KR20220022226A - Il-33 binding antibodies or antigen binding fragments thereof - Google Patents
Il-33 binding antibodies or antigen binding fragments thereof Download PDFInfo
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- KR20220022226A KR20220022226A KR1020200103135A KR20200103135A KR20220022226A KR 20220022226 A KR20220022226 A KR 20220022226A KR 1020200103135 A KR1020200103135 A KR 1020200103135A KR 20200103135 A KR20200103135 A KR 20200103135A KR 20220022226 A KR20220022226 A KR 20220022226A
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Abstract
Description
본 발명은 IL-33에 특이적으로 결합하는 항체 또는 이의 면역학적 활성을 가진 단편에 관한 것이다.The present invention relates to an antibody or fragment having immunological activity that specifically binds to IL-33.
인터루킨-33 (Interleukin-33, IL-33)은 염증성 상태에서 역할을 하는 인터루킨-1 패밀리에 속하는 사이토카인이다. IL-33은 상피 세포나 혈관 내피 세포의 핵 내에서 항상 발현되고 있으며, 감염이나 물리적·화학적 스트레스에 의한 조직 손상에 의한 세포 파괴와 함께 방출되어 알라민(alarmin) 역할을 한다. 또한 IL-33의 발현은 리포 다당류 등의 자극에 의해 상승되고, 분비되는 메커니즘도 있다고 생각되고 있다. 세포 밖으로 방출된 IL-33은 세포 상에 발현하는 IL-33 수용체에 결합하여 세포 내 신호를 활성화할 수 있다. IL-33 수용체는 다양한 면역 세포나 상피 세포 등에서 발현되어, IL-33 유도성 세포 내 신호 전달이 발생한다. IL-33은 IL-33 수용체를 발현하는 면역 체계 세포 중 Th2 세포, 비만세포, 호산구, 호염기구, NK(natural killer) T 세포나 2형 선천성 림프구(group 2 innate lymphocyte) 등의 면역 세포 표면에 존재하는 수용체 ST2와 결합해 작동하며, IL-33과 결합한 ST2는 악세사리 수용체 IL-1RAcP과 헤테로다이머(heterodimer)를 형성한 뒤 하위 신호전달 경로(downstream signaling pathway)로 MAPK 및 NF-κB 경로를 활성화시킨다. 이들의 활성화는 Th2 사이토카인(IL-4, IL-5, IL-6, IL-13 등)의 생산을 유도함으로써 알레르기성 염증 (천식, 아토피성 피부염, 화분증, 아나필락시스 등)을 유도하는 것으로 생각되고 있다 (Tatsukuni Ohno et al., Allergy, 2012, Vol. 67, p1203). 또한 IL-33 수용체를 발현하는 면역 체계 세포 중 비만세포(mast cell)와 대식세포는 IL-33 자극에 의해 IL-1β, IL-6 및 TNF(tumor necrosis factor)-α의 생산이 유도되고, 이것이 자가 항체 유도 관절염 (류마티스 관절염의 모델)의 발병에 관여하는 것이 시사된다 (Damo Xu et al., Journal of Immunology, 2010, Vol. 184, p2620). 인간에서는 IL-33의 발현 증가가 각종 염증성 질환 (류마티스 관절염, 천식, 전신성 경화증, 간 섬유증, 폐 섬유증 등의 섬유증, 건선, 궤양성 대장염, 크론병, 다발성 경화증, 강직성 척추염 등)에 연관되어 있는 것으로 인정되고 있으며, IL-33이 각종 질병의 발병·유지에 관여하고 있다고 생각되고 있다 (Yasushi Matsuyama et al., Journal of Rheumatology, 2010, Vol. 37, p18;David Pre´et al., Journal of Allergy and Clinical Immunology, 2010, Vol. 125, p752;Koichi Yanaba et al., Clinical Rheumatology, 2011, Vol. 30, p825;A. L. Rankin et al., Journal of Immunology, 2010, Vol. 184, p1526;Tamar Mchedlidze et al., Immunity, 2013, Vol. 39, p357;Liang-An Hu et al., Asian Pacific Journal of Cancer Prevention, 2013, Vol. 14, p2563;Luca Pastorelli et al., Proceedings of the National Academy of Sciences of the United States of America, 2010, vol. 107, p8017. 이처럼 다양한 질환, 특히 염증성 질환에 관한 IL-33의 관여가 알려져 있기 때문에 IL-33의 작용제와 길항제의 개발이 이루어지고 있으나 지금까지 개발되어 온 항체는 에피토프의 특정이 없는 마우스 항체나 염소 다클론 항체가 알려져 있다. Interleukin-33 (IL-33) is a cytokine belonging to the Interleukin-1 family that plays a role in inflammatory conditions. IL-33 is always expressed in the nucleus of epithelial cells or vascular endothelial cells, and is released along with cell destruction due to tissue damage caused by infection or physical and chemical stress, and acts as an alarm. In addition, it is thought that there is a mechanism for IL-33 expression to be increased and secreted by stimulation such as lipopolysaccharide. IL-33 released out of the cell can bind to the IL-33 receptor expressed on the cell and activate an intracellular signal. IL-33 receptor is expressed in various immune cells or epithelial cells, etc., and IL-33 induced intracellular signal transduction occurs. IL-33 is expressed on the surface of immune cells such as Th2 cells, mast cells, eosinophils, basophils, natural killer (NK) T cells, and group 2 innate lymphocytes among the cells of the immune system expressing the IL-33 receptor. It works by binding to the existing receptor ST2, and ST2 bound to IL-33 forms a heterodimer with the accessory receptor IL-1RAcP and then activates the MAPK and NF-κB pathways as a downstream signaling pathway. make it Their activation is thought to induce allergic inflammation (asthma, atopic dermatitis, hay fever, anaphylaxis, etc.) by inducing the production of Th2 cytokines (IL-4, IL-5, IL-6, IL-13, etc.) (Tatsukuni Ohno et al., Allergy, 2012, Vol. 67, p1203). In addition, the production of IL-1β, IL-6 and TNF (tumor necrosis factor)-α is induced by IL-33 stimulation in mast cells and macrophages among immune system cells expressing IL-33 receptors, It is suggested that this is involved in the pathogenesis of autoantibody-induced arthritis (a model of rheumatoid arthritis) (Damo Xu et al., Journal of Immunology, 2010, Vol. 184, p2620). In humans, increased expression of IL-33 is associated with various inflammatory diseases (rheumatoid arthritis, asthma, systemic sclerosis, liver fibrosis, fibrosis such as pulmonary fibrosis, psoriasis, ulcerative colitis, Crohn's disease, multiple sclerosis, ankylosing spondylitis, etc.). It is recognized that IL-33 is involved in the onset and maintenance of various diseases (Yasushi Matsuyama et al., Journal of Rheumatology, 2010, Vol. 37, p18; David Pre´ et al., Journal of Allergy and Clinical Immunology, 2010, Vol. 125, p752; Koichi Yanaba et al., Clinical Rheumatology, 2011, Vol. 30, p825; AL Rankin et al., Journal of Immunology, 2010, Vol. 184, p1526; Tamar Mchedlidze et al., Immunity, 2013, Vol. 39, p357; Liang-An Hu et al., Asian Pacific Journal of Cancer Prevention, 2013, Vol. 14, p2563; Luca Pastorelli et al., Proceedings of the National Academy of Sciences of the United States of America, 2010, vol. 107, p8017. Because the involvement of IL-33 in various diseases, particularly inflammatory diseases, is known, the development of IL-33 agonists and antagonists is being made, but it has been developed so far. As for the whole antibody, a mouse antibody and goat polyclonal antibody without epitope specification are known.
한편, 항체의약품은 높은 치료 효과 및 표적 치료성 등으로 인해 바이오 의약품 분야에서도 가장 급속도로 성장 중이다. 항체의약품의 세계 시장 규모는 연평균 10-15%의 성장을 지속하고 있는 가운데, 2010년 447억 달러의 시장을 형성한 것으로 알려져 있다. 항체의약품의 주요 표적이 되는 질환은 대부분이 난치성 암(49%) 및 면역질환(35%)과 같이 특정 질환 적응증에 집중되어 있어, 유사 적응증 제품간의 판매경쟁이 치열한 상황이다. 그럼에도 불구하고, 질환들 내 세분화되는 치료 표적들이 존재하기 때문에 향후에도 항암용 항체치료제 개발 분야는 성장세를 지속할 것으로 판단된다.On the other hand, antibody drugs are growing the fastest in the biopharmaceutical field due to their high therapeutic effect and targeted therapeutic properties. The global market for antibody drugs is growing at an average annual rate of 10-15%, and it is known to have formed a market of $44.7 billion in 2010. Most of the diseases targeted by antibody drugs are concentrated on specific disease indications, such as intractable cancer (49%) and immune diseases (35%), and competition among products for similar indications is fierce. Nevertheless, as there are subdivided therapeutic targets within diseases, the field of anticancer antibody therapy development is expected to continue to grow in the future.
본 발명에서는 IL-33에 특이적인 신규한 항체 또는 이의 면역학적 활성을 가진 단편을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a novel antibody specific for IL-33 or a fragment having immunological activity thereof.
상기 목적을 달성하기 위해, 본 발명은 IL-33에 특이적인 항체 또는 이의 면역학적 활성을 가진 단편을 제공한다.In order to achieve the above object, the present invention provides an antibody specific for IL-33 or a fragment having immunological activity thereof.
또한, 본 발명은 항체 또는 이의 면역학적 활성을 가진 단편을 코딩하는 핵산분자, 이를 포함하는 벡터 및 상기 벡터로 형질전환된 숙주 세포를 제공한다.In addition, the present invention provides a nucleic acid molecule encoding an antibody or a fragment having immunological activity thereof, a vector comprising the same, and a host cell transformed with the vector.
또한, 본 발명은 IL-33에 특이적인 항체 또는 이의 면역학적 활성을 가진 단편을 제조하는 방법을 제공한다.In addition, the present invention provides a method for producing an antibody specific for IL-33 or a fragment having immunological activity thereof.
또한, 본 발명은 염증성 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating inflammatory diseases.
아울러, 본 발명은 염증성 질환의 진단을 위한 정보를 제공하는 방법을 제공한다.In addition, the present invention provides a method for providing information for the diagnosis of inflammatory diseases.
본 발명에 따른 IL-33의 특정 에피토프에 결합하는 단일클론 항체 또는 이의 면역학적 활성을 가진 단편들은 높은 항원 특이성을 가지고, IL-33에 높은 친화도로 결합하여 IL-33과 ST2의 결합을 방해함으로써, IL-33로 유도된 MAPK 및 NF-κB 신호전달을 억제하는 중화항체로서 작용하므로, 이를 IL-33의 방출과 관련된 다양한 질환, 특히, 염증성 질환의 예방 또는 치료에 유용하게 적용할 수 있다.The monoclonal antibody or fragments having immunological activity that bind to a specific epitope of IL-33 according to the present invention have high antigen specificity, bind to IL-33 with high affinity and interfere with the binding of IL-33 to ST2. Since it acts as a neutralizing antibody that inhibits MAPK and NF-κB signaling induced by , IL-33, it can be usefully applied to the prevention or treatment of various diseases related to the release of IL-33, in particular, inflammatory diseases.
도 1은 IL-33에 대해 높은 결합 신호를 나타내는 상위 6 클론인 C1_1E1, C2_1D5, C2_2A10, C2_2E1, C2_2E12 및 C2_2H5의 아미노산 서열을 비교한 도이다.
도 2는 패닝을 통하여 얻은 scFv-파아지 항체 풀에서 항원 특이적 scFv를 선별하는 것을 나타낸 도이다:
A: ELISA 분석값이 높은 10개의 scFv들;
B: C1_1E1, C2_1D5, C2_2A10, C2_2E1, C2_2E12 및 C2_2H5의 아미노산 서열 비교; 및
C: 정제된 재조합 C2_2E12 scFv 항체의 SDA-PAGE 분석 결과 (M: 크기 마커; S: 항체 분비된 배지; P: 세포 펠릿; FT: Ni-NTA 아가로스 결합 후 용액; W: 세척액; 및 E: C2_2E12 용출액)
도 3은 C1_1E1, C2_1D5, C2_2A10, C2_2E1, C2_2E12 및 C2_2H5의 IL-33에 대한 결합력을 확인한 도이다.
도 4는 C2_2E12의 IL-33에 대한 결합력을 확인한 도이다.
도 5는 C1_1E1, C2_1D5, C2_2A10, C2_2E1 및 C2_2H5의 항원 결합부위를 확인한 도이다.
도 6은 C2_2E12의 항원 결합부위를 확인한 도이다:
A: IL-33의 에피토프 맵핑;
B: IL-33의 149-158 잔기 중 에피토프 맵핑;
C: C2_2E12가 인식하는 IL-33의 에피토프 영역 중의 잔기들의 stick 모델; 및
D: C2_2E12 및 IL-33 간의 정전기 상호작용.
도 7은 C2_2E12의 항원 특이성을 확인한 도이다.
도 8은 C2_2E12의 중화항체 기능을 확인한 도이다.
도 9는 C2_2E12의 중화항체로서의 역할을 확인하기 위해, IL-33로 유도된 MAPK 및 NF-κB 신호전달에 대한 영향을 확인한 도이다.1 is a diagram comparing the amino acid sequences of the top 6 clones C1_1E1, C2_1D5, C2_2A10, C2_2E1, C2_2E12 and C2_2H5 showing a high binding signal to IL-33.
2 is a diagram showing the selection of antigen-specific scFv from the scFv-phage antibody pool obtained through panning:
A: 10 scFvs with high ELISA assay values;
B: Comparison of amino acid sequences of C1_1E1, C2_1D5, C2_2A10, C2_2E1, C2_2E12 and C2_2H5; and
C: SDA-PAGE analysis result of purified recombinant C2_2E12 scFv antibody (M: size marker; S: antibody secreted medium; P: cell pellet; FT: Ni-NTA agarose binding solution; W: wash solution; and E: C2_2E12 eluate)
3 is a view confirming the binding force of C1_1E1, C2_1D5, C2_2A10, C2_2E1, C2_2E12 and C2_2H5 to IL-33.
4 is a view confirming the binding force of C2_2E12 to IL-33.
5 is a diagram confirming the antigen binding sites of C1_1E1, C2_1D5, C2_2A10, C2_2E1 and C2_2H5.
6 is a diagram confirming the antigen-binding site of C2_2E12:
A: epitope mapping of IL-33;
B: epitope mapping among residues 149-158 of IL-33;
C: stick model of residues in the epitope region of IL-33 recognized by C2_2E12; and
D: Electrostatic interaction between C2_2E12 and IL-33.
7 is a diagram confirming the antigen specificity of C2_2E12.
8 is a diagram confirming the neutralizing antibody function of C2_2E12.
9 is a diagram confirming the effect of C2_2E12 on MAPK and NF-κB signaling induced by IL-33 in order to confirm the role of the neutralizing antibody.
이하, 첨부된 도면을 참조하여 본 발명의 구현예로 본 발명을 상세히 설명하기로 한다. 다만, 하기 구현예는 본 발명에 대한 예시로 제시되는 것으로, 당업자에게 주지 저명한 기술 또는 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우에는 그 상세한 설명을 생략할 수 있고, 이에 의해 본 발명이 제한되지는 않는다. 본 발명은 후술하는 특허청구범위의 기재 및 그로부터 해석되는 균등 범주 내에서 다양한 변형 및 응용이 가능하다. Hereinafter, the present invention will be described in detail by way of embodiments of the present invention with reference to the accompanying drawings. However, the following embodiments are presented as examples of the present invention, and when it is determined that detailed descriptions of well-known techniques or configurations known to those skilled in the art may unnecessarily obscure the gist of the present invention, the detailed description may be omitted, and , the present invention is not limited thereby. Various modifications and applications of the present invention are possible within the scope of equivalents interpreted therefrom and the description of the claims to be described later.
