KR20190084886A - PHARMACEUTICAL COMPOSITION COMPRISING RECOMBINANT EXTRACELLULAR DOMAIN OF IgE Fc RECEPTOR SUBUNIT ALPHA - Google Patents
PHARMACEUTICAL COMPOSITION COMPRISING RECOMBINANT EXTRACELLULAR DOMAIN OF IgE Fc RECEPTOR SUBUNIT ALPHA Download PDFInfo
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- KR20190084886A KR20190084886A KR1020190002037A KR20190002037A KR20190084886A KR 20190084886 A KR20190084886 A KR 20190084886A KR 1020190002037 A KR1020190002037 A KR 1020190002037A KR 20190002037 A KR20190002037 A KR 20190002037A KR 20190084886 A KR20190084886 A KR 20190084886A
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- Prior art keywords
- glu
- lys
- ser
- thr
- gly
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Abstract
Description
본원 발명은 변형된 IgE Fc 수용체의 용도에 관한 것이다. The present invention relates to the use of modified IgE Fc receptors.
천식을 비롯한 알러지비염, 아토피피부염, 식품알러지 등 알러지 질환은 산업화, 서구화된 현대사회에서 높은 속도로 확산되고 있으며, 중증 알러지 질환인 아나필락시스의 발생도 증가하고 있다. 이러한 만성 면역질환은 개인 삶의 질을 매우 떨어트리며 이에 따른 사회경제적 비용도 급증하고 있어, 이를 극복하기 위한 대책이 절실한 실정이다.Allergic diseases such as asthma, allergic rhinitis, atopic dermatitis and food allergy are spreading at a high rate in modernized industrialized and westernized society, and the incidence of anaphylactic diseases, which are severe allergic diseases, is also increasing. These chronic immune diseases severely impair the quality of individual life and the socioeconomic costs are also soaring, and measures are needed to overcome them.
대부분의 알러지 질환은 면역글로불린 E(IgE)의 과잉 면역반응에 의해 유발된다. IgE는 정상 상태에서는 혈청 중에 아주 낮은 농도로 존재하는 항체이다. IgE는 일반적으로 무해한 항원에 의해서 생성되기도 하며, 특별한 자극 없이도 IgE가 증가되는 경우가 있는데 이러한 경우에 알러지 질환이 야기될 수 있다. 비정상적으로 증가된 IgE가 비만 세포(Mast cell)와 호염기성 과립구(basophils) 등의 표면에 발현되는 고친화성 IgE Fc 수용체(FcεRI)에 결합할 수 있다. 이러한 결합에 의해 비만 세포나 호염기성 과립구는 히스타민, 류코트리엔, 프로스타글란딘, 브라디키닌 및 혈소판-활성화 인자 등 화학 매개자를 방출 하게 된다. 이러한 화학 매개자의 방출에 의해 알러지 증상이 발생하게 된다. 특히, 알러지 질환은 IgE 및 FcεRI 사이의 결합으로 증상이 악화 될 수 있다. FcεRI-발현 세포는 알러지 환자에서 증가한다고 알려져 있다.Most allergic diseases are caused by an excess of immunoglobulin E (IgE). IgE is an antibody that is present in serum at very low concentrations under normal conditions. IgE is usually produced by innocuous antigens, and IgE may be elevated without special stimuli, which can lead to allergic diseases. Abnormally increased IgE can bind to high affinity IgE Fc receptors (FcεRI) expressed on the surface of mast cells and basophils. By this combination, mast cells or basophilic granulocytes will release chemical mediators such as histamine, leukotrienes, prostaglandins, bradykinin and platelet-activating factors. The release of these chemical mediators results in allergic symptoms. In particular, allergic diseases can worsen symptoms due to the linkage between IgE and Fc? RI. FcεRI-expressing cells are known to increase in allergic patients.
현재 알러지 질환을 치료하기 위하여, 알레르겐 회피, 항알러지 약물 투여, 체내 IgE 합성 조절, 항 IgE 항체 개발 등 여러가지 방법이 제안되었다. 그러나, 현재까지 알려진 치료 방법은 알러지의 근본 원인을 치료할 수 없고, 약제의 효능이 불충분하거나, 심각한 부작용이 발생하는 등 많은 단점을 가지고 있다. Currently, various methods have been proposed to treat allergic diseases, such as allergen avoidance, administration of antiallergic drugs, modulation of body IgE synthesis, development of anti-IgE antibodies. However, the treatment methods known so far have many drawbacks, such as the inability to cure the underlying cause of allergy, insufficient efficacy of the drug, and serious side effects.
또한, IgE 및 FcγRIIb에 고친화성으로 결합하며, IgE를 발현하는 세포를 억제할 수 있는 면역글로불린 조성물이 연구되고 있다(KR10-1783272B1). 이러한 조성물은 알러지 및 천식을 포함하여 IgE-매개된 장애를 치료하는데 유용하다고 보고된 바 있다. 또한, IgE 항체의 Fc 일부분을 표적으로 하는 오말리주맙(Omalizumab, 상품명: 졸레어(Xolair))이 개발되어 난치성 중증 천식과 난치성 두드러기 치료제로 사용되고 있다.In addition, immunoglobulin compositions capable of binding to IgE and FcγRIIb with high affinity and inhibiting cells expressing IgE have been studied (KR10-1783272B1). Such compositions have been reported to be useful for treating IgE-mediated disorders, including allergies and asthma. In addition, Omalizumab (Xolair), which targets a fraction of Fc of IgE antibodies, has been developed and used as a treatment for intractable severe asthma and intractable urticaria.
하지만, 효과를 유지하기 위해서는 고용량으로 투여되어야 하기 때문에 비용부담이 크고, 혈관부종, 아나필락시스 반응 등의 부작용이 있다는 것이 보고되었다(The Journal of Clinical Investigation Volume 99, Number 5, March 1997, 915-925). 그뿐 아니라, 시판 후 결과를 통해 알러지성 육아종 혈관염, 특발성 중증 혈소판감소증이 보고되고 있어, 부작용 없이 알러지 질환을 효율적으로 치료할 수 있는 치료제 개발에 대한 필요성이 증가하고 있는 실정이다.However, in order to maintain the effect, it is reported that there is a side effect such as angioedema, anaphylactic reaction and the like because it is required to be administered at a high dose because of a high cost burden (The Journal of Clinical Investigation Volume 99,
본원 발명의 목적은 IgE 매개 알러지 질환을 치료하기 위한 폴리펩티드 이량체 단백질을 유효성분으로 포함하는 약학적 조성물 및 식품 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition and a food composition containing a polypeptide dimer protein as an active ingredient for treating an IgE mediated allergic disease.
본원 발명의 일 측면으로, IgE Fc 수용체의 알파 서브유닛의 세포외 도메인을 포함하는 단량체 두 개를 포함하는 폴리펩티드 이량체를 유효성분으로 포함하는 알러지성 질환 치료용 또는 예방용 약학적 조성물로서, 상기 단량체는 변형된 Fc 영역을 포함하며, 상기 변형된 Fc 영역과 IgE Fc 수용체의 알파 서브유닛의 세포외 도메인은 IgD 항체의 힌지를 통해 연결된 것을 특징으로 하는 약학적 조성물를 제공한다. 또 다른 측면으로, 상기 폴리펩티드 이량체를 유효성분으로 포함하는 알러지성 증상의 개선 및 완화용 식품 조성물을 제공한다.As one aspect of the present invention, there is provided a pharmaceutical composition for treating or preventing an allergic disease comprising, as an active ingredient, a polypeptide dimer comprising two monomers comprising an extracellular domain of an alpha subunit of an IgE Fc receptor, Wherein the monomer comprises a modified Fc region and wherein the modified Fc region and the extracellular domain of the alpha subunit of the IgE Fc receptor are linked via the hinge of the IgD antibody. In another aspect, there is provided a food composition for improving and alleviating allergic symptoms comprising the polypeptide dimer as an active ingredient.
본원 발명에 따른 폴리펩티드 이량체 단백질은 기존에 사용되는 항-IgE 항체에 비하여 안전성 및 체내 지속성이 우수할 뿐만 아니라, IgE와의 결합력이 기존에 사용되는 항-IgE 항체인 오말리주맙 대비 70배로 높아 IgE에 매우 강하게 결합하므로, 투여 주기를 늘릴 수 있다. 또한, 본원 발명에 따른 폴리펩티드 이량체 단백질은 IgE 만을 단일표적으로 하고, Fc gamma receptor에는 결합하지 않음으로 ADCC(antibody dependent Cellular Cytotoxicity) 및 CDC(Complement dependent Cytotoxicity) 기능이 결여된 변형된 Fc가 적용된 물질이다. 따라서, IgG1 Fc 영역을 포함하고 있는 기존 항 IgE 항체와 달리 Fc gamma 수용체와 결합하지 않기 때문에 비만 세포 표면의 Fc gamma 수용체와의 결합에 의한 매개자 방출을 억제할 수 있어, IgG1과 비만세포의 Fc gamma 수용체 III와의 결합에 의해 유발될 수 있는 아나필락시스 발생 등의 심각한 부작용을 최소화할 수 있다. 따라서, 종래의 항-IgE 항체를 포함하는 치료제를 대체할 수 있는 새로운 약학적 조성물로 활용될 수 있다.The polypeptide dimeric protein according to the present invention is superior to the conventional anti-IgE antibody in safety and persistence in body, and its binding ability to IgE is 70 times higher than the conventional anti-IgE antibody, omalizumab, So that the administration period can be increased. In addition, the polypeptide dimeric protein according to the present invention has IgE only as a single target and does not bind to the Fc gamma receptor. Thus, the modified dimeric Fc protein lacking antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) to be. Therefore, unlike conventional anti-IgE antibodies containing the IgG1 Fc region, it does not bind to the Fc gamma receptor and thus can inhibit mediator release by binding to the Fc gamma receptor on the surface of mast cells. Thus, IgG1 and mast cell Fc gamma Serious side effects such as the generation of anaphylaxis which can be caused by binding with receptor III can be minimized. Therefore, it can be utilized as a new pharmaceutical composition which can replace the therapeutic agent containing the conventional anti-IgE antibody.
도 1은 각 세포주에서 생산된 단백질의 SDS-PAGE 및 Gel IEF(isoelectric focusing) 결과이다. 이때, 환원성 및 비환원성 모두에서 절단형이 생성되지 않고, 시알산 전이효소 유전자 도입에 의한 시알산 함량 증가로 인해 acidic 단백질의 함량이 증가하였음을 알 수 있다.
도 2는 본원 발명의 일 구체예에 따른 폴리펩티드 이량체 단백질의 비환원된 형태 및 환원된 형태 단백질의 SDS-PAGE 결과이다. 특히, Input에 해당하는 배양 상등액에서도 폴리펩티드 이량체의 순도가 높은 것을 알 수 있다.
도 3은 오말리주맙의 IgE에 대한 결합능을 나타내는 그래프이다. 오말리주맙을 고정하고 IgE의 처리 농도에 따른 결합능을 분석한 결과이다.
도 4는 본원 발명의 일 구체예에 따른 폴리펩티드 이량체 단백질의 IgE에 대한 결합능을 나타내는 그래프로서, 이량체 단백질을 고정하고 IgE의 처리 농도에 따른 결합능을 분석한 결과이다.
도 5는 본 발명의 일 구체예인 폴리펩티드 이량체 단백질(IgETRAP)과 오말리주맙의 IgG 수용체 FcγRI(도 5a), FcγRIIA(도 5b), FcγRIIB(도 5c), FcγRIIIA(도 5d) 및 FcγRIIIB(도 5e)와의 상호 작용을 bio-layer interferometry(BLI) 분석법으로 확인한 결과이다.
도 6은 IgETRAP과 IgG 수용체 및 오말리주맙과 IgG 수용체의 결합력을 수치화한 그래프이다.
도 7은 본원 발명의 일 구체예에 따른 폴리펩티드 이량체 단백질(IgETRAP)의 농도에 따른 마우스 유래 비만 세포의 활성 억제력을 보여주는 그래프이다.
도 8은 본원 발명의 일 구체예에 따른 폴리펩티드 이량체 단백질(IgETRAP) 및 Xolair(오말리주맙)의 농도에 따른 인간 FcεRI 발현 마우스 유래 비만 세포의 활성 억제력을 비교해서 보여주는 그래프이다.
도 9는 식품 알러지 모델에서 본원 발명의 일 구체예에 따른 폴리펩티드 이량체 단백질의 투여 효과를 나타내는 그래프이다.Figure 1 shows SDS-PAGE and Gel IEF (isoelectric focusing) results of the proteins produced in each cell line. At this time, it can be seen that the truncated form is not generated in both reducing and non-reducing, and that the content of acidic protein is increased due to the increase of sialic acid content by sialic acid transferase gene introduction.
Figure 2 shows SDS-PAGE results of the reduced form of the polypeptide dimer protein and the reduced form protein according to one embodiment of the present invention. Particularly, it can be seen that the purity of the polypeptide dimer is high even in the culture supernatant corresponding to the input.
3 is a graph showing the binding ability of omalizumab to IgE. OMALI JUVAW was fixed and the binding ability of IgE was analyzed according to the treatment concentration.
FIG. 4 is a graph showing the binding capacity of a polypeptide dimer protein to IgE according to one embodiment of the present invention. As a result, the dimeric protein was immobilized and the binding potency was analyzed according to the treatment concentration of IgE.
FIG. 5 is a graph showing the effect of the polypeptide dimeric protein (IgE TRAP ) and omalizumab IgG receptor Fc? RI (FIG. 5A), Fc? RIA (FIG. 5B), Fc? RIIB (FIG. 5C), Fc? RIIA 5e) by bio-layer interferometry (BLI) analysis.
FIG. 6 is a graph quantifying the binding force between IgE TRAP and IgG receptor and omalizumab and IgG receptor.
FIG. 7 is a graph showing the activity of inhibiting the activity of mouse-derived mast cells according to the concentration of a polypeptide dimer protein (IgE TRAP ) according to one embodiment of the present invention.
FIG. 8 is a graph showing a comparison of the inhibitory activity against the activity of human FcεRI-expressing mouse-derived mast cells according to the concentrations of polypeptide dimeric proteins (IgE TRAP ) and Xolair (omalizumab) according to one embodiment of the present invention.
9 is a graph showing the administration effect of a polypeptide dimer protein according to one embodiment of the present invention in a food allergy model.
본원 발명은 IgE Fc 수용체의 알파 서브유닛의 세포외 도메인(FcεRIa-ECD)을 포함하는 단량체 두 개를 포함하는 폴리펩티드 이량체를 유효성분으로 포함하는 알러지성 질환 치료용 또는 예방용 약학적 조성물에 대한 것으로서, 상기 단량체는 변형된 Fc 영역을 포함하며, 상기 변형된 Fc 영역과 FcεRIa-ECD는 IgD 항체의 힌지를 통해 연결된 것을 특징으로 하는 약학적 조성물을 제공한다.The present invention relates to a pharmaceutical composition for the treatment or prevention of an allergic disease comprising, as an active ingredient, a polypeptide dimer comprising two monomers comprising an extracellular domain of an alpha subunit of an IgE Fc receptor (Fc? RIA-ECD) Wherein the monomer comprises a modified Fc region, wherein the modified Fc region and Fc < RTI ID = 0.0 > RIa-ECD < / RTI > are linked via a hinge of an IgD antibody.
본 명세서에서 사용한 용어, "IgE"는 면역글로불린 E로 알려진 항체 단백질을 의미한다. IgE는 비만세포나 혈중의 호염기구 등에 친화성을 가진다. 또한, IgE 항체와 그것에 대응하는 항원(알레르겐)이 반응하면 염증반응을 일으킨다. 또한, IgE는 비만 세포 또는 호염기구가 갑자기 분비되어 나타나는 아나필락시스(anaphylaxis)를 일으키는 항체로 알려져 있다.As used herein, the term "IgE " refers to an antibody protein known as immunoglobulin E. IgE has affinity for mast cells and blood basophils. In addition, an IgE antibody and its corresponding antigen (allergen) react to produce an inflammatory reaction. In addition, IgE is known to be an antibody that causes anaphylaxis, which is a sudden secretion of mast cells or basophils.
본 명세서에서 사용한 용어, "IgE Fc 수용체"란 Fcε수용체라고도 불리우며, IgE의 Fc 부분과 결합한다. 상기 수용체는 2 종류가 존재한다. IgE Fc에 대해 고친화성인 수용체는 Fcε수용체I(FcεRI)라고 한다. IgE Fc에 대해 저친화성인 수용체는 Fcε수용체II(FcεRⅡ)라고 한다. FcεRI은 비만세포, 호염기구에서 발현된다. FcεRI에 결합한 IgE 항체가 다가 항원에 의해 가교되면, 비만세포 또는 호염 기구에서 탈과립이 생겨 히스타민을 비롯한 여러 가지 화학 전달 물질을 방출한다. 이러한 방출에 의해 즉시형 알러지 반응이 나타난다.As used herein, the term "IgE Fc receptor" is also referred to as the Fcε receptor and binds to the Fc portion of IgE. There are two types of receptors. High affinity receptor for IgE Fc is called Fcε receptor I (FcεRI). The low affinity receptor for IgE Fc is called Fcε receptor II (FcεR II). FcεRI is expressed in mast cells, basophils. When IgE antibodies bound to FcεRI are cross-linked by polyvalent antigens, degranulation occurs in mast cells or basophils, releasing various chemical messengers including histamine. This release causes an immediate allergic reaction.
상기 FcεRI는 하나의 α사슬과 한 개의 β사슬 및 2황화 결합한 2개의 γ사슬로 구성된 막단백질이다. 이 중 IgE가 결합하는 부분은 α사슬(FcεRIα)로서, FcεRIα는 60 kDa 정도의 크기를 가지며, 세포막 안에 존재하는 소수성 도메인과 세포막 외부에 존재하는 친수성 도메인으로 구성된다. 특히, α사슬의 세포외 도메인에 IgE가 결합하게 된다.The Fc [epsilon] RI is a membrane protein composed of one [alpha] chain and two [gamma] chains linked by a [beta] chain and a disulfide bond. Among these, IgE binds to the α chain (FcεRIα), FcεRIα has a size of about 60 kDa, and consists of a hydrophobic domain existing in the cell membrane and a hydrophilic domain existing outside the cell membrane. In particular, IgE binds to the extracellular domain of the? Chain.
구체적으로, 상기 IgE Fc 수용체의 알파 서브유닛은 NP_001992.1에 기재된 아미노산 서열을 가질 수 있다. 또한, IgE Fc 수용체의 알파 서브유닛의 세포외 도메인(FcεRIa-ECD)은 서열번호 1의 아미노산 서열을 가질 수 있다. 본 명세서에서 IgE Fc 수용체의 알파 서브유닛의 세포외 도메인은 IgE와 결합을 할 수 있는 한, IgE Fc 수용체의 알파 서브유닛의 세포외 도메인의 단편 또는 변이체일 수 있다.Specifically, the alpha subunit of the IgE Fc receptor may have the amino acid sequence described in NP_001992.1. In addition, the extracellular domain (Fc? RIA-ECD) of the alpha subunit of the IgE Fc receptor may have the amino acid sequence of SEQ ID NO: 1. As used herein, the extracellular domain of the alpha subunit of the IgE Fc receptor may be a fragment or variant of the extracellular domain of the alpha subunit of the IgE Fc receptor, so long as it is capable of binding IgE.
상기 변이체는 FcεRⅠ의 α사슬의 기능을 변형시키지 않는 한, 야생형 FcεRIa-ECD(Extracellular domain)에서 하나 이상의 단백질을 치환, 결실 또는 추가하는 방법을 통하여 수행될 수 있다. 이러한 다양한 단백질 또는 펩타이드는 서열번호 1의 아미노산 서열과 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 또는 99% 이상 동일한 것일 수 있다. 또한, 서열번호 1의 FcεRIa-ECD는 서열번호 5의 서열을 갖는 폴리뉴클레오티드에 의해 코딩될 수 있다.The mutant can be carried out through a method of replacing, deleting or adding one or more proteins in the wild-type FcεRIa-ECD (Extracellular domain), so long as it does not alter the function of the α chain of FcεR I. Such various proteins or peptides may be 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: In addition, the FcεRIa-ECD of SEQ ID NO: 1 may be encoded by a polynucleotide having the sequence of SEQ ID NO: 5.
또한, 본 명세서에서 사용한 용어, "변형된 Fc 영역"은 항체의 Fc 부분 중 일부가 변형된 영역을 의미한다. 이때, 용어 "Fc 영역"는 면역글로불린의 중쇄 불변 영역 2(CH2) 및 중쇄 불변 영역 3(CH3)을 포함하며, 면역글로불린의 중쇄 및 경쇄의 가변 영역 및 경쇄 불변 영역 1(CH1)은 포함하지 않는 단백질을 말한다. 특히, 변형된 Fc 영역은 Fc 영역 중 일부 아미노산이 치환되거나, 서로 다른 종류의 Fc 영역을 조합하여 제조된 것을 의미한다. 구체적으로, 상기 변형된 Fc 영역은 서열번호 2의 아미노산 서열을 가질 수 있다. 또한, 서열번호 2의 변형된 Fc 영역은 서열번호 6의 서열을 갖는 폴리뉴클레오티드에 의해 코딩될 수 있다.As used herein, the term "modified Fc region" means a region in which some of the Fc portion of the antibody has been modified. The term "Fc region" includes heavy chain constant region 2 (CH2) and heavy chain constant region 3 (CH3) of immunoglobulin and does not include variable region and light chain constant region 1 (CH1) of heavy and light chains of immunoglobulin Does not say protein. In particular, the modified Fc region means that some amino acids in the Fc region are substituted or produced by combining different Fc regions. Specifically, the modified Fc region may have the amino acid sequence of SEQ ID NO: 2. In addition, the modified Fc region of SEQ ID NO: 2 may be encoded by a polynucleotide having the sequence of SEQ ID NO: 6.
또한, 본원 발명의 "변형된 Fc 영역"은 천연형 당쇄, 천연형에 비해 증가된 당쇄, 천연형에 비해 감소한 당쇄, 또는 당쇄가 제거된 형태일 수 있다. 화학적 방법, 효소적 방법 및 미생물을 사용한 유전공학적 엔지니어링 방법 등과 같이 통상적인 방법으로 면역글로불린 Fc 당쇄를 변형시킬 수 있다.Further, the "modified Fc region" of the present invention may be a natural type sugar chain, an increased sugar chain compared to the native type, a reduced sugar chain compared to the native type, or a form in which the sugar chain is removed. The immunoglobulin Fc sugar chain can be modified by conventional methods such as chemical methods, enzymatic methods, and genetic engineering methods using microorganisms.
이때, 본원 발명의 “변형된 Fc 영역”은 FcγR 또는 C1q에 대한 결합 부위를 갖지 않음으로 ADCC(antibody dependent Cellular Cytotoxicity) 및 CDC(Complement dependent Cytotoxicity) 기능이 결여된 것일 수 있다. 또한, 상기 변형된 Fc 영역과 FcεRIa-ECD는 IgD 항체의 힌지를 통해 연결될 수 있다. 상기 IgD 항체의 힌지는 64개 아미노산으로 이루어져 있으며, 20 내지 60개의 연속된 아미노산, 또는 25 내지 50개의 연속된 아미노산, 또는 30 내지 40개의 아미노산으로 선택되어 포함될 수 있다. 일 구체예로 IgD 항체의 힌지는 하기의 30개 또는 49개의 아미노산으로 이루어질 수 있다. 이때, 상기 힌지는 상기 힌지 영역을 변형시킨 힌지 변이체 일 수 있으며, 상기 힌지는 적어도 하나의 시스테인을 포함할 수 있다. 이때, 상기 힌지 변이체는 단백질 생산 과정에서 절단형 발생을 최소화하기 위해 IgD 항체의 힌지 서열에서 일부를 변형한 것일 수 있다.Here, the " modified Fc region " of the present invention may lack ADCC (antibody dependent cellular cytotoxicity) and CDC (complement dependent cytotoxicity) functions because it has no binding site for Fc [gamma] R or C1q. In addition, the modified Fc region and the FcεRIa-ECD can be linked via the hinge of an IgD antibody. The hinge of the IgD antibody is composed of 64 amino acids and may be selected from 20 to 60 consecutive amino acids or 25 to 50 consecutive amino acids or 30 to 40 amino acids. In one embodiment, the hinge of an IgD antibody may comprise 30 or 49 amino acids as follows. In this case, the hinge may be a hinge variant in which the hinge region is modified, and the hinge may include at least one cysteine. At this time, the hinge mutant may be a modification of the hinge sequence of the IgD antibody in order to minimize the incidence of truncation during protein production.
일 실시예로, 힌지는 다음과 같은 서열을 포함할 수 있다:In one embodiment, the hinge may comprise a sequence as follows:
Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa1 Xaa2 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro (서열번호 17), 이때, Xaa1은 Lys 또는 Gly 일 수 있으며, Xaa2는 Glu, Gly 또는 Ser일 수 있다. 구체적으로, 상기 힌지는 서열번호 3 및 서열번호 19의 아미노산 서열을 가질 수 있고, 이를 통해 단백질 생산 과정에서 절단형 발생을 최소화할 수 있다.Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa1 Xaa2 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro (SEQ ID NO: 17) wherein Xaa1 can be Lys or Gly, Xaa2 is Glu , GIy or Ser. Specifically, the hinge may have the amino acid sequence of SEQ ID NO: 3 and SEQ ID NO: 19, thereby minimizing the occurrence of truncations during the production of proteins.
힌지의 또 다른 실시예로 다음과 같은 서열을 포함할 수 있다:Another embodiment of the hinge can include the following sequence:
Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa3 Xaa4 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro (서열번호 18)이며, 이때, Xaa3은 Lys 또는 Gly 이며, Xaa4는 Glu, Gly 또는 Ser일 수 있다. 구체적으로, 상기 힌지는 서열번호 4의 아미노산 서열을 가질 수 있고, 이를 통해 단백질 생산 과정에서 절단형 발생을 최소화할 수 있다.Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa3 Xaa4 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro ( SEQ ID NO: 18), wherein Xaa3 is Lys or Gly, and Xaa4 is GIu, GIy or Ser. Specifically, the hinge may have the amino acid sequence of SEQ ID NO: 4, thereby minimizing the occurrence of truncations during the production of proteins.
특히, 서열번호 4의 서열을 갖는 힌지에 있어서, Thr 중 적어도 하나는 글리코실레이션 될 수 있다. 구체적으로, 서열번호 18의 아미노산 중, 13번째, 14번째, 18번째 및 19번째의 Thr이 글리코실레이션 될 수 있다. 바람직하게 4개의 아미노산이 모두 글리코실레이션 될 수 있다. 이때, 상기 글리코실레이션은 O-글리코실레이션일 수 있다.In particular, in the hinge having the sequence of SEQ ID NO: 4, at least one of Thr can be glycosylated. Specifically, among the amino acids of SEQ ID NO: 18, the 13th, 14th, 18th and 19th Thr can be glycosylated. Preferably all four amino acids can be glycosylated. At this time, the glycosylation may be O-glycosylation.
또한, 본원 발명에서 제공하는 폴리펩티드 이량체는 상술한 바와 같이, IgE Fc 수용체의 알파 서브유닛의 세포외 도메인과 변형된 Fc 영역이 결합된 단량체 두 개가 결합된 형태일 수 있다. 상기 폴리펩티드 이량체는 동일한 두 개의 단량체가 힌지 부위에 위치한 시스테인에 의해 결합된 형태일 수 있다. 또한, 상기 폴리펩티드 이량체는 서로 상이한 단량체 두 개가 결합된 형태일 수 있다. 예를 들어, 두 개의 단량체가 서로 다른 경우는, 하나의 단량체는 IgE Fc 수용체의 알파 서브유닛의 세포외 도메인을 포함하고, 다른 단량체는 IgE Fc 수용체의 알파 서브유닛의 세포외 도메인의 단편을 포함한 형태일 수 있다. 이때, 상기 단량체의 일 구체예는 서열번호 20, 서열번호 21 또는 서열번호 22의 아미노산 서열을 가질 수 있다.In addition, the polypeptide dimer provided by the present invention may be in the form of a combination of two extracellular domains of the alpha subunit of the IgE Fc receptor and two modified Fc region-bound monomers, as described above. The polypeptide dimer may be a form in which the same two monomers are bound by cysteine located at the hinge region. In addition, the polypeptide dimer may be a form in which two different monomers are combined. For example, where two monomers are different, one monomer comprises the extracellular domain of the alpha subunit of the IgE Fc receptor and the other monomer contains a fragment of the extracellular domain of the alpha subunit of the IgE Fc receptor Lt; / RTI > Here, one specific example of the monomer may have the amino acid sequence of SEQ ID NO: 20, SEQ ID NO: 21 or SEQ ID NO: 22.
또한, 본원 발명에서 제공하는 폴리펩티드 이량체는 항-IgE 항체인 오말리주맙 대비 10 내지 100배, 20 내지 90배, 20 내지 70배, 30 내지 70배, 40 내지 70배 높은 IgE 결합력을 나타내며, 바람직하게는 오말리주맙 대비 70배 높은 IgE 결합력을 나타낼 수 있다.In addition, the polypeptide dimer provided by the present invention exhibits 10 to 100 times, 20 to 90 times, 20 to 70 times, 30 to 70 times, and 40 to 70 times higher IgE binding ability as compared with omalizumab, which is an anti-IgE antibody, Can exhibit 70-fold higher IgE binding to omalizumab.
또한, 본 명세서에서, "알러지성 질환"은 비만세포의 탈과립 등 비만세포의 활성화가 매개된 알러지 반응으로 인하여 초래되는 병리적 증상을 의미하며, 이러한 알러지 질환에는 식품 알러지, 아토피 피부염(atopic dermatitis), 천식(asthma), 알러지성 비염(allergic rhinitis), 알러지성 결막염(allergic conjunctivitis), 알러지성 피부염(allergic dermatitis), 알러지성 접촉성 피부염(allergic contact dermatitis), 과민성(anaphylaxis), 두드러기, 소양증, 곤충 알러지, 만성 특발성 두드러기(Chronic idiopathic urticarial) 및 약품 알러지 등이 포함된다. 특히, 상기 알러지 질환은 IgE 매개성일 수 있다.In the present specification, the term "allergic disease" means a pathological symptom caused by an allergic reaction mediated by mast cell activation such as degranulation of mast cells. Such allergic diseases include food allergy, atopic dermatitis, Asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, allergic contact dermatitis, anaphylaxis, urticaria, pruritus, allergic rhinitis, allergic rhinitis, Insect allergies, chronic idiopathic urticarial, and drug allergies. In particular, the allergic disease may be IgE mediated.
본원 발명의 알러지 치료용 또는 예방용 조성물에서 그 유효성분은 항알러지 활성을 나타낼 수 있는 한, 용도, 제형, 배합 목적 등에 따라 임의의 양(유효량)으로 포함될 수 있는데, 통상적인 유효량은 조성물 전체 중량을 기준으로 할 때 0.001 중량 % 내지 20.0 중량 % 범위 내에서 결정될 것이다. 여기서 "유효량"이란 항알러지 효과를 유도할 수 있는 유효성분의 양을 말한다. 이러한 유효량은 당업자의 통상의 능력 범위 내에서 실험적으로 결정될 수 있다.In the composition for the treatment or prevention of allergy of the present invention, the active ingredient may be contained in any amount (effective amount) as long as it can exhibit anti-allergic activity, depending on the purpose of use, formulation, compounding purpose and the like. By weight based on the total weight of the composition. Here, "effective amount" refers to the amount of active ingredient capable of inducing an allergic effect. Such effective amounts can be determined experimentally within the ordinary skill of those skilled in the art.
이때, 상기 약학적 조성물은 약학적으로 허용 가능한 담체를 더 포함할 수 있다. 상기 약학적으로 허용 가능한 담체는 환자에게 전달하기에 적절한 비-독성 물질이면 어떠한 담체라도 가능하다. 증류수, 알코올, 지방, 왁스 및 비활성 고체가 담체로 포함될 수 있다. 약물학적으로 허용되는 애쥬번트(완충제, 분산제) 또한 약물학적 조성물에 포함될 수 있다.The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be any carrier that is non-toxic to the patient. Distilled water, alcohols, fats, waxes and inert solids may be included as carriers. Pharmacologically acceptable adjuvants (buffers, dispersants) may also be included in the pharmacological composition.
구체적으로, 본원 발명의 약제학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함하여 당업계에 공지된 통상의 방법으로 투여 경로에 따라 경구용 제형 또는 비경구용 제형으로 제조될 수 있다. 여기서 "약제학적으로 허용되는" 의미는 유효성분의 활성을 억제하지 않으면서 적용(처방) 대상이 적응 가능한 이상의 독성을 지니지 않는다는 의미이다.Specifically, the pharmaceutical composition of the present invention may be prepared into oral or parenteral formulations according to the route of administration by a conventional method known in the art, including pharmaceutically acceptable carriers in addition to the active ingredient. The term "pharmaceutically acceptable" as used herein means that the application (prescribing) subject does not have the above-mentioned toxicity that is adaptable without inhibiting the activity of the active ingredient.
본원 발명의 약제학적 조성물이 경구용 제형으로 제조될 경우, 적합한 담체와 함께 당업계에 공지된 방법에 따라 분말, 과립, 정제, 환제, 당의정제, 캡슐제, 액제, 겔제, 시럽제, 현탁액, 웨이퍼 등의 제형으로 제조될 수 있다. 이때 약제학적으로 허용되는 적합한 담체의 예로서는 락토스, 글루코스, 슈크로스, 덱스트로스, 솔비톨, 만니톨, 자일리톨 등의 당류, 옥수수 전분, 감자 전분, 밀 전분 등의 전분류, 셀룰로오스, 메틸셀룰로오스, 에틸셀룰로오스, 나트륨 카르복시메틸셀룰로오스, 하이드록시프로필메틸셀룰로오스 등의 셀룰로오스류, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 마그네슘 스테아레이트, 광물유, 맥아, 젤라틴, 탈크, 폴리올, 식물성유 등을 들 수 있다. 제제화할 경우 필요에 따라 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 및/또는 부형제를 포함하여 제제화할 수 있다.When the pharmaceutical composition of the present invention is prepared into an oral formulation, it may be formulated into powder, granules, tablets, pills, sugar tablets, capsules, liquids, gels, syrups, suspensions, wafers And the like. Examples of suitable pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, dextrose, sorbitol, mannitol, xylitol, starch such as corn starch, potato starch and wheat starch, cellulose, methylcellulose, ethylcellulose, Cellulose derivatives such as sodium carboxymethyl cellulose and hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate, mineral oil, malt, gelatin, talc, And the like. In the case of formulation, it may be formulated to include a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and / or an excipient, if necessary.
본원 발명의 약제학적 조성물이 비경구용 제형으로 제조될 경우, 적합한 담체와 함께 당업계에 공지된 방법에 따라 주사제, 경피 투여제, 비강 흡입제 및 좌제의 형태로 제제화될 수 있다. 주사제로 제제화할 경우 적합한 담체로서는 멸균수, 에탄올, 글리세롤이나 프로필렌 글리콜 등의 폴리올 또는 이들의 혼합물을 사용할 수 있으며, 바람직하게는 링거 용액, 트리에탄올 아민이 함유된 PBS(phosphate buffered saline)나 주사용 멸균수, 5% 덱스트로스 같은 등장 용액 등을 사용할 수 있다. When the pharmaceutical composition of the present invention is prepared into a parenteral dosage form, it may be formulated in the form of an injection, transdermal drug delivery, nasal inhalation, and suppository together with a suitable carrier according to methods known in the art. As the carrier suitable for injection preparation, sterilized water, ethanol, polyol such as glycerol or propylene glycol, or a mixture thereof, may be used, and preferably, a solution of Ringer's solution, phosphate buffered saline containing triethanolamine or sterilized by injection Water, or isotonic solution such as 5% dextrose may be used.
약제학적 조성물의 제제화와 관련하여서는 당업계에 공지되어 있으며, 구체적으로 문헌[Remington's Pharmaceutical Sciences(19th ed., 1995)] 등을 참조할 수 있다. 상기 문헌은 본 명세서의 일부로서 간주 된다.The formulation of pharmaceutical compositions is well known in the art and can be specifically described in Remington ' s Pharmaceutical Sciences (19th ed., 1995). This document is considered part of this specification.
본원 발명의 약제학적 조성물의 바람직한 투여량은 환자의 상태, 체중, 성별, 연령, 환자의 중증도, 투여 경로에 따라 1일 0.01 ug/kg ~ 10 g/kg 범위, 바람직하게는 0.01 mg/kg ~ 1 g/kg 범위일 수 있다. 투여는 1일 1회 또는 수회로 나누어 이루어질 수 있다. 이러한 투여량은 어떠한 측면으로든 본원 발명의 범위를 제한하는 것으로 해석되어서는 아니 된다. A preferable dosage of the pharmaceutical composition of the present invention is 0.01 to 10 g / kg, preferably 0.01 to 10 g / kg, per day depending on the condition, body weight, sex, age, 1 g / kg. The administration can be carried out once or several times a day. Such dosages should in no way be interpreted as limiting the scope of the invention.
본원 발명의 조성물이 적용(처방)될 수 있는 대상은 포유동물 및 사람이며, 특히 사람인 경우가 바람직하다. 본원 발명의 항알러지용 조성물은 유효성분 이외에, 항알러지 활성의 상승·보강을 위하여 이미 안전성이 검증되고 항알러지 활성을 갖는 것으로 공지된 임의의 화합물이나 천연 추출물을 추가로 포함할 수 있다.The subject to which the composition of the present invention can be applied (prescription) is preferably a mammal and a person, particularly a human. The composition for anti-allergy of the present invention may further comprise, in addition to the active ingredient, any compound or natural extract known to have safety and anti-allergic activity for the purpose of raising or reinforcing the anti-allergic activity.
본원 발명의 또 다른 측면으로, 상기 폴리펩티드 이량체를 유효성분으로 포함하는 알러지성 증상의 개선 및 완화용 식품 조성물을 제공한다. In another aspect of the present invention, there is provided a food composition for improving and alleviating allergic symptoms comprising the polypeptide dimer as an active ingredient.
이때, 상기 폴리펩티드 이량체는 장내로 효율적인 전달을 위해 적절한 전달 수단과 결합될 수 있다. 또한, 본원 발명의 식품 조성물은 어떠한 형태로도 제조될 수 있으며, 예컨대 차, 쥬스, 탄산음료, 이온음료 등의 음료류, 우유, 요구루트 등의 가공 유류, 정제, 캡슐, 환, 과립, 액상, 분말, 편상, 페이스트상, 시럽, 겔, 젤리, 바 등의 건강기능식품 제제류 등으로 제조될 수 있다. 또 본원 발명의 식품 조성물은 법률상·기능상의 구분에 있어서 제조·유통 시점의 시행 법규에 부합하는 한 임의의 제품 구분을 띨 수 있다. 예컨대 건강기능식품에 관한 법률에 따른 건강기능식품이거나, 식품위생법의 식품공전(식약처 고시, 식품의 기준 및 규격)상 각 식품유형에 따른 과자류, 두류, 다류, 음료류, 특수용도식품 등일 수 있다. 본원 발명의 식품 조성물에 포함될 수 있는 기타의 식품첨가물과 관련하여서는 식품위생법에 따른 식품공전이나 식품첨가물 공전을 참조할 수 있다.At this time, the polypeptide dimer may be combined with appropriate delivery means for efficient delivery into the intestines. The food composition of the present invention can be prepared in any form and can be used in various forms such as beverages such as tea, juice, carbonated beverage, ionic drink, processed oil such as milk and request route, tablets, capsules, Powders, flakes, pastes, syrups, gels, jellies, bars, and the like. In addition, the food composition of the present invention may be classified into any product category as long as it comply with the laws and regulations on the time of manufacture and distribution in the legal and functional category. For example, it may be a health functional food according to the Act on Health Functional Foods, or a confectionery, bean curd, beverage, beverage, special-purpose food, etc. according to each food type in the Food Code of Food Sanitation Act . With regard to other food additives that may be included in the food composition of the present invention, reference may be made to the Food Code or the Food Additive Code in accordance with the Food Sanitation Act.
본원 발명의 또 다른 측면으로, 변형된 Fc 영역이 결합된 IgE Fc 수용체의 알파 서브유닛의 세포외 도메인을 포함하는 단량체를 코딩하는 폴리뉴클레오티드를 제공한다. In yet another aspect of the invention there is provided a polynucleotide encoding a monomer comprising an extracellular domain of an alpha subunit of an IgE Fc receptor coupled to a modified Fc region.
한편, 상기 폴리뉴클레오티드는 신호서열(signal sequence) 또는 리더 서열(leader sequence)을 추가적으로 포함할 수 있다. 여기에서 사용된 용어 "신호서열"은 목적 단백질의 분비를 지시하는 신호펩타이드를 코딩하는 핵산을 의미한다. 상기 신호펩타이드는 숙주 세포에서 번역된 후에 절단된다. 구체적으로, 본원 발명의 신호서열은 ER(endoplasmic reticulum) 막을 관통하는 단백질의 이동을 개시하는 아미노산 서열을 코딩하는 뉴클레오티드이다. 본원 발명에서 유용한 신호서열은 항체 경쇄 신호서열, 예를 들면 항체 14.18(Gillies et al., J. Immunol. Meth 1989. 125:191-202), 항체 중쇄 신호서열, 예를 들면, MOPC141 항체 중쇄 신호서열(Sakano et al., Nature, 1980. 286: 676-683), 및 당업계에 알려진 다른 신호서열(예, Watson et al., Nucleic Acid Research, 1984. 12:5145-5164를 참조)을 포함한다. Meanwhile, the polynucleotide may additionally include a signal sequence or a leader sequence. As used herein, the term "signal sequence" refers to a nucleic acid that encodes a signal peptide that directs secretion of a protein of interest. The signal peptide is cleaved after translation in the host cell. Specifically, the signal sequence of the present invention is a nucleotide encoding an amino acid sequence that initiates the movement of a protein through an ER (endoplasmic reticulum) membrane. Signal sequences useful in the present invention include, but are not limited to, antibody light chain signal sequences such as antibody 14.18 (Gillies et al., J. Immunol. Meth. 1989. 125: 191-202), antibody heavy chain signal sequences such as the MOPC141 antibody heavy chain signal And other signal sequences known in the art (see, for example, Watson et al., Nucleic Acid Research, 1984. 12: 5145-5164). do.
신호서열은 당업계에 그 특징이 잘 알려져 있으며, 통상 16 내지 30개의 아미노산 잔기를 포함하나, 그보다 더 많거나 적은 아미노산 잔기를 포함할 수 있다. 통상적인 신호 펩타이드는 기본 N-말단 영역, 중심의 소수성 영역, 및 보다 극성인(polar) C-말단 영역의 세 영역으로 구성된다. 중심 소수성 영역은 미성숙 폴리펩티드가 이동하는 동안 막지질 이중층을 통하여 신호서열을 고정시키는 4 내지 12개의 소수성 잔기를 포함한다.Signal sequences are well known in the art and typically comprise 16 to 30 amino acid residues, but may include more or fewer amino acid residues. Conventional signal peptides consist of three regions: a basic N-terminal region, a central hydrophobic region, and a more polar C-terminal region. The central hydrophobic region comprises 4 to 12 hydrophobic residues that immobilize the signal sequence through the membrane lipid bilayer during migration of the immature polypeptide.
개시 이후에, 신호서열은 흔히 신호 펩티다아제(signal peptidases)로 알려진 세포 효소에 의하여 ER의 루멘(lumen) 내에서 절단된다. 이때, 상기 신호서열은 tPa(tissue Plasminogen Activation), HSV gDs(signal sequence of Herpes simplex virus glycoprotein D), 또는 성장 호르몬(growth hormone)의 분비신호서열일 수 있다. 바람직하게, 포유동물 등을 포함하는 고등 진핵 세포에서 사용되는 분비 신호서열을 사용할 수 있다. 또한, 분비 신호서열은 숙주세포에서 발현 빈도가 높은 코돈으로 치환하여 사용할 수 있다.After initiation, signal sequences are often cleaved in the lumen of the ER by cellular enzymes known as signal peptidases. In this case, the signal sequence may be a secretion signal sequence of tPa (tissue plasminogen activating), HSV gDs (signal sequence of Herpes simplex virus glycoprotein D), or growth hormone. Preferably, secretory signal sequences used in higher eukaryotic cells, including mammals and the like, can be used. In addition, the secretory signal sequence can be used by substituting a codon having a high frequency of expression in the host cell.
한편, 신호서열, 변형된 Fc 영역이 결합된 IgE Fc 수용체의 알파 서브유닛의 세포외 도메인 단량체는 서열번호 11 또는 서열번호 13의 아미노산 서열을 가질 수 있다. 상기 서열번호 11 또는 서열번호 13의 단백질은 각각 서열번호 12 및 서열번호 14의 서열을 가지는 폴리뉴클레오티드에 의해 코딩될 수 있다.On the other hand, the extracellular domain monomer of the alpha subunit of the IgE Fc receptor to which the signal sequence, modified Fc region is bound, may have the amino acid sequence of SEQ ID NO: 11 or SEQ ID NO: The protein of SEQ ID NO: 11 or SEQ ID NO: 13 may be encoded by a polynucleotide having the sequence of SEQ ID NO: 12 and SEQ ID NO: 14, respectively.
본원 발명의 또 다른 측면으로, 상기 단량체를 코딩하는 폴리뉴클레오티드가 적재된 발현 벡터를 제공한다. 이때, 상기 폴리뉴클레오티드는 서열번호 12 및 서열번호 14의 서열을 가질 수 있다.In yet another aspect of the present invention, there is provided an expression vector loaded with a polynucleotide encoding said monomer. Here, the polynucleotide may have the sequence of SEQ ID NO: 12 and SEQ ID NO: 14.
본원 발명에서 사용된 용어 "벡터"는 숙주 세포에 도입되어 숙주 세포 유전체 내로 재조합 및 삽입될 수 있다. 또는 상기 벡터는 에피좀으로서 자발적으로 복제될 수 있는 뉴클레오티드 서열을 포함하는 핵산 수단으로 이해된다. 상기 벡터는 선형 핵산, 플라스미드, 파지미드, 코스미드, RNA 벡터, 바이러스 벡터 및 이의 유사체들을 포함한다. 바이러스 벡터의 예로는 레트로바이러스, 아데노바이러스, 및 아데노-관련 바이러스를 포함하나 이에 제한되지 않는다. 또한, 상기 플라스미드는 항생제 내성 유전자와 같은 선별 마커를 포함할 수 있고, 플라스미드를 유지하는 숙주 세포는 선택적인 조건하에서 배양될 수 있다. The term "vector" as used herein can be introduced into a host cell and recombined and inserted into a host cell genome. Or the vector is understood as nucleic acid means comprising a nucleotide sequence that can be spontaneously replicated as an episome. Such vectors include linear nucleic acids, plasmids, phagemids, cosmids, RNA vectors, viral vectors and analogs thereof. Examples of viral vectors include, but are not limited to, retroviruses, adenoviruses, and adeno-associated viruses. In addition, the plasmid may comprise a selectable marker such as an antibiotic resistance gene, and the host cell harboring the plasmid may be cultured under selective conditions.
본원 발명에서 사용된 용어, 목적 단백질의 "유전자 발현" 또는 "발현"은, DNA 서열의 전사, mRNA 전사체의 번역 및 융합 단백질 생산물 또는 이의 단편의 분비를 의미하는 것으로 이해된다. 유용한 발현 벡터는 RcCMV(Invitrogen, Carlsbad) 또는 이의 변이체일 수 있다. 상기 발현 벡터는 포유류 세포에서 목적 유전자의 연속적인 전사를 촉진하기 위한 인간 CMV(cytomegalovirus) 프로모터, 및 전사 후 RNA의 안정상태 수준을 높이기 위한 우태 성장 인자(bovine growth hormone) 폴리아데닐레이션 신호서열을 포함할 수 있다.As used herein, the term "gene expression" or "expression" of a protein of interest is understood to mean transcription of a DNA sequence, translation of an mRNA transcript, and secretion of a fusion protein product or fragment thereof. A useful expression vector may be RcCMV (Invitrogen, Carlsbad) or a variant thereof. The expression vector includes a human CMV (cytomegalovirus) promoter for promoting continuous transcription of a target gene in mammalian cells, and a bovine growth hormone polyadenylation signal sequence for raising the level of post-transcriptional RNA stability can do.
본원 발명의 또 다른 측면으로, 상기 발현 벡터가 도입된 숙주 세포를 제공한다. 본원 발명에서 사용된 용어 "숙주 세포"는 재조합 발현 벡터가 도입될 수 있는 원핵 및 진핵 세포를 나타낸다. 본원 발명에서 사용된 용어, "형질주입된", "형질전환된" 및 "형질감염된"은 당업계에 공지된 기술을 사용하여 세포 내로 핵산(예를 들어, 벡터)을 도입하는 것을 의미한다.In another aspect of the present invention, there is provided a host cell into which the expression vector is introduced. The term "host cell" as used herein refers to prokaryotic and eukaryotic cells into which a recombinant expression vector can be introduced. As used herein, the terms "transfected," "transformed," and "transfected" refer to the introduction of a nucleic acid (eg, a vector) into a cell using techniques known in the art.
본원 발명에 사용될 수 있는 바람직한 숙주 세포는 불사의 하이브리도마 세포, NS/0 골수종 세포, 293 세포, 중국 햄스터 난소 세포(CHO cell), HeLa 세포, 인간 양수 유래 세포(CapT cell) 또는 COS 세포를 포함한다. 바람직하게는, CHO 세포일 수 있다. 한편, 상기 숙주 세포는 상기 벡터와 시알산 전이효소 유전자가 적재된 벡터가 도입된 것일 수 있다. 이때, 상기 시알산 전이효소는 2,3-시알산 전이효소 또는 2,6-시알산 전이효소 일 수 있다. 이때, 상기 2,6-시알산 전이효소는 서열번호 15의 아미노산 서열을 가질 수 있다.Preferred host cells that may be used in the present invention include immortal hybridoma cells, NS / 0 myeloma cells, 293 cells, Chinese hamster ovary cells (CHO cells), HeLa cells, human amniotic fluid cells (CapT cells) . Preferably, it may be a CHO cell. On the other hand, the host cell may be one in which the vector and the vector carrying the sialic acid transferase gene are introduced. The sialic acid transferase may be a 2,3-sialic acid transferase or a 2,6-sialic acid transferase. Here, the 2,6-sialyltransferase may have the amino acid sequence of SEQ ID NO: 15.
본원 발명의 또 다른 측면으로, 1) 폴리펩티드 단량체를 코딩하는 폴리뉴클레오티드와 시알산 전이효소 유전자가 도입된 세포를 배양하는 단계; 및 2) 폴리펩티드 이량체를 회수하는 단계를 통해 수득된, IgE Fc 수용체의 알파 서브유닛의 세포외 도메인(FcεRIa-ECD)을 포함하는 단량체 두 개를 포함하는 폴리펩티드 이량체를 유효성분으로 포함하는 알러지성 질환 치료용 또는 예방용 약학적 조성물을 제공한다. 이때, 상기 단량체는 변형된 Fc 영역을 포함한다. 또한, 상기 변형된 Fc 영역과 FcεRIa-ECD는 힌지를 통해 결합된 것일 수 있다.In another aspect of the present invention, there is provided a method for producing a polypeptide comprising: 1) culturing a cell into which a polynucleotide encoding a polypeptide monomer and a sialic acid transferase gene have been introduced; And 2) an allergen containing, as an active ingredient, a polypeptide dimer comprising two monomers including the extracellular domain (Fc? RIA-ECD) of the alpha subunit of the IgE Fc receptor obtained through recovering the polypeptide dimer A pharmaceutical composition for the treatment or prevention of sexual diseases is provided. Wherein the monomer comprises a modified Fc region. In addition, the modified Fc region and Fc [epsilon] RIa-ECD may be joined through a hinge.
본원 발명의 또 다른 측면으로, 상술한 이량체 제조방법으로 제조된 폴리펩티드 이량체를 유효성분으로 포함하는 알러지성 증상의 개선 또는 완화용 식품 조성물을 제공한다.In another aspect of the present invention, there is provided a food composition for improving or alleviating an allergic symptom comprising a polypeptide dimer prepared by the above-mentioned method for producing a dimer as an active ingredient.
본원 발명의 또 다른 측면으로, 상기 IgE Fc 수용체의 알파 서브유닛의 세포외 도메인(FcεRIa-ECD)을 포함하는 단량체 두 개를 포함하는 폴리펩티드 이량체를 개체에 투여하는 단계를 포함하는 알러지 질환 치료 또는 예방 방법을 제공한다.In another aspect of the present invention there is provided a method for treating or preventing an allergic disease comprising administering to a subject a polypeptide dimer comprising two monomers comprising the extracellular domain of the alpha subunit of the IgE Fc receptor (FcεRIa-ECD) Provide prevention methods.
상기 개체는 포유 동물일 수 있으며, 바람직하게는 인간일 수 있다. 이때, 투여는 경구 또는 비경구를 통하여 투여할 수 있다. 이때, 비경구는 피하 투여, 정맥 투여, 점막 투여, 근육 투여 등의 방법으로 수행될 수 있다.The subject may be a mammal, preferably a human. In this case, administration can be administered orally or parenterally. At this time, parenteral administration can be performed by subcutaneous administration, intravenous administration, mucosal administration, muscle administration, and the like.
이하, 본원 발명을 하기 실시예에 의하여 더욱 상세하게 설명한다. 단, 하기 실시예는 본원 발명을 예시하기 위한 것일 뿐, 본원 발명의 범위가 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.
실시예 1. FcεRIαECD과 변형된 Fc 영역을 포함하는 폴리펩티드의 제조Example 1. Preparation of a polypeptide comprising FcεRIαECD and a modified Fc region
IgE Fc 수용체의 알파 서브유닛의 세포외 도메인(FcεRIα ECD: Extracellular domain)의 C 말단이 변형된 폴리펩티드는 미국 특허 7,867,491에 개시된 방법에 따라 제조하였다. The C-terminal modified polypeptide of the extracellular domain of the alpha subunit of the IgE Fc receptor (Fc? R? ECD: ECD) was prepared according to the method disclosed in U.S. Patent No. 7,867,491.
먼저, 서열번호 1의 아미노산 서열을 갖는 FcεRI의 α사슬의 세포외 도메인과 서열번호 2의 변형된 면역글로불린 Fc가 각각, 서열번호 19의 힌지로 연결된 단백질(FcεRIαECD-Fc1), 서열번호 3의 힌지로 연결된 단백질(FcεRIαECD-Fc2) 및 서열번호 4의 힌지로 연결된 단백질(FcεR1αECD-Fc3)을 발현시키기 위하여, 각각의 단백질을 코딩하는 유전자를 연결한 카세트를 pAD15 벡터(제넥신)에 클로닝하여, FcεRIαECD-Fc 단백질 발현 벡터를 제작하였다. 그 후, 상기 발현 벡터를 각각 CHO DG44 (from Dr. Chasin, Columbia University, USA) 세포에 형질주입하였다.First, the extracellular domain of the? Chain of Fc? RI having the amino acid sequence of SEQ ID NO: 1 and the modified immunoglobulin Fc of SEQ ID NO: 2 are replaced with a hinge linked protein (Fc? RIECD-Fc1) of SEQ ID NO: 19, (FcεRIαECD-Fc2) and a hinge-linked protein (FcεR1αECD-Fc3) of SEQ ID NO: 4 were cloned into a pAD15 vector (genexin) to which a gene coding for each protein was ligated to obtain FcεRIαECD -Fc protein expression vector. The expression vector was then transfected into CHO DG44 (from Dr. Chasin, Columbia University, USA).
이때, 세포주에 형질 주입시 pCI Hygro 벡터(Invitrogen)에 α-2,6-시알산 전이효소 유전자가 클로닝된 발현 벡터를 동시에 형질주입하여, 시알산이 부가된 FcεRIαECD-Fc2ST 및 FcεRIαECD-Fc3ST 단백질을 발현할 수 있는 세포주를 별도로 제조하였다.At this time, an expression vector in which an α-2,6-sialyltransferase gene was cloned into pCI Hygro vector (Invitrogen) at the time of transfection of the cell line was simultaneously transfected to express sialic acid-added FcεRIαECD-Fc2ST and FcεRIαECD-Fc3ST protein Were prepared separately.
1차 스크리닝 과정으로 HT(5-hydroxytrypamine)가 없는 10% dFBS(Gibco, USA, 30067-334), MEMα(Gibco, 12561, USA, Cat No. 12561-049), HT+ (Gibco, USA, 11067-030)) 배지를 사용하여 HT 선별을 수행하였다. 이후, DHFR(dihydrofolate reductase)-시스템을 이용하여 생산성을 증폭시키기 위해, HT 선별된 클론들을 이용하여 메토트렉사트(MTX) 증폭을 수행하였다. (Gibco, USA, 30067-334), MEM (Gibco, 12561, USA, Cat No. 12561-049) and HT + (Gibco, USA, 11067-334) without HT (5-hydroxytrypamine) 030)) medium. Then, methotrexate (MTX) amplification was performed using HT-selected clones to amplify productivity using the DHFR (dihydrofolate reductase) -system.
MTX 증폭이 완료된 후 생산성 평가를 위한 세포 안정화를 위해 1~5회 정도 계대배양하였다. 그 후, MTX 증폭이 된 세포의 단위 생산성 평가를 수행하였고, 그 결과는 하기 표 1에 나타내었다.After completion of MTX amplification, cells were subcultured 1-5 times for cell stabilization for productivity evaluation. Thereafter, the unit productivity of the MTX-amplified cells was evaluated. The results are shown in Table 1 below.
VersionVersion
MediaMedia
MTX conc.MTX conc.
DHFREx-cell
DHFR
표 1에 기재된 바와 같이, FcεRIαECD-Fc3 세포주는 2 uM 메토트렉사트 증폭 후 16.9 ug/106 cells 생산성을 나타내었다. 반면, 2,6-시알산 전이효소가 공동 형질주입된 FcεRIαECD-Fc3 세포주(FcεRIαECD-Fc3ST)는 1 uM 메토트렉사트 증폭후 17.5 ug/106 cells 생산성을 나타내었다. 또한, FcεRIαECD-Fc2 세포주는 0.5 uM 메토트렉사트 증폭 조건에서 20.9 ug/106 cells 생산성을 나타내었다. 또한, 2,6-시알산 전이효소가 공동 형질주입된 FcεRIαECD-Fc2 세포주(FcεRIαECD-Fc2ST)는 0.1 uM 메토트렉사트 증폭 후 25.1 ug/106 cells 생산성을 나타내었다. 즉, 0.1 uM 메토트렉사트 증폭 조건에서 선별된 2,6-시알산 전이효소가 공동 형질주입된 FcεRIαECD-Fc2 세포주가 생산성이 가장 우수한 것을 확인하였다.As shown in Table 1, the FcεRIαECD-Fc3 cell line showed 16.9 ug / 10 6 cells productivity after 2 μM methotrexate amplification. On the other hand, the FcεRIαECD-Fc3 cell line (FcεRIαECD-Fc3ST) co-transfected with the 2,6-sialyltransferase showed a productivity of 17.5 μg / 10 6 cells after 1 μM methotrexate amplification. In addition, FcεRIαECD-Fc2 cell line showed 20.9 ug / 10 6 cells productivity under the condition of 0.5 uM methotrexate amplification. In addition, FcεRIαECD-Fc2 cell line (FcεRIαECD-Fc2ST) co-transfected with 2,6-sialyltransferase exhibited productivity of 25.1 μg / 10 6 cells after 0.1 μM methotrexate amplification. That is, it was confirmed that the FcεRIαECD-Fc2 cell line injected with the 2,6-sialic acid transferase co-transfected under the condition of 0.1 uM methotrexate amplification was the most excellent.
실시예 2. FcεRIα ECD 융합 단백질의 정제 및 순도 확인Example 2. Purification and purification of FcεRIa ECD fusion protein
상기 실시예 1에서 선별된 세포주 중 i) FcεRIαECD-Fc3, ii) FcεRIαECD-Fc3ST, iii) FcεRIαECD-Fc2ST를 60 ml 규모에서 배치배양법으로 배양하였다. 상기 배양된 배양액을 Protein-A affinity column을 이용하여 정제한 후, 정제된 단백질을 SDS-PAGE 및 크기-배제(Size-Exclusion) HPLC(SE-HPLC)를 수행하여 단백질의 순도를 확인하였다.I) FcεRIαECD-Fc3, ii) FcεRIαECD-Fc3ST and iii) FcεRIαECD-Fc2ST among the cell lines selected in Example 1 were cultured in a 60 ml scale by a batch culture method. The cultured medium was purified using Protein-A affinity column, and purified protein was subjected to SDS-PAGE and size-exclusion HPLC (SE-HPLC) to confirm protein purity.
도 1에 나타난 바와 같이, SE-HPLC 방법으로 정제된 각 단백질의 순도는 모두 93% 이상인 것을 확인하였다. 또한, SDS-PAGE 분석결과, 비환원 조건 및 환원 조건에서 각각 약 150 kDa, 약 75 kDa 크기의 단백질이 검출되는 것으로 확인되었으며(도 1, Lane 1 내지 6), 이를 통해 Fc와 결합된 FcεRIαECD가 이량체를 형성하고 있음을 알 수 있었다. 또한, SDS-PAGE 결과에서 절단된 형태 등의 불순물이 나타나지 않았으며, 특히, 해동(thawing)/냉동(freezing)의 과정을 거친 후에도(도 1, Lane 7 내지 8) 모두 순도가 93% 이상이었고 불순물이 없는 것을 확인하였으며, 야생형 IgD hinge가 적용된 FcεRIαECD-Fc1 대비 단백질 절단형의 생산이 줄어들었음을 알 수 있었다.As shown in Fig. 1, it was confirmed that the purity of each protein purified by the SE-HPLC method was 93% or more. As a result of SDS-PAGE analysis, it was confirmed that proteins of about 150 kDa and about 75 kDa were detected in the non-reducing condition and the reducing condition, respectively (Fig. 1,
이때, 시알산 전이효소 도입에 따른 단백질 시알산 함량 정도를 확인하기 위해 Gel-IEF를 아래의 시험조건으로 수행하였으며, 이를 통해 시알산 함량 증가로 인해 acidic 단백질의 함량이 증가되었음을 확인하였다.At this time, Gel-IEF was performed under the following test conditions to confirm the content of sialic acid transfection enzyme-introduced protein sialic acid, and it was confirmed that the content of acidic protein was increased due to the increase of sialic acid content.
또한, 정제 수율 재현성을 확인하기 위하여, FcεRIαECD-Fc2ST 세포주를 1L 플라스크에서 250 ml 규모에서 배치 배양하고, Protein-A affinity column을 이용하여 정제하였다. 그 후, 배양 상등액 및 정제물에 대해 4-15% TGXTM 겔(BIO-RAD사)에 트리스글라이신 SDS(TGS) 버퍼, 200V 조건으로 30분 동안 러닝 후 SDS PAGE 분석을 수행하였다. 그 결과, 1 단계 정제만으로도 매우 높은 순도(98% 이상)의 단백질이 정제되었을 뿐 아니라, 배양 상등액에서도 매우 높은 순도로 단백질이 발현되는 것을 확인하였다. 이는 해당 세포주에서 발현된 FcεRIαECD-Fc 단백질을 의약품으로 개발하는 데 있어, 공정 개발 단계가 간소화될 수 있고 결과적으로 의약품으로의 개발 비용이 현저히 절감될 수 있는 가능성이 매우 높음을 의미한다.In order to confirm the reproducibility of purification yield, FcεRIαECD-Fc2ST cell line was batch-cultured in a 1 L flask at a volume of 250 ml and purified using Protein-A affinity column. Subsequently, the culture supernatant and the purified product were subjected to SDS PAGE analysis after running for 30 minutes with 4% 15% TGX ™ gel (BIO-RAD) with Tris-Glycine SDS (TGS) buffer at 200V. As a result, it was confirmed that not only the protein with a very high purity (98% or more) was purified by the first step purification but also the protein was expressed with a very high purity even in the culture supernatant. This means that the process development stage can be simplified in developing FcεRIαECD-Fc protein expressed in the cell line as a drug, and as a result, the development cost as a drug can be significantly reduced.
실시예 3. FcεRIα ECD 융합 단백질과 IgE의 결합능 확인Example 3. Confirmation of Binding Ability of FcεRIα ECD Fusion Protein and IgE
상기 실시예 2의 방법을 통해 정제된 i) FcεRIαECD-Fc2, ii) FcεRIαECD-Fc2ST, iii) FcεRIαECD-Fc3 및 iv) FcεRIαECD-Fc3ST의 4 종 단백질과 시중에 판매되고 있는 항 IgE 항체인 오말리주맙(Omalizumab, 상품명: 졸레어(Xolair))에 대하여 IgE 결합능을 비교 측정하였다. 구체적으로, IgE 결합능은 Protein GLC sensor chip(Bio-Rad, Cat #. 176-5011)의 채널에 IgE를 코팅하고, 오말리주맙 혹은 FceR1αECD-Fc 단백질 각각을 여러 농도로 분당 30 ul의 속도로 흘려주었다.FcεRIαECD-Fc2, FcεRIαECD-Fc3, and iv) FcεRIαECD-Fc3ST, which are purified through the method of Example 2 above, and omalizumab Omalizumab (trade name: Xolair)). Specifically, IgE binding ability was measured by coating IgE on the channel of a protein GLC sensor chip (Bio-Rad, Cat # 176-5011), and omalizumab or FceR1αECD-Fc protein was flowed at various concentrations at a rate of 30 μl per minute .
실험은 재생 버퍼인 25 mM NaOH를 이용하여 제로베이스를 확인한 후, 상기 단계를 반복하여 진행하였다. 그 후, 단백질 결합 분석기기(Proteon XPR36, BIO-RAD, USA)를 이용하여 결합곡선을 확인하였으며, 그 결과를 표 3, 도 3 및 도 4에 나타내었다.The experiment was carried out by repeating the above steps after confirming the zero base using 25 mM NaOH as the regeneration buffer. Thereafter, the binding curve was confirmed using a protein binding analyzer (Proteon XPR36, BIO-RAD, USA), and the results are shown in Tables 3, 3 and 4.
ItemsItems
affinityBinding
affinity
표 3에 나타난 바와 같이, 본원 발명의 일 구체예에 따른 폴리펩티드 이량체의 결합상수(Association rate, ka) 값은 오말리주맙과 비교하여 1.5 내지 2.0 배 작은 것으로 측정되었다. 즉, IgE 외의 물질과의 결합력이 오말리주맙에 비해 1.5 ~ 2.0 배 정도 낮은 것을 알 수 있었다. 또한, 본원 발명의 일 구체예에 따른 폴리펩티드 이량체의 해리상수(Dissociation rate, kd) 값은 오말리주맙과 비교하여 40 내지 106 배 큰 것으로 측정되었다. 또한, 도 3 및 도 4에서 개시된 바와 같이, 오말리주맙은 IgE와 결합한 후 일정 시간이 지나면 결합이 떨어지는 반면, 본원 발명의 FcεRIαECD 융합 단백질의 폴리펩티드 이량체는 일단 IgE와 결합한 후에는 IgE와 떨어지지 않는 것을 확인할 수 있었다. 즉, 본원 발명의 폴리펩티드 이량체는 IgE와 쉽게 분리되지 않고, 결합된 상태로 유지되는 능력이 오말리주맙에 비해 월등히 좋은 것을 알 수 있다. 결과적으로, 본원 발명의 일 구체예에 따른 폴리펩티드 이량체의 평형상수(Equilibrium dissociation constant, KD <kd/ka>) 값은 오말리주맙과 비교하여 22 내지 69배 높은 것을 알 수 있으며, 이를 통해, 본원 발명의 FcεRIαECD 융합 단백질은 오말리주맙과 비교하여 IgE에 대한 결합능이 현저히 증가한 것을 확인하였다. 특히, 시알산이 부가된 FcεRIαECD-Fc2(FcεRIαECD-Fc2ST)가 오말리주맙 대비 69배로 IgE 결합력이 가장 우수함을 확인하였다.As shown in Table 3, the association rate (ka) value of the polypeptide dimer according to one embodiment of the present invention was measured to be 1.5 to 2.0 times smaller than that of omalizumab. That is, the binding ability to substances other than IgE was 1.5 to 2.0 times lower than that of omalizumab. Also, the dissociation rate (kd) value of the polypeptide dimer according to one embodiment of the present invention was measured to be 40 to 106 times larger than that of omalizumab. Also, as shown in FIG. 3 and FIG. 4, omalizumab decreases binding after a certain time after binding with IgE, whereas the polypeptide dimer of the FcεRIαECD fusion protein of the present invention has a property that once bound to IgE, I could confirm. That is, the polypeptide dimer of the present invention is not easily separated from IgE, and its ability to be maintained in a bound state is much better than omalizumab. As a result, the value of the equilibrium dissociation constant (KD < kd / ka) of the polypeptide dimer according to one embodiment of the present invention is 22 to 69 times higher than that of omalizumab, The FcεRIαECD fusion protein of the present invention was found to have a significantly increased binding capacity to IgE as compared to omalizumab. In particular, it was confirmed that the sialic acid-added FcεRIαECD-Fc2 (FcεRIαECD-Fc2ST) had the highest IgE binding capacity at 69-fold compared with omalizumab.
실시예 4. FcεRIα ECD 융합 단백질과 IgG 수용체의 결합능 확인Example 4. Confirmation of Binding Ability of FcεRIα ECD Fusion Protein and IgG Receptor
IgE TRAP와 오말리주맙의 IgG 수용체에 대한 결합 정도는 Octet RED384 시스템(Pall ForteBio, CA, USA)을 사용하여 확인하였다. 활성화된 AR2G 바이오 센서에 FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA 및 FcγRIIIB 재조합 단백질(R & D 시스템, 5 μg/ml)을 300 mM 아세테이트 완충액(pH 5)에 고정화 하였다. Running buffer는 0.1 % Tween-20 및 1 % bovine serum을 포함한 PBS를 사용하였다. 모든 실험은 샘플 플레이트 쉐이커 1000 rpm 속도로 30℃에서 이루어졌다. 그 결과는 도면 도 5a 내지 도 5e에 나타내었고, 오말리주맙과 IgETRAP의 IgG 수용체와의 결합능을 수치화하여 도 6에 나타내었다.The degree of binding of IgE TRAP and omalizumab to IgG receptors was confirmed using the Octet RED384 system (Pall ForteBio, CA, USA). FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA and FcγRIIIB recombinant proteins (R & D system, 5 μg / ml) were immobilized in 300 mM acetate buffer (pH 5) to the activated AR2G biosensor. The running buffer was PBS containing 0.1% Tween-20 and 1% bovine serum. All experiments were carried out at 30 DEG C with a sample plate shaker at 1000 rpm. The results are shown in Figs. 5A to 5E, and the ability of omalizumab to bind IgG receptors of IgE TRAP was quantified and shown in Fig.
실시예 5. 마우스 골수 유래 비만 세포에서 베타-헥소사미니다제 어세이를 통한 FcεRIα ECD 융합 단백질의 활성 확인Example 5. Confirmation of activity of FcεRIα ECD fusion protein through beta-hexosaminidase assays in mouse bone marrow-derived mast cells
본원 발명의 FcεRIαECD 융합 단백질의 in vitro 활성 분석을 위하여 베타 헥소사미니다제 분석을 수행하였다. 구체적으로, 본원 발명의 일 구체예에 따른 FcεRIαECD-Fc2 단백질을 농도별로 마우스 IgE(1 ug/mL)와 혼합하여 상온(20℃)에서 30분간 인큐베이션(incubation)시켜 시료를 준비하였다. 비만 세포 활성화를 위해 배양중인 마우스 골수 유래 비만세포(mast cell)를 HBSS(Hank's balanced salt solution) 버퍼로 세척하여 배지를 제거하였으며, 세포수를 측정한 후 5x105 개의 세포들이 40 uL의 HBSS 버퍼에 주입되도록 조절하였다.Beta hexosaminidase assay was performed for in vitro activity analysis of the FcεRIαECD fusion protein of the present invention. Specifically, the FcεRIαECD-Fc2 protein according to one embodiment of the present invention was mixed with mouse IgE (1 ug / mL) for each concentration and incubated at room temperature (20 ° C) for 30 minutes to prepare a sample. For mast cell activation, mast cells derived from mouse bone marrow were washed with Hank's balanced salt solution (HBSS) buffer to remove the medium. After measuring the number of cells, 5 × 10 5 cells were suspended in 40 μL of HBSS buffer Lt; / RTI >
그 후, 상기 프리 인큐베이션을 통해 준비된 시료 용액 50 uL를 활성화된 비만 세포에 첨가하였다. 그 후, 37℃에서 30분간 5% CO2 배양기에서 30분 동안 배양하였다. 이후 외래 항원인 DNP(2,4-dinitrophenol, 100 ng/mL)를 10 uL씩 첨가한 후, 다시 37℃에서 30분간 5% CO2 배양시킨 다음 상층액을 30 uL 분리하였다. 분리된 상층액 30 uL와 기질(4-Nitrophenyl N-acetyl-β-D-glucosaminide, 5.84 mM) 30 uL를 잘 혼합한 후 37℃에서 20분간, 5% CO2에서 배양하였다. 그 후, 정지용액(Stop solution)인 0.1 M 소디움 카보네이트 버퍼(sodium carbonate buffer)(pH 10) 140 uL를 넣고 반응을 종결시켰다. 이 후, 405 nm에서 흡광도를 측정하여 활성화된 비만 세포에서 외래 항원에 의해 분비되는 베타-헥소사미니다아제(β-hexosaminidase)의 분비량을 확인하였고, 그 결과를 도 7에 나타내었다.Then, 50 uL of the sample solution prepared through the preincubation was added to the activated mast cells. Then, the cells were cultured in a 5% CO 2 incubator for 30 minutes at 37 ° C for 30 minutes. Subsequently, 10 μL of DNP (2,4-dinitrophenol, 100 ng / mL) was added to the culture supernatant, followed by incubation at 37 ° C for 30 minutes with 5% CO 2, followed by 30 μL of the supernatant. 30 uL of the separated supernatant and 30 uL of the substrate (4-Nitrophenyl N-acetyl-β-D-glucosaminide, 5.84 mM) were mixed well and incubated at 37 ° C for 20 minutes in 5% CO 2 . Then, 140 μL of 0.1 M sodium carbonate buffer (pH 10) as a stop solution was added to terminate the reaction. Thereafter, the absorbance at 405 nm was measured to determine the secretion amount of beta -hexosaminidase secreted by the foreign antigen in the activated mast cells, and the results are shown in FIG.
도 7에 나타난 바와 같이, 본원 발명의 일 구체예의 폴리펩티드 이량체의 농도가 마우스 IgE의 절반(0.5 ug/mL)일 때 약 49.4 %의 억제율을 보여주었으며, 마우스 IgE와 동일한 농도(1 ug/mL)일 때 약 99.4 %의 비만 세포 억제율을 보여주었다. 즉, 본원 발명의 FceRIa-ECD 폴리펩티드 이량체에 의해 IgE에 의한 골수 유래 비만세포의 활성이 크게 억제되는 것을 알 수 있다.As shown in FIG. 7, when the concentration of the polypeptide dimer of one embodiment of the present invention was half (0.5 ug / mL) of mouse IgE, the inhibition rate was about 49.4%, and the same concentration (1 ug / mL ) Showed a mast cell inhibition rate of about 99.4%. That is, it can be seen that the activity of IgE-induced bone marrow-derived mast cells is greatly suppressed by the FceRIa-ECD polypeptide dimer of the present invention.
실시예 6. 인간 FcεRI 발현 마우스 골수 유래 비만 세포에서 베타-헥소사미니다제 어세이를 이용한 FcεRIα ECD 융합 단백질 및 anti-human IgE 항체의 활성 비교Example 6. Comparison of the activity of FcεRIα ECD fusion protein and anti-human IgE antibody using β-hexosaminidase assay in bone marrow-derived mast cells from human FcεRI-expressing mice
in vitro 활성 분석을 통해 FcεRIα ECD 융합 단백질의 Xolair 대비 우수성을 확인하기 위하여 베타-핵소사미니다제 분석을 진행하였다. 각 약물 FcεRIαECD-Fc2ST(IgETRAP)과 Xolair를 농도별로 준비한 후 인간 IgE (1 ug/mL)와 혼합한 후 상온에서 30분간 인큐베이션 시켰다. 약물을 프리(pre)-인큐베이션 하는 동안 인간 FcεRI 유전자가 도입되고, 마우스 FcεRI 유전자가 제거된 마우스의 골수로부터 유래 및 분화된 비만세포를 준비하였다. 준비한 비만 세포들을 HBSS 버퍼로 세척해준 후, 5x105 개의 세포들을 60 uL의 HBSS 버퍼에 주입하였다. 준비가 끝난 비만세포에 프리(pre)-인큐베이션한 시료 20 uL를 비만세포에 첨가한 후 37℃, 5% CO2 배양기에서 30분 동안 배양하였다.In vitro activity assays were performed to confirm the superiority of FcεRIα ECD fusion protein versus Xolair. Each drug, FcεRIαECD-Fc2ST (IgE TRAP ) and Xolair were prepared by concentration, mixed with human IgE (1 ug / mL) and incubated at room temperature for 30 minutes. During pre-incubation of the drug, the human Fc [epsilon] RI gene was introduced, and mast cells derived from and differentiated from the bone marrow of mice in which the mouse Fc [epsilon] RI gene had been removed were prepared. The prepared mast cells were washed with HBSS buffer, and then 5 × 10 5 cells were injected into 60 μL of HBSS buffer. 20 μL of pre-incubated samples were added to the prepared mast cells and then cultured in a 5% CO 2 incubator at 37 ° C. for 30 minutes.
이후 anti-human IgE 항체 (Biolegend, Cat No. 325502, 0.5 ug/mL)를 20 uL 첨가한 후 다시 37℃ 5% CO2 배양기에서 30분 동안 배양하였다. 이후 1,500 rpm, 4℃, 원심분리 한 후 상층액 30 uL를 분리하였다. 분리한 상층액 30 uL와 기질(4-Nitrophenyl N-acetyl-βglucosaminide, 5.84 mM) 30 uL를 잘 혼합한 후 37℃ 5% CO2 배양기에서 25분 동안 배양하였다. 그 후, 0.1 M 소디움 카보네이트 버퍼(sodium carbonate buffer) (pH 10) 140 uL를 넣고 반응을 종결시켰다.After the addition of 20 uL of anti-human IgE antibody (Biolegend, Cat No. 325502, 0.5 ug / mL), the cells were cultured in a 37 °
이 후, 405 nm에서 흡광도를 측정하여분비된 베타-헥소사미니다아제 (β-hexosaminidase)의 상대량을 비교하여 각 약물의 농도에 따른 비만 세포 억제효과를 확인하였다. 그 결과는 도 8에 나타내었다. 도 8에 표시한 바와 같이, FcεRIα ECD 융합 단백질의 IC50은 대략 11.16 ng/mL로 측정되었고, Xolair 단백질의 IC50은 대략 649.8 ng/mL로 측정되었다. 따라서, FcεRIα ECD 융합 단백질은 Xolair에 비해 58배 정도 높은 비만 세포 활성 억제력이 있음을 확인하였다.After that, the absorbance at 405 nm was measured to compare the amount of secreted β-hexosaminidase, and the inhibitory effect of each drug on mast cell inhibition was confirmed. The results are shown in Fig. As shown in FIG. 8, the IC 50 of the FcεRIα ECD fusion protein was measured to be approximately 11.16 ng / mL, and the IC 50 of the Xolair protein was estimated to be approximately 649.8 ng / mL. Thus, the FcεRIα ECD fusion protein was found to have a 58-fold higher inhibitory effect on mast cell activity than Xolair.
실시예 7. FcεRIα ECD 융합 단백질의 in vivo assay(식품 알러지 모델)Example 7. In vivo assay of FcεRIα ECD fusion protein (food allergy model)
Balb/c 마우스(오리엔트바이오)들에 대하여 OVA(ovalbumin) 50 ug 및 알럼(Alum) 1 mg을 14일 간격으로 2회 복강 투여하여 감작(sensitization)을 유발하였다. 이후, 28, 30, 32, 34, 36일째, 총 5회에 걸쳐 OVA 50 mg을 경구 투여하여 장에 음식물 알러지를 유발하였다.50 ug of OVA (ovalbumin) and 1 mg of Alum were administered to Balb / c mice (Oriental bio) two times at intervals of 14 days to induce sensitization. Thereafter,
상기 OVA를 경구 투여 2회 후 즉, 31일째에 상기 마우스를 7마리씩 3개의 그룹으로 분류하였다. 제 1 그룹인 FcεRIαECD-Fc2ST 융합 단백질을 고농도(200 ug)로 투여하는 군, 제 2 그룹인 저농도(20 ug)로 투여하는 군 및 제 3 그룹인 투여하지 않는 군으로 분류하였다. 상기 OVA를 경구 투여하면서 음식물 알러지 유발에 따라 설사 발생 여부를 확인하였으며, 37일째 상기 마우스를 희생시켜 각 그룹에 속한 마우스에 대하여 소장 내 비만세포의 수, 혈중 IgE 농도 및 혈중 비만세포의 탈과립 효소 농도(MCPT-1, Mast cell protease-1)를 분석하였다.After 2 doses of the OVA, i.e., on the 31st day, the mice were divided into three groups of 7 mice. The first group, FcεRIαECD-Fc2ST fusion protein, was divided into two groups: high dose (200 ug), low dose (20 ug), and third dose. The mice were sacrificed at
도 9에 나타난 바와 같이, FcεRIαECD-Fc2ST인 폴리펩티드 이량체를 고농도로 투여한 군에 속한 마우스에서, 아무것도 투여하지 않은 군에 속한 마우스에 비하여 농도 의존적으로 식품 알러지가 완화되는 효과를 나타남을 확인하였다.As shown in FIG. 9, it was confirmed that mice belonging to the group to which FcεRIαECD-Fc2ST was administered at a high concentration showed the effect of alleviating the food allergy in a concentration-dependent manner compared with the mice belonging to the non-administered group.
<110> PROGEN CO., LTD. <120> PHARMACEUTICAL COMPOSITION COMPRISING RECOMBINANT EXTRACELLULAR DOMAIN OF IgE Fc RECEPTOR SUBUNIT ALPHA <130> FPD/201901-0002/c <150> KR 10-2018-0002262 <151> 2018-01-08 <160> 22 <170> KopatentIn 2.0 <210> 1 <211> 180 <212> PRT <213> Artificial Sequence <220> <223> FCeRI1 ECD <400> 1 Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile 1 5 10 15 Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe 20 25 30 Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu 35 40 45 Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly 50 55 60 Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr 65 70 75 80 Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val 85 90 95 Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn 100 105 110 Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys 115 120 125 Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu 130 135 140 Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr 145 150 155 160 Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys 165 170 175 Tyr Trp Leu Gln 180 <210> 2 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> Modified Fc <400> 2 Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys 1 5 10 15 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 20 25 30 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 35 40 45 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 50 55 60 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 65 70 75 80 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 85 90 95 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 100 105 110 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 115 120 125 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 130 135 140 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 145 150 155 160 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 165 170 175 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 180 185 190 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 195 200 205 Leu Ser Leu Ser Leu Gly Lys 210 215 <210> 3 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> IgD hinge variant <400> 3 Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Gly Ser Lys Glu Lys 1 5 10 15 Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro 20 25 30 <210> 4 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> IgD hinge variant <400> 4 Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro 1 5 10 15 Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Gly Ser 20 25 30 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys 35 40 45 Pro <210> 5 <211> 540 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of FCeRI1 ECD <400> 5 gtgccccaga agcccaaggt gagcctgaac cctccctgga acagaatctt caagggcgag 60 aacgtgaccc tgacctgcaa cggcaacaac ttcttcgagg tgagcagcac caagtggttc 120 cacaatggca gcctgagcga ggagaccaac agctccctga acatcgtgaa cgccaagttc 180 gaggacagcg gcgagtacaa gtgccagcac cagcaggtga acgagagcga gcccgtgtac 240 ctggaggtgt tcagcgactg gctgctgctg caggccagcg ccgaggtggt gatggagggc 300 cagcccctgt tcctgagatg ccacggctgg agaaactggg acgtgtacaa ggtgatctac 360 tacaaggatg gcgaggccct gaagtactgg tacgagaacc acaacatctc catcaccaac 420 gccaccgtgg aggacagcgg cacctactac tgcacaggca aggtgtggca gctggactac 480 gagagcgagc ccctgaacat caccgtgatc aaggctccca gagagaagta ctggctgcag 540 540 <210> 6 <211> 561 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of modified Fc <400> 6 tgcgtggtcg tggatgtgag ccaggaagat cccgaagtgc agttcaactg gtacgtggat 60 ggcgtggaag tgcacaacgc caagaccaag cccagagaag agcagttcaa ctccacctac 120 agagtggtga gcgtgctgac cgtgctgcac caggactggc tgaacggcaa ggagtacaag 180 tgcaaggtgt ccaacaaagg cctgcccagc tccatcgaga agaccatcag caaagccaaa 240 ggccagccca gagaacccca ggtgtacacc ctgcctccca gccaggaaga gatgaccaag 300 aaccaggtgt ccctgacctg cctggtgaaa ggcttctacc ccagcgacat cgccgtggag 360 tgggaaagca acggccagcc cgagaacaat tacaagacaa cccctcccgt gctggatagc 420 gatggcagct tctttctgta cagcagactg accgtggaca agagcagatg gcaggaaggc 480 aacgtgttca gctgcagcgt gatgcacgaa gccctgcaca accactacac ccagaagagc 540 ctgtccctga gcctgggcaa g 561 <210> 7 <211> 174 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of IgD hinge variant <400> 7 aggaacaccg gcagaggagg cgaggaaaag aaaggaagca aggagaagga ggagcaggag 60 gaaagagaaa ccaagacccc cgagtgcccc agccacaccc agcccctggg cgtgttcctg 120 ttccccccca agcccaagga caccctgatg atcagcagaa cccccgaggt gacc 174 <210> 8 <211> 231 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of IgD hinge variant <400> 8 gcccagcccc aggccgaggg cagcctggct aaggccacca cagctcccgc caccaccagg 60 aacaccggca gaggaggcga ggaaaagaaa ggaagcaagg agaaggagga gcaggaggaa 120 agagaaacca agacccccga gtgccccagc cacacccagc ccctgggcgt gttcctgttc 180 ccccccaagc ccaaggacac cctgatgatc agcagaaccc ccgaggtgac c 231 <210> 9 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> signal peptide <400> 9 Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Ser His Ala 20 25 <210> 10 <211> 75 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of signal peptide <400> 10 atggacgcca tgctgagagg cctgtgctgt gtgctgctgc tgtgcggcgc cgtgttcgtg 60 tcccctagcc acgcc 75 <210> 11 <211> 450 <212> PRT <213> Artificial Sequence <220> <223> FceRIa ECD-hinge-Fc2 <400> 11 Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Ser His Ala Val Pro Gln Lys Pro Lys Val 20 25 30 Ser Leu Asn Pro Pro Trp Asn Arg Ile Phe Lys Gly Glu Asn Val Thr 35 40 45 Leu Thr Cys Asn Gly Asn Asn Phe Phe Glu Val Ser Ser Thr Lys Trp 50 55 60 Phe His Asn Gly Ser Leu Ser Glu Glu Thr Asn Ser Ser Leu Asn Ile 65 70 75 80 Val Asn Ala Lys Phe Glu Asp Ser Gly Glu Tyr Lys Cys Gln His Gln 85 90 95 Gln Val Asn Glu Ser Glu Pro Val Tyr Leu Glu Val Phe Ser Asp Trp 100 105 110 Leu Leu Leu Gln Ala Ser Ala Glu Val Val Met Glu Gly Gln Pro Leu 115 120 125 Phe Leu Arg Cys His Gly Trp Arg Asn Trp Asp Val Tyr Lys Val Ile 130 135 140 Tyr Tyr Lys Asp Gly Glu Ala Leu Lys Tyr Trp Tyr Glu Asn His Asn 145 150 155 160 Ile Ser Ile Thr Asn Ala Thr Val Glu Asp Ser Gly Thr Tyr Tyr Cys 165 170 175 Thr Gly Lys Val Trp Gln Leu Asp Tyr Glu Ser Glu Pro Leu Asn Ile 180 185 190 Thr Val Ile Lys Ala Pro Arg Glu Lys Tyr Trp Leu Gln Arg Asn Thr 195 200 205 Gly Arg Gly Gly Glu Glu Lys Lys Gly Ser Lys Glu Lys Glu Glu Gln 210 215 220 Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro 225 230 235 240 Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 260 265 270 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 435 440 445 Gly Lys 450 <210> 12 <211> 1350 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of FceRIa ECD-hinge-Fc2 <400> 12 atggacgcca tgctgagagg cctgtgctgt gtgctgctgc tgtgcggcgc cgtgttcgtg 60 tcccctagcc acgccgtgcc ccagaagccc aaggtgagcc tgaaccctcc ctggaacaga 120 atcttcaagg gcgagaacgt gaccctgacc tgcaacggca acaacttctt cgaggtgagc 180 agcaccaagt ggttccacaa tggcagcctg agcgaggaga ccaacagctc cctgaacatc 240 gtgaacgcca agttcgagga cagcggcgag tacaagtgcc agcaccagca ggtgaacgag 300 agcgagcccg tgtacctgga ggtgttcagc gactggctgc tgctgcaggc cagcgccgag 360 gtggtgatgg agggccagcc cctgttcctg agatgccacg gctggagaaa ctgggacgtg 420 tacaaggtga tctactacaa ggatggcgag gccctgaagt actggtacga gaaccacaac 480 atctccatca ccaacgccac cgtggaggac agcggcacct actactgcac aggcaaggtg 540 tggcagctgg actacgagag cgagcccctg aacatcaccg tgatcaaggc tcccagagag 600 aagtactggc tgcagaggaa caccggcaga ggaggcgagg aaaagaaagg aagcaaggag 660 aaggaggagc aggaggaaag agaaaccaag acccccgagt gccccagcca cacccagccc 720 ctgggcgtgt tcctgttccc ccccaagccc aaggacaccc tgatgatcag cagaaccccc 780 gaggtgacct gcgtggtcgt ggatgtgagc caggaagatc ccgaagtgca gttcaactgg 840 tacgtggatg gcgtggaagt gcacaacgcc aagaccaagc ccagagaaga gcagttcaac 900 tccacctaca gagtggtgag cgtgctgacc gtgctgcacc aggactggct gaacggcaag 960 gagtacaagt gcaaggtgtc caacaaaggc ctgcccagct ccatcgagaa gaccatcagc 1020 aaagccaaag gccagcccag agaaccccag gtgtacaccc tgcctcccag ccaggaagag 1080 atgaccaaga accaggtgtc cctgacctgc ctggtgaaag gcttctaccc cagcgacatc 1140 gccgtggagt gggaaagcaa cggccagccc gagaacaatt acaagacaac ccctcccgtg 1200 ctggatagcg atggcagctt ctttctgtac agcagactga ccgtggacaa gagcagatgg 1260 caggaaggca acgtgttcag ctgcagcgtg atgcacgaag ccctgcacaa ccactacacc 1320 cagaagagcc tgtccctgag cctgggcaag 1350 <210> 13 <211> 469 <212> PRT <213> Artificial Sequence <220> <223> FceRIa ECD-hinge-Fc3 <400> 13 Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Ser His Ala Val Pro Gln Lys Pro Lys Val 20 25 30 Ser Leu Asn Pro Pro Trp Asn Arg Ile Phe Lys Gly Glu Asn Val Thr 35 40 45 Leu Thr Cys Asn Gly Asn Asn Phe Phe Glu Val Ser Ser Thr Lys Trp 50 55 60 Phe His Asn Gly Ser Leu Ser Glu Glu Thr Asn Ser Ser Leu Asn Ile 65 70 75 80 Val Asn Ala Lys Phe Glu Asp Ser Gly Glu Tyr Lys Cys Gln His Gln 85 90 95 Gln Val Asn Glu Ser Glu Pro Val Tyr Leu Glu Val Phe Ser Asp Trp 100 105 110 Leu Leu Leu Gln Ala Ser Ala Glu Val Val Met Glu Gly Gln Pro Leu 115 120 125 Phe Leu Arg Cys His Gly Trp Arg Asn Trp Asp Val Tyr Lys Val Ile 130 135 140 Tyr Tyr Lys Asp Gly Glu Ala Leu Lys Tyr Trp Tyr Glu Asn His Asn 145 150 155 160 Ile Ser Ile Thr Asn Ala Thr Val Glu Asp Ser Gly Thr Tyr Tyr Cys 165 170 175 Thr Gly Lys Val Trp Gln Leu Asp Tyr Glu Ser Glu Pro Leu Asn Ile 180 185 190 Thr Val Ile Lys Ala Pro Arg Glu Lys Tyr Trp Leu Gln Ala Gln Pro 195 200 205 Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro Ala Thr Thr 210 215 220 Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Gly Ser Lys Glu Lys 225 230 235 240 Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His 245 250 255 Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 260 265 270 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 275 280 285 Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 290 295 300 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 305 310 315 320 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 325 330 335 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser 340 345 350 Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 355 360 365 Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 370 375 380 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 385 390 395 400 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 405 410 415 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu 420 425 430 Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 435 440 445 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 450 455 460 Leu Ser Leu Gly Lys 465 <210> 14 <211> 1407 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of FceRIa ECD-hinge-Fc3 <400> 14 atggacgcca tgctgagagg cctgtgctgt gtgctgctgc tgtgcggcgc cgtgttcgtg 60 tcccctagcc acgccgtgcc ccagaagccc aaggtgagcc tgaaccctcc ctggaacaga 120 atcttcaagg gcgagaacgt gaccctgacc tgcaacggca acaacttctt cgaggtgagc 180 agcaccaagt ggttccacaa tggcagcctg agcgaggaga ccaacagctc cctgaacatc 240 gtgaacgcca agttcgagga cagcggcgag tacaagtgcc agcaccagca ggtgaacgag 300 agcgagcccg tgtacctgga ggtgttcagc gactggctgc tgctgcaggc cagcgccgag 360 gtggtgatgg agggccagcc cctgttcctg agatgccacg gctggagaaa ctgggacgtg 420 tacaaggtga tctactacaa ggatggcgag gccctgaagt actggtacga gaaccacaac 480 atctccatca ccaacgccac cgtggaggac agcggcacct actactgcac aggcaaggtg 540 tggcagctgg actacgagag cgagcccctg aacatcaccg tgatcaaggc tcccagagag 600 aagtactggc tgcaggccca gccccaggcc gagggcagcc tggctaaggc caccacagct 660 cccgccacca ccaggaacac cggcagagga ggcgaggaaa agaaaggaag caaggagaag 720 gaggagcagg aggaaagaga aaccaagacc cccgagtgcc ccagccacac ccagcccctg 780 ggcgtgttcc tgttcccccc caagcccaag gacaccctga tgatcagcag aacccccgag 840 gtgacctgcg tggtcgtgga tgtgagccag gaagatcccg aagtgcagtt caactggtac 900 gtggatggcg tggaagtgca caacgccaag accaagccca gagaagagca gttcaactcc 960 acctacagag tggtgagcgt gctgaccgtg ctgcaccagg actggctgaa cggcaaggag 1020 tacaagtgca aggtgtccaa caaaggcctg cccagctcca tcgagaagac catcagcaaa 1080 gccaaaggcc agcccagaga accccaggtg tacaccctgc ctcccagcca ggaagagatg 1140 accaagaacc aggtgtccct gacctgcctg gtgaaaggct tctaccccag cgacatcgcc 1200 gtggagtggg aaagcaacgg ccagcccgag aacaattaca agacaacccc tcccgtgctg 1260 gatagcgatg gcagcttctt tctgtacagc agactgaccg tggacaagag cagatggcag 1320 gaaggcaacg tgttcagctg cagcgtgatg cacgaagccc tgcacaacca ctacacccag 1380 aagagcctgt ccctgagcct gggcaag 1407 <210> 15 <211> 406 <212> PRT <213> Artificial Sequence <220> <223> human a-2,6 sialic acid transferase <400> 15 Met Ile His Thr Asn Leu Lys Lys Lys Phe Ser Cys Cys Val Leu Val 1 5 10 15 Phe Leu Leu Phe Ala Val Ile Cys Val Trp Lys Glu Lys Lys Lys Gly 20 25 30 Ser Tyr Tyr Asp Ser Phe Lys Leu Gln Thr Lys Glu Phe Gln Val Leu 35 40 45 Lys Ser Leu Gly Lys Leu Ala Met Gly Ser Asp Ser Gln Ser Val Ser 50 55 60 Ser Ser Ser Thr Gln Asp Pro His Arg Gly Arg Gln Thr Leu Gly Ser 65 70 75 80 Leu Arg Gly Leu Ala Lys Ala Lys Pro Glu Ala Ser Phe Gln Val Trp 85 90 95 Asn Lys Asp Ser Ser Ser Lys Asn Leu Ile Pro Arg Leu Gln Lys Ile 100 105 110 Trp Lys Asn Tyr Leu Ser Met Asn Lys Tyr Lys Val Ser Tyr Lys Gly 115 120 125 Pro Gly Pro Gly Ile Lys Phe Ser Ala Glu Ala Leu Arg Cys His Leu 130 135 140 Arg Asp His Val Asn Val Ser Met Val Glu Val Thr Asp Phe Pro Phe 145 150 155 160 Asn Thr Ser Glu Trp Glu Gly Tyr Leu Pro Lys Glu Ser Ile Arg Thr 165 170 175 Lys Ala Gly Pro Trp Gly Arg Cys Ala Val Val Ser Ser Ala Gly Ser 180 185 190 Leu Lys Ser Ser Gln Leu Gly Arg Glu Ile Asp Asp His Asp Ala Val 195 200 205 Leu Arg Phe Asn Gly Ala Pro Thr Ala Asn Phe Gln Gln Asp Val Gly 210 215 220 Thr Lys Thr Thr Ile Arg Leu Met Asn Ser Gln Leu Val Thr Thr Glu 225 230 235 240 Lys Arg Phe Leu Lys Asp Ser Leu Tyr Asn Glu Gly Ile Leu Ile Val 245 250 255 Trp Asp Pro Ser Val Tyr His Ser Asp Ile Pro Lys Trp Tyr Gln Asn 260 265 270 Pro Asp Tyr Asn Phe Phe Asn Asn Tyr Lys Thr Tyr Arg Lys Leu His 275 280 285 Pro Asn Gln Pro Phe Tyr Ile Leu Lys Pro Gln Met Pro Trp Glu Leu 290 295 300 Trp Asp Ile Leu Gln Glu Ile Ser Pro Glu Glu Ile Gln Pro Asn Pro 305 310 315 320 Pro Ser Ser Gly Met Leu Gly Ile Ile Ile Met Met Thr Leu Cys Asp 325 330 335 Gln Val Asp Ile Tyr Glu Phe Leu Pro Ser Lys Arg Lys Thr Asp Val 340 345 350 Cys Tyr Tyr Tyr Gln Lys Phe Phe Asp Ser Ala Cys Thr Met Gly Ala 355 360 365 Tyr His Pro Leu Leu Tyr Glu Lys Asn Leu Val Lys His Leu Asn Gln 370 375 380 Gly Thr Asp Glu Asp Ile Tyr Leu Leu Gly Lys Ala Thr Leu Pro Gly 385 390 395 400 Phe Arg Thr Ile His Cys 405 <210> 16 <211> 1218 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of human a-2,6 sialic acid transferase <400> 16 atgatccaca ccaacctgaa gaagaagttc agctgctgcg tgctggtgtt cctgctgttc 60 gccgtgatct gcgtgtggaa ggagaagaag aaaggcagct actacgacag cttcaagctg 120 cagaccaagg agttccaggt gctgaagagc ctgggcaagc tggccatggg cagcgacagc 180 cagagcgtgt ccagctcctc cacccaggat ccccacagag gcagacagac cctgggcagc 240 ctgagaggcc tggccaaggc caagcccgag gccagcttcc aggtgtggaa caaggacagc 300 agcagcaaga acctgatccc cagactgcag aagatctgga agaactacct gagcatgaac 360 aagtacaagg tgagctacaa aggacccgga cccggcatca agttcagcgc cgaggccctg 420 aggtgccacc tgagagacca cgtgaacgtg agcatggtgg aagtgaccga cttccccttc 480 aacaccagcg agtgggaagg ctacctgccc aaggagagca tcaggaccaa ggctggcccc 540 tggggcagat gcgccgtggt gagcagcgct ggcagcctga agagctccca gctgggcaga 600 gagatcgacg accacgatgc cgtgctgagg ttcaatggcg ctcccaccgc caacttccag 660 caggacgtgg gcaccaagac cacaatccgg ctgatgaaca gccagctggt gacaaccgag 720 aagcggttcc tgaaggacag cctgtacaac gagggcatcc tgatcgtgtg ggatcccagc 780 gtgtaccaca gcgacatccc caagtggtac cagaatcccg actacaactt cttcaacaac 840 tacaagacct atagaaagct gcaccccaac cagcccttct acatcctgaa gccccagatg 900 ccctgggagc tgtgggacat cctgcaggag atcagccctg aagagatcca gcccaaccct 960 ccctccagcg gcatgctggg cattatcatc atgatgaccc tgtgcgacca ggtggacatc 1020 tacgagttcc tgcccagcaa gagaaagacc gacgtgtgct actactatca gaagttcttc 1080 gacagcgcct gcaccatggg cgcctaccac cccctgctgt acgagaagaa cctggtgaag 1140 cacctgaacc agggcaccga cgaggacatc tacctgctgg gcaaagccac cctgcccggc 1200 ttcagaacca tccactgc 1218 <210> 17 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> IgD hinge variant <400> 17 Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa Xaa Lys Glu Lys 1 5 10 15 Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro 20 25 30 <210> 18 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> IgD hinge variant <400> 18 Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro 1 5 10 15 Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa Xaa 20 25 30 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys 35 40 45 Pro <210> 19 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> IgD hinge <400> 19 Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys 1 5 10 15 Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro 20 25 30 <210> 20 <211> 425 <212> PRT <213> Artificial Sequence <220> <223> FceRIa ECD-hinge-Fc1 <400> 20 Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile 1 5 10 15 Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe 20 25 30 Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu 35 40 45 Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly 50 55 60 Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr 65 70 75 80 Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val 85 90 95 Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn 100 105 110 Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys 115 120 125 Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu 130 135 140 Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr 145 150 155 160 Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys 165 170 175 Tyr Trp Leu Gln Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys 180 185 190 Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu 195 200 205 Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys 210 215 220 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 225 230 235 240 Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 245 250 255 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 260 265 270 Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 275 280 285 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 290 295 300 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 305 310 315 320 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met 325 330 335 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 340 345 350 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 355 360 365 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 370 375 380 Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val 385 390 395 400 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 405 410 415 Lys Ser Leu Ser Leu Ser Leu Gly Lys 420 425 <210> 21 <211> 425 <212> PRT <213> Artificial Sequence <220> <223> FceRIa ECD-hinge-Fc2 <400> 21 Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile 1 5 10 15 Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe 20 25 30 Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu 35 40 45 Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly 50 55 60 Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr 65 70 75 80 Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val 85 90 95 Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn 100 105 110 Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys 115 120 125 Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu 130 135 140 Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr 145 150 155 160 Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys 165 170 175 Tyr Trp Leu Gln Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Gly 180 185 190 Ser Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu 195 200 205 Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys 210 215 220 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 225 230 235 240 Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 245 250 255 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 260 265 270 Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 275 280 285 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 290 295 300 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 305 310 315 320 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met 325 330 335 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 340 345 350 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 355 360 365 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 370 375 380 Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val 385 390 395 400 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 405 410 415 Lys Ser Leu Ser Leu Ser Leu Gly Lys 420 425 <210> 22 <211> 444 <212> PRT <213> Artificial Sequence <220> <223> FceRIa ECD-hinge-Fc3 <400> 22 Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile 1 5 10 15 Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe 20 25 30 Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu 35 40 45 Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly 50 55 60 Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr 65 70 75 80 Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val 85 90 95 Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn 100 105 110 Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys 115 120 125 Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu 130 135 140 Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr 145 150 155 160 Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys 165 170 175 Tyr Trp Leu Gln Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala 180 185 190 Thr Thr Ala Pro Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu 195 200 205 Lys Lys Gly Ser Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys 210 215 220 Thr Pro Glu Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255 Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285 Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 385 390 395 400 Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 <110> PROGEN CO., LTD. <120> PHARMACEUTICAL COMPOSITION COMPRISING RECOMBINANT EXTRACELLULAR DOMAIN OF IgE Fc RECEPTOR SUBUNIT ALPHA <130> FPD / 201901-0002 / c <150> KR 10-2018-0002262 <151> 2018-01-08 <160> 22 <170> Kopatentin 2.0 <210> 1 <211> 180 <212> PRT <213> Artificial Sequence <220> <223> FCeRI1 ECD <400> 1 Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile 1 5 10 15 Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe 20 25 30 Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu 35 40 45 Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly 50 55 60 Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr 65 70 75 80 Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val 85 90 95 Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn 100 105 110 Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys 115 120 125 Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu 130 135 140 Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr 145 150 155 160 Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys 165 170 175 Tyr Trp Leu Gln 180 <210> 2 <211> 215 <212> PRT <213> Artificial Sequence <220> <223> Modified Fc <400> 2 Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys 1 5 10 15 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 20 25 30 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 35 40 45 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 50 55 60 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 65 70 75 80 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 85 90 95 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 100 105 110 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 115 120 125 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 130 135 140 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 145 150 155 160 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 165 170 175 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 180 185 190 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 195 200 205 Leu Ser Leu Ser Leu Gly Lys 210 215 <210> 3 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> IgD hinge variant <400> 3 Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Gly Ser Lys Glu Lys 1 5 10 15 Glu Glu Glu Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro 20 25 30 <210> 4 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> IgD hinge variant <400> 4 Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Ala Pro 1 5 10 15 Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Gly Ser 20 25 30 Lys Glu Lys Glu Glu Glu Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys 35 40 45 Pro <210> 5 <211> 540 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of FCeRI1 ECD <400> 5 gtgccccaga agcccaaggt gagcctgaac cctccctgga acagaatctt caagggcgag 60 aacgtgaccc tgacctgcaa cggcaacaac ttcttcgagg tgagcagcac caagtggttc 120 cacaatggca gcctgagcga ggagaccaac agctccctga acatcgtgaa cgccaagttc 180 gaggacagcg gcgagtacaa gtgccagcac cagcaggtga acgagagcga gcccgtgtac 240 ctggaggtgt tcagcgactg gctgctgctg caggccagcg ccgaggtggt gatggagggc 300 cagcccctgt tcctgagatg ccacggctgg agaaactggg acgtgtacaa ggtgatctac 360 tacaaggatg gcgaggccct gaagtactgg tacgagaacc acaacatctc catcaccaac 420 gccaccgtgg aggacagcgg cacctactac tgcacaggca aggtgtggca gctggactac 480 gagagcgagc ccctgaacat caccgtgatc aaggctccca gagagaagta ctggctgcag 540 540 <210> 6 <211> 561 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of modified Fc <400> 6 tgcgtggtcg tggatgtgag ccaggaagat cccgaagtgc agttcaactg gtacgtggat 60 ggcgtggaag tgcacaacgc caagaccaag cccagagaag agcagttcaa ctccacctac 120 agagtggtga gcgtgctgac cgtgctgcac caggactggc tgaacggcaa ggagtacaag 180 tgcaaggtgt ccaacaaagg cctgcccagc tccatcgaga agaccatcag caaagccaaa 240 ggccagccca gagaacccca ggtgtacacc ctgcctccca gccaggaaga gatgaccaag 300 aaccaggtgt ccctgacctg cctggtgaaa ggcttctacc ccagcgacat cgccgtggag 360 tgggaaagca acggccagcc cgagaacaat tacaagacaa cccctcccgt gctggatagc 420 gatggcagct tctttctgta cagcagactg accgtggaca agagcagatg gcaggaaggc 480 aacgtgttca gctgcagcgt gatgcacgaa gccctgcaca accactacac ccagaagagc 540 ctgtccctga gcctgggcaa g 561 <210> 7 <211> 174 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of IgD hinge variant <400> 7 aggaacaccg gcagaggagg cgaggaaaag aaaggaagca aggagaagga ggagcaggag 60 gaaagagaaa ccaagacccc cgagtgcccc agccacaccc agcccctggg cgtgttcctg 120 ttccccccca agcccaagga caccctgatg atcagcagaa cccccgaggt gacc 174 <210> 8 <211> 231 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of IgD hinge variant <400> 8 gcccagcccc aggccgaggg cagcctggct aaggccacca cagctcccgc caccaccagg 60 aacaccggca gaggaggcga ggaaaagaaa ggaagcaagg agaaggagga gcaggaggaa 120 agagaaacca agacccccga gtgccccagc cacacccagc ccctgggcgt gttcctgttc 180 ccccccaagc ccaaggacac cctgatgatc agcagaaccc ccgaggtgac c 231 <210> 9 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> signal peptide <400> 9 Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Ser Ser Ala 20 25 <210> 10 <211> 75 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of signal peptide <400> 10 atggacgcca tgctgagagg cctgtgctgt gtgctgctgc tgtgcggcgc cgtgttcgtg 60 tcccctagcc acgcc 75 <210> 11 <211> 450 <212> PRT <213> Artificial Sequence <220> <223> FceRIa ECD-hinge-Fc2 <400> 11 Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Ser Ala Val Pro Gln Lys Pro Lys Val 20 25 30 Ser Leu Asn Pro Pro Trp Asn Arg Ile Phe Lys Gly Glu Asn Val Thr 35 40 45 Leu Thr Cys Asn Gly Asn Asn Phe Phe Glu Val Ser Ser Thr Lys Trp 50 55 60 Phe His Asn Gly Ser Leu Ser Glu Glu Thr Asn Ser Ser Leu Asn Ile 65 70 75 80 Val Asn Ala Lys Phe Glu Asp Ser Gly Glu Tyr Lys Cys Gln His Gln 85 90 95 Gln Val Asn Glu Ser Glu Pro Val Tyr Leu Glu Val Phe Ser Asp Trp 100 105 110 Leu Leu Leu Gln Ala Ser Ala Glu Val Val Met Glu Gly Gln Pro Leu 115 120 125 Phe Leu Arg Cys His Gly Trp Arg Asn Trp Asp Val Tyr Lys Val Ile 130 135 140 Tyr Tyr Lys Asp Gly Glu Ala Leu Lys Tyr Trp Tyr Glu Asn His Asn 145 150 155 160 Ile Ser Ile Thr Asn Ala Thr Val Glu Asp Ser Gly Thr Tyr Tyr Cys 165 170 175 Thr Gly Lys Val Trp Gln Leu Asp Tyr Glu Ser Glu Pro Leu Asn Ile 180 185 190 Thr Val Ile Lys Ala Pro Arg Glu Lys Tyr Trp Leu Gln Arg Asn Thr 195 200 205 Gly Arg Gly Gly Glu Glu Lys Lys Gly Ser Lys Glu Lys Glu Glu Gln 210 215 220 Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro 225 230 235 240 Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 260 265 270 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 435 440 445 Gly Lys 450 <210> 12 <211> 1350 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of FceRIa ECD-hinge-Fc2 <400> 12 atggacgcca tgctgagagg cctgtgctgt gtgctgctgc tgtgcggcgc cgtgttcgtg 60 tcccctagcc acgccgtgcc ccagaagccc aaggtgagcc tgaaccctcc ctggaacaga 120 atcttcaagg gcgagaacgt gaccctgacc tgcaacggca acaacttctt cgaggtgagc 180 agcaccaagt ggttccacaa tggcagcctg agcgaggaga ccaacagctc cctgaacatc 240 gtgaacgcca agttcgagga cagcggcgag tacaagtgcc agcaccagca ggtgaacgag 300 agcgagcccg tgtacctgga ggtgttcagc gactggctgc tgctgcaggc cagcgccgag 360 gtggtgatgg agggccagcc cctgttcctg agatgccacg gctggagaaa ctgggacgtg 420 tacaaggtga tctactacaa ggatggcgag gccctgaagt actggtacga gaaccacaac 480 atctccatca ccaacgccac cgtggaggac agcggcacct actactgcac aggcaaggtg 540 tggcagctgg actacgagag cgagcccctg aacatcaccg tgatcaaggc tcccagagag 600 aagtactggc tgcagaggaa caccggcaga ggaggcgagg aaaagaaagg aagcaaggag 660 aaggaggagc aggaggaaag agaaaccaag acccccgagt gccccagcca cacccagccc 720 ctgggcgtgt tcctgttccc ccccaagccc aaggacaccc tgatgatcag cagaaccccc 780 gaggtgacct gcgtggtcgt ggatgtgagc caggaagatc ccgaagtgca gttcaactgg 840 tacgtggatg gcgtggaagt gcacaacgcc aagaccaagc ccagagaaga gcagttcaac 900 tccacctaca gagtggtgag cgtgctgacc gtgctgcacc aggactggct gaacggcaag 960 gagtacaagt gcaaggtgtc caacaaaggc ctgcccagct ccatcgagaa gaccatcagc 1020 aaagccaaag gccagcccag agaaccccag gtgtacaccc tgcctcccag ccaggaagag 1080 atgaccaaga accaggtgtc cctgacctgc ctggtgaaag gcttctaccc cagcgacatc 1140 gccgtggagt gggaaagcaa cggccagccc gagaacaatt acaagacaac ccctcccgtg 1200 ctggatagcg atggcagctt ctttctgtac agcagactga ccgtggacaa gagcagatgg 1260 caggaaggca acgtgttcag ctgcagcgtg atgcacgaag ccctgcacaa ccactacacc 1320 cagaagagcc tgtccctgag cctgggcaag 1350 <210> 13 <211> 469 <212> PRT <213> Artificial Sequence <220> <223> FceRIa ECD-hinge-Fc3 <400> 13 Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Ser Ala Val Pro Gln Lys Pro Lys Val 20 25 30 Ser Leu Asn Pro Pro Trp Asn Arg Ile Phe Lys Gly Glu Asn Val Thr 35 40 45 Leu Thr Cys Asn Gly Asn Asn Phe Phe Glu Val Ser Ser Thr Lys Trp 50 55 60 Phe His Asn Gly Ser Leu Ser Glu Glu Thr Asn Ser Ser Leu Asn Ile 65 70 75 80 Val Asn Ala Lys Phe Glu Asp Ser Gly Glu Tyr Lys Cys Gln His Gln 85 90 95 Gln Val Asn Glu Ser Glu Pro Val Tyr Leu Glu Val Phe Ser Asp Trp 100 105 110 Leu Leu Leu Gln Ala Ser Ala Glu Val Val Met Glu Gly Gln Pro Leu 115 120 125 Phe Leu Arg Cys His Gly Trp Arg Asn Trp Asp Val Tyr Lys Val Ile 130 135 140 Tyr Tyr Lys Asp Gly Glu Ala Leu Lys Tyr Trp Tyr Glu Asn His Asn 145 150 155 160 Ile Ser Ile Thr Asn Ala Thr Val Glu Asp Ser Gly Thr Tyr Tyr Cys 165 170 175 Thr Gly Lys Val Trp Gln Leu Asp Tyr Glu Ser Glu Pro Leu Asn Ile 180 185 190 Thr Val Ile Lys Ala Pro Arg Glu Lys Tyr Trp Leu Gln Ala Gln Pro 195 200 205 Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro Ala Thr Thr 210 215 220 Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Gly Ser Lys Glu Lys 225 230 235 240 Glu Glu Glu Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His 245 250 255 Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 260 265 270 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 275 280 285 Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 290 295 300 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 305 310 315 320 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 325 330 335 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser 340 345 350 Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 355 360 365 Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 370 375 380 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 385 390 395 400 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 405 410 415 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu 420 425 430 Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 435 440 445 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 450 455 460 Leu Ser Leu Gly Lys 465 <210> 14 <211> 1407 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of FceRIa ECD-hinge-Fc3 <400> 14 atggacgcca tgctgagagg cctgtgctgt gtgctgctgc tgtgcggcgc cgtgttcgtg 60 tcccctagcc acgccgtgcc ccagaagccc aaggtgagcc tgaaccctcc ctggaacaga 120 atcttcaagg gcgagaacgt gaccctgacc tgcaacggca acaacttctt cgaggtgagc 180 agcaccaagt ggttccacaa tggcagcctg agcgaggaga ccaacagctc cctgaacatc 240 gtgaacgcca agttcgagga cagcggcgag tacaagtgcc agcaccagca ggtgaacgag 300 agcgagcccg tgtacctgga ggtgttcagc gactggctgc tgctgcaggc cagcgccgag 360 gtggtgatgg agggccagcc cctgttcctg agatgccacg gctggagaaa ctgggacgtg 420 tacaaggtga tctactacaa ggatggcgag gccctgaagt actggtacga gaaccacaac 480 atctccatca ccaacgccac cgtggaggac agcggcacct actactgcac aggcaaggtg 540 tggcagctgg actacgagag cgagcccctg aacatcaccg tgatcaaggc tcccagagag 600 aagtactggc tgcaggccca gccccaggcc gagggcagcc tggctaaggc caccacagct 660 cccgccacca ccaggaacac cggcagagga ggcgaggaaa agaaaggaag caaggagaag 720 gaggagcagg aggaaagaga aaccaagacc cccgagtgcc ccagccacac ccagcccctg 780 ggcgtgttcc tgttcccccc caagcccaag gacaccctga tgatcagcag aacccccgag 840 gtgacctgcg tggtcgtgga tgtgagccag gaagatcccg aagtgcagtt caactggtac 900 gtggatggcg tggaagtgca caacgccaag accaagccca gagaagagca gttcaactcc 960 acctacagag tggtgagcgt gctgaccgtg ctgcaccagg actggctgaa cggcaaggag 1020 tacaagtgca aggtgtccaa caaaggcctg cccagctcca tcgagaagac catcagcaaa 1080 gccaaaggcc agcccagaga accccaggtg tacaccctgc ctcccagcca ggaagagatg 1140 accaagaacc aggtgtccct gacctgcctg gtgaaaggct tctaccccag cgacatcgcc 1200 gtggagtggg aaagcaacgg ccagcccgag aacaattaca agacaacccc tcccgtgctg 1260 gatagcgatg gcagcttctt tctgtacagc agactgaccg tggacaagag cagatggcag 1320 gaaggcaacg tgttcagctg cagcgtgatg cacgaagccc tgcacaacca ctacacccag 1380 aagagcctgt ccctgagcct gggcaag 1407 <210> 15 <211> 406 <212> PRT <213> Artificial Sequence <220> <223> human a-2,6 sialic acid transferase <400> 15 Met Ile His Thr Asn Leu Lys Lys Lys Phe Ser Cys Cys Val Leu Val 1 5 10 15 Phe Leu Leu Phe Ala Val Ile Cys Val Trp Lys Glu Lys Lys Lys Gly 20 25 30 Ser Tyr Tyr Asp Ser Phe Lys Leu Gln Thr Lys Glu Phe Gln Val Leu 35 40 45 Lys Ser Leu Gly Lys Leu Ala Met Gly Ser Asp Ser Gln Ser Ser Ser 50 55 60 Ser Ser Thr Gln Asp Pro His Arg Gly Arg Gln Thr Leu Gly Ser 65 70 75 80 Leu Arg Gly Leu Ala Lys Ala Lys Pro Glu Ala Ser Phe Gln Val Trp 85 90 95 Asn Lys Asp Ser Ser Ser Lys Asn Leu Ile Pro Arg Leu Gln Lys Ile 100 105 110 Trp Lys Asn Tyr Leu Ser Met Asn Lys Tyr Lys Val Ser Tyr Lys Gly 115 120 125 Pro Gly Pro Gly Ile Lys Phe Ser Ala Glu Ala Leu Arg Cys His Leu 130 135 140 Arg Asp His Val Asn Val Ser Met Val Glu Val Thr Asp Phe Pro Phe 145 150 155 160 Asn Thr Ser Glu Trp Glu Gly Tyr Leu Pro Lys Glu Ser Ile Arg Thr 165 170 175 Lys Ala Gly Pro Trp Gly Arg Cys Ala Val Val Ser Ser Ala Gly Ser 180 185 190 Leu Lys Ser Ser Gln Leu Gly Arg Glu Ile Asp Asp His Asp Ala Val 195 200 205 Leu Arg Phe Asn Gly Ala Pro Thr Ala Asn Phe Gln Gln Asp Val Gly 210 215 220 Thr Lys Thr Thr Ile Arg Leu Met Asn Ser Gln Leu Val Thr Thr Glu 225 230 235 240 Lys Arg Phe Leu Lys Asp Ser Leu Tyr Asn Glu Gly Ile Leu Ile Val 245 250 255 Trp Asp Pro Ser Val Tyr His Ser Asp Ile Pro Lys Trp Tyr Gln Asn 260 265 270 Pro Asp Tyr Asn Phe Phe Asn Asn Tyr Lys Thr Tyr Arg Lys Leu His 275 280 285 Pro Asn Gln Pro Phe Tyr Ile Leu Lys Pro Gln Met Pro Trp Glu Leu 290 295 300 Trp Asp Ile Leu Gln Glu Ile Ser Pro Glu Glu Ile Gln Pro Asn Pro 305 310 315 320 Pro Ser Ser Gly Met Leu Gly Ile Ile Ile Met Met Thr Leu Cys Asp 325 330 335 Gln Val Asp Ile Tyr Glu Phe Leu Pro Ser Lys Arg Lys Thr Asp Val 340 345 350 Cys Tyr Tyr Tyr Gln Lys Phe Phe Asp Ser Ala Cys Thr Met Gly Ala 355 360 365 Tyr His Pro Leu Leu Tyr Glu Lys Asn Leu Val Lys His Leu Asn Gln 370 375 380 Gly Thr Asp Glu Asp Ile Tyr Leu Leu Gly Lys Ala Thr Leu Pro Gly 385 390 395 400 Phe Arg Thr Ile His Cys 405 <210> 16 <211> 1218 <212> DNA <213> Artificial Sequence <220> <223> nucleotides sequence of human a-2,6 sialic acid transferase <400> 16 atgatccaca ccaacctgaa gaagaagttc agctgctgcg tgctggtgtt cctgctgttc 60 gccgtgatct gcgtgtggaa ggagaagaag aaaggcagct actacgacag cttcaagctg 120 cagaccaagg agttccaggt gctgaagagc ctgggcaagc tggccatggg cagcgacagc 180 cagagcgtgt ccagctcctc cacccaggat ccccacagag gcagacagac cctgggcagc 240 ctgagaggcc tggccaaggc caagcccgag gccagcttcc aggtgtggaa caaggacagc 300 agcagcaaga acctgatccc cagactgcag aagatctgga agaactacct gagcatgaac 360 aagtacaagg tgagctacaa aggacccgga cccggcatca agttcagcgc cgaggccctg 420 aggtgccacc tgagagacca cgtgaacgtg agcatggtgg aagtgaccga cttccccttc 480 aacaccagcg agtgggaagg ctacctgccc aaggagagca tcaggaccaa ggctggcccc 540 tggggcagat gcgccgtggt gagcagcgct ggcagcctga agagctccca gctgggcaga 600 gagatcgacg accacgatgc cgtgctgagg ttcaatggcg ctcccaccgc caacttccag 660 caggacgtgg gcaccaagac cacaatccgg ctgatgaaca gccagctggt gacaaccgag 720 aagcggttcc tgaaggacag cctgtacaac gagggcatcc tgatcgtgtg ggatcccagc 780 gtgtaccaca gcgacatccc caagtggtac cagaatcccg actacaactt cttcaacaac 840 tacaagacct atagaaagct gcaccccaac cagcccttct acatcctgaa gccccagatg 900 ccctgggagc tgtgggacat cctgcaggag atcagccctg aagagatcca gcccaaccct 960 ccctccagcg gcatgctggg cattatcatc atgatgaccc tgtgcgacca ggtggacatc 1020 tacgagttcc tgcccagcaa gagaaagacc gacgtgtgct actactatca gaagttcttc 1080 gacagcgcct gcaccatggg cgcctaccac cccctgctgt acgagaagaa cctggtgaag 1140 cacctgaacc agggcaccga cgaggacatc tacctgctgg gcaaagccac cctgcccggc 1200 ttcagaacca tccactgc 1218 <210> 17 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> IgD hinge variant <400> 17 Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa Xaa Lys Glu Lys 1 5 10 15 Glu Glu Glu Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro 20 25 30 <210> 18 <211> 49 <212> PRT <213> Artificial Sequence <220> <223> IgD hinge variant <400> 18 Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Ala Pro 1 5 10 15 Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa Xaa 20 25 30 Lys Glu Lys Glu Glu Glu Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys 35 40 45 Pro <210> 19 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> IgD hinge <400> 19 Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys 1 5 10 15 Glu Glu Glu Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro 20 25 30 <210> 20 <211> 425 <212> PRT <213> Artificial Sequence <220> <223> FceRIa ECD-hinge-Fc1 <400> 20 Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile 1 5 10 15 Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe 20 25 30 Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu 35 40 45 Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly 50 55 60 Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr 65 70 75 80 Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val 85 90 95 Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn 100 105 110 Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys 115 120 125 Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu 130 135 140 Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr 145 150 155 160 Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys 165 170 175 Tyr Trp Leu Gln Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys 180 185 190 Glu Lys Glu Lys Glu Glu Glu Glu Glu Arg Glu Thr Lys Thr Pro Glu 195 200 205 Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys 210 215 220 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 225 230 235 240 Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 245 250 255 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 260 265 270 Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 275 280 285 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 290 295 300 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 305 310 315 320 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met 325 330 335 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 340 345 350 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 355 360 365 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 370 375 380 Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val 385 390 395 400 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 405 410 415 Lys Ser Leu Ser Leu Ser Leu Gly Lys 420 425 <210> 21 <211> 425 <212> PRT <213> Artificial Sequence <220> <223> FceRIa ECD-hinge-Fc2 <400> 21 Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile 1 5 10 15 Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe 20 25 30 Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu 35 40 45 Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly 50 55 60 Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr 65 70 75 80 Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val 85 90 95 Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn 100 105 110 Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys 115 120 125 Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu 130 135 140 Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr 145 150 155 160 Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys 165 170 175 Tyr Trp Leu Gln Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Gly 180 185 190 Ser Lys Glu Lys Glu Glu Glu Glu Glu Arg Glu Thr Lys Thr Pro Glu 195 200 205 Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys 210 215 220 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 225 230 235 240 Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 245 250 255 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 260 265 270 Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 275 280 285 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 290 295 300 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 305 310 315 320 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met 325 330 335 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 340 345 350 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 355 360 365 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 370 375 380 Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val 385 390 395 400 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 405 410 415 Lys Ser Leu Ser Leu Ser Leu Gly Lys 420 425 <210> 22 <211> 444 <212> PRT <213> Artificial Sequence <220> <223> FceRIa ECD-hinge-Fc3 <400> 22 Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile 1 5 10 15 Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe 20 25 30 Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu 35 40 45 Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly 50 55 60 Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr 65 70 75 80 Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val 85 90 95 Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn 100 105 110 Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys 115 120 125 Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu 130 135 140 Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr 145 150 155 160 Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys 165 170 175 Tyr Trp Leu Gln Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala 180 185 190 Thr Ala Pro Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu 195 200 205 Lys Lys Gly Ser Lys Glu Lys Glu Glu Glu Glu Glu Arg Glu Thr Lys 210 215 220 Thr Pro Glu Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255 Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285 Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 385 390 395 400 Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440
Claims (11)
상기 단량체는 변형된 Fc 영역을 포함하며,
상기 변형된 Fc 영역과 FcεRIa-ECD는 힌지를 통해 결합된, 약학적 조성물.A pharmaceutical composition for treating or preventing an allergic disease comprising as an active ingredient a polypeptide dimer comprising two monomers comprising an extracellular domain of an alpha subunit of an IgE Fc receptor (Fc? RIA-ECD)
Wherein the monomer comprises a modified Fc region,
Wherein said modified Fc region and Fc < RTI ID = 0.0 > RIa-ECD < / RTI > are joined via a hinge.
상기 IgE Fc 수용체의 알파 서브유닛의 세포외 도메인은 서열번호 1의 아미노산 서열 또는 이의 단편인, 약학적 조성물.The method according to claim 1,
Wherein the extracellular domain of the alpha subunit of the IgE Fc receptor is the amino acid sequence of SEQ ID NO: 1 or a fragment thereof.
상기 변형된 Fc 영역은 서열번호 2인, 약학적 조성물.The method according to claim 1,
Wherein the modified Fc region is SEQ ID NO: 2.
상기 힌지는 면역글로불린 IgD에서 유래한 힌지 영역 또는 이의 변이체인 것인, 약학적 조성물.The method according to claim 1,
Wherein the hinge is a hinge region derived from immunoglobulin IgD or a variant thereof.
상기 면역글로불린 IgD에서 유래한 힌지 영역 또는 이의 변이체는 적어도 하나의 시스테인을 포함하는, 약학적 조성물.5. The method of claim 4,
Wherein the immunoglobulin IgD-derived hinge region or variant thereof comprises at least one cysteine.
상기 면역글로불린 IgD에서 유래한 힌지 영역 또는 이의 변이체는
Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa1 Xaa2 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro (서열번호 17)이며,
Xaa1은 Lys 또는 Gly 이며,
Xaa2는 Glu, Gly또는 Ser인, 약학적 조성물.5. The method of claim 4,
The immunoglobulin IgD-derived hinge region or variant thereof
Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa1 Xaa2 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro (SEQ ID NO: 17)
Xaa1 is Lys or Gly,
Xaa2 is Glu, Gly or Ser.
상기 면역글로불린 IgD에서 유래한 힌지 영역 또는 이의 변이체는
Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa3 Xaa4 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro (서열번호 18)이며,
Xaa1은 Lys 또는 Gly 이며,
Xaa2는 Glu, Gly 또는 Ser인, 약학적 조성물.5. The method of claim 4,
The immunoglobulin IgD-derived hinge region or variant thereof
Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa3 Xaa4 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro ( SEQ ID NO: 18)
Xaa1 is Lys or Gly,
Xaa2 is Glu, Gly or Ser.
상기 힌지는 서열번호 서열번호 3, 서열번호 4 및 서열번호 19에서 선택되는 어느 하나의 아미노산 서열을 갖는, 약학적 조성물.The method according to claim 1,
Wherein the hinge has an amino acid sequence selected from SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 19.
상기 알러지성 질환은 식품 알러지, 아토피 피부염(atopic dermatitis), 천식(asthma), 알러지성 비염(allergic rhinitis), 알러지성 결막염(allergic conjunctivitis), 알러지성 피부염(allergic dermatitis), 만성 특발성 두드러기(Chronic idiopathic urticarial), 및 알러지성 접촉성 피부염(allergic contact dermatitis)으로 구성된 군에서 선택된 하나인 것을 특징으로 하는, 약학적 조성물.The method according to claim 1,
The allergic disease may be selected from food allergies, atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, chronic idiopathic urticarial, