL-1α, and the effects of anti-IL-1α antibodies on anti-cancer, inflammatory treatment, etc. have been studied, for example, see the following records: WO2012109373, WO2013043973, WO2020176738, WO2007135546, WO2009148575, CN102296050A, Liu Wenli et al. (Shanghai Journal of Immunology, Study on Immunomodulation of Lupus-Prone NZB/W F1 Mice by Anti-Mouse IL-1α and IL-6 Monoclonal Antibodies, Vol. 5: 270-272), Morten Svenson et al. (Cytokine, Effects of human anti-IL-1α autoantibodies on receptor binding and biological activities of IL-1, Vol. 4(2): 125-133). However, to date, no antibody drug targeting human IL-1α has been marketed. The only IL-1α antibody drug currently in clinical research, Bermekimab, is used in clinical studies to treat inflammatory diseases such as atopic dermatitis and suppurative hidradenitis, or to treat cancer (non-small cell lung cancer, pancreatic cancer, colorectal cancer, etc.).

Therefore, more antibodies targeting IL-1α need to be developed in order to obtain drugs with desired clinical benefits.

Summary of the invention

The present application relates to an isolated anti-IL-1α antibody or an antigen-binding fragment thereof, comprising:

(1) HCDR1 (heavy chain CDR1), HCDR2 (heavy chain CDR2) and HCDR3 (heavy chain CDR3), wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 1, 2 and 3, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences set forth in SEQ ID NOs: 1, 2 and 3;

(2) HCDR1, HCDR2 and HCDR3, wherein the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences set forth in SEQ ID NOs: 11, 12 and 13, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences set forth in SEQ ID NOs: 11, 12 and 13;

(3) HCDR1, HCDR2 and HCDR3, wherein the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences set forth in SEQ ID NOs: 21, 22 and 23, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences set forth in SEQ ID NOs: 21, 22 and 23; or

(4) HCDR1, HCDR2 and HCDR3, wherein the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NOs: 31, 32 and 33, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences shown in SEQ ID NOs: 31, 32 and 33.

Alternatively, the present application relates to an isolated anti-IL-1α antibody or an antigen-binding fragment thereof, comprising:

(a) HCDR1, HCDR2 and HCDR3, LCDR1 (light chain CDR1), LCDR2 (light chain CDR2) and LCDR3 (light chain CDR3), wherein HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3 or are identical to SEQ ID NOs: NOs: 1, 2 and 3 have an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NOs: 108, 5 and 6, respectively, and the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence shown in SEQ ID NOs: 108, 5 and 6, respectively, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NOs: 108, 5 and 6;

(b) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequences as shown in SEQ ID NOs: 11, 12 and 13, respectively, or have at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 151%, 152%, 153%, 154%, 155%, 156%, 157%, 158%, 159%, 160%, 161%, 162%, 163%, 164%, 165%, 166%, 167%, 168%, 169%, an amino acid sequence having at least 7%, 98% or 99% identity to an amino acid sequence of SEQ ID NOs: 14, 15 and 16, respectively, wherein LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences shown in SEQ ID NOs: 14, 15 and 16, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences shown in SEQ ID NOs: 14, 15 and 16;

(c) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequences as shown in SEQ ID NOs: 21, 22 and 23, respectively, or have at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% similarity to the amino acid sequences as shown in SEQ ID NOs: 21, 22 and 23, respectively. %, 98% or 99% identical amino acid sequences, wherein LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences shown in SEQ ID NOs: 24, 25 and 26, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences shown in SEQ ID NOs: 24, 25 and 26; or

(d) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequences as shown in SEQ ID NOs: 31, 32 and 33, respectively, or have at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 151%, 152%, 153%, 154%, 155%, 156%, 157%, 158%, 159%, 160%, 161%, 162%, 163%, 164%, 165%, 166%, 167%, 168%, 169%, The invention relates to an amino acid sequence having at least 7%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NOs: 34, 35 and 36, wherein LCDR1, LCDR2 and LCDR3 respectively comprise the amino acid sequence shown in SEQ ID NOs: 34, 35 and 36, or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NOs: 34, 35 and 36.

In some aspects, the present application relates to an isolated anti-IL-1α antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH), wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 47, 7, 17, 27, 37 or 39 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NO: 47, 7, 17, 27, 37 or 39.

(1) a heavy chain variable region and a light chain variable region (VL), wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 47 or is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NO: 47. The light chain variable region comprises the amino acid sequence of SEQ ID NO: 110 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 110;

(2) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:7, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:7, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:8, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:8;

(3) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:17, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:17, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:18, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:18;

(4) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:27, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:27, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:28, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:28;

(5) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:37, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:37, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:38, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:38;

(6) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 39 or has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO: 39. an amino acid sequence of the type A, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 109 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 109;

(7) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 39 or has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO: 39. an amino acid sequence of the type A, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 110 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 110;

(8) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:45, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:45;

(9) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 47 or has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO: 47. An amino acid sequence, wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 109 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth in SEQ ID NO: 109; or

(10) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 47 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 45 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 45.

In some aspects, the present application relates to an isolated anti-IL-1α antibody or an antigen-binding fragment thereof, comprising:

(1) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:112, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:112;

(2) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:9, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:9, and the light chain comprises the amino acid sequence of SEQ ID NO:10, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:10;

(3) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:19, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:19, and the light chain comprises the amino acid sequence of SEQ ID NO:20, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:20;

(4) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:29, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:29, and the light chain comprises the amino acid sequence of SEQ ID NO:30, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:30;

(5) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:112, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:112;

(6) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:111, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:111;

(7) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:46, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:46;

(8) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:111, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:111; or

(9) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 48 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 48, and the light chain comprises the amino acid sequence of SEQ ID NO: 46 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 46.

In some aspects, the present application relates to a polynucleotide encoding an anti-IL-1α antibody or an antigen-binding fragment thereof described herein.

In some aspects, the present application relates to a recombinant vector comprising a polynucleotide described herein.

In some aspects, the present application relates to a host cell comprising the vector described herein or having the polynucleotide described herein integrated into its genome.

In some aspects, the present application relates to a pharmaceutical composition comprising the anti-IL-1α antibody or antigen-binding fragment thereof described in the present application.

In some aspects, the present application relates to the use of the anti-IL-1α antibody or antigen-binding fragment thereof described herein, or the pharmaceutical composition described herein, in the preparation of a medicament for preventing or treating a disease associated with IL-1α. Alternatively, the present application relates to the anti-IL-1α antibody or antigen-binding fragment thereof described herein, or the pharmaceutical composition described herein, for preventing or treating a disease associated with IL-1α.

In some aspects, the present application relates to a method for preventing or treating an IL-1α-related disease, comprising administering the anti-IL-1α antibody or antigen-binding fragment thereof described herein, or the pharmaceutical composition described herein to a subject in need thereof.

The anti-IL-1α antibody or antigen-binding fragment thereof described herein can specifically bind to IL-1α (affinity constant can be below 1.149×10 ^-10 M), thereby blocking the binding of IL-1α to IL1R1 and IL1RAP. In addition, the cross-binding of the anti-IL-1α antibody or antigen-binding fragment thereof described herein to IL-1β is very weak, indicating that the antibody or antigen-binding fragment thereof described in the present application can have good selective specificity. In addition, the anti-IL-1α antibody or antigen-binding fragment thereof described herein can effectively block the release of IL-6, IL-8 and CCL20 induced by IL-1α, and therefore can exhibit the desired in vivo efficacy. The anti-IL-1α antibody or antigen-binding fragment thereof described herein can also exhibit good stability, low immunogenicity, and have good prospects for drugability.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 shows the activation effect of human IL-1α on reporter gene cell lines.

FIG. 2 is a graph showing the results of detecting the activities of mouse antibodies and the positive control MABP1 by the reporter gene method.

FIG. 3 is a graph showing the results of detecting the activities of the chimeric antibody and the positive control MABP1 by the reporter gene method.

FIG4 is an SDS-PAGE profile of humanized antibodies and chimeric antibodies.

FIG. 5 is a graph showing the results of detecting the activities of humanized antibodies and the positive control MABP1 by a reporter gene method.

6 is a graph showing the results of ELISA assays of the binding activities of humanized antibodies and the positive control MABP1 to human IL-1α (upper left subgraph), cynomolgus monkey IL-1α (upper right subgraph), mouse IL-1α (lower left subgraph), and rat IL-1α (lower right subgraph).

FIG. 7 is a graph showing the results of ELISA detection of the binding activities of humanized antibodies and positive control MABP1 to human IL-1β.

FIG8 shows the affinity test results of humanized antibodies to human IL-1α.

FIG. 9 shows the affinity test results of humanized antibodies to cynomolgus monkey IL-1α.

FIG. 10 is a graph showing the results of detecting the activities of humanized antibodies and the positive control MABP1 by a cytokine method.

FIG. 11 is a graph showing the results of detecting the activities of humanized antibody mutants expressed in CHO-K1 cells and the positive control MABP1 by a reporter gene method.

FIG. 12 shows the blocking effect of humanized antibody mutants on human IL-1α-induced mouse IL-6 release.

FIG. 13 shows the blocking effect of humanized antibody mutants on human IL-1α-induced mouse IL-8 release.

FIG. 14 shows the blocking effect of humanized antibody mutants on human IL-1α-induced mouse CCL20 release.

Detailed ways

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. See, for example, Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989); Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing Inc., New York, USA (2012); Abbas et al., Cellular and Molecular Immunology, Elsevier Science Health Science div (2009); He Wei et al., Medical Immunology (2nd ed.), People's Medical Publishing House, 2010.

Unless otherwise specified, the terms "comprise, comprises and comprising" or their equivalents (contain, contains, containing, include, includes, including) used herein are open-ended expressions and mean that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

Unless otherwise indicated, all numbers used herein expressing the amounts of ingredients, measurements or reaction conditions are to be understood as being modified in all cases by the term "about". When connected with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

Unless the context clearly indicates otherwise, singular terms herein include plural referents and vice versa. Similarly, the word "or" herein is intended to include "and" unless the context clearly indicates otherwise.

Unless otherwise stated, the terms "optional" or "optionally" as used herein mean that the object or event it modifies may or may not exist, or may or may not occur.

Unless otherwise indicated, the term "treatment" as used herein means that after administration, the disease or its related symptoms can be inhibited, contained, alleviated, improved, mitigated, relieved or eliminated, the progression of the disease or its related symptoms can be delayed, postponed, slowed, stopped or terminated, or the recurrence of the disease or its related symptoms can be prevented, controlled or reduced.

Unless otherwise indicated, the term "subject" as used herein encompasses any vertebrate, e.g., mammals and non-mammals, such as humans, non-human primates, sheep, dogs, cats, horses, cows, chickens, pigs, mice, etc. Preferably, the subject in the present application is a human. The term "subject" as used herein can be used interchangeably with the term "patient".

Unless otherwise indicated, the notation "Xaa" or "X" as used herein represents an unspecified amino acid.

In the present context, the percent identity (degree of homology) between sequences can be determined by comparing two sequences, for example, using freely available computer programs commonly used for this purpose on the World Wide Web (eg www.ncbi.nlm.nih.gov), such as BLASTp or BLASTn with default settings.

In some embodiments, the present application provides an isolated anti-IL-1α antibody or an antigen-binding fragment thereof, comprising:

In some embodiments, the anti-IL-1α antibody or antigen-binding fragment thereof provided herein further comprises:

(i) LCDR1 (light chain CDR1), LCDR2 (light chain CDR2) and LCDR3 (light chain CDR3), wherein LCDR1, LCDR2 and LCDR3 respectively comprise the amino acid sequences set forth in SEQ ID NOs: 108, 5 and 6, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences set forth in SEQ ID NOs: 108, 5 and 6;

(ii) LCDR1, LCDR2 and LCDR3, wherein LCDR1, LCDR2 and LCDR3 respectively comprise the amino acid sequences set forth in SEQ ID NOs: 14, 15 and 16, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences set forth in SEQ ID NOs: 14, 15 and 16;

(iii) LCDR1, LCDR2 and LCDR3, wherein LCDR1, LCDR2 and LCDR3 respectively comprise the amino acid sequences set forth in SEQ ID NOs: 24, 25 and 26, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences set forth in SEQ ID NOs: 24, 25 and 26; or

(iv) LCDR1, LCDR2 and LCDR3, wherein LCDR1, LCDR2 and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NOs: 34, 35 and 36 or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences shown in SEQ ID NOs: 34, 35 and 36.

Herein, the amino acid sequence QDIXSF shown in SEQ ID NO: 108 covers the sequence of the light chain CDR1 of the humanized antibody and the sequence of the mutated CDR1 obtained by mutating the asparagine residue (N) in the CDR1 to other amino acids. Herein, the X can be selected from I, N, F, V, S, R, A, T, E, G, H, K, L, P, W, Y, C, M, Q or D; in some embodiments, the X can be selected from I, N, F, V, S, R, A, T, E, G, H, K, L, P, W or Y; preferably, the X can be I, F, V, S, R, A or T.

In some embodiments, the LCDR1 may comprise an amino acid sequence selected from the group consisting of:

QDIQSF (SEQ ID NO: 115), or

In some embodiments, the anti-IL-1α antibody or antigen-binding fragment thereof provided herein comprises:

(1) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 50, 5 and 6, respectively;

(2) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 4, 5 and 6, respectively;

(3) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 49, 5 and 6, respectively;

(4) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 51, 5 and 6, respectively;

(5) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 52, 5 and 6, respectively;

(6) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 53, 5 and 6, respectively;

(7) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 54, 5 and 6, respectively;

(8) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 55, 5 and 6, respectively;

(9) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 56, 5 and 6, respectively;

(10) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 57, 5 and 6, respectively;

(11) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 58, 5 and 6, respectively;

(12) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 59, 5 and 6, respectively;

(13) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 60, 5 and 6, respectively;

(14) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 61, 5 and 6, respectively;

(15) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 62, 5 and 6, respectively;

(16) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 63, 5 and 6, respectively;

(17) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 113, 5 and 6, respectively;

(18) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 114, 5 and 6, respectively;

(19) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 115, 5 and 6, respectively;

(20) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 116, 5 and 6, respectively;

(21) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 11, 12 and 13, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 14, 15 and 16, respectively;

(22) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 21, 22 and 23, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 24, 25 and 26, respectively; or

(23) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 31, 32 and 33, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 34, 35 and 36, respectively.

The scope of the above-mentioned CDR has been defined according to the ImMunoGenTics (IMGT) numbering rules (see Lefranc, M.P., Unique database numbering system for immunogenetic analysis., Immunology Today, 18:509 (1997); Lefranc, M.P., The IMGT unique numbering for Immunoglobulins, T cell receptors and Ig-like domains, The Immunologist, 7:132-136 (1999)), but those skilled in the art will understand that CDR sequences numbered according to any one or more of the Kabat numbering rules, Chothia numbering rules, AbM numbering rules and Contact numbering rules (based on analysis of available complex crystal structures) also fall within the scope of protection of this application.

In some embodiments, the present application provides an isolated anti-IL-1α antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NOs: 47, 7, 17, 27, 37 or 39 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NOs: 47, 7, 17, 27, 37 or 39.

In some embodiments, the anti-IL-1α antibody or its antigen-binding fragment provided by the present application further comprises a light chain variable region, which comprises the amino acid sequence shown in SEQ ID NOs: 110, 8, 18, 28, 38, 45 or 109, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NOs: 110, 8, 18, 28, 38, 45 or 109.

In some embodiments, the present application relates to an isolated anti-IL-1α antibody or an antigen-binding fragment thereof, comprising:

(1) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:95, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:95;

(6) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:40, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:40;

(7) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:43, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:43;

(9) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:40, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:40;

(10) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:43, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:43;

(11) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:45, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:45;

(12) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 39 or has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence, wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:64, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth in SEQ ID NO:64;

(13) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:65, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:65;

(14) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:66, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:66;

(15) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:67, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:67;

(16) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:68, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:68;

(17) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:69, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:69;

(18) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:70, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:70;

(19) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:71, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:71;

(20) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:72, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:72;

(21) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:73, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:73;

(22) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:74, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:74;

(23) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:75, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:75;

(24) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:76, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:76;

(25) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:77, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:77;

(26) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:39, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:39, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:78, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:78;

(27) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:94, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:94;

(28) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:96, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:96;

(29) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:97, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:97;

(30) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:98, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:98;

(31) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:99, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:99;

(32) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 47 or has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO: 47. an amino acid sequence of the type A, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 100 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 100;

(33) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:64, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:64;

(34) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:65, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:65;

(35) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:66, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:66;

(36) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:67, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:67;

(37) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:47, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:68, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:68;

(38) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 47 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 69 Amino acid sequence; or

(39) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 47 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 70 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 70.

(1) a heavy chain variable region and a light chain variable region, the heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region having the amino acid sequence shown in SEQ ID NO: 95;

(2) a heavy chain variable region and a light chain variable region, the heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 7, and the light chain variable region having the amino acid sequence shown in SEQ ID NO: 8;

(3) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 17, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 18;

(4) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 27, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 28;

(5) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 37, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 38;

(6) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 40;

(7) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 43;

(8) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 45;

(9) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 40;

(10) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 43;

(11) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 45;

(12) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 64;

(13) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 65;

(14) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 66;

(15) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 67;

(16) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 68;

(17) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 69;

(18) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 70;

(19) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 71;

(20) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 72;

(21) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 73;

(22) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 74;

(23) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 75;

(24) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 76;

(25) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 77;

(26) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 78;

(27) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 94;

(28) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 96;

(29) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 97;

(30) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 98;

(31) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 99;

(32) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 100;

(33) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 64;

(34) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 65;

(35) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 66;

(36) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 67;

(37) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 68;

(38) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 69; or

(39) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 70.

In some embodiments, the anti-IL-1α antibody or antigen-binding fragment thereof provided by the present application further comprises a heavy chain constant region and a light chain constant region. Preferably, the heavy chain constant region is the constant region of human IgG1, IgG2, IgG3 or IgG4 (preferably the constant region of human IgG1 or IgG4), and the light chain constant region is the constant region of human antibody κ chain or λ chain; more preferably, the heavy chain constant region comprises the amino acid sequence shown in SEQ ID NO: 117 or has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 1177, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 151%, 152%, 153%, 154%, 155%, 156%, 157%, 158%, 15 and the light chain constant region comprises the amino acid sequence shown in SEQ ID NO:118 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NO:118.

(1) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:102, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:102;

(5) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:42, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:42;

(6) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:44, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:44;

(8) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:42, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:42;

(9) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:44, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:44;

(10) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:46, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:46;

(11) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:79, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:79;

(12) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:80, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:80;

(13) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:81, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:81;

(14) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:82, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:82;

(15) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:83, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:83;

(16) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:84, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:84;

(17) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:85, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:85;

(18) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:86, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:86;

(19) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:87, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:87;

(20) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:88, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:88;

(21) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:89, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:89;

(22) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:90, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:90;

(23) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:91, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:91;

(24) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:92, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:92;

(25) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:41, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:41, and the light chain comprises the amino acid sequence of SEQ ID NO:93, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:93;

(26) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:101, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:101;

(27) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:103, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:103;

(28) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:104, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:104;

(29) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:105, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:105;

(30) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:106, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:106;

(31) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:107, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:107;

(32) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:79, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:79;

(33) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:80, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:80;

(34) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:81, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:81;

(35) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:82, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:82;

(36) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:83, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:83;

(37) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:48, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:48, and the light chain comprises the amino acid sequence of SEQ ID NO:84, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:84; or

(38) A heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 48 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 48, and the light chain comprises the amino acid sequence of SEQ ID NO: 85 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 85.

In this article, for the heavy chain/heavy chain variable region or the light chain/light chain variable region, "an amino acid sequence that has at least 80% identity with the amino acid sequence shown in SEQ ID NO:..." may mean that the amino acids in the region other than CDR (such as the framework region or constant region) in the heavy chain/heavy chain variable region or the light chain/light chain variable region are changed, and after comparison with the sequence before the change, the changed sequence has at least 80% identity.

In some preferred embodiments, the present application provides an isolated anti-IL-1α antibody or an antigen-binding fragment thereof, comprising:

(1) a heavy chain and a light chain, the heavy chain having the amino acid sequence shown in SEQ ID NO: 48, and the light chain having the amino acid sequence shown in SEQ ID NO: 102;

(2) a heavy chain and a light chain, the heavy chain having the amino acid sequence shown in SEQ ID NO: 9, and the light chain having the amino acid sequence shown in SEQ ID NO: 10;

(3) a heavy chain and a light chain, the heavy chain having the amino acid sequence shown in SEQ ID NO: 19, and the light chain having the amino acid sequence shown in SEQ ID NO: 20;

(4) a heavy chain and a light chain, the heavy chain having the amino acid sequence shown in SEQ ID NO: 29, and the light chain having the amino acid sequence shown in SEQ ID NO: 30;

(5) a heavy chain and a light chain, the heavy chain having the amino acid sequence shown in SEQ ID NO: 41, and the light chain having the amino acid sequence shown in SEQ ID NO: 42;

(6) a heavy chain and a light chain, the heavy chain having the amino acid sequence shown in SEQ ID NO: 41, and the light chain having the amino acid sequence shown in SEQ ID NO: 44;

(7) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 46;

(8) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 42;

(9) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 44;

(10) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 46;

(11) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 79;

(12) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 80;

(13) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 81;

(14) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 82;

(15) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 83;

(16) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 84;

(17) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 85;

(18) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 86;

(19) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 87;

(20) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 88;

(21) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 89;

(22) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 90;

(23) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 91;

(24) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 92;

(25) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 93;

(26) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 101;

(27) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 103;

(28) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 104;

(29) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 105;

(30) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 106;

(31) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 107;

(32) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 79;

(33) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 80;

(34) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 81;

(35) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 82;

(36) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 83;

(37) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 84; or

(38) A heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 85.

In some embodiments, the anti-IL-1α antibody provided herein is a murine antibody, a chimeric antibody, or a humanized antibody.

In the present application, the anti-IL-1α antibody or its antigen-binding fragment may also be conservatively modified. Conservative modification refers to amino acid modification that does not significantly affect or change the binding properties of the antibody. For example, conservative amino acid substitution may be substitution with another amino acid of the same type (having similar chemical properties or functions). As an example, the amino acids can be divided into the following categories according to their side chain properties: (1) non-polar amino acids: Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M); (2) uncharged polar amino acids: Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q); (3) acidic amino acids: Asp (D), Glu (E); (4) basic amino acids: Lys (K), Arg (R), His (H). Alternatively, amino acids can be divided based on common side chain properties: (1) hydrophobic amino acids: Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic amino acids: Cys, Ser, Thr, Asn, Gln; (3) acidic amino acids: Asp, Glu; (4) basic amino acids: His, Lys, Arg; (5) amino acids that affect chain orientation: Gly, Pro; (6) aromatic amino acids: Trp, Tyr, Phe.

The anti-IL-1α antibodies or antigen-binding fragments thereof and variants thereof described in the present application can specifically bind to IL-1α.

In some embodiments, the antibodies or antigen-binding fragments thereof provided herein are selected from monoclonal antibodies, Fab fragments, Fab' fragments, F(ab')2 fragments, Fd fragments, Fv fragments, dAb fragments, isolated CDR regions, scFv and nanobodies.

As non-limiting examples, the anti-IL-1α antibodies or antigen-binding fragments thereof described herein may exhibit a combination of one or more of the following properties:

(1) Binds to human IL-1α with a _KD value of 1.149E-10M or less;

(2) blocking the binding of IL-1α to IL1R1 and IL1RAP;

(3) Blocking the release of IL-6, IL-8 and CCL20 induced by IL-1α.

In some embodiments, the present application provides a pharmaceutical composition comprising the anti-IL-1α antibody or antigen-binding fragment thereof described in the present application. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. Unless otherwise specified, the term "pharmaceutically acceptable excipient" used herein refers to any excipient known in the art that has no obvious irritation to an organism, is biocompatible with an active ingredient, and does not impair the activity and properties of the active ingredient.

The pharmaceutical composition of the present application may be suitable for parenteral, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal administration. For example, administration may be by injection or infusion, but is not limited thereto. Based on the route of administration, the active ingredient may be coated in different suitable materials to protect it from irritants (e.g., acids, alkalis, metal ions) and other natural conditions (e.g., high temperature, high humidity) that may inactivate it.

The pharmaceutical composition of the present application may be in the form of a sterile aqueous solution or dispersion. The anti-IL-1α antibody or antigen-binding fragment thereof described in the present application may also be formulated in a microemulsion (also known as a nanoemulsion) or a liposome.

The appropriate dosage of the anti-IL-1α antibody or antigen-binding fragment thereof described in the present application can be determined by a clinician according to factors such as the age, weight, sex, general condition, and severity of the disease of the subject. As an example, the dosage of the anti-IL-1α antibody or antigen-binding fragment thereof of the present application can be administered within a dosage range of about 0.0001 to 3000 mg/kg, such as 0.001 mg/kg, 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 3 mg/kg, 5 mg/kg, 10 mg/kg, 50 mg/kg, 100 mg/kg, 200 mg/kg, 500 mg/kg, 1000 mg/kg, 1200 mg/kg, 1500 mg/kg, 1800 mg/kg, 2000 mg/kg.

Those skilled in the art can adjust the dosage regimen to provide the best desired response (e.g., clinical response) based on common knowledge in the art. For example, a single large dose can be administered, multiple divided doses can be administered over time, or the single dose can be reduced or increased in proportion to the severity of the treatment situation. For example, when the antibody is administered as a sustained release formulation, it can be administered at a reduced frequency.

In some embodiments, the present application provides a polynucleotide encoding an anti-IL-1α antibody or an antigen-binding fragment thereof as described herein. In some embodiments, the polynucleotide comprises a polynucleotide encoding a heavy chain variable region or/and a light chain variable region of an anti-IL-1α antibody or an antigen-binding fragment thereof as described herein, respectively. In other embodiments, the polynucleotide comprises a polynucleotide encoding a heavy chain and a light chain of an anti-IL-1α antibody or an antigen-binding fragment thereof, respectively.

In some embodiments, the present application provides a recombinant vector comprising the polynucleotide. In some embodiments, the vector is a cloning vector; in other embodiments, the vector is an expression vector. The expression vector may optionally be any expression vector capable of expressing the antibody or antigen-binding fragment thereof described herein.

In some embodiments, the present application provides a host cell comprising the vector or having the polynucleotide integrated into its genome. The host cell herein may be any suitable host cell for expressing an anti-IL-1α antibody or an antigen-binding fragment thereof. In some embodiments, the host cell is a prokaryotic cell. In other embodiments, the host cell is a eukaryotic cell. In some embodiments, the host cell is selected from yeast cells, mammalian cells, or other cells suitable for preparing antibodies or antigen-binding fragments thereof. Mammalian cells are, for example, Chinese hamster ovary cells (CHO), human kidney epithelial cell line 293 cells, or 293T cells.

In some embodiments, the present application relates to the use of the anti-IL-1α antibody or antigen-binding fragment thereof described herein, or the pharmaceutical composition described herein, in the preparation of a medicament for blocking the release of inflammatory cytokines. Alternatively, the present application relates to the anti-IL-1α antibody or antigen-binding fragment thereof described herein, or the pharmaceutical composition described herein, for blocking the release of inflammatory cytokines. Alternatively, the present application relates to a method for blocking the release of inflammatory cytokines in a subject, comprising administering the anti-IL-1α antibody or antigen-binding fragment thereof described herein, or the pharmaceutical composition described herein, to a subject in need thereof.

In some preferred embodiments, the inflammatory cytokines are IL-6, IL-8 and CCL20.

In some embodiments, the present application relates to the use of the anti-IL-1α antibody or antigen-binding fragment thereof described herein, or the pharmaceutical composition described herein, in the preparation of a medicament for preventing or treating a disease associated with IL-1α. Alternatively, the present application relates to the anti-IL-1α antibody or antigen-binding fragment thereof described herein, or the pharmaceutical composition described herein, for preventing or treating a disease associated with IL-1α.

In some embodiments, the present application relates to a method for preventing or treating an IL-1α-related disease, comprising administering the anti-IL-1α antibody or antigen-binding fragment thereof described herein, or the pharmaceutical composition described herein to a subject in need thereof.

In some preferred embodiments, the IL-1α-related disease can be selected from atopic dermatitis, hidradenitis suppurativa, pyoderma gangrenosum, Sweet syndrome, Sjögren's syndrome (

syndrome), systemic sclerosis, progressive fibrosis, chronic obstructive pulmonary disease, pulmonary fibrosis, cystic fibrosis, bronchopulmonary dysplasia, pericarditis, myositis, myocarditis, myocarditis, myocardial infarction, ischemia-reperfusion injury, respiratory diseases, colitis, Behcet's syndrome, Erdheim-Chester disease, vasculitis, IL-1Ra deficiency (DIRA), Kawasaki disease, aneurysm, lung cancer (non-small cell and small cell), kidney cancer, thyroid cancer, neuroendocrine cancer, pseudomyxoma peritonei, Castleman disease, rectal cancer, pancreatic cancer, and colorectal cancer.

In some preferred embodiments, the subject is a mammal, such as a human.

Example

The scheme of the present application will be further described below in conjunction with embodiments, but those skilled in the art will appreciate that the protection scope of the present application is not limited to these embodiments.

Unless otherwise specified, the reagents, materials or instruments involved in the following examples are commercially available.

Example 1: Construction of reporter gene cell lines for functional activity evaluation

The nucleic acid sequence information of the coding regions of human IL1R1 and IL1RAP was obtained from the UniProt database, and the genes were synthesized and subcloned into lentiviral expression vectors. Lentivirus was prepared (see, for example, Neha Tandon et al., Bio Protoc. 2018 Nov 5; 8(21): e3073), and 293 cells were infected respectively. The recombinant cell lines that stably overexpressed IL1R1 and IL1RAP were screened using 2 μg/mL puromycin antibiotics, and the cells were further infected with Lenti-NF-κB-Luciferase-Hygro lentivirus, and 200 μg/mL Hygromycin B was added to screen the stable transfected cell lines to obtain the 293F-IL1RI-IL1RAP-NFkB-Luc reporter gene cell line. The activation effect of IL-1α on the reporter gene cell line was verified according to the following steps.

(1) Human IL-1α was adjusted to a concentration of 0.2 μg/mL using HybGro serum-free medium, and then diluted 10-fold in a series of 9 dilutions (2×10 ^-1 to 2×10 ^-9 μg/mL).

(2) Pipette 2×10 ⁶ 293F-IL1RI-IL1RAP-NFkB-Luc cells in the logarithmic growth phase into a 15 mL centrifuge tube, centrifuge at 500 g for 5 min, remove the supernatant, add 10 mL PBS buffer (1×) to resuspend, centrifuge at 500 g for 5 min, remove the supernatant, resuspend the cells in 10 mL HybGro serum-free medium, mix thoroughly, and then pipette 100 μL of the cell suspension and add it to a 96-well plate.

(3) 100 μL of the diluted IL-1α gradient concentration protein was added to the above 96-well plate, with two replicate wells for each concentration gradient, and cultured at 37°C and 5% _CO2 for 18 h.

(4) After the culture, the 96-well plate was removed, 20 μL of Bright-Glo ^TM detection reagent (purchased from Promega) was added, and the plate was placed at room temperature away from light for 5 min. The Luciferase fluorescence value was read using a Tecan M1000 multifunctional microplate reader. The data are shown in FIG1 , indicating that the reporter gene cell line can be activated by human IL-1α in a dose-dependent manner.

Example 2: Hybridoma Screening

Take 10 Balb/c and 10 CD1 mice, use 50μg of human and cynomolgus monkey IL-1α emulsified with Freund's adjuvant, and immunize the mice subcutaneously at multiple points, for a total of 3 immunizations, with an interval of 14 days. Take mice with good immune titer detection for shock immunization, and kill them by cervical dislocation 3 days later. Obtain the mouse spleen under sterile conditions, prepare B cell single cell suspension, and mix it with SP2/0 myeloma cells in a ratio of 1:1, and use BTX cell electrofusion instrument for cell fusion. After electrofusion, all cells are immediately suspended in complete culture medium (DMEM, containing 20% FBS and HAT) and inoculated into 96-well plates. About 10 days after fusion, change to HT culture medium and culture for two days, and take the supernatant to detect specific antibodies.

100 μL of culture supernatant was taken out from each well of the 96-well plate, and fresh HT medium was added to each well. The culture supernatant was tested for binding to human IL-1α by ELISA (HRP Anti-Mouse IgG H&L was purchased from Biolon, and TMB colorimetric solution was purchased from Huzhou Yingchuang). At the same time, the cross-binding with cynomolgus monkey and mouse IL-1α was rechecked by ELISA. Clones that can cross-bind with human, cynomolgus monkey, and mouse IL-1α were preferred. If none of the candidate clones could bind to mouse IL-1α, clones that can cross-bind with human and cynomolgus monkey IL-1α were preferred. Monoclones that can secrete antibodies that specifically bind to human and cynomolgus monkey IL-1α were obtained through two rounds of subcloning.

Example 3: Detection of the activity of mouse antibodies by reporter gene method

The hybridomas of monoclonal 14-D8-A6-D7, 30-E12-E4-G9, 17-B12-C9, and 48-G12-G2 obtained from the above two rounds of subclone screening were amplified and cultured, and then the mouse antibodies were purified by protein A column affinity chromatography. The purified antibodies were detected by the reporter gene method according to the following steps, and the IC50 value was calculated, wherein Xbiotech's IL-1α antibody Bermekimab (MABP1) was used as a positive control, and the amino acid sequence of MABP1 was derived from patent CN200980125033, as shown below.

Heavy chain sequence: QVQLVESGGGVVQPGRSLRLSCTASGFTFSMFGVHWVRQAPGKGLEWVAAVSYDGSNKYYAESVKGRFTISRDNSKNILFLQMDSLRLEDTAVYYCARGRPKVVIPAPLAHWGQGTLVTFSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:119)

Light chain sequence: DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYEASNLETGVPSRFSGSGSGSDFTLTISSLQPEDFATYYCQQTSSFLLSFGGGTKVEHKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 120)

(1) The concentration of human IL-1α protein was adjusted to 0.004 μg/mL using HybGro serum-free medium (purchased from Basalmedia).

(2) The purified mouse antibody or positive control antibody MABP1 was diluted 10-fold starting from the highest concentration of 400 μg/mL, and 9 dilutions were made in succession (4×10 ² to 4×10 ^-6 μg/mL).

(3) Take 50 μL of the diluted gradient concentration antibody and add it to a 96-well plate, with two replicate wells for each concentration gradient. Then add 50 μL of 0.004 μg/mL human IL-1α (final concentration is 0.001 μg/mL) to each of the corresponding wells. At the same time, select 2 empty wells and add 100 μL of HybGro serum-free medium to each well as blank background wells. Gently shake the 96-well plate to mix well and incubate at 37°C for 1 hour.

(4) After the incubation, 2×10 ⁶ 293F-IL1RI-IL1RAP-NFkB-Luc cells in the logarithmic growth phase were transferred to a 15 mL centrifuge tube, centrifuged at 500 g for 5 min, the supernatant was removed, 10 mL PBS was added for resuspending, centrifuged at 500 g for 5 min, the supernatant was removed, and the cells were resuspended in 10 mL HybGro serum-free medium. After thorough mixing, 100 μL of the cell suspension was aspirated and added to a 96-well plate. 200 μL HybGro serum-free medium was added to the blank background well. The plates were cultured at 37°C and 5% CO ₂ for 18 h.

(5) After the incubation period, remove the 96-well plate, add 20 μL Bright-Glo detection reagent, place it at room temperature away from light for 5 min, and use a Tecan M1000 multifunctional microplate reader to read the Luciferase fluorescence value.

Table 1 shows the activity detection results of the reporter gene method, in which the candidate mouse antibodies can block the fluorescence signal induced by IL-1α. The representative results are shown in Figure 2, and it can be seen that the activity of the mouse antibody 30-E12-E4-G9 is significantly better than the positive control MABP1.

Table 1 Activity detection results of mouse antibody reporter gene method

Example 4: Construction and expression of chimeric antibodies

The amino acid sequences of the light chain and heavy chain variable regions of the mouse antibodies 30-E12-E4-G9, 17-B12-C9-D6, and 48-G12-G2 with higher activity were obtained by hybridoma sequencing. The heavy chain variable region was subcloned into the pcDNA3.4-hIgG1 expression vector, and the light chain variable region was subcloned into the pcDNA3.4-hIgKc expression vector to obtain the heavy chain expression vector and the light chain expression vector.

Take 2 mL of PBS buffer (1×) and add it to a 6-well plate. Then add 40 μg of heavy chain expression vector pcDNA3.4-hIgG1 and 80 μg of light chain expression vector pcDNA3.4-hIgKc respectively. After mixing, add 360 μL of LVTransm transfection reagent (prepared by iCarTab) and mix thoroughly. Let stand at room temperature for 10 minutes.

The DNA/LVTransm complex obtained above was added to 100 mL of 293F cells (cell density 1×10 ⁶ /mL) and gently shaken to mix thoroughly. The cells were placed in a carbon dioxide shaker and cultured continuously for 7 days at 37°C, 5% CO ₂ , and 130 rpm. The culture supernatant was collected by centrifugation, filtered with a 0.45 μm filter membrane, and the chimeric antibody was purified by protein A affinity chromatography. The chimeric antibody was tested by reporter gene method according to the steps described above. Table 2 shows the activity test results. It can be seen that the activity of 30-E12-E4-G9 chimeric antibody and 48-G12-G2-G2 chimeric antibody is still significantly better than the positive control MABP1. The representative results are shown in Figure 3.

Table 2 Activity detection results of chimeric antibody reporter gene method

Example 5: Antibody humanization

The chimeric antibody 30-E12-E4-G9 with the highest activity was humanized. The humanization design was based on the amino acid sequence of the heavy and light chains of the mouse antibody, and the CDR region sequence of the original antibody was kept unchanged. According to the results of germline alignment and antibody structure simulation, different humanized antibody templates were selected for the heavy and light chains, and the framework regions were back mutated after humanization to design candidate humanized antibody sequences. The heavy and light chains of the designed humanized antibodies were gene synthesized separately, and the heavy chain was subcloned into the pcDNA3.4-hIgG1 expression vector, and the light chain was subcloned into the pcDNA3.4-hIgKc expression vector. After the constructed vector was verified by sequencing, it was transiently expressed in 293 cells and the expression was verified by SDS-PAGE electrophoresis. Figure 4 shows that the purity of humanized antibodies 30-E12-1, 30-E12-2, 30-E12-3, 30-E12-4, 30-E12-5, and 30-E12-6 was greater than 90%.

Example 6: Reporter gene activity detection of humanized antibodies

As described above, the activity of chimeric antibodies and humanized antibodies was detected using the reporter gene method, which showed that the humanized antibodies 30-E12-1, 30-E12-2, 30-E12-4 and 30-E12-5 still maintained high activity, and their IC50 was significantly better than the positive control MABP1. The results are shown in Table 3 and Figure 5.

Table 3 Results of reporter gene activity detection of humanized antibodies

Example 7: Binding activity determination of humanized antibodies

The chimeric antibodies and humanized antibodies 30-E12-1, 30-E12-2, 30-E12-4 and 30-E12-5 with higher activity were selected to detect the binding activity with different species of IL-1α and homologous protein human IL-1β by ELISA method. The experimental steps are as follows:

1. Antigen coating: dilute the antigen to 1 μg/mL with coating solution (1×CBS), add 100 μL/well to the ELISA plate, and place it at 4°C for overnight coating;

2. Blocking: Take out the ELISA plate, discard the solution in the wells, add 300μL PBST buffer (1×), soak for 5 seconds, wash the plate once, and pat the remaining droplets on the plate on absorbent paper as much as possible after washing. Add 200μl of blocking solution (2% BSA/PBST) to each well, cover the plate with a sealing film, and block at 37℃ for 2h;

3. Anti-IL-1α antibody gradient dilution: dilute the anti-IL-1α antibody 3.5 times from the highest concentration of 10 μg/mL (take 50 μL of the test sample stock solution and add it to 125 μL of diluent (0.5% BSA/PBST) and perform gradient dilution in sequence), and dilute 11 gradients continuously (10000, 2857.14, 816.33, 233.24, 66.64, 19.04, 5.44, 1.55, 0.44, 0.13, 0.036, 0 ng/ml);

4. Washing: Take out the ELISA plate, discard the solution in the well, add 300 μL of PBST buffer (1×), soak for 5 seconds, wash the plate 3 times, and pat the remaining droplets on the plate on absorbent paper as much as possible after washing;

5. Sample addition: transfer the gradient diluted anti-IL-1α antibody solution to the ELISA plate, 100 μL/well, cover with sealing film, and incubate at 37°C for 1 hour;

6. Secondary antibody dilution: dilute Anti-human IgG-HRP 50,000 times with diluent;

7. Sample addition: transfer the diluted secondary antibody solution to the ELISA plate, 100 μL/well, cover with sealing film, and incubate at 37°C for 1 hour;

8. Washing: Take out the ELISA plate, discard the solution in the well, add 300 μL of PBST buffer (1×), soak for 5 seconds, wash the plate 5 times, and pat the remaining droplets on the plate on absorbent paper as much as possible after washing;

10. Color development: Add 100 μL/well of TMB substrate solution to the ELISA plate, cover with sealing film, and incubate at 37°C in the dark for 10 minutes for color development;

11. Termination: Add 100 μL/well of the stop solution to the ELISA plate to terminate the reaction;

12. Reading: Place the ELISA plate in an ELISA reader and read the absorbance values at 450nm and 630nm wavelengths, with sample concentration as the horizontal axis and the absorbance difference as the vertical axis. Use the analysis software that comes with the ELISA reader to fit the drug dose-effect curve, and select the four-parameter equation regression model to fit the drug dose-effect curve, and calculate the relative binding activity of the test article (relative binding activity = reference article _EC50 /test article _EC50 ×100%).

The test results are shown in Table 4, Figure 6 and Figure 7. The humanized antibody has strong cross-binding with human and cynomolgus monkey IL-1α, and weak cross-binding with mouse and rat IL-1α. In addition, the cross-binding of the humanized antibody to IL-1β, a homologous protein of IL-1α, is very weak, indicating that the humanized antibody has good selective specificity.

Table 4 Binding activity of humanized antibodies to human and cynomolgus monkey IL-1α

Example 8: Affinity determination of humanized antibodies

The affinity of chimeric and humanized antibodies to human and cynomolgus monkey IL-1α was detected using the Fortebio instrument. Human and cynomolgus monkey IL-1α were coupled to the NTA sensor, respectively, with a coupling time of 60s, and the antibody to be tested was diluted 2-fold to 12.5, 6.25, 3.13, 1.56, 0.7813, and 0nM with PBST buffer (PBS+0.02% tween20). Then the Fortebio instrument moved the sensor to read in the analyte wells of each concentration gradient, and the binding and dissociation of the antibody to be tested with IL-1α were monitored in real time, with an equilibrium time of 150s, a binding time of 180s, a dissociation time of 300s, and a detection temperature of 25°C. The experimental data were fitted using the instrument supporting software in the Steady affinity mode.

The test results show that the humanized antibody has a very high affinity for human IL-1α, with the highest KD reaching the pM order of magnitude, and also has a very high affinity for cynomolgus monkey IL-1α. The results are shown in Table 5, Figures 8 and 9.

Table 5 Affinity of humanized antibodies to human and cynomolgus monkey IL-1α

Example 9: Cytokine Activity Detection of Humanized Antibodies

The functional activity of humanized antibodies was evaluated by detecting the release of cytokine IL-8 from MRC-5 cells. The experimental steps are as follows:

(1) Take MRC-5 cells in the logarithmic growth phase (purchased from the Chinese Academy of Sciences) and add them to a 15 mL centrifuge tube, mix them, and centrifuge them at 200 g for 5 min. After centrifugation, resuspend the cells in DMEM + 10% FBS medium. After sufficient mixing, adjust the cell suspension density to 1×10 ⁵ cells/mL, take 200 μL of the cell suspension, add it to a 96-well plate, and add 2×10 ⁴ cells per well. Transfer the 96-well plate to a carbon dioxide incubator and continue to culture at 37°C and 5% CO ₂ for 18 h.

(2) Preparation of IL-1α protein: human IL-1α (purchased from Suzhou Nearshore Protein Technology Co., Ltd.) was adjusted to 0.02 μg/mL using DMEM basal medium;

(3) Humanized antibody gradient dilution: The humanized antibody and the positive control MABP1 were diluted 3.5 times from the highest concentration of 20 μg/mL, and 10 gradients were continuously diluted (20, 5.71, 1.63, 0.47, 0.13, 0.038, 0.011, 0.0031, 0.00089, 0.00025 μg/mL).

(4) Take out the MRC-5 cells cultured overnight, remove the culture medium, and wash twice with DMEM basal culture medium. Add 100 μL of diluted humanized antibody gradient dilution and 100 μL of IL-1α solution to each well. Transfer the 96-well plate to a carbon dioxide incubator and continue to culture for 18 hours at 37°C and 5% _CO2 . After the culture is completed, take out the 96-well plate and centrifuge it at 800g for 5 minutes at room temperature.

(5) After centrifugation, 50 μL of supernatant was taken from each well, diluted 1:200, and the expression level of cytokine IL-8 in the supernatant was detected using a human IL-8 ELISA detection kit (purchased from Lianke Bio).

The test data showed that humanized antibodies 30-E12-1, 30-E12-2, 30-E12-4 and 30-E12-5 could block IL-1α-induced IL-8 release from MRC-5 cells. Their activity was comparable to that of the chimeric antibody 30-E12-E4-G9 and significantly superior to the positive control MABP1. They were highly consistent with the results of the reporter gene method. The results are shown in Table 6 and Figure 10.

Table 6 Results of cytokine activity assay of humanized antibodies

Example 10: Transformation of humanized antibodies

For the three humanized antibodies with better functional activities, 30-E12-2, 30-E12-4, and 30-E12-5, one asparagine residue (N) in the light chain CDR1 of these humanized antibodies (this site can be referred to as the deamidation site in this article) was mutated to other amino acids to study the possibility of further improving the activity or stability of the antibodies. The expression vectors of various mutants of humanized antibodies were constructed as shown in Table 7, and they were transiently expressed in 293 cells or CHO-K1 cells, respectively. The functional activities of the mutants were detected by the reporter gene method according to the steps described above, and the positive control antibody MABP1 was used as a control. Since the activities of proteins expressed by different expression systems may be different, for the mutants expressed in 293 cells, MABP1 expressed in 293 cells was used as a control; for the mutants expressed in CHO-K1 cells, MABP1 expressed in CHO-K1 cells was used as a control. The results showed that the point mutation of the asparagine residue enabled the modified humanized antibody to maintain a high activity, and the activity of each antibody mutant was significantly better than that of the positive control MABP1, as shown in Table 8 and Figure 11.

Table 7 Mutation scheme of humanized antibodies

Table 8 Results of reporter gene activity detection of humanized antibody mutants

Example 11: In vivo efficacy test of humanized antibody mutants in mice

The in vivo efficacy of the humanized antibody mutants was evaluated by detecting the blocking effect of two humanized antibody mutants 30-E12-4-I and 30-E12-2-V on the release of mouse cytokines IL-6, IL-8, and CCL20 induced by human IL-1α. Eight-week-old Balb/c mice weighing 18-22g, half male and half female, were used and grouped and dosed as follows, with 8 mice in each group, 4 males and 4 females, and a single dose.

(1) Antibody 1 low-dose group: 10 μg/kg human IL-1α (purchased from Suzhou Nearshore Protein Technology Co., Ltd.) was intraperitoneally injected, followed by 1 mg/kg humanized antibody mutant 30-E12-4-I was subcutaneously injected.

(2) Antibody 1 high-dose group: intraperitoneal injection of 10 μg/kg human IL-1α, followed by subcutaneous injection of 3 mg/kg humanized antibody mutant 30-E12-4-I.

(3) Antibody 2 low-dose group: intraperitoneal injection of 10 μg/kg human IL-1α, followed by subcutaneous injection of 1 mg/kg humanized antibody mutant 30-E12-2-V.

(4) Antibody 2 high-dose group: intraperitoneal injection of 10 μg/kg human IL-1α, followed by subcutaneous injection of 3 mg/kg humanized antibody mutant 30-E12-2-V.

(5) Positive control low-dose group: intraperitoneal injection of 10 μg/kg human IL-1α, followed by subcutaneous injection of 1 mg/kg positive control MABP1.

(6) Positive control high-dose group: intraperitoneal injection of 10 μg/kg human IL-1α, followed by subcutaneous injection of 3 mg/kg positive control MABP1.

(7) Negative control group: intraperitoneal injection of 10 μg/kg human IL-1α, followed by subcutaneous injection of sterile PBS (purchased from Beijing Zhongshan Jinqiao Biotechnology Co., Ltd., pH 7.3).

(8) Blank control group: sterile PBS was injected intraperitoneally and then subcutaneously.

All mice in all groups were killed 2 hours later and blood was collected. The blood samples were centrifuged at 4000g for 10 min at 4°C to separate the serum and store at -80°C. The corresponding commercial ELISA kits (all purchased from Hangzhou Lianke Biotechnology Co., Ltd.) were used to detect the content of mouse IL-6, IL-8 and CCL20 in each serum according to the instructions provided by the manufacturer.

The test results are shown in Table 9 and Figures 12 to 14. The results of this experiment showed that the humanized antibody mutants and the positive control MABP1 were able to significantly block the release of mouse cytokines IL-6, IL-8 and CCL20 induced by human IL-1α in a dose-dependent manner, among which the blocking effects of the antibody mutants 30-E12-4-I and 30-E12-2-V were higher than those of the positive control MABP1, especially for the release of mouse CCL20.

Table 9 Detection results of the blocking effect of humanized antibody mutants on human IL-1α-induced mouse cytokine release (unit: pg/ml)

The sequences of the present application are listed in Table 10 below.

Table 10 Sequence of this application

Note: X can be I, N, F, V, S, R, A, T, E, G, H, K, L, P, W, Y, C, M, Q or D.

For the purpose of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements about the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission of the correctness of the dates of these documents or the contents of these documents. Moreover, any reference to these publications in this document does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

Those skilled in the art will recognize that the scope of the present application is not limited to the various specific implementations and examples described above, but that various modifications, replacements, or recombinations can be made without departing from the spirit of the present application, which all fall within the scope of protection of the present application.

Claims

An isolated anti-IL-1α antibody or an antigen-binding fragment thereof, comprising:

(1) HCDR1, HCDR2 and HCDR3, wherein the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3 or amino acid sequences that are at least 80% identical to the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3;

(2) HCDR1, HCDR2 and HCDR3, wherein the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NOs: 11, 12 and 13 or amino acid sequences that are at least 80% identical to the amino acid sequences shown in SEQ ID NOs: 11, 12 and 13;

(3) HCDR1, HCDR2 and HCDR3, wherein the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NOs: 21, 22 and 23 or amino acid sequences that have at least 80% identity with the amino acid sequences shown in SEQ ID NOs: 21, 22 and 23; or

(4) HCDR1, HCDR2 and HCDR3, wherein HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NOs: 31, 32 and 33 or amino acid sequences that have at least 80% identity with the amino acid sequences shown in SEQ ID NOs: 31, 32 and 33.
The anti-IL-1α antibody or antigen-binding fragment thereof according to claim 1, further comprising:

(i) LCDR1, LCDR2 and LCDR3, wherein LCDR1, LCDR2 and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NOs: 108, 5 and 6 or amino acid sequences having at least 80% identity with the amino acid sequences shown in SEQ ID NOs: 108, 5 and 6;

(ii) LCDR1, LCDR2 and LCDR3, wherein LCDR1, LCDR2 and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NOs: 14, 15 and 16 or amino acid sequences having at least 80% identity with the amino acid sequences shown in SEQ ID NOs: 14, 15 and 16;

(iii) LCDR1, LCDR2 and LCDR3, wherein LCDR1, LCDR2 and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NOs: 24, 25 and 26 or amino acid sequences that have at least 80% identity with the amino acid sequences shown in SEQ ID NOs: 24, 25 and 26; or

(iv) LCDR1, LCDR2 and LCDR3, wherein LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences shown in SEQ ID NOs: 34, 35 and 36 or amino acid sequences that have at least 80% identity with the amino acid sequences shown in SEQ ID NOs: 34, 35 and 36.
The anti-IL-1α antibody or antigen-binding fragment thereof according to claim 1 or 2, comprising:

(1) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 50, 5 and 6, respectively;

(2) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 4, 5 and 6, respectively;

(3) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 49, 5 and 6, respectively;

(4) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 51, 5 and 6, respectively;

(5) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 52, 5 and 6, respectively;

(6) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 53, 5 and 6, respectively;

(7) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 54, 5 and 6, respectively;

(8) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 55, 5 and 6, respectively;

(9) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 56, 5 and 6, respectively;

(10) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 57, 5 and 6, respectively;

(11) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 58, 5 and 6, respectively;

(12) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 59, 5 and 6, respectively;

(13) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 60, 5 and 6, respectively;

(14) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 61, 5 and 6, respectively;

(15) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 62, 5 and 6, respectively;

(16) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 63, 5 and 6, respectively;

(17) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 113, 5 and 6, respectively;

(18) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 114, 5 and 6, respectively;

(19) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 115, 5 and 6, respectively;

(20) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 116, 5 and 6, respectively;

(21) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 11, 12 and 13, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 14, 15 and 16, respectively;

(22) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 21, 22 and 23, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 24, 25 and 26, respectively; or

(23) HCDR1, HCDR2 and HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 31, 32 and 33, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 34, 35 and 36, respectively.
The anti-IL-1α antibody or antigen-binding fragment thereof as described in any one of claims 1 to 3, comprising a heavy chain variable region, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NOs: 47, 7, 17, 27, 37 or 39 or an amino acid sequence that has at least 80% identity with the amino acid sequence shown in SEQ ID NOs: 47, 7, 17, 27, 37 or 39.
The anti-IL-1α antibody or its antigen-binding fragment as described in claim 4 further comprises a light chain variable region, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NOs: 110, 8, 18, 28, 38, 45 or 109 or an amino acid sequence that has at least 80% identity with the amino acid sequence shown in SEQ ID NOs: 110, 8, 18, 28, 38, 45 or 109.
The anti-IL-1α antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, comprising:

(1) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 47 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 110 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 110;

(2) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 7 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 7, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 8;

(3) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 17 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 17, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 18 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 18;

(4) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 27 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 27, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 28 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 28;

(5) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 37 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 37, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 38 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 38;

(6) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 39 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 39, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 109 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 109;

(7) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 39 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 39, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 110 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 110;

(8) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 39 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 39, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 45 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 45;

(9) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 47 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 47, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 109 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 109; or

(10) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 47 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 47, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 45 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 45;

Preferably, the anti-IL-1α antibody or antigen-binding fragment thereof comprises:

(1) a heavy chain variable region and a light chain variable region, the heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region having the amino acid sequence shown in SEQ ID NO: 95;

(2) a heavy chain variable region and a light chain variable region, the heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 7, and the light chain variable region having the amino acid sequence shown in SEQ ID NO: 8;

(3) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 17, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 18;

(4) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 27, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 28;

(5) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 37, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 38;

(6) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 40;

(7) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 43;

(8) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 45;

(9) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 40;

(10) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 43;

(11) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 45;

(12) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 64;

(13) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 65;

(14) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 66;

(15) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 67;

(16) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 68;

(17) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 69;

(18) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 70;

(19) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 71;

(20) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 72;

(21) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 73;

(22) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 74;

(23) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 75;

(24) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 76;

(25) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 77;

(26) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 39, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 78;

(27) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 94;

(28) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 96;

(29) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 97;

(30) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 98;

(31) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 99;

(32) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 100;

(33) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 64;

(34) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 65;

(35) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 66;

(36) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 67;

(37) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 68;

(38) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 69; or

(39) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence shown in SEQ ID NO: 47, and the light chain variable region has the amino acid sequence shown in SEQ ID NO: 70.
The anti-IL-1α antibody or antigen-binding fragment thereof as described in any one of claims 1 to 6, further comprising a heavy chain constant region and a light chain constant region, the heavy chain constant region is the constant region of human IgG1, IgG2, IgG3 or IgG4, and the light chain constant region is the constant region of human antibody κ chain or λ chain; preferably, the heavy chain constant region comprises the amino acid sequence shown in SEQ ID NO: 117 or an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 117; and the light chain constant region comprises the amino acid sequence shown in SEQ ID NO: 118 or an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 118.
The anti-IL-1α antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, comprising:

(1) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 48 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 48, and the light chain comprises the amino acid sequence of SEQ ID NO: 112 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 112;

(2) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 9 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 9, and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 10 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 10;

(3) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 19 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 19, and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 20 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 20;

(4) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 29 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 29, and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 30 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 30;

(5) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 41, and the light chain comprises the amino acid sequence of SEQ ID NO: 112 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 112;

(6) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 41, and the light chain comprises the amino acid sequence of SEQ ID NO: 111 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 111;

(7) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 41, and the light chain comprises the amino acid sequence of SEQ ID NO: 46 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 46;

(8) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 48 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 48, and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 111 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 111; or

(9) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 48 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 48, and the light chain comprises the amino acid sequence of SEQ ID NO: 46 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 46;

Preferably, the anti-IL-1α antibody or antigen-binding fragment thereof comprises:

(1) a heavy chain and a light chain, the heavy chain having the amino acid sequence shown in SEQ ID NO: 48, and the light chain having the amino acid sequence shown in SEQ ID NO: 102;

(2) a heavy chain and a light chain, the heavy chain having the amino acid sequence shown in SEQ ID NO: 9, and the light chain having the amino acid sequence shown in SEQ ID NO: 10;

(3) a heavy chain and a light chain, the heavy chain having the amino acid sequence shown in SEQ ID NO: 19, and the light chain having the amino acid sequence shown in SEQ ID NO: 20;

(4) a heavy chain and a light chain, the heavy chain having the amino acid sequence shown in SEQ ID NO: 29, and the light chain having the amino acid sequence shown in SEQ ID NO: 30;

(5) a heavy chain and a light chain, the heavy chain having the amino acid sequence shown in SEQ ID NO: 41, and the light chain having the amino acid sequence shown in SEQ ID NO: 42;

(6) a heavy chain and a light chain, the heavy chain having the amino acid sequence shown in SEQ ID NO: 41, and the light chain having the amino acid sequence shown in SEQ ID NO: 44;

(7) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 46;

(8) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 42;

(9) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 44;

(10) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 46;

(11) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 79;

(12) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 80;

(13) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 81;

(14) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 82;

(15) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 83;

(16) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 84;

(17) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 85;

(18) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 86;

(19) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 87;

(20) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 88;

(21) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 89;

(22) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 90;

(23) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 91;

(24) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 92;

(25) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 41, and the light chain has the amino acid sequence shown in SEQ ID NO: 93;

(26) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 101;

(27) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 103;

(28) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 104;

(29) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 105;

(30) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 106;

(31) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 107;

(32) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 79;

(33) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 80;

(34) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 81;

(35) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 82;

(36) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 83;

(37) a heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 84; or

(38) A heavy chain and a light chain, wherein the heavy chain has the amino acid sequence shown in SEQ ID NO: 48, and the light chain has the amino acid sequence shown in SEQ ID NO: 85.
The anti-IL-1α antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, wherein the anti-IL-1α antibody is a murine antibody, a chimeric antibody, or a humanized antibody;

Preferably, the antibody or antigen-binding fragment thereof is selected from the group consisting of a monoclonal antibody, 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.
A pharmaceutical composition comprising the anti-IL-1α antibody or antigen-binding fragment thereof according to any one of claims 1 to 9.
A polynucleotide encoding the anti-IL-1α antibody or antigen-binding fragment thereof according to any one of claims 1 to 9.
A recombinant vector comprising the polynucleotide according to claim 11.
A host cell comprising the vector of claim 12 or having the polynucleotide of claim 11 integrated into its genome.
An anti-IL-1α antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, or a pharmaceutical composition according to claim 10 for blocking the release of inflammatory cytokines; preferably, the inflammatory cytokines are IL-6, IL-8 and CCL20.
An anti-IL-1α antibody or an antigen-binding fragment thereof according to any one of claims 1 to 9, or a pharmaceutical composition according to claim 10 for preventing or treating an IL-1α-related disease; preferably, the IL-1α-related disease can be selected from atopic dermatitis, suppurative hidradenitis, pyoderma gangrenosum, Sweet syndrome, Sjögren's syndrome, systemic sclerosis, progressive fibrosis, chronic obstructive pulmonary disease, pulmonary fibrosis, cystic fibrosis, bronchopulmonary dysplasia, pericarditis, myositis, myocarditis, myocardial infarction, ischemia-reperfusion injury, respiratory disease, colitis, Behcet's syndrome, Erdheim-Chester disease, vasculitis, IL-1Ra deficiency, Kawasaki disease, aneurysm, lung cancer, renal cancer, thyroid cancer, neuroendocrine cancer, pseudomyxoma peritonei, Castleman's disease, rectal cancer, pancreatic cancer and colorectal cancer.