또한, 본 명세서에서 사용되는 용어(terminology)들은 본 발명의 바람직한 실시예를 적절히 표현하기 위해 사용된 용어들로서, 이는 사용자, 운용자의 의도 또는 본 발명이 속하는 분야의 관례 등에 따라 달라질 수 있다. 따라서, 본 용어들에 대한 정의는 본 명세서 전반에 걸친 내용을 토대로 내려져야 할 것이다. 명세서 전체에서, 어떤 부분이 어떤 구성요소를 "포함"한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.In addition, the terms used in this specification are terms used to properly express the preferred embodiment of the present invention, which may vary depending on the intention of a user or operator or customs in the field to which the present invention belongs. Accordingly, definitions of these terms should be made based on the content throughout this specification. Throughout the specification, when a part "includes" a certain component, it means that other components may be further included, rather than excluding other components, unless otherwise stated.
본 명세서 전반을 통하여, 천연적으로 존재하는 아미노산에 대한 통상의 1문자 및 3문자 코드가 사용될 뿐만 아니라 Aib(α-아미노이소부티르산), Sar(N-methylglycine) 등과 같은 다른 아미노산에 대해 일반적으로 허용되는 3문자 코드가 사용된다. 또한 본 발명에서 약어로 언급된 아미노산은 하기와 같이 IUPAC-IUB 명명법에 따라 기재되었다:Throughout this specification, common one-letter and three-letter codes for naturally occurring amino acids are used as well as generally accepted for other amino acids such as Aib (α-aminoisobutyric acid), Sar ( N -methylglycine), etc. A three-character code is used. Amino acids referred to by abbreviation in the present invention are also described according to the IUPAC-IUB nomenclature as follows:
알라닌: A, 아르기닌: R, 아스파라긴: N, 아스파르트산: D, 시스테인: C, 글루탐산: E, 글루타민: Q, 글리신: G, 히스티딘: H, 이소류신: I, 류신: L, 리신: K, 메티오닌: M, 페닐알라닌: F, 프롤린: P, 세린: S, 트레오닌: T, 트립토판: W, 티로신: Y 및 발린: V. Alanine: A, Arginine: R, Asparagine: N, Aspartic Acid: D, Cysteine: C, Glutamic Acid: E, Glutamine: Q, Glycine: G, Histidine: H, Isoleucine: I, Leucine: L, Lysine: K, Methionine : M, phenylalanine: F, proline: P, serine: S, threonine: T, tryptophan: W, tyrosine: Y and valine: V.
일 측면에서, 본 발명은 IL-33에 특이적인 항체 또는 이의 면역학적 활성을 가진 단편에 관한 것이다.In one aspect, the present invention relates to an antibody specific for IL-33 or a fragment having immunological activity thereof.
일 구현예에서, 상기 항체 또는 이의 면역학적 활성을 가진 단편은 서열번호 1의 아미노산으로 이루어진 전구체 형태(precursor form) IL-33의 149번째 잔기 내지 158번째 잔기로 이루어진 에피토프 DLKKDEKKDK (서열번호 46)에 결합할 수 있으며, 서열번호 1의 아미노산으로 이루어진 IL-33의 150번째 잔기 (류신, L) 또는 151번째 잔기 (리신, K)에 결합할 수 있다. In one embodiment, the antibody or fragment having immunological activity thereof is an epitope DLKKDEKKDK (SEQ ID NO: 46) consisting of residues 149 to 158 of the precursor form IL-33 consisting of the amino acid of SEQ ID NO: 1 It can bind to, and can bind to the 150th residue (leucine, L) or the 151st residue (lysine, K) of IL-33 consisting of the amino acid of SEQ ID NO: 1.
일 구현예에서, 상기 전구체 형태의 IL-33의 112번째 아미노산 잔기부터 시작한 서열이 성숙 형태(mature form)의 IL-33일 수 있다.In one embodiment, the sequence starting from the 112th amino acid residue of the precursor form of IL-33 may be the mature form of IL-33.
일 구현예에서, 상기 IL-33은 인간 유래일 수 있다.In one embodiment, the IL-33 may be of human origin.
일 구현예에서, 상기 항체 또는 이의 면역학적 활성을 가진 단편은 단일클론 항체일 수 있으며, IL-33 및 ST2의 복합체 형성을 저해하고 MAPK 또는 NF-κB 신호전달 경로의 활성화를 저해하는 중화항체일 수 있다.In one embodiment, the antibody or fragment having immunological activity thereof may be a monoclonal antibody, and is a neutralizing antibody that inhibits IL-33 and ST2 complex formation and inhibits activation of MAPK or NF-κB signaling pathway can
일 구현예에서, 상기 항체의 면역학적 활성을 가진 단편은 Fab, Fd, Fab', dAb, F(ab'), F(ab')2, scFv(single chain fragment variable), Fv, 단일쇄 항체, Fv 이량체, 상보성 결정 영역 단편, 인간화 항체, 키메라 항체 및 디아바디(diabody)로 이루어진 군으로부터 선택되는 어느 하나일 수 있으며, scFv인 것이 가장 바람직하다.In one embodiment, the fragment having immunological activity of the antibody is Fab, Fd, Fab', dAb, F(ab'), F(ab') 2 , single chain fragment variable (scFv), Fv, single chain antibody , Fv dimers, complementarity determining region fragments, humanized antibodies, chimeric antibodies, and diabodies may be any one selected from the group consisting of, most preferably scFv.
일 구현예에서, 상기 항체 또는 이의 면역학적 활성을 가진 단편은 서열번호 8의 아미노산 서열을 포함하는 CDRH(Complementarity determining regions Heavy chain)1, 서열번호 9의 아미노산 서열을 포함하는 CDRH2, 및 서열번호 10 내지 15의 아미노산 서열로 이루어지는 군으로부터 선택되는 어느 하나를 포함하는 CDRH3를 포함하는 VH 도메인을 포함할 수 있다.In one embodiment, the antibody or fragment having immunological activity thereof comprises a complementarity determining regions heavy chain (CDRH)1 comprising the amino acid sequence of SEQ ID NO: 8, CDRH2 comprising the amino acid sequence of SEQ ID NO: 9, and SEQ ID NO: 10 to a VH domain comprising a CDRH3 comprising any one selected from the group consisting of the amino acid sequence of 15.
일 구현예에서, 상기 항체 또는 이의 면역학적 활성을 가진 단편은 서열번호 16 내지 20의 아미노산 서열로 이루어지는 군으로부터 선택되는 어느 하나를 포함하는 CDRL1, 서열번호 21 내지 26의 아미노산 서열로 이루어지는 군으로부터 선택되는 어느 하나를 포함하는 CDRL2, 및 서열번호 27 내지 31 아미노산 서열로 이루어지는 군으로부터 선택되는 어느 하나를 포함하는 CDRL3를 포함하는 VL 도메인을 포함할 수 있다.In one embodiment, the antibody or fragment having immunological activity thereof is CDRL1 comprising any one selected from the group consisting of the amino acid sequence of SEQ ID NOs: 16 to 20, selected from the group consisting of the amino acid sequence of SEQ ID NOs: 21 to 26 It may include a VL domain comprising a CDRL2 comprising any one of
일 구현예에서, 상기 항체 또는 이의 면역학적 활성을 가진 단편은 (i) 서열번호 8의 아미노산 서열을 포함하는 CDRH(Complementarity determining regions Heavy chain)1, 서열번호 9의 아미노산 서열을 포함하는 CDRH2, 및 서열번호 10 내지 15의 아미노산 서열로 이루어지는 군으로부터 선택되는 어느 하나를 포함하는 CDRH3를 포함하는 VH 도메인; 및/또는 (ⅱ) 서열번호 16 내지 20의 아미노산 서열로 이루어지는 군으로부터 선택되는 어느 하나를 포함하는 CDRL1, 서열번호 21 내지 26의 아미노산 서열로 이루어지는 군으로부터 선택되는 어느 하나를 포함하는 CDRL2, 및 서열번호 27 내지 31 아미노산 서열로 이루어지는 군으로부터 선택되는 어느 하나를 포함하는 CDRL3를 포함하는 VL 도메인을 포함하는 V 도메인을 포함할 수 있다.In one embodiment, the antibody or fragment having immunological activity thereof comprises (i) CDRH (Complementarity determining regions Heavy chain)1 comprising the amino acid sequence of SEQ ID NO: 8, CDRH2 comprising the amino acid sequence of SEQ ID NO: 9, and a VH domain comprising a CDRH3 comprising any one selected from the group consisting of the amino acid sequences of SEQ ID NOs: 10 to 15; and/or (ii) a CDRL1 comprising any one selected from the group consisting of the amino acid sequence of SEQ ID NOs: 16 to 20, a CDRL2 comprising any one selected from the group consisting of the amino acid sequence of SEQ ID NOs: 21 to 26, and a sequence It may include a V domain comprising a VL domain comprising CDRL3 comprising any one selected from the group consisting of No. 27 to 31 amino acid sequence.
상기 항체는 전체(whole) 항체 형태일 뿐 아니라 항체 분자의 기능적인 단편을 포함한다. 전체 항체는 2개의 전체 길이의 경쇄(light chain) 및 2개의 전체 길이의 중쇄(heavy chain)를 가지는 구조이며 각각의 경쇄는 중쇄와 다이설파이드 결합(disulfide bond)으로 연결되어 있다. 항체 분자의 기능적인 단편이란 항원 결합 기능을 보유하고 있는 단편을 뜻하며, 항체 단편의 예는 (i) 경쇄의 가변영역(VL) 및 중쇄의 가변영역(VH)과 경쇄의 불변영역(CL) 및 중쇄의 첫번째 불변 영역(CH1)으로 이루어진 Fab 단편; (ii) VH 및 CH1 도메인으로 이루어진 Fd 단편; (iii) 단일 항체의 VL 및 VH 도메인으로 이루어진 Fv 단편; (iv) VH 도메인으로 이루어진 dAb 단편(Ward ES et al., Nature 341:544-546 (1989)]; (v) 분리된 CDR 영역; (vi) 2개의 연결된 Fab 단편을 포함하는 2가 단편인 F(ab')2 단편; (vii) VH 도메인 및 VL 도메인이 항원 결합 부위를 형성하도록 결합시키는 펩타이드 링커에 의해 결합된 단일쇄 Fv 분자(scFv); (viii) 이특이적인 단일쇄 Fv 이량체(PCT/US92/09965) 및 (ix) 유전자 융합에 의해 제작된 다가 또는 다특이적인 단편인 디아바디(diabody) WO94/13804) 등을 포함한다. The antibody is not only in the form of a whole antibody, but also includes functional fragments of antibody molecules. The whole antibody has a structure having two full-length light chains and two full-length heavy chains, and each light chain is connected to the heavy chain by a disulfide bond. A functional fragment of an antibody molecule refers to a fragment having antigen-binding function, and examples of antibody fragments include (i) a light chain variable region (VL) and a heavy chain variable region (VH) and a light chain constant region (CL) and a Fab fragment consisting of the first constant region of the heavy chain (CH1); (ii) an Fd fragment consisting of the VH and CH1 domains; (iii) an Fv fragment consisting of the VL and VH domains of a single antibody; (iv) a dAb fragment consisting of a VH domain (Ward ES et al., Nature 341:544-546 (1989)); (v) an isolated CDR region; (vi) a bivalent fragment comprising two linked Fab fragments F(ab')2 fragments: (vii) single chain Fv molecules (scFv) joined by a peptide linker joining the VH and VL domains to form an antigen binding site (viii) bispecific single chain Fv dimers (PCT/US92/09965) and (ix) diabody WO94/13804, which is a multivalent or multispecific fragment produced by gene fusion), and the like.
일 구현예에서, 상기 항체 또는 이의 면역학적 활성을 가진 단편은 가변 가변 영역 (V 도메인)에 서열번호 2 내지 45의 아미노산 서열들로 이루어지는 군으로부터 선택되는 어느 하나 이상을 포함할 수 있다.In one embodiment, the antibody or fragment having immunological activity thereof may include any one or more selected from the group consisting of amino acid sequences of SEQ ID NOs: 2 to 45 in the variable variable region (V domain).
일 구현예에서, 상기 항체 또는 이의 면역학적 활성을 가진 단편은 서열번호 8 내지 15 및 32 내지 39의 아미노산 서열 중 선택되는 어느 하나를 포함하는 VH, 및/또는 서열번호 16 내지 31 및 40 내지 45의 아미노산 서열 중 선택되는 어느 하나를 포함하는 VL을 포함할 수 있다. In one embodiment, the antibody or fragment having immunological activity thereof is a VH comprising any one selected from the amino acid sequences of SEQ ID NOs: 8 to 15 and 32 to 39, and/or SEQ ID NOs: 16 to 31 and 40 to 45 It may include a VL comprising any one selected from the amino acid sequence of
일 구현예에서, 상기 항체 또는 이의 면역학적 활성을 가진 단편은 서열번호 2 내지 7의 아미노산 서열들 중 어느 하나를 포함할 수 있다.In one embodiment, the antibody or fragment having immunological activity thereof may include any one of the amino acid sequences of SEQ ID NOs: 2 to 7.
일 구현예에서, 상기 항체 또는 이의 면역학적 활성을 가진 단편은 가변 영역의 중쇄 (VH 도메인)에 상보성 결정 영역인 CDRH1, CDRH2 및 CDRH3을 포함할 수 있으며, CDRH1은 서열번호 8의 아미노산 서열을 포함할 수 있으며, CDRH2는 서열번호 9의 아미노산 서열을 포함할 수 있고, 및 CDRH3는 서열번호 10 내지 15의 아미노산 서열로 이루어지는 군으로부터 선택되는 어느 하나를 포함할 수 있다.In one embodiment, the antibody or immunologically active fragment thereof may include complementarity determining regions CDRH1, CDRH2 and CDRH3 in the heavy chain (VH domain) of the variable region, wherein CDRH1 comprises the amino acid sequence of SEQ ID NO: 8 and CDRH2 may include the amino acid sequence of SEQ ID NO: 9, and CDRH3 may include any one selected from the group consisting of the amino acid sequence of SEQ ID NOs: 10 to 15.
일 구현예에서, 상기 항체 또는 이의 면역학적 활성을 가진 단편은 가변 영역의 경쇄 (VL 도메인)에 상보성 결정 영역인 CDRL1, CDRL2 및 CDRL3을 포함할 수 있으며, CDRL1은 서열번호 16 내지 20의 아미노산 서열들로 이루어지는 군으로부터 선택되는 어느 하나를 포함할 수 있으며, CDRL2는 서열번호 21 내지 26의 아미노산 서열들로 이루어지는 군으로부터 선택되는 어느 하나를 포함할 수 있고, 및 CDRL3는 서열번호 27 내지 31의 아미노산 서열들로 이루어지는 군으로부터 선택되는 어느 하나를 포함할 수 있다.In one embodiment, the antibody or fragment having immunological activity thereof may include complementarity determining regions CDRL1, CDRL2 and CDRL3 in the light chain (VL domain) of the variable region, wherein CDRL1 is the amino acid sequence of SEQ ID NOs: 16 to 20 It may include any one selected from the group consisting of, CDRL2 may include any one selected from the group consisting of amino acid sequences of SEQ ID NOs: 21 to 26, and CDRL3 is amino acids of SEQ ID NOs: 27 to 31 It may include any one selected from the group consisting of sequences.
일 구현예에서, 상기 항체 또는 이의 면역학적 활성을 가진 단편은 In one embodiment, the antibody or fragment having immunological activity
ⅰ) 서열번호 32의 아미노산 서열을 포함하는 FR1, 서열번호 8의 아미노산 서열을 포함하는 CDRH1, 서열번호 33 또는 34의 아미노산 서열을 포함하는 FR2, 서열번호 9의 아미노산 서열을 포함하는 CDRH2, 서열번호 35 내지 37의 아미노산 서열들 중 선택되는 어느 하나를 포함하는 FR3, 서열번호 10 내지 15의 아미노산 서열들 중 선택되는 어느 하나를 포함하는 CDRH3 및 서열번호 38 또는 39의 아미노산 서열을 포함하는 FR4를 포함하는 VH 도메인; 및/또는 i) FR1 comprising the amino acid sequence of SEQ ID NO: 32, CDRH1 comprising the amino acid sequence of SEQ ID NO: 8, FR2 comprising the amino acid sequence of SEQ ID NO: 33 or 34, CDRH2 comprising the amino acid sequence of SEQ ID NO: 9, SEQ ID NO: FR3 comprising any one of the amino acid sequences of 35 to 37, CDRH3 comprising any one of the amino acid sequences of SEQ ID NOs: 10 to 15, and FR4 comprising the amino acid sequence of SEQ ID NOs: 38 or 39 a VH domain; and/or
ⅱ) 서열번호 40의 아미노산 서열을 포함하는 FR1, 서열번호 16 내지 20의 아미노산 서열들 중 어느 하나를 포함하는 CDRL1, 서열번호 41의 아미노산 서열을 포함하는 FR2, 서열번호 27 또는 28의 아미노산 서열을 포함하는 CDRL2, 서열번호 42 내지 44의 아미노산 서열들 중 선택되는 어느 하나를 포함하는 FR3, 서열번호 27 내지 31의 아미노산 서열들 중 선택되는 어느 하나를 포함하는 CDRL3 및 서열번호 45의 아미노산 서열을 포함하는 FR4를 포함하는 VL 도메인을 포함하는 V 도메인을 포함할 수 있다.ii) FR1 comprising the amino acid sequence of SEQ ID NO: 40, CDRL1 comprising any one of the amino acid sequences of SEQ ID NOs: 16 to 20, FR2 comprising the amino acid sequence of SEQ ID NO: 41, and the amino acid sequence of SEQ ID NO: 27 or 28 CDRL2 comprising, FR3 comprising any one of the amino acid sequences of SEQ ID NOs: 42 to 44, CDRL3 comprising any one selected from the amino acid sequences of SEQ ID NOs: 27 to 31, and the amino acid sequence of SEQ ID NO: 45 and a V domain comprising a VL domain comprising FR4.
본 발명에서 항체 또는 이의 면역학적 활성을 가진 단편은 동물 유래 항체, 키메릭 항체, 인간화 항체, 인간 항체, 및 이들의 면역학적 활성을 가진 단편으로 이루어진 군에서 선택된 것일 수 있다. 상기 항체는 재조합적 또는 합성적으로 생산된 것일 수 있다.In the present invention, the antibody or fragment having immunological activity thereof may be selected from the group consisting of an animal-derived antibody, a chimeric antibody, a humanized antibody, a human antibody, and a fragment having immunological activity thereof. The antibody may be recombinantly or synthetically produced.
원하는 항원을 피면역 동물에게 면역시켜 생산하는 동물 유래 항체는 일반적으로 치료 목적으로 인간에 투여시 면역거부반응이 일어날 수 있으며, 이러한 면역거부반응을 억제하고자 키메릭 항체(chimeric antibody)가 개발되었다. 키메릭 항체는 유전공학적 방법을 이용하여 항-아이소타입(anti-isotype) 반응의 원인이 되는 동물 유래 항체의 불변 영역을 인간 항체의 불변 영역으로 치환한 것이다. 키메릭 항체는 동물 유래 항체에 비하여 항-아이소타입 반응에 있어서 상당 부분 개선되었으나, 여전히 동물 유래 아미노산들이 가변 영역에 존재하고 있어 잠재적인 항-이디오타입(anti-idiotypic) 반응에 대한 부작용을 내포하고 있다. 이러한 부작용을 개선하고자 개발된 것이 인간화 항체(humanized antibody)이다. 이는 키메릭 항체의 가변 영역 중 항원의 결합에 중요한 역할을 하는 CDR(Complementarity determining regions) 부위를 인간 항체 골격(framework)에 이식하여 제작된다.An animal-derived antibody produced by immunizing an animal to be immunized with a desired antigen may cause immune rejection when administered to humans for therapeutic purposes, and a chimeric antibody has been developed to suppress such immune rejection. A chimeric antibody is one obtained by substituting a constant region of an animal-derived antibody that causes an anti-isotype reaction with that of a human antibody using a genetic engineering method. Chimeric antibodies have significantly improved anti-isotype response compared to animal-derived antibodies, but still have animal-derived amino acids in the variable region, potentially resulting in anti-idiotypic side effects. are doing A humanized antibody was developed to improve these side effects. This is produced by grafting complementarity determining regions (CDR) regions that play an important role in antigen binding among the variable regions of a chimeric antibody into a human antibody framework.
인간화 항체를 제작하기 위한 CDR 이식(grafting) 기술에 있어서 가장 중요한 것은 동물 유래 항체의 CDR 부위를 가장 잘 받아들일 수 있는 최적화된 인간 항체를 선정하는 것이며, 이를 위하여 항체 데이터베이스의 활용, 결정구조(crystal structure)의 분석, 분자모델링 기술 등이 활용된다. 그러나, 최적화된 인간 항체 골격에 동물 유래 항체의 CDR 부위를 이식할지라도 동물 유래 항체의 골격에 위치하면서 항원 결합에 영향을 미치는 아미노산이 존재하는 경우가 있기 때문에, 항원 결합력이 보존되지 못하는 경우가 상당수 존재하므로, 항원 결합력을 복원하기 위한 추가적인 항체 공학 기술의 적용은 필수적이라고 할 수 있다.The most important thing in the CDR grafting technology for producing a humanized antibody is to select an optimized human antibody that can best accept the CDR region of an animal-derived antibody. structure analysis, molecular modeling technology, etc. are used. However, even when the CDR regions of an animal-derived antibody are transplanted into the optimized human antibody framework, there are cases in which amino acids that affect antigen binding are present while being located in the framework of the animal-derived antibody, so that antigen-binding ability is not preserved in many cases. Therefore, it can be said that the application of additional antibody engineering technology to restore antigen binding force is essential.
상기 항체 또는 이의 면역학적 활성을 가진 단편은 생체에서 분리된 (생체에 존재하지 않는) 것 또는 비자연적으로 생산(non-naturally occurring)된 것일 수 있으며, 예컨대, 합성적 또는 재조합적으로 생산된 것일 수 있다.The antibody or fragment having immunological activity thereof may be isolated from a living body (not present in the living body) or non-naturally occurring, for example, synthetically or recombinantly produced. can
본 발명에서 "항체"라 함은, 면역계 내에서 항원의 자극에 의하여 만들어지는 물질을 의미하는 것으로서, 그 종류는 특별히 제한되지 않으며, 자연적 또는 비자연적(예컨대, 합성적 또는 재조합적)으로 얻어질 수 있다. 항체는 생체 외뿐 아니라 생체 내에서도 매우 안정하고 반감기가 길기 때문에 대량 발현 및 생산에 유리하다. 또한, 항체는 본질적으로 다이머(dimer) 구조를 가지므로 접착능(avidity)이 매우 높다. 완전한 항체는 2개의 전장(full length) 경쇄 및 2개의 전장 중쇄를 가지는 구조이며 각각의 경쇄는 중쇄와 이황화 결합으로 연결되어 있다. 항체의 불변 영역은 중쇄 불변 영역과 경쇄 불변 영역으로 나뉘어지며, 중쇄 불변 영역은 감마(γ), 뮤(μ), 알파(α), 델타(δ) 및 엡실론(ε) 타입을 가지고, 서브클래스로 감마1(γ1), 감마2(γ2), 감마3(γ3), 감마4(γ4), 알파1(α1) 및 알파2(α2)를 가진다. 경쇄의 불변 영역은 카파(κ) 및 람다(λ) 타입을 가진다.In the present invention, the term "antibody" refers to a substance produced by stimulation of an antigen in the immune system, the type is not particularly limited, and can be obtained naturally or non-naturally (eg, synthetically or recombinantly). can Antibodies are advantageous for mass expression and production because they are very stable and have a long half-life not only in vitro but also in vivo. In addition, since the antibody essentially has a dimer structure, the adhesion (avidity) is very high. A complete antibody has a structure having two full-length light chains and two full-length heavy chains, and each light chain is linked to a heavy chain by a disulfide bond. The constant region of an antibody is divided into a heavy chain constant region and a light chain constant region, and the heavy chain constant region has gamma (γ), mu (μ), alpha (α), delta (δ) and epsilon (ε) types, subclasses gamma 1 (γ1), gamma 2 (γ2), gamma 3 (γ3), gamma 4 (γ4), alpha 1 (α1) and alpha 2 (α2). The constant region of the light chain has kappa (κ) and lambda (λ) types.
본 발명에서 용어, "중쇄(heavy chain)"는 항원에 특이성을 부여하기 위해 충분한 가변 영역 서열을 갖는 아미노산 서열을 포함하는 가변 영역 도메인 VH 및 3개의 불변 영역 도메인 CH1 , CH2 및 CH3 과 힌지(hinge)를 포함하는 전장 중쇄 및 이의 단편을 모두 포함하는 의미로 해석된다. 또한, 용어 "경쇄(light chain)"는 항원에 특이성을 부여하기 위한 충분한 가변 영역 서열을 갖는 아미노산 서열을 포함하는 가변 영역 도메인 VL 및 불변 영역 도메인 CL을 포함하는 전장 경쇄 및 이의 단편을 모두 포함하는 의미로 해석된다.As used herein, the term "heavy chain" refers to a variable region domain V H and three constant region domains C H1 , C H2 and C H3 comprising an amino acid sequence having a variable region sequence sufficient to confer specificity to an antigen. and a full-length heavy chain including a hinge and a fragment thereof. In addition, the term "light chain" refers to both full-length light chains and fragments thereof comprising a variable region domain VL and a constant region domain CL comprising an amino acid sequence having sufficient variable region sequence to confer specificity to an antigen. interpreted as including
본 발명에서 용어, "가변 영역(variable region) 또는 가변 부위 (variable domain)"는 항원과 특이적으로 결합하는 기능을 수행하면서 서열상의 많은 변이를 보이는 항체 분자의 부분을 의미하고, 가변 영역에는 상보성 결정 영역인 CDR1, CDR2 및 CDR3가 존재한다. 상기 CDR 사이에는 프레임 워크 영역(framework region, FR) 부분이 존재하여 CDR 고리를 지지해주는 역할을 한다. 상기 "상보성 결정 영역"은 항원의 인식에 관여하는 고리모양의 부위로서 이 부위의 서열이 변함에 따라 항체의 항원에 대한 특이성이 결정된다.As used herein, the term "variable region or variable domain" refers to a portion of an antibody molecule that exhibits many variations in sequence while performing a function of specifically binding to an antigen, and complementarity in the variable region There are determining regions CDR1, CDR2 and CDR3. Between the CDRs, a framework region (FR) portion exists to support the CDR ring. The "complementarity determining region" is a ring-shaped region involved in antigen recognition, and the specificity of the antibody for the antigen is determined as the sequence of this region changes.
본 발명에서 사용되는 용어 "scFv(single chain fragment variable)"는 유전자 재조합을 통해 항체의 가변영역만을 발현시켜 만든 단쇄항체를 말하며, 항체의 VH 영역과 VL 영역을 짧은 펩티드 사슬로 연결한 단일쇄 형태의 항체를 말한다. 상기 용어 "scFv"는 달리 명시되지 않거나, 문맥상 달리 이해되는 것이 아니라면, 항원 결합 단편을 비롯한 scFv 단편을 포함하고자 한다. 이는 통상의 기술자에게 자명한 것이다.As used herein, the term "scFv (single chain fragment variable)" refers to a single-chain antibody made by expressing only the variable region of an antibody through genetic recombination, and a single-chain form in which the VH region and the VL region of the antibody are connected by a short peptide chain. refers to the antibody of The term “scFv” is intended to include scFv fragments, including antigen-binding fragments, unless otherwise indicated or understood otherwise by context. This is obvious to those skilled in the art.
본 발명에서 용어, "상보성결정영역(complementarity determining region, CDR)"은 면역글로불린의 중쇄 및 경쇄의 고가변 영역 (hypervariable region)의 아미노산 서열을 의미한다. 중쇄 및 경쇄는 각각 3개의 CDR을 포함할 수 있다 (CDRH1, CDRH2,CDRH3 및 CDRL1, CDRL2, CDRL3). 상기 CDR은 항체가 항원 또는 항원결정부위에 결합하는 데 있어서 주요한 접촉 잔기를 제공할 수 있다. As used herein, the term "complementarity determining region (CDR)" refers to the amino acid sequence of the hypervariable region of the heavy chain and light chain of an immunoglobulin. The heavy and light chains may each comprise three CDRs (CDRH1, CDRH2, CDRH3 and CDRL1, CDRL2, CDRL3). The CDRs may provide key contact residues for the binding of an antibody to an antigen or epitope.
본 발명에서, 용어, "특이적으로 결합" 또는 "특이적으로 인식"은 당업자에게 통상적으로 공지되어 있는 의미와 동일한 것으로서, 항원 및 항체가 특이적으로 상호작용하여 면역학적 반응을 하는 것을 의미한다.In the present invention, the terms "specifically binding" or "specifically recognized" have the same meaning as commonly known to those skilled in the art, and mean that an antigen and an antibody specifically interact to conduct an immunological reaction. .
본 발명에서 용어, 항체의 "면역학적 활성을 가진 단편" 또는 "항원 결합 단편(antigen binding fragments)"은 면역글로불린 전체 구조에 대한 그의 단편으로, 항원이 결합할 수 있는 부분을 포함하는 폴리펩타이드의 일부를 의미한다. 예를 들어, scFv, (scFv)2 , scFv-Fc, Fab, Fab' 또는 F(ab')2일 수 있으나, 이에 한정되지 않는다. 상기 항원결합단편 중 Fab는 경쇄 및 중쇄의 가변 영역과 경쇄의 불변 영역 및 중쇄의 첫 번째 불변 영역(CH1)을 가지는 구조로 1개의 항원 결합 부위를 가진다. Fab'는 중쇄 CH1 도메인의 C-말단에 하나 이상의 시스테인 잔기를 포함하는 힌지 영역(hinge region)을 가진다는 점에서 Fab와 차이가 있다. F(ab') 2 항체는 Fab'의 힌지 영역의 시스테인 잔기가 디설파이드 결합을 이루면서 생성된다. Fv는 중쇄 가변 영역 및 경쇄 가변 부위만을 가지고 있는 최소의 항체조각으로 Fv 단편을 생성하는 재조합 기술은 당업계에 널리 공지되어 있다. 이중쇄 Fv(two-chain Fv)는 비공유 결합으로 중쇄 가변 부위와 경쇄 가변 부위가 연결되어 있고 단쇄 Fv(single-chain Fv)는 일반적으로 펩타이드 링커를 통하여 중쇄의 가변 영역과 단쇄의 가변 영역이 공유 결합으로 연결되거나 또는 C-말단에서 바로 연결되어 있어서 이중쇄 Fv와 같이 다이머와 같은 구조를 이룰 수 있다. 상기 링커는 1 내지 100개 또는 2 내지 50개의 임의의 아미노산으로 이루어진 펩타이드 링커일 수 있으며, 당업계에 적절한 서열이 알려져 있다. 상기 항원결합단편은 단백질 가수분해 효소를 이용해서 얻을 수 있고(예를 들어, 전체 항체를 파파인으로 제한 절단하면 Fab를 얻을 수 있고 펩신으로 절단하면 F(ab') 2 단편을 얻을 수 있다), 유전자 재조합 기술을 통하여 제작할 수 있다.As used herein, the term "immunologically active fragment" or "antigen binding fragments" of an antibody refers to a fragment of the entire immunoglobulin structure, comprising a portion capable of binding an antigen. means some For example, it may be scFv, (scFv)2 , scFv-Fc, Fab, Fab' or F(ab')2, but is not limited thereto. Among the antigen-binding fragments, Fab has a structure having a light chain and heavy chain variable regions, a light chain constant region and a heavy chain first constant region (C H1 ), and has one antigen-binding site. Fab' differs from Fab in that it has a hinge region comprising one or more cysteine residues at the C-terminus of the heavy chain C H1 domain. The F(ab') 2 antibody is produced by forming a disulfide bond with a cysteine residue in the hinge region of Fab'. Fv is a minimal antibody fragment having only a heavy chain variable region and a light chain variable region, and a recombinant technique for generating an Fv fragment is well known in the art. In a double-chain Fv (two-chain Fv), the heavy chain variable region and the light chain variable region are linked by a non-covalent bond, and in single-chain Fv (single-chain Fv), the heavy chain variable region and the single chain variable region are generally shared through a peptide linker. Since they are linked by a bond or are linked directly at the C-terminus, they can form a dimer-like structure like a double-stranded Fv. The linker may be a peptide linker consisting of any amino acids from 1 to 100 or 2 to 50 amino acids, and an appropriate sequence is known in the art. The antigen-binding fragment can be obtained using a proteolytic enzyme (for example, Fab can be obtained by restriction digestion of the entire antibody with papain, and F(ab') 2 fragment can be obtained by digestion with pepsin), It can be produced through genetic recombination technology.
본 발명에서 용어 "힌지 영역(hinge region)"은 항체의 중쇄에 포함되어 있는 영역으로서, CH1 및 CH2 영역 사이에 존재하며, 항체 내 항원 결합 부위의 유연성(flexibility)를 제공하는 기능을 하는 영역을 의미한다. 예컨대, 상기 힌지는 인간 항체로부터 유래한 것일 수 있으며, 구체적으로, IgA, IgE, 또는 IgG, 예컨대, IgG1, IgG2, IgG 3, 또는 IgG4로부터 유래한 것일 수 있다.As used herein, the term "hinge region" refers to a region included in the heavy chain of an antibody, which exists between the C H1 and C H2 regions, and functions to provide flexibility of the antigen-binding site in the antibody. means area. For example, the hinge may be derived from a human antibody, and specifically, may be derived from IgA, IgE, or IgG, such as IgG1, IgG2, IgG3, or IgG4.
일 측면에서, 본 발명은 본 발명의 항체 또는 이의 면역학적 활성을 가진 단편을 코딩하는 핵산분자, 이를 포함하는 벡터 및 상기 벡터로 형질전환된 숙주 세포에 관한 것이다.In one aspect, the present invention relates to a nucleic acid molecule encoding an antibody of the present invention or an immunologically active fragment thereof, a vector comprising the same, and a host cell transformed with the vector.
본 발명의 핵산 분자는 단리된 것이거나 재조합된 것일 수 있으며, 단일쇄 및 이중쇄 형태의 DNA 및 RNA뿐만 아니라 대응하는 상보성 서열이 포함된다. 단리된 핵산은 천연 생성 원천에서 단리된 핵산의 경우, 핵산이 단리된 개체의 게놈에 존재하는 주변 유전 서열로부터 분리된 핵산이다. 주형으로부터 효소적으로 또는 화학적으로 합성된 핵산, 예컨대 PCR 산물, cDNA 분자, 또는 올리고뉴클레오타이드의 경우, 이러한 절차로부터 생성된 핵산이 단리된 핵산분자로 이해될 수 있다. 단리된 핵산분자는 별도 단편의 형태 또는 더 큰 핵산 구축물의 성분으로서의 핵산 분자를 나타낸다. 핵산은 다른 핵산 서열과 기능적 관계로 배치될 때 작동가능하게 연결된다. 예를 들면, 전서열 또는 분비 리더(leader)의 DNA는 폴리펩타이드가 분비되기 전의 형태인 전단백질(preprotein)로서 발현되는 경우 폴리펩타이드의 DNA에 작동가능하게 연결되고, 프로모터 또는 인핸서는 폴리펩타이드 서열의 전사에 영향을 주는 경우 코딩 서열에 작동가능하게 연결되며, 또는 리보솜 결합 부위는 번역을 촉진하도록 배치될 때 코딩 서열에 작동가능하게 연결된다. 일반적으로 작동가능하게 연결된은 연결될 DNA 서열들이 인접하여 위치함을 의미하며, 분비 리더의 경우 인접하여 동일한 리딩 프레임 내에 존재하는 것을 의미한다. 그러나 인핸서는 인접하여 위치할 필요는 없다. 연결은 편리한 제한 효소 부위에서 라이게이션에 의해 달성된다. 이러한 부위가 존재하지 않는 경우, 합성 올리고뉴클레오타이드 어댑터 또는 링커를 통상적인 방법에 따라 사용한다.The nucleic acid molecules of the present invention may be isolated or recombinant, and include single-stranded and double-stranded forms of DNA and RNA as well as corresponding complementary sequences. An isolated nucleic acid is a nucleic acid that has been separated from surrounding genetic sequences present in the genome of the individual from which the nucleic acid was isolated, in the case of a nucleic acid isolated from a naturally occurring source. In the case of a nucleic acid synthesized enzymatically or chemically from a template, such as a PCR product, a cDNA molecule, or an oligonucleotide, a nucleic acid resulting from such a procedure can be understood as an isolated nucleic acid molecule. An isolated nucleic acid molecule refers to a nucleic acid molecule in the form of separate fragments or as a component of a larger nucleic acid construct. Nucleic acids are operably linked when placed into a functional relationship with another nucleic acid sequence. For example, the DNA of the presequence or secretion leader is operably linked to the DNA of the polypeptide when expressed as a preprotein in the form before the polypeptide is secreted, and the promoter or enhancer is the polypeptide sequence is operably linked to a coding sequence when it affects the transcription of, or a ribosome binding site is operably linked to a coding sequence when positioned to facilitate translation. In general, operably linked means that the DNA sequences to be linked are located contiguously, and in the case of a secretory leader, they are contiguous and in the same reading frame. However, enhancers need not be located adjacent to each other. Linkage is achieved by ligation at convenient restriction enzyme sites. If such sites do not exist, synthetic oligonucleotide adapters or linkers are used according to conventional methods.
본 발명의 항체 또는 이의 면역학적 활성을 가진 단편을 코딩하는 핵산분자는 코돈의 축퇴성(degeneracy)으로 인하여 또는 상기 항체를 발현시키고자 하는 생물에서 선호되는 코돈을 고려하여, 코딩영역으로부터 발현되는 항체의 아미노산 서열을 변화시키지 않는 범위 내에서 코딩영역에 다양한 변형이 이루어질 수 있고, 코딩영역을 제외한 부분에서도 유전자의 발현에 영향을 미치지 않는 범위 내에서 다양한 변형 또는 수식이 이루어질 수 있으며, 그러한 변형 유전자 역시 본 발명의 범위에 포함됨을 당업자는 잘 이해할 수 있을 것이다. 즉, 본 발명의 핵산 분자는 이와 동등한 활성을 갖는 단백질을 코딩하는 한, 하나 이상의 핵산 염기가 치환, 결실, 삽입 또는 이들의 조합에 의해 변이될 수 있으며, 이들 또한 본 발명의 범위에 포함된다. 이러한 핵산 분자의 서열은 단쇄 또는 이중쇄일 수 있으며, DNA 분자 또는 RNA(mRNA)분자일 수 있다.The nucleic acid molecule encoding the antibody or immunologically active fragment of the present invention is an antibody expressed from the coding region due to codon degeneracy or considering codons preferred in the organism in which the antibody is to be expressed. Various modifications may be made to the coding region within a range that does not change the amino acid sequence of It will be appreciated by those skilled in the art that it is included within the scope of the present invention. That is, as long as the nucleic acid molecule of the present invention encodes a protein having an equivalent activity, one or more nucleic acid bases may be mutated by substitution, deletion, insertion, or a combination thereof, and these are also included in the scope of the present invention. The sequence of such a nucleic acid molecule may be single-stranded or double-stranded, and may be a DNA molecule or an RNA (mRNA) molecule.
본 발명에 따른 본 발명의 항체 또는 이의 면역학적 활성을 가진 단편을 코딩하는 핵산분자는 단백질 발현을 위해 발현벡터에 삽입될 수 있다. 발현벡터는, 통상 조절 또는 제어 (regulatory) 서열, 선별마커, 임의의 융합 파트너, 및/또는 추가적 요소와 작동가능하게 연결된, 즉, 기능적 관계에 놓인 단백질을 포함한다. 적절한 상태에서, 핵산으로 형질전환된 숙주세포, 바람직하게는, 본 발명에 따른 항체 또는 이의 면역학적 활성을 가진 단편을 코딩하는 핵산분자 함유 발현벡터를 배양하여 단백질 발현을 유도하는 방법에 의해 본 발명에 따른 항체 또는 이의 면역학적 활성을 가진 단편이 생산될 수 있다. 포유류 세포, 박테리아, 곤충 세포, 및 효모를 포함하는 다양한 적절한 숙주세포가 사용될 수 있으나, 이에 제한하는 것은 아니다. 외인성 핵산을 숙주세포에 도입하는 방법은 당해 기술분야에 공지되어 있으며, 사용되는 숙주세포에 따라 달라질 것이다. 바람직하게는, 생산비가 저렴하여 산업적 이용가치가 높은 대장균을 숙주세포로 생산할 수 있다.The nucleic acid molecule encoding the antibody or fragment having immunological activity of the present invention according to the present invention may be inserted into an expression vector for protein expression. Expression vectors usually comprise a protein operably linked, ie, placed in a functional relationship, with regulatory or regulatory sequences, selectable markers, optional fusion partners, and/or additional elements. In an appropriate state, the present invention by culturing a host cell transformed with a nucleic acid, preferably an expression vector containing a nucleic acid molecule encoding an antibody according to the present invention or an immunologically active fragment thereof, to induce protein expression. Antibodies or fragments having immunological activity thereof according to the present invention can be produced. A variety of suitable host cells can be used, including, but not limited to, mammalian cells, bacteria, insect cells, and yeast. Methods for introducing an exogenous nucleic acid into a host cell are known in the art and will vary depending on the host cell used. Preferably, E. coli, which has a high industrial use value due to low production cost, can be produced as a host cell.
본 발명의 벡터는 플라스미드 벡터, 코즈미드 벡터, 박테리오 파아지 벡터 및 바이러스 벡터 등을 포함하나 이에 제한되지 않는다. 적합한 벡터는 프로모터, 오퍼레이터, 개시코돈, 종결코돈, 폴리아데닐화 시그널 및 인핸서 같은 발현 조절 엘리먼트 외에도 막 표적화 또는 분비를 위한 시그널 서열 또는 리더 서열을 포함하며 목적에 따라 다양하게 제조될 수 있다. 벡터의 프로모터는 구성적 또는 유도성일 수 있다. 상기 시그널 서열에는 숙주가 에쉐리키아속(Escherichia sp.)균인 경우에는 PhoA 시그널 서열, OmpA 시그널 서열 등이, 숙주가 바실러스속(Bacillus sp.)균인 경우에는 α-아밀라아제 시그널 서열, 서브틸리신 시그널 서열 등이, 숙주가 효모(yeast)인 경우에는 MFα 시그널 서열, SUC2 시그널 서열 등이, 숙주가 동물세포인 경우에는 인슐린 시그널 서열, α-인터페론 시그널 서열, 항체 분자 시그널 서열 등을 이용할 수 있으나, 이에 제한되지 않는다. 또한 벡터는 벡터를 함유하는 숙주 세포를 선택하기 위한 선택 마커를 포함할 수 있고, 복제 가능한 발현벡터인 경우 복제 기원을 포함한다.The vector of the present invention includes, but is not limited to, a plasmid vector, a cosmid vector, a bacteriophage vector, and a viral vector. Suitable vectors include a signal sequence or leader sequence for membrane targeting or secretion in addition to expression control elements such as promoter, operator, start codon, stop codon, polyadenylation signal and enhancer, and may be prepared in various ways depending on the purpose. The promoter of the vector may be constitutive or inducible. The signal sequence includes a PhoA signal sequence and an OmpA signal sequence when the host is Escherichia sp., and an α-amylase signal sequence and a subtilisin signal when the host is a Bacillus sp. When the host is yeast, the MFα signal sequence, SUC2 signal sequence, etc., and when the host is an animal cell, an insulin signal sequence, α-interferon signal sequence, antibody molecule signal sequence, etc. can be used, It is not limited thereto. The vector may also contain a selection marker for selecting a host cell containing the vector, and in the case of a replicable expression vector, an origin of replication.
본 발명에서 용어, "벡터"는 핵산 서열을 복제할 수 있는 세포로의 도입을 위해서 핵산 서열을 삽입할 수 있는 전달체를 의미한다. 핵산 서열은 외생 (exogenous) 또는 이종 (heterologous)일 수 있다. 벡터로서는 플라스미드, 코스미드 및 바이러스(예를 들면 박테리오파지)를 들 수 있으나, 이에 제한되지 않는다. 당업자는 표준적인 재조합 기술에 의해 벡터를 구축할 수 있다(Maniatis, et al., Molecular Cloning , A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, N.Y., 1988; 및 Ausubel et al., In: Current Protocols in Molecular Biology , John, Wiley & Sons, Inc, NY, 1994 등).As used herein, the term "vector" refers to a carrier capable of inserting a nucleic acid sequence for introduction into a cell capable of replicating the nucleic acid sequence. Nucleic acid sequences may be exogenous or heterologous. Vectors include, but are not limited to, plasmids, cosmids, and viruses (eg, bacteriophages). One of ordinary skill in the art can construct vectors by standard recombinant techniques (Maniatis, et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, NY, 1988; and Ausubel et al., In: Current Protocols in Molecular Biology, John, Wiley & Sons, Inc, NY, 1994 et al.).
일 구현예에서, 상기 벡터의 제작 시, 상기 항체를 생산하고자 하는 숙주세포의 종류에 따라 프로모터(promoter), 종결자(terminator), 인핸서(enhancer) 등과 같은 발현조절 서열, 막 표적화 또는 분비를 위한 서열 등을 적절히 선택하고 목적에 따라 다양하게 조합할 수 있다.In one embodiment, when constructing the vector, expression control sequences such as promoter, terminator, enhancer, etc., membrane targeting or secretion according to the type of host cell in which the antibody is to be produced. Sequences and the like can be appropriately selected and combined in various ways depending on the purpose.
본 발명에서, 용어 "발현 벡터"는 전사되는 유전자 산물 중 적어도 일부분을 코딩하는 핵산 서열을 포함한 벡터를 의미한다. 일부의 경우에는 그 후 RNA 분자가 단백질, 폴리펩타이드, 또는 펩타이드로 번역된다. 발현 벡터에는 다양한 조절서열을 포함할 수 있다. 전사 및 번역을 조절하는 조절서열과 함께 벡터 및 발현 벡터에는 또 다른 기능도 제공하는 핵산 서열도 포함될 수 있다.As used herein, the term "expression vector" refers to a vector comprising a nucleic acid sequence encoding at least a portion of a transcribed gene product. In some cases, the RNA molecule is then translated into a protein, polypeptide, or peptide. The expression vector may include various regulatory sequences. In addition to regulatory sequences that control transcription and translation, vectors and expression vectors may contain nucleic acid sequences that also serve other functions.
본 발명에서, 용어 "숙주세포"는 진핵생물 및 원핵생물을 포함하며, 상기 벡터를 복제할 수 있거나 벡터에 의해 코딩되는 유전자를 발현할 수 있는 임의의 형질 전환 가능한 생물을 의미한다. 숙주세포는 상기 벡터에 의해 형질감염(transfected) 또는 형질전환(transformed) 될 수 있으며, 이는 외생의 핵산분자가 숙주세포 내에 전달되거나 도입되는 과정을 의미한다.In the present invention, the term "host cell" includes eukaryotes and prokaryotes, and refers to any transformable organism capable of replicating the vector or expressing a gene encoded by the vector. A host cell may be transfected or transformed by the vector, which refers to a process in which an exogenous nucleic acid molecule is delivered or introduced into a host cell.
일 구현예에서, 상기 숙주 세포는 박테리아 또는 동물세포일 수 있으며, 동물 세포주는 CHO 세포, HEK 세포 또는 NSO 세포일 수 있고, 박테리아는 대장균일 수 있다.In one embodiment, the host cell may be a bacterium or an animal cell, the animal cell line may be a CHO cell, a HEK cell or an NSO cell, and the bacterium may be E. coli.
일 측면에서, 본 발명은 제 1항의 항체 또는 이의 면역학적 활성을 가진 단편을 코딩하는 핵산분자를 포함하는 벡터를 포함하는 숙주 세포를 배양하는 단계; 및 숙주 세포 배양물로부터 항체 또는 이의 면역학적 활성을 가진 단편을 회수하는 단계를 포함하는 IL-33에 특이적인 항체 또는 이의 면역학적 활성을 가진 단편을 제조하는 방법에 관한 것이다.In one aspect, the present invention provides a method comprising: culturing a host cell comprising a vector comprising a nucleic acid molecule encoding the antibody of
일 구현예에서, 숙주 세포 배양물로부터 항체 또는 이의 면역학적 활성을 가진 단편을 회수하는 단계 이후에 항체 또는 이의 면역학적 활성을 가진 단편을 정제하는 단계를 추가로 포함할 수 있다. In one embodiment, after recovering the antibody or the immunologically active fragment from the host cell culture, the method may further include purifying the antibody or the immunologically active fragment.
본 발명의 항체 또는 이의 면역학적 활성을 가진 단편은 당해 기술분야에서 공지된 다양한 방법으로 분리 또는 정제될 수 있다. 표준 정제방법은 크로마토그래피 기술, 전기영동, 면역, 침강, 투석, 여과, 농축, 및 크로마토포커싱 (chromatofocusing) 기술을 포함한다. 당해 기술분야에 공지된 바와 같이, 예를 들어 박테리아 단백질 A, G, 및 L과 같은 다양한 천연 단백질이 항체와 결합하며, 상기 단백질은 정제에 이용될 수 있다. 종종, 특정 융합 파트너에 의한 정제가 가능할 수 있다. The antibody or fragment having immunological activity of the present invention may be isolated or purified by various methods known in the art. Standard purification methods include chromatography techniques, electrophoresis, immunization, sedimentation, dialysis, filtration, concentration, and chromatofocusing techniques. As is known in the art, various native proteins, such as, for example, bacterial proteins A, G, and L, bind antibodies and these proteins can be used for purification. Often, purification by a specific fusion partner may be possible.
본 발명에 따른 상기 벡터를 적절한 숙주 세포, 예를 들어, 대장균 또는 효모 세포 등에 형질전환시킨 후, 형질전환된 숙주 세포를 배양함으로써 본 발명에 따른 항체 또는 이의 면역학적 활성을 가진 단편을 대량 생산할 수 있다. 숙주 세포의 종류에 따른 적절한 배양 방법 및 배지 조건 등은 당해 분야의 통상의 기술자에게 알려진 공지 기술로부터 당업자가 용이하게 선택할 수 있다. 상기 숙주 세포는 대장균(E. coli) 또는 바실러스 서브틸러스(Bacillus subtilis)와 같은 원핵 생물일 수 있다. 또한, 사카로마이세스 세르비시아(Saccharomyces cerevisiae)와 같은 효모, 곤충 세포, 식물 세포, 동물 세포로부터 유래한 진핵 세포일 수 있다. 더욱 바람직하게는, 상기 동물 세포는 자가 또는 동종 이계 동물 세포일 수 있다. 자가 또는 동종 이계 동물 세포에 도입하여 제조된 형질전환체는 개체에 투여되어 암을 치료하는 세포치료 등에 이용될 수도 있다. 상기 숙주 세포로의 벡터 도입방법은 당업자에게 공지된 어느 방법을 사용해도 무방하다. 트랜스제닉(예를 들면, 유전공학처리된) 마우스, 또는 다른 포유동물을 비롯한 다른 유기체들이 본 발명의 항체 또는 이의 면역학적 활성을 가진 단편을 생산하는데 사용될 수 있다 (예를 들어 US 6,300,129 참조). 예를 들어, 마우스 면역 유전자의 가변 영역 (중쇄 V, D, 및 J 세그먼트, 및 경쇄 V 및 J 세그먼트)만을 상응하는 인간 가변 서열로 대체시켜 공학처리된 마우스가 인간 가변 서열을 갖는 고친화성 항체를 대량 생산하는데 사용될 수 있다는 것이 알려져 있다 (예를 들면, US 6,586,251; US 6,596,541, 및 US 7,105,348 참조).After transforming the vector according to the present invention into an appropriate host cell, for example, E. coli or yeast cell, and then culturing the transformed host cell, the antibody according to the present invention or a fragment having immunological activity thereof can be mass-produced there is. Appropriate culture methods and medium conditions according to the type of host cells can be easily selected by those skilled in the art from known techniques known to those skilled in the art. The host cell may be a prokaryotic organism such as E. coli or Bacillus subtilis . It may also be a eukaryotic cell derived from yeast, such as Saccharomyces cerevisiae , an insect cell, a plant cell, or an animal cell. More preferably, the animal cells may be autologous or allogeneic animal cells. Transformants prepared by introducing autologous or allogeneic animal cells can also be administered to an individual and used for cell therapy to treat cancer. Any method known to those skilled in the art may be used for the vector introduction method into the host cell. Other organisms, including transgenic (eg, genetically engineered) mice, or other mammals, can be used to produce antibodies of the invention or fragments having immunological activity thereof (see, eg, US 6,300,129). For example, mice engineered by replacing only the variable regions (heavy chain V, D, and J segments, and light chain V and J segments) of a mouse immune gene with the corresponding human variable sequences can generate high-affinity antibodies with human variable sequences. It is known that it can be used for mass production (see, eg, US 6,586,251; US 6,596,541, and US 7,105,348).
일 측면에서, 본 발명은 본 발명의 IL-33에 특이적인 항체 또는 이의 면역학적 활성을 가진 단편; 이를 코딩하는 핵산분자; 또는 상기 핵산분자를 포함하는 벡터;로 구성된 군으로부터 선택되는 적어도 어느 하나를 유효성분으로 함유하는 염증성 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.In one aspect, the present invention provides an antibody specific for IL-33 of the present invention or a fragment having immunological activity thereof; a nucleic acid molecule encoding it; Or a vector comprising the nucleic acid molecule; relates to a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing at least one selected from the group consisting of as an active ingredient.
일 구현예에서, 상기 염증성 질환은 독성쇼크증후군 및 궤양성 대장염, 골다공증, 통풍, 건염, 건막염, 루프스, 섬유근통 (fibromyalgia), 부비동염, 중이염, 폐렴, 위염, 소장결장염, 대장염, 관절염, 간염, 피부염, 골관절염, 천식, 아토피성 피부염, 화분증, 아나필락시스, 류마티스 관절염, 건선, 궤양성 대장염, 크론병, 강직성 척추염, 염증성 장 질환, 알레르기, 알레르기성 비염, 알레르기성 결막염, 춘계 각결막염, 계절성 알레르기, 애완동물 알레르기, 식품 알레르기, 땅콩 알레르기, 아토피성 피부염, 비강 폴립을 동반한 만성 비부비동염 (CRSwNP), 기관지염, 만성 폐쇄성 폐 질환 (COPD), 호흡기 질환의 바이러스 악화, 소아 및 성인에서의 바이러스 감염 (호흡기 세포융합 바이러스 (RSV), 리노바이러스, 인플루엔자), 두드러기, 호산구성 식도염, 만성 섬유증, 간 섬유증, 전신성 경화증, 특발성 폐 섬유증 (IPF), 경피증, 간 섬유증, 폐 섬유증 등의 섬유증, 비-알콜성 지방간염 (NASH), 만성 신장 질환, 급성 신장 손상, 패혈증, 췌장염, 제1형 당뇨병, 이식편-대-숙주 질환(GVHD), 알츠하이머병, 류마티스 관절염, 과민성 장 증후군 (IBS), 궤양성 결장염, 다발성 경화증, 건선, 복강 질환 및 레이노병 또는 레이노 현상으로 이루어진 군에서 선택된 어느 하나 이상일 수 있다.In one embodiment, the inflammatory disease is toxic shock syndrome and ulcerative colitis, osteoporosis, gout, tendinitis, tendonitis, lupus, fibromyalgia, sinusitis, otitis media, pneumonia, gastritis, enterocolitis, colitis, arthritis, hepatitis, Dermatitis, osteoarthritis, asthma, atopic dermatitis, hay fever, anaphylaxis, rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, inflammatory bowel disease, allergy, allergic rhinitis, allergic conjunctivitis, spring keratoconjunctivitis, seasonal allergy, Pet allergy, food allergy, peanut allergy, atopic dermatitis, chronic rhinosinusitis with nasal polyps (CRSwNP), bronchitis, chronic obstructive pulmonary disease (COPD), viral exacerbation of respiratory diseases, viral infections in children and adults ( Respiratory syncytial virus (RSV), rhinovirus, influenza), urticaria, eosinophilic esophagitis, chronic fibrosis, liver fibrosis, systemic sclerosis, idiopathic pulmonary fibrosis (IPF), scleroderma, liver fibrosis, fibrosis including pulmonary fibrosis, non-alcoholic steatohepatitis (NASH), chronic kidney disease, acute kidney injury, sepsis, pancreatitis, type 1 diabetes, graft-versus-host disease (GVHD), Alzheimer's disease, rheumatoid arthritis, irritable bowel syndrome (IBS), ulcerative colitis , multiple sclerosis, psoriasis, celiac disease, and may be any one or more selected from the group consisting of Raynaud's disease or Raynaud's phenomenon.
본 발명에서, 용어 "예방"이란 본 발명에 따른 조성물의 투여에 의해 염증성 질환의 발생, 확산 및 재발을 억제 또는 지연시키는 모든 행위를 의미한다.In the present invention, the term "prevention" refers to any action that suppresses or delays the occurrence, spread, and recurrence of an inflammatory disease by administration of the composition according to the present invention.
본 발명에서 사용된 용어 "치료"란 본 발명에 따른 조성물의 투여로 염증성 질환 및 이로 인한 합병증의 증세를 호전시키거나 이롭게 변경하는 모든 행위를 의미한다. 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자라면, 대한의학협회 등에서 제시된 자료를 참조하여 본원의 조성물이 효과가 있는 질환의 정확한 기준을 알고, 개선, 향상 및 치료된 정도를 판단할 수 있을 것이다.As used herein, the term “treatment” refers to any action that improves or advantageously changes symptoms of inflammatory diseases and complications resulting therefrom by administration of the composition according to the present invention. Those of ordinary skill in the art to which the present invention pertains, with reference to the data presented by the Korean Medical Association, etc., know the exact standard of the disease for which the composition of the present application is effective, and can determine the degree of improvement, improvement and treatment will be.
본 발명에서 유효성분과 결합하여 사용된 "치료학적으로 유효한 양"이란 용어는 염증성 질환을 예방 또는 치료하는데 유효한 양을 의미하며, 본 발명의 조성물의 치료적으로 유효한 양은 여러 요소, 예를 들면 투여방법, 목적부위, 환자의 상태 등에 따라 달라질 수 있다. 따라서, 인체에 사용 시 투여량은 안전성 및 효율성을 함께 고려하여 적정량으로 결정되어야 한다. 동물실험을 통해 결정한 유효량으로부터 인간에 사용되는 양을 추정하는 것도 가능하다. 유효한 양의 결정시 고려할 이러한 사항은, 예를 들면 Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed.(2001), Pergamon Press; 및 E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed.(1990), Mack PublishingCo.에 기술되어있다.The term "therapeutically effective amount" used in combination with an active ingredient in the present invention means an amount effective to prevent or treat an inflammatory disease, and the therapeutically effective amount of the composition of the present invention depends on several factors, for example, the administration method. , the target site, the patient's condition, etc. Therefore, when used in the human body, the dosage should be determined as an appropriate amount in consideration of both safety and efficiency. It is also possible to estimate the amount used in humans from the effective amount determined through animal experiments. These considerations in determining effective amounts are found, for example, in Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. (2001), Pergamon Press; and E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed. (1990), Mack Publishing Co.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에서 사용되는 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 염증성 질환의 종류, 염증성 질환의 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여, 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level is determined by the patient's Health status, type of inflammatory disease, severity of inflammatory disease, drug activity, drug sensitivity, administration method, administration time, administration route and excretion rate, treatment period, factors including drugs used in combination or concurrently, and other medical fields can be determined according to well-known factors in The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
본 발명의 약학적 조성물은 생물학적 제제에 통상적으로 사용되는 담체, 희석제, 부형제 또는 둘 이상의 이들의 조합을 포함할 수 있다. 본 발명에서 사용되는 용어, "약학적으로 허용가능한"이란 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다. 상기 담체는 조성물을 생체 내 전달에 적합한 것이면 특별히 제한되지 않으며, 예를 들면, Merck Index, 13th ed., Merck & Co. Inc. 에 기재된 화합물, 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로스 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 이용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한, 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주이용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 더 나아가 당 분야의 적정한 방법으로 또는 Remington's Pharmaceutical Science(Mack PublishingCompany, Easton PA, 18th, 1990)에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화할 수 있다.The pharmaceutical composition of the present invention may include a carrier, diluent, excipient, or a combination of two or more commonly used in biological agents. As used herein, the term “pharmaceutically acceptable” refers to exhibiting properties that are not toxic to cells or humans exposed to the composition. The carrier is not particularly limited as long as it is suitable for in vivo delivery of the composition, and for example, Merck Index, 13th ed., Merck & Co. Inc. Compounds described in , saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components can be mixed and used, and if necessary, other antioxidants, buffers, bacteriostats, etc. Conventional additives may be added. In addition, diluents, dispersants, surfactants, binders and lubricants may be additionally added to form an injectable dosage form such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules or tablets. Furthermore, it can be preferably formulated according to each disease or component using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990).
일 구현예에서, 상기 약학적 조성물은 경구형 제형, 외용제, 좌제, 멸균 주사용액 및 분무제를 포함하는 군으로부터 선택되는 하나 이상의 제형일 수 있으며, 경구형 또는 주사 제형이 더욱 바람직하다. In one embodiment, the pharmaceutical composition may be one or more formulations selected from the group including oral formulations, external preparations, suppositories, sterile injection solutions and sprays, and oral or injection formulations are more preferred.
본 발명에서 사용되는 용어, "투여"란, 임의의 적절한 방법으로 개체 또는 환자에게 소정의 물질을 제공하는 것을 의미하며, 목적하는 방법에 따라 비 경구 투여(예를 들어 정맥 내, 피하, 복강 내 또는 국소에 주사 제형으로 적용)하거나 경구 투여할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양하다. 본 발명의 조성물의 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 통상적으로 사용되는 단순 희석제인 물, 액체 파라핀 이외에 다양한 부형제, 예컨대 습윤제, 감미제, 방향제, 보존제 등이 함께 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제, 좌제 등이 포함된다. 본 발명의 약학적 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥 주사제, 피하 주사제, 피내주사제, 근육 주사제, 점적 주사제 등이다. 주사제는 생리식염액, 링겔액 등의 수성 용제, 식물유, 고급 지방산 에스테르(예, 올레인산에칠 등), 알코올 류(예, 에탄올, 벤질알코올, 프로필렌글리콜, 글리세린 등) 등의 비수성 용제 등을 이용하여 제조할 수 있고, 변질 방지를 위한 안정화제(예, 아스코르빈산, 아황산수소나트륨, 피로아황산나트륨, BHA, 토코페롤, EDTA 등), 유화제, pH 조절을 위한 완충제, 미생물 발육을 저지하기 위한 보존제 (예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레솔, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.As used herein, the term "administration" means providing a predetermined substance to a subject or patient by any suitable method, and parenteral administration (eg, intravenous, subcutaneous, intraperitoneal) according to a desired method Alternatively, it can be applied locally as an injection formulation) or orally administered, and the dosage varies according to the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease. Liquid formulations for oral administration of the composition of the present invention include suspensions, internal solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweetening agents, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. and the like may be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. The pharmaceutical composition of the present invention may be administered by any device capable of transporting an active substance to a target cell. Preferred administration methods and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip injections, and the like. For injection, aqueous solvents such as physiological saline and Ringel's solution, vegetable oil, higher fatty acid esters (eg, ethyl oleate), and non-aqueous solvents such as alcohols (eg, ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) Stabilizers for preventing deterioration (e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH control, to inhibit the growth of microorganisms Pharmaceutical carriers such as preservatives (eg, phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.
본 발명에서 사용되는 용어, "개체"란, 상기 염증성 질환이 발병하였거나 발병할 수 있는 인간을 포함한 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 박쥐, 낙타, 쥐, 토끼 또는 기니아 피그를 포함한 모든 동물을 의미하고, "검체"란 이로부터 분리한 비말, 가래, 전혈, 혈장, 혈청, 뇨 또는 타액일 수 있다. As used herein, the term "individual" refers to monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, bats, and camels including humans that have or may develop the inflammatory disease. , rats, rabbits, or all animals including guinea pigs, and the "sample" may be droplets, sputum, whole blood, plasma, serum, urine or saliva isolated therefrom.
본 발명의 약학적 조성물은 약제학적으로 허용 가능한 첨가제를 더 포함할 수 있으며, 이때 약제학적으로 허용 가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바 납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당, 덱스트로스, 소르비톨 및 탈크 등이 사용될 수 있다. 본 발명에 따른 약제학적으로 허용 가능한 첨가제는 상기 조성물에 대해 0.1 중량부 내지 90 중량부 포함되는 것이 바람직하나, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive includes starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate. , lactose, mannitol, syrup, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, Calcium stearate, sucrose, dextrose, sorbitol and talc and the like may be used. The pharmaceutically acceptable additive according to the present invention is preferably included in an amount of 0.1 to 90 parts by weight based on the composition, but is not limited thereto.
일 측면에서, 본 발명은 피검자로부터 체외로 분리된 시료를 취득하는 단계; 본 발명의 항체 또는 이의 면역학적 활성을 가진 단편을 상기 시료에 처리하는 단계; 및 상기 피검자의 시료 중에 포함된 IL-33의 수준이 정상군 시료 중에 포함된 IL-33의 수준보다 높은지 여부를 확인하는 단계;를 포함하는 염증성 질환의 진단을 위한 정보를 제공하는 방법에 관한 것이다.In one aspect, the present invention comprises the steps of obtaining a sample separated from the body from the subject; treating the sample with the antibody or fragment having immunological activity of the present invention; And it relates to a method of providing information for diagnosing an inflammatory disease comprising a; confirming whether the level of IL-33 contained in the sample of the subject is higher than the level of IL-33 contained in the sample of the normal group .
일 구현예에서, 상기 피검자의 시료 중에 포함된 IL-33의 수준이 정상군 시료 중에 포함된 IL-33의 수준보다 높은 경우 피검자가 염증성 질환에 걸린 것으로 판단하는 단계를 추가로 포함할 수 있다. In one embodiment, when the level of IL-33 contained in the sample of the subject is higher than the level of IL-33 contained in the sample of the normal group, the method may further include determining that the subject has an inflammatory disease.
하기의 실시예를 통하여 본 발명을 보다 상세하게 설명한다. 그러나 하기 실시예는 본 발명의 내용을 구체화하기 위한 것일 뿐 이에 의해 본 발명이 한정되는 것은 아니다.The present invention will be described in more detail through the following examples. However, the following examples are only intended to embody the contents of the present invention, and the present invention is not limited thereto.
실시예 1. IL-33에 특이적인 scFv의Example 1. IL-33 specific scFv 스크리닝screening
1-1. 바이오패닝1-1. biopanning
Immunotube에 항원 Large synthetic human scFv library 10μg을 넣어 37℃에서 1시간 동안 코팅시키고 5% 스킴밀크가 포함된 PBS 완충용액으로 상온(room temperature, RT)에서 1시간 동안 블로킹하였다. 1.0 X1012의 다양성을 가진 1세트의 scFv 라이브러리 세포들을 파아지 감염시킨 후 30℃에 16시간 배양하고 폴리에틸렌글리콜8000으로 농축한 뒤 PBS 완충용액에 부유시켜 제작한 라이브러리 파아지를 상기 블로킹한 Immunotube 넣어 1시간 동안 반응시켰다. 그 후 1xPBST로 세척하고 용출용액을 통해 항원에 특이적으로 결합한 단일 사슬 항체-파아지들만 추출한 뒤, 상기 파아지를 다시 대장균에 감염시켜 증폭시키는 패닝과정을 통해 양성 파아지 풀을 얻었다. 1회 차의 패닝에서 증폭된 파아지를 가지고 세척 단계에서 횟수만 늘렸으며, 나머지는 동일한 방법으로 2, 3, 4 및 5회 차의 패닝을 수행하여 이를 하기 표 1에 나타내었다.10 μg of antigen Large synthetic human scFv library was put into an immunotube, coated at 37° C. for 1 hour, and blocked with PBS buffer containing 5% skim milk at room temperature (room temperature, RT) for 1 hour. One set of scFv library cells having a diversity of 1.0 X 10 12 were phage-infected, incubated at 30° C. for 16 hours, concentrated with polyethylene glycol 8000, and suspended in PBS buffer solution. The phage prepared by suspension in PBS buffer was placed in the blocked Immunotube for 1 hour. reacted while After washing with 1xPBST and extracting only single-chain antibody-phages that specifically bind to the antigen through the elution solution, positive phage pools were obtained through a panning process in which the phages were again infected with E. coli and amplified. In the first round of panning, only the number of times was increased in the washing step with the amplified phage, and 2, 3, 4, and 5 rounds of panning were performed in the same manner for the rest, and are shown in Table 1 below.
1-2. IL-33 특이적 scFv 선별1-2. IL-33 specific scFv selection
상기 패닝을 통하여 얻은 scFv-파아지 항체 풀에서 항원 특이적 scFv를 선별하기 위해, scFv 파아지 ELISA를 수행하였다. 구체적으로, 상기 실시예 1-1에서 5회 차 패닝을 통해 얻은 scFv를 LB(Luria-Bertani) 플레이트에 스프레드해서 키운 후 384개의 scFv 클론들을 선별하였다. 이들을 96-웰 세포 배양 플레이트에서 배양하였고 GST 택(tag)이 달린 IL-33이 코팅된 플레이트에 접종하여 ELISA를 수행하였다. 여기서, 항원 IL-33이 아닌 GST 단백질만 제시된 플레이트에 scFv를 넣은 것을 ELISA의 음성 대조군으로 사용되었다. ELISA 분석결과 450 nm에서 흡광도 값이 높은 10개의 scFv들을 선발하였으며 (도 2A), IL-33에 대해 높은 결합 신호를 나타내는 상위 6 클론 C1_1E1, C2_1D5, C2_2A10, C2_2E1, C2_2E12 및 C2_2H5을 선발하였다. 선발한 C1_1E1 (서열번호 3), C2_1D5 (서열번호 4), C2_2A10 (서열번호 5), C2_2E1 (서열번호 6), C2_2E12 (서열번호 2) 및 C2_2H5 (서열번호 7)의 서열을 분석하였으며 (도 1 및 도 2B), 웨스턴 블롯으로 C2_2E12의 크기 (kDa)를 확인하였다 (도 2C). 상기 클론 C1_1E1, C2_1D5, C2_2A10, C2_2E1, C2_2E12 및 C2_2H5의 IL-33에 대한 친화도(Affinity) Kd 값을 ELISA 분석으로 측정하였다 (도 3 및 표 2).In order to select antigen-specific scFv from the scFv-phage antibody pool obtained through the panning, scFv phage ELISA was performed. Specifically, the scFv obtained through the fifth round of panning in Example 1-1 was spread and grown on an LB (Luria-Bertani) plate, and then 384 scFv clones were selected. They were cultured in 96-well cell culture plates, and ELISA was performed by inoculating the GST-tagged IL-33-coated plates. Here, a plate containing only GST protein, not IL-33 antigen, containing scFv was used as a negative control for ELISA. As a result of ELISA analysis, 10 scFvs with high absorbance values at 450 nm were selected (FIG. 2A), and the top 6 clones C1_1E1, C2_1D5, C2_2A10, C2_2E1, C2_2E12 and C2_2H5 showing a high binding signal to IL-33 were selected. The sequences of the selected C1_1E1 (SEQ ID NO: 3), C2_1D5 (SEQ ID NO: 4), C2_2A10 (SEQ ID NO: 5), C2_2E1 (SEQ ID NO: 6), C2_2E12 (SEQ ID NO: 2) and C2_2H5 (SEQ ID NO: 7) were analyzed (Fig. 1 and 2B), the size (kDa) of C2_2E12 was confirmed by Western blot (FIG. 2C). Affinity K d values of the clones C1_1E1, C2_1D5, C2_2A10, C2_2E1, C2_2E12 and C2_2H5 for IL-33 were measured by ELISA analysis (FIG. 3 and Table 2).
실시예 2. IL-33 특이적 scFv의 항원 결합력 확인Example 2. Confirmation of antigen binding affinity of IL-33 specific scFv
상기 패닝을 통해 얻어진 IL-33 특이적 항체들 중 C2_2E12의 항원과의 결합력을 확인하기 위해 항원의 농도를 고정하고 항체의 농도를 변화하면서 ELISA 분석으로 K d값을 구했다 (도 4 및 표 2).Among the IL-33-specific antibodies obtained through the panning, in order to confirm the binding affinity of C2_2E12 with the antigen, the K d value was obtained by ELISA analysis while the concentration of the antigen was fixed and the concentration of the antibody was changed (Fig. 4 and Table 2). .
실시예 3. IL-33 특이적 scFv의 항원 결합부위 확인Example 3. Identification of antigen binding site of IL-33 specific scFv
3-1. C1_1E1, C2_1D5, C2_2A10, C2_2E1 및 C2_2H5의 항원 결합부위 확인3-1. Identification of antigen binding sites of C1_1E1, C2_1D5, C2_2A10, C2_2E1 and C2_2H5
상기 패닝을 통해 얻어진 IL-33 특이적 항체 C1_1E1, C2_1D5, C2_2A10, C2_2E1 및 C2_2H5의 항원 결합 부위를 확인하기 위해, IL-33의 아미노산 서열 중 138, 148, 158 및 169번의 아미노산 잔기 뒤에 종결 코돈(stop codon)을 각각 삽입하여 재조합 GST-IL-33들을 제작한 뒤 이들 각각에 대한 C1_1E1, C2_1D5, C2_2A10, C2_2E1 또는 C2_2H5의 결합력을 확인한 결과, IL-33의 149 내지 158의 아미노산 잔기가 C1_1E1, C2_1D5, C2_2A10, C2_2E1 또는 C2_2H5와의 결합에 중요함을 확인하였다 (도 5). To identify the antigen binding sites of the IL-33-specific antibodies C1_1E1, C2_1D5, C2_2A10, C2_2E1 and C2_2H5 obtained through the panning, a stop codon ( stop codon) was inserted to construct recombinant GST-IL-33, and the binding affinity of C1_1E1, C2_1D5, C2_2A10, C2_2E1 or C2_2H5 to each of them was confirmed. As a result, amino acid residues 149 to 158 of IL-33 are C1_1E1, C2_1D5 , it was confirmed that it is important for binding to C2_2A10, C2_2E1 or C2_2H5 ( FIG. 5 ).
3-2. C2_2E12의 항원 결합부위 확인3-2. Identification of the antigen binding site of C2_2E12
상기 패닝을 통해 얻어진 IL-33 특이적 항체 C2_2E12의 항원 결합 부위를 확인하기 위해, IL-33의 아미노산 서열 중 127, 138, 148, 158, 169, 187, 197, 206, 216, 222, 232, 243 및 251번의 아미노산 잔기 뒤에 종결 코돈(stop codon)을 각각 삽입하여 재조합 GST-IL-33들을 제작한 뒤 이들 각각에 대한 C2_2E12의 결합력을 확인한 결과, IL-33의 149 내지 158의 아미노산 잔기가 C2_2E12와의 결합에 중요함을 확인하였다 (도 6A). 이에, IL-33의 149 내지 158의 아미노산 잔기를 각각 하나씩 알라닌(A)으로 치환하여 C2_2E12와의 결합력을 확인하였고, IL-33의 150번 및 151번 아미노산 잔기가 C2_2E12와의 결합에 중요한 것을 확인하였다 (도 6B). 이에, C2_2E12의 IL-33으로의 HADDOCK(High Ambiguity-Driven biomolecular DOCKing)-유래 분자 도킹을 확인하여 하기 표 3에 나타내었으며, C2_2E12가 인식하는 IL-33의 에피토프 영역에서의 잔기를 stick 모델로 확인하고 C2_2E12 및 IL-33의 정전기 상호작용(Electrostatic interaction)을 확인하여 PyMOL (Schrodinger)로 나타냈다 (도 6C 및 D).In order to confirm the antigen binding site of the IL-33 specific antibody C2_2E12 obtained through the panning, 127, 138, 148, 158, 169, 187, 197, 206, 216, 222, 232, among the amino acid sequences of IL-33, After constructing recombinant GST-IL-33 by inserting a stop codon after amino acid residues 243 and 251, respectively, the binding affinity of C2_2E12 to each of them was confirmed. As a result, amino acid residues 149 to 158 of IL-33 were C2_2E12 It was confirmed that it is important for binding to (FIG. 6A). Accordingly, by substituting alanine (A) for amino acid residues 149 to 158 of IL-33, binding affinity to C2_2E12 was confirmed, and amino acid residues 150 and 151 of IL-33 were confirmed to be important for binding to C2_2E12 ( 6B). Accordingly, HADDOCK (High Ambiguity-Driven biomolecular DOCKing)-derived molecular docking of C2_2E12 to IL-33 was confirmed and shown in Table 3 below. Residues in the epitope region of IL-33 recognized by C2_2E12 were identified as a stick model. and PyMOL (Schrodinger) by confirming the electrostatic interaction of C2_2E12 and IL-33 ( FIGS. 6C and D).
a A.U., arbitrary unit. a AU, arbitrary unit.
상기 결과들을 통해, 모든 클론들이 동일한 에피토프를 인식하는 것을 확인할 수 있었다.Through the above results, it was confirmed that all clones recognized the same epitope.
실시예 4. IL-33 특이적 scFv의 항원 특이성 확인Example 4. Confirmation of antigen specificity of IL-33 specific scFv
상기 패닝을 통해 얻어진 IL-33 특이적 항체들 중 C2_2E12의 항원 특이성을 확인하기 위해 cross-reactivity 실험을 수행하였다. 구체적으로, C2_2E12를 1차 항체 (0.5 mg/ml, 1:100 희석)로, 항-HA-HRP를 2차 항체 (0.2 mg/ml, 1:5000 dilution)로 이용하여, 인터루킨 단백질 중에서 IL-33과 통계학적으로 가장 가까운 IL-1b, 가장 먼 IL-6 및 인터루킨과 연관이 없는 GST, BSA 및 IlvC 단백질들에 대한 면역블롯 분석을 수행한 결과, C2_2E12가 IL-33에만 특이적으로 결합하는 것을 확인할 수 있었다 (도 7). A cross-reactivity experiment was performed to confirm the antigen specificity of C2_2E12 among the IL-33-specific antibodies obtained through the panning. Specifically, using C2_2E12 as a primary antibody (0.5 mg/ml, 1:100 dilution) and anti-HA-HRP as a secondary antibody (0.2 mg/ml, 1:5000 dilution), IL- As a result of immunoblot analysis of IL-1b, which is statistically closest to 33, IL-6, and GST, BSA, and IlvC proteins that are not related to interleukin, C2_2E12 specifically binds only to IL-33. was confirmed (FIG. 7).
실시예 5. IL-33 특이적 scFv의 중화항체 기능 확인Example 5. Confirmation of neutralizing antibody function of IL-33 specific scFv
5-1.C2_2E12의 IL-33 및 ST2 복합체 형성 저해 작용5-1. Inhibition of IL-33 and ST2 complex formation of C2_2E12
IL-33 특이적 항체 C2_2E12가 IL-33과 ST2간의 결합을 저해할 수 있는 중화항체로 기능할 수 있는지 확인하기 위해 in vitro pull-down 분석을 수행하였다. 구체적으로, GST 태깅된 IL-33을 글루타치온 레진(glutathione resin) (Glutathione Sepharose 4B)에 고정/결합시키고 ST2-Fc 융합 단백질을 첨가하여 IL-33과 반응시킨 뒤, C2_2E12의 양을 늘려주며 IL-33 및 ST2 간의 결합이 저해되는지를 SDS-PAGE 및 웨스턴 블롯 분석으로 확인하였다 (단백질 몰 농도 비율은 각각 GST-IL-33: ST2-Fc: C2_2E12 = 1: 1: 0.1, 1:1:1, 1:1:10 및 1:1:100 (M)). 그 결과, C2_2E12가 IL-33과 ST2의 결합을 방해하는 것을 확인할 수 있었다 (도 8). In vitro pull-down analysis was performed to confirm that the IL-33-specific antibody C2_2E12 can function as a neutralizing antibody capable of inhibiting the binding between IL-33 and ST2. Specifically, GST-tagged IL-33 was fixed/conjugated to glutathione resin (Glutathione Sepharose 4B), reacted with IL-33 by adding ST2-Fc fusion protein, and then increased the amount of C2_2E12 and IL- Whether the binding between 33 and ST2 was inhibited was confirmed by SDS-PAGE and Western blot analysis (protein molar concentration ratios were GST-IL-33: ST2-Fc: C2_2E12 = 1: 1: 0.1, 1:1:1, respectively. 1:1:10 and 1:1:100 (M)). As a result, it was confirmed that C2_2E12 interfered with the binding of IL-33 to ST2 ( FIG. 8 ).
5-2. 인간 세포에서의 C2_2E12 중화 효능 확인5-2. Confirmation of C2_2E12 Neutralization Efficacy in Human Cells
IL-33 특이적 항체 C2_2E12가 세포 내에서도 중화항체로서의 기능을 나타내는지 확인하기 위해, 내재적으로 ST2 및 IL-1RAcP을 발현하는 HMC(human mast cell)-1 세포와 ST2 및 IL-1RAcP을 발현하지 않는 HeLa 세포를 인간 IL-33 (1 ng/ml, 8 min)로 자극하고, C2_2E12의 양을 늘려주며 처리한 뒤, 각 세포를 파쇄하여 MAPK 및 NF-κB 신호전달 경로 내의 ERK, JNK 및 IκBα의 인산화 밴드 변화 양상을 면역블롯 분석으로 확인하였다. 그 결과, ST2 및 IL-1RAcP을 발현하는 HMC-1 세포에서 IL-33의 처리로 인해 JNK 발현이 증가하고 JNK 및 ERK의 인산화가 증가하였으며, JNK 및 ERK의 인산화는 C2_2E12의 농도 의존적으로 감소하였다 (도 9). 또한, IκBα는 IL-33 처리로 인해 감소되었다가, C2_2E12의 농도 의존적으로 증가하는 것으로 나타났다 (도 9). 즉, IL-33로 유도된 MAPK 및 NF-κB 신호전달을 C2_2E12가 농도 의존적으로 억제하는 것을 확인할 수 있었으며, 이를 통해 C2_2E12가 세포 내에서도 중화항체로 작용하는 것을 알 수 있다.To determine whether the IL-33 specific antibody C2_2E12 functions as a neutralizing antibody even in cells, human mast cell (HMC)-1 cells that endogenously express ST2 and IL-1RAcP and those that do not express ST2 and IL-1RAcP HeLa cells were stimulated with human IL-33 (1 ng/ml, 8 min), treated with increasing amounts of C2_2E12, and then each cell was disrupted to release ERK, JNK and IκBα in the MAPK and NF-κB signaling pathways. The pattern of phosphorylation band change was confirmed by immunoblot analysis. As a result, in HMC-1 cells expressing ST2 and IL-1RAcP, treatment with IL-33 increased JNK expression, increased JNK and ERK phosphorylation, and decreased JNK and ERK phosphorylation in a concentration-dependent manner of C2_2E12. (Fig. 9). In addition, IκBα was decreased due to IL-33 treatment, and then increased in a concentration-dependent manner of C2_2E12 ( FIG. 9 ). That is, it was confirmed that C2_2E12 inhibits IL-33-induced MAPK and NF-κB signaling in a concentration-dependent manner, and this shows that C2_2E12 also acts as a neutralizing antibody in cells.
<110> Research and Business Foundation SUNGKYUNKWAN UNIVERSITY <120> IL-33 BINDING ANTIBODIES OR ANTIGEN BINDING FRAGMENTS THEREOF <130> R-2020-0327-KR-1 <160> 46 <170> KoPatentIn 3.0 <210> 1 <211> 270 <212> PRT <213> Homo sapiens <400> 1 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30 Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45 Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60 Thr Lys Arg Pro Ser Leu Lys Thr Gly Arg Lys His Lys Arg His Leu 65 70 75 80 Val Leu Ala Ala Cys Gln Gln Gln Ser Thr Val Glu Cys Phe Ala Phe 85 90 95 Gly Ile Ser Gly Val Gln Lys Tyr Thr Arg Ala Leu His Asp Ser Ser 100 105 110 Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser Thr 115 120 125 Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr Glu 130 135 140 Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys Val Leu 145 150 155 160 Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp Gly 165 170 175 Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp Phe 180 185 190 Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys Cys 195 200 205 Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met His 210 215 220 Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe Ile 225 230 235 240 Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser Glu 245 250 255 Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr 260 265 270 <210> 2 <211> 242 <212> PRT <213> Artificial Sequence <220> <223> C2_2E12 <400> 2 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Thr Leu Ser Phe Asp Tyr Trp Gly Gln Gly Thr Pro Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 130 135 140 Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile 145 150 155 160 Gly Ser Asn Asp Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Ala Asp Ser Lys Arg Pro Ser Gly Val Pro Asp 180 185 190 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 195 200 205 Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp 210 215 220 Ser Ser Leu Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val 225 230 235 240 Leu Gly <210> 3 <211> 264 <212> PRT <213> Artificial Sequence <220> <223> C1_1E1 <400> 3 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Thr Ser Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Asp Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 130 135 140 Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile 145 150 155 160 Gly Ser Asn Asp Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Ser Asp Asn Lys Arg Pro Ser Gly Val Pro Asp 180 185 190 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 195 200 205 Gly Leu Arg Ser Glu Glu Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp 210 215 220 Ser Ser Leu Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val 225 230 235 240 Leu Gly Gln Ala Gly Gln His His His His His His Gly Ala Tyr Pro 245 250 255 Tyr Asp Val Pro Asp Tyr Ala Ser 260 <210> 4 <211> 264 <212> PRT <213> Artificial Sequence <220> <223> C2_1D5 <400> 4 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Leu Ser Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 130 135 140 Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile 145 150 155 160 Gly Ser Asn Asp Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Ser Asp Ser Asn Arg Pro Ser Gly Val Pro Asp 180 185 190 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 195 200 205 Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp 210 215 220 Ser Ser Leu Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val 225 230 235 240 Leu Gly Gln Ala Gly Gln His His His His His His Gly Ala Tyr Pro 245 250 255 Tyr Asp Val Pro Asp Tyr Ala Ser 260 <210> 5 <211> 264 <212> PRT <213> Artificial Sequence <220> <223> C2_2A10 <400> 5 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Gly Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Leu Thr Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 130 135 140 Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile 145 150 155 160 Gly Asn Asn Ala Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Asp Asp Asn His Arg Pro Ser Gly Val Pro Asp 180 185 190 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 195 200 205 Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp 210 215 220 Ser Ser Leu Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val 225 230 235 240 Leu Gly Gln Ala Gly Gln His His His His His His Gly Ala Tyr Pro 245 250 255 Tyr Asp Val Pro Asp Tyr Ala Ser 260 <210> 6 <211> 264 <212> PRT <213> Artificial Sequence <220> <223> C2_2E1 <400> 6 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Met Thr Ser Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 130 135 140 Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile 145 150 155 160 Gly Asn Asn Asp Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Ser Asp Ser Gln Arg Pro Ser Gly Val Pro Asp 180 185 190 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 195 200 205 Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp 210 215 220 Tyr Ser Leu Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val 225 230 235 240 Leu Gly Gln Ala Gly Gln His His His His His His Gly Ala Tyr Pro 245 250 255 Tyr Asp Val Pro Asp Tyr Ala Ser 260 <210> 7 <211> 264 <212> PRT <213> Artificial Sequence <220> <223> C2_2H5 <400> 7 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Gln Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Ser Gln Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Ser Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 130 135 140 Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile 145 150 155 160 Gly Asn Asn Gly Ile Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Asp Asn Ser His Arg Pro Ser Gly Val Pro Asp 180 185 190 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 195 200 205 Gly Leu Arg Ser Glu Asp Glu Thr Asp Tyr Tyr Cys Ala Ser Trp Asp 210 215 220 Ser Ser Leu Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val 225 230 235 240 Leu Gly Gln Ala Gly Gln His His His His His His Gly Ala Tyr Pro 245 250 255 Tyr Asp Val Pro Asp Tyr Ala Ser 260 <210> 8 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-H1 <400> 8 Ser Tyr Tyr Met Ser 1 5 <210> 9 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 <400> 9 Ala Ile Ser Pro Gly Ser Ser Asn Lys 1 5 <210> 10 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3(C1_1E1) <400> 10 Lys Leu Thr Ser Ala Phe Asp Tyr 1 5 <210> 11 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3(C2_1D5) <400> 11 Arg Leu Leu Ser Ala Phe Asp Tyr 1 5 <210> 12 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3(C2_2E1) <400> 12 Arg Met Thr Ser Ser Phe Asp Tyr 1 5 <210> 13 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3(C2_2E12) <400> 13 Arg Leu Thr Leu Ser Phe Asp Tyr 1 5 <210> 14 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3(C2_2A10) <400> 14 Lys Leu Leu Thr Gly Phe Asp Tyr 1 5 <210> 15 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3(C2_2H5) <400> 15 Lys Leu Ser Gln Ser Phe Asp Tyr 1 5 <210> 16 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1(C1_1E1) <400> 16 Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn Asp Val Thr 1 5 10 <210> 17 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1(C2_2E1) <400> 17 Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Asp Val Ser 1 5 10 <210> 18 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1(C2_2E12/C2_1D5) <400> 18 Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Asp Val Ser 1 5 10 <210> 19 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1(C2_2A10) <400> 19 Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Ala Val Ser 1 5 10 <210> 20 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1(C2_2H5) <400> 20 Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn Gly Ile Ser 1 5 10 <210> 21 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2(C1_1E1) <400> 21 Ser Asp Asn Lys Arg 1 5 <210> 22 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2(C2_1D5) <400> 22 Ser Asp Ser Asn Arg 1 5 <210> 23 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2(C2_2E1) <400> 23 Ser Asp Ser Gln Arg 1 5 <210> 24 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2(C2_2E12) <400> 24 Ala Asp Ser Lys Arg 1 5 <210> 25 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2(C2_2A10) <400> 25 Asp Asp Asn His Arg 1 5 <210> 26 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2(C2_2H5) <400> 26 Asp Asn Ser His Arg 1 5 <210> 27 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3(C1_1E1/C2_1D5) <400> 27 Gly Ala Trp Asp Ser Ser Leu Ser Gly 1 5 <210> 28 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3(C2_2E1) <400> 28 Gly Ser Trp Asp Tyr Ser Leu Ser Ala 1 5 <210> 29 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3(C2_2E12) <400> 29 Ala Ser Trp Asp Ser Ser Leu Ser Ala 1 5 <210> 30 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3(C2_2A10) <400> 30 Gly Thr Trp Asp Ser Ser Leu Ser Ala 1 5 <210> 31 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3(C2_2H5) <400> 31 Ala Ser Trp Asp Ser Ser Leu Ser Gly 1 5 <210> 32 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH-FR1 <400> 32 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30 <210> 33 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> VH-FR2 (C1_1E1/C2_1D5/C2_2E12/C2_2A10/C2_2H5) <400> 33 Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser 1 5 10 <210> 34 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> VH-FR2 (C2_2E1) <400> 34 Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val Ser 1 5 10 <210> 35 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> VH-FR3 (C1_1E1/C2_1D5/C2_2E1/C2_2E12) <400> 35 Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 1 5 10 15 Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 20 25 30 Thr Ala Val Tyr Tyr Cys Ala 35 <210> 36 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> VH-FR3 (C2_2A10) <400> 36 Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 1 5 10 15 Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Gly Ala Glu Asp 20 25 30 Thr Ala Val Tyr Tyr Cys Ala 35 <210> 37 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> VH-FR3 (C2_2H5) <400> 37 Tyr Tyr Ala Asp Ser Val Lys Gly Gln Phe Thr Ile Ser Arg Asp Asn 1 5 10 15 Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 20 25 30 Thr Ala Val Tyr Tyr Cys Ala 35 <210> 38 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> VH-FR4 (C1_1E1/C2_1D5/C2_2E1/C2_2A10/C2_2H5) <400> 38 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 39 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> VH-FR4 (C2_2E12) <400> 39 Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser 1 5 10 <210> 40 <211> 22 <212> PRT <213> Artificial Sequence <220> <223> VL-FR1 <400> 40 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys 20 <210> 41 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> VL-FR2 <400> 41 Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> 42 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> VL-FR3 (C1_1E1) <400> 42 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser 1 5 10 15 Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Glu Glu Ala Asp Tyr 20 25 30 Tyr Cys <210> 43 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> VL-FR3 (C2_2E12/C2_1D5/C2_2E1/C2_2A10) <400> 43 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser 1 5 10 15 Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr 20 25 30 Tyr Cys <210> 44 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> VL-FR3 (C2_2H5) <400> 44 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser 1 5 10 15 Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Thr Asp Tyr 20 25 30 Tyr Cys <210> 45 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> VL-FR4 <400> 45 Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 1 5 10 <210> 46 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> epitope <400> 46 Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys 1 5 10 <110> Research and Business Foundation SUNGKYUNKWAN UNIVERSITY <120> IL-33 BINDING ANTIBODIES OR ANTIGEN BINDING FRAGMENTS THEREOF <130> R-2020-0327-EN-1 <160> 46 <170> KoPatentIn 3.0 <210> 1 <211> 270 <212> PRT <213> Homo sapiens <400> 1 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30 Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45 Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60 Thr Lys Arg Pro Ser Leu Lys Thr Gly Arg Lys His Lys Arg His Leu 65 70 75 80 Val Leu Ala Ala Cys Gln Gln Gln Ser Thr Val Glu Cys Phe Ala Phe 85 90 95 Gly Ile Ser Gly Val Gln Lys Tyr Thr Arg Ala Leu His Asp Ser Ser 100 105 110 Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser Thr 115 120 125 Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr Glu 130 135 140 Ile Tyr Val Glu Asp Leu Lys Lys Lys Asp Glu Lys Lys Asp Lys Val Leu 145 150 155 160 Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp Gly 165 170 175 Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp Phe 180 185 190 Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys Cys 195 200 205 Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met His 210 215 220 Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe Ile 225 230 235 240 Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser Glu 245 250 255 Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr 260 265 270 <210> 2 <211> 242 <212> PRT <213> Artificial Sequence <220> <223> C2_2E12 <400> 2 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Thr Leu Ser Phe Asp Tyr Trp Gly Gln Gly Thr Pro Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 130 135 140 Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile 145 150 155 160 Gly Ser Asn Asp Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Ala Asp Ser Lys Arg Pro Ser Gly Val Pro Asp 180 185 190 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 195 200 205 Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Asp 210 215 220 Ser Ser Leu Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val 225 230 235 240 Leu Gly <210> 3 <211> 264 <212> PRT <213> Artificial Sequence <220> <223> C1_1E1 <400> 3 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Thr Ser Ala Phe Asp Tyr Trp Gly Gly Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Asp Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 130 135 140 Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile 145 150 155 160 Gly Ser Asn Asp Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Ser Asp Asn Lys Arg Pro Ser Gly Val Pro Asp 180 185 190 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 195 200 205 Gly Leu Arg Ser Glu Glu Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp 210 215 220 Ser Ser Leu Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val 225 230 23 5 240 Leu Gly Gln Ala Gly Gln His His His His His His Gly Ala Tyr Pro 245 250 255 Tyr Asp Val Pro Asp Tyr Ala Ser 260 <210> 4 <211> 264 <212> PRT <213> Artificial Sequence <220> <223> C2_1D5 <400> 4 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Leu Ser Ala Phe Asp Tyr Trp Gly Gly Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 130 135 140 Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Ser Asn Ile 145 150 155 160 Gly Ser Asn Asp Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Ser Asp Ser Asn Arg Pro Ser Gly Val Pro Asp 180 185 190 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 195 200 205 Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ala Trp Asp 210 215 220 Ser Ser Leu Ser Gly Tyr Val Phe Gly Gly Gly Gly Thr Lys Leu Thr Val 225 230 235 240 Leu Gly Gln Ala Gly Gln His His His His His His Gly Ala Tyr Pro 245 250 255 Tyr Asp Val Pro Asp Tyr Ala Ser 260 <210> 5 <211> 264 <212> PRT <213> Artificial Sequence <220> <223> C2_2A10 <400> 5 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Gly Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Leu Thr Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 130 135 140 Pro Gly Gin Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile 145 150 155 160 Gly Asn Asn Ala Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Asp Asp Asn His Arg Pro Ser Gly Val Pro Asp 180 185 190 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 195 200 205 Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp 210 215 220 Ser Ser Leu Ser Ala Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val 225 230 235 240 Leu Gly Gln Ala Gly Gln His His His His His His Gly Ala Tyr Pro 245 250 255 Tyr Asp Val Pro Asp Tyr Ala Ser 260 <210> 6 <211 > 264 <212> PRT <213> Artificial Sequence <220> <223> C2_2E1 <400> 6 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Met Thr Ser Ser Phe Asp Tyr Trp Gly Gly Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 130 135 140 Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Ser Asn Ile 145 150 155 160 Gly Asn Asn Asp Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Ser Asp Ser Gln Arg Pro Ser Gly Val Pro Asp 180 185 190 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 195 200 205 Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp 210 215 220 Tyr Ser Leu Ser Ala Tyr Va l Phe Gly Gly Gly Thr Lys Leu Thr Val 225 230 235 240 Leu Gly Gln Ala Gly Gln His His His His His His His Gly Ala Tyr Pro 245 250 255 Tyr Asp Val Pro Asp Tyr Ala Ser 260 <210> 7 <211> 264 <212> PRT <213> Artificial Sequence <220> <223> C2_2H5 <400> 7 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Pro Gly Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Gln Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Leu Ser Gln Ser Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 S er Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 130 135 140 Pro Gly Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile 145 150 155 160 Gly Asn Asn Gly Ile Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Asp Asn Ser His Arg Pro Ser Gly Val Pro Asp 180 185 190 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 195 200 205 Gly Leu Arg Ser Glu Asp Glu Thr Asp Tyr Tyr Cys Ala Ser Trp Asp 210 215 220 Ser Ser Leu Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val 225 230 235 240 Leu Gly Gln Ala Gly Gln His His His His His His His Gly Ala Tyr Pro 245 250 255 Tyr Asp Val Pro Asp Tyr Ala Ser 260 <210> 8 <211> 5 <212> PRT <213> Artificial Sequence <220> <22 3> CDR-H1 <400> 8 Ser Tyr Tyr Met Ser 1 5 <210> 9 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-H2 <400> 9 Ala Ile Ser Pro Gly Ser Ser Asn Lys 1 5 <210> 10 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3(C1_1E1) <400> 10 Lys Leu Thr Ser Ala Phe Asp Tyr 1 5 <210> 11 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3(C2_1D5) <400> 11 Arg Leu Leu Ser Ala Phe Asp Tyr 1 5 <210> 12 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3(C2_2E1) <400> 12 Arg Met Thr Ser Ser Phe Asp Tyr 1 5 <210> 13 <211> 8 <212> PRT <213 > Artificial Sequence <220> <223> CDR-H3(C2_2E12) <400> 13 Arg Leu Thr Leu Ser Phe Asp Tyr 1 5 <210> 14 <211> 8 <212> PRT <213> Artificial Sequence <220> < 223> CDR-H3(C2_2A10) <400> 14 Lys Leu Leu Thr Gly Phe Asp Tyr 1 5 <210> 15 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> CDR-H3(C2_2H5) ) <400> 15 Lys Leu Ser Gln Ser Phe A sp Tyr 1 5 <210> 16 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1(C1_1E1) <400> 16 Thr Gly Ser Ser Ser Asn Ile Gly Ser Asn Asp Val Thr 1 5 10 <210> 17 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1(C2_2E1) <400> 17 Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Asp Val Ser 1 5 10 <210> 18 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1(C2_2E12/C2_1D5) <400> 18 Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Asp Val Ser 1 5 10 <210> 19 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1(C2_2A10) <400> 19 Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Ala Val Ser 1 5 10 <210> 20 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> CDR-L1(C2_2H5) <400> 20 Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn Gly Ile Ser 1 5 10 <210> 21 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2(C1_1E1) <400> 21 Ser Asp Asn Lys Arg 1 5 <210> 22 <211> 5 < 212> P RT <213> Artificial Sequence <220> <223> CDR-L2(C2_1D5) <400> 22 Ser Asp Ser Asn Arg 1 5 <210> 23 <211> 5 <212> PRT <213> Artificial Sequence <220> < 223> CDR-L2(C2_2E1) <400> 23 Ser Asp Ser Gln Arg 1 5 <210> 24 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2(C2_2E12) <400 > 24 Ala Asp Ser Lys Arg 1 5 <210> 25 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2(C2_2A10) <400> 25 Asp Asp Asn His Arg 1 5 < 210> 26 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CDR-L2(C2_2H5) <400> 26 Asp Asn Ser His Arg 1 5 <210> 27 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3(C1_1E1/C2_1D5) <400> 27 Gly Ala Trp Asp Ser Ser Leu Ser Gly 1 5 <210> 28 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3(C2_2E1) <400> 28 Gly Ser Trp Asp Tyr Ser Leu Ser Ala 1 5 <210> 29 <211> 9 <212> PRT <213> Artificial Sequence <220> < 223> CDR-L3 (C2_2E12) <400> 29 Ala Ser Trp Asp Ser Ser Leu Ser Ala 1 5 <210> 30 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3(C2_2A10) <400> 30 Gly Thr Trp Asp Ser Ser Leu Ser Ala 1 5 <210> 31 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CDR-L3(C2_2H5) <400> 31 Ala Ser Trp Asp Ser Ser Leu Ser Gly 1 5 <210 > 32 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> VH-FR1 <400> 32 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 20 25 30 <210> 33 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> VH-FR2 (C1_1E1/C2_1D5/C2_2E12/C2_2A10/ C2_2H5) <400> 33 Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser 1 5 10 <210> 34 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> VH-FR2 ( C2_2E1) <400> 34 Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val Ser 1 5 10 <210> 35 <211> 39 <212> PRT <213> Artificial Sequence <220> <2 23> VH-FR3 (C1_1E1/C2_1D5/C2_2E1/C2_2E12) <400> 35 Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 1 5 10 15 Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 20 25 30 Thr Ala Val Tyr Tyr Cys Ala 35 <210> 36 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> VH-FR3 (C2_2A10) <400> 36 Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 1 5 10 15 Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Gly Ala Glu Asp 20 25 30 Thr Ala Val Tyr Tyr Cys Ala 35 <210> 37 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> VH-FR3 (C2_2H5) <400> 37 Tyr Tyr Ala Asp Ser Val Lys Gly Gln Phe Thr Ile Ser Arg Asp Asn 1 5 10 15 Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 20 25 30 Thr Ala Val Tyr Tyr Cys Ala 35 <210> 38 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> VH-FR4 (C1_1E1/C2_1D5/C2_2E1/C2_2A10/C2_2H5) <400> 38 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210 > 39 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> VH-FR4 (C2_2E12) <400> 39 Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser 1 5 10 <210> 40 < 211> 22 <212> PRT <213> Artificial Sequence <220> <223> VL-FR1 <400> 40 Gln Ser Val Leu Thr Gln Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys 20 <210> 41 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> VL-FR2 <400> 41 Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> 42 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> VL-FR3 (C1_1E1) <400> 42 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser 1 5 10 15 Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Glu Glu Ala Asp Tyr 20 25 30 Tyr Cys <210> 43 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> VL-FR3 (C2_2E12/C2_1D5/C2_2E1/C2_2A10) <400> 43 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser 1 5 10 15 Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr 20 25 30 Tyr Cys <210> 44 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> VL-FR3 (C2_2H5) <400> 44 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser 1 5 10 15 Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Thr Asp Tyr 20 25 30 Tyr Cys <210> 45 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> VL-FR4 <400> 45 Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 1 5 10 <210> 46 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> epitope<400> 46 Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys 1 5 10
Claims (18)
(ⅱ) 서열번호 16 내지 20의 아미노산 서열로 이루어지는 군으로부터 선택되는 어느 하나를 포함하는 CDRL1, 서열번호 21 내지 26의 아미노산 서열로 이루어지는 군으로부터 선택되는 어느 하나를 포함하는 CDRL2, 및 서열번호 27 내지 31 아미노산 서열로 이루어지는 군으로부터 선택되는 어느 하나를 포함하는 CDRL3를 포함하는 VL 도메인을 포함하는 V 도메인을 포함하는, IL-33에 특이적인 항체 또는 이의 면역학적 활성을 가진 단편.According to claim 1, (i) CDRH (Complementarity determining regions Heavy chain) 1 comprising the amino acid sequence of SEQ ID NO: 8, CDRH2 comprising the amino acid sequence of SEQ ID NO: 9, and consisting of the amino acid sequence of SEQ ID NOs: 10 to 15 a VH domain comprising CDRH3 comprising any one selected from the group; and/or
(ii) CDRL1 comprising any one selected from the group consisting of the amino acid sequence of SEQ ID NOs: 16 to 20, CDRL2 comprising any one selected from the group consisting of the amino acid sequence of SEQ ID NOs: 21 to 26, and SEQ ID NOs: 27 to An antibody or fragment having immunological activity specific for IL-33, comprising a V domain comprising a VL domain comprising CDRL3 comprising any one selected from the group consisting of a 31 amino acid sequence.
b) 숙주 세포 배양물로부터 항체 또는 이의 면역학적 활성을 가진 단편을 회수하는 단계를 포함하는 IL-33에 특이적인 항체 또는 이의 면역학적 활성을 가진 단편을 제조하는 방법.a) culturing a host cell comprising a vector comprising a nucleic acid molecule encoding the antibody of claim 1 or a fragment having immunological activity; and
b) a method for producing an antibody specific for IL-33 or a fragment having immunological activity thereof, comprising the step of recovering the antibody or fragment having immunological activity thereof from a host cell culture.
(b) 제 1항의 항체 또는 이의 면역학적 활성을 가진 단편을 상기 시료에 처리하는 단계; 및
(c) 상기 피검자의 시료 중에 포함된 IL-33의 수준이 정상군 시료 중에 포함된 IL-33의 수준보다 높은지 여부를 확인하는 단계;를 포함하는 염증성 질환의 진단을 위한 정보를 제공하는 방법.(a) obtaining a sample isolated from the subject in vitro;
(b) treating the sample with the antibody of claim 1 or a fragment having immunological activity thereof; and
(c) determining whether the level of IL-33 contained in the sample of the subject is higher than the level of IL-33 contained in the sample of the normal group; a method of providing information for diagnosing an inflammatory disease comprising a.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020200103135A KR20220022226A (en) | 2020-08-18 | 2020-08-18 | Il-33 binding antibodies or antigen binding fragments thereof |
PCT/KR2021/010812 WO2022039455A1 (en) | 2020-08-18 | 2021-08-13 | Antibody or antigen-binding fragment thereof that specifically binds to il-33 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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KR1020200103135A KR20220022226A (en) | 2020-08-18 | 2020-08-18 | Il-33 binding antibodies or antigen binding fragments thereof |
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KR20220022226A true KR20220022226A (en) | 2022-02-25 |
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KR1020200103135A KR20220022226A (en) | 2020-08-18 | 2020-08-18 | Il-33 binding antibodies or antigen binding fragments thereof |
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Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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JO3532B1 (en) * | 2013-03-13 | 2020-07-05 | Regeneron Pharma | Anti-il-33 antibodies and uses thereof |
AU2014370883B2 (en) * | 2013-12-26 | 2020-09-24 | Mitsubishi Tanabe Pharma Corporation | Human anti-IL-33 neutralizing monoclonal antibody |
CN106103480B (en) * | 2014-01-10 | 2021-10-22 | 安奈普泰斯生物有限公司 | Antibodies against interleukin-33 (IL-33) |
RU2740309C2 (en) * | 2016-04-27 | 2021-01-13 | Пфайзер Инк. | Antibodies against il-33, compositions, methods and their application |
WO2019183639A1 (en) * | 2018-03-23 | 2019-09-26 | Anaptysbio, Inc. | Inhibition of allergic reaction to peanut allergen using an il-33 inhibitor |
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2020
- 2020-08-18 KR KR1020200103135A patent/KR20220022226A/en not_active Application Discontinuation
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- 2021-08-13 WO PCT/KR2021/010812 patent/WO2022039455A1/en active Application Filing
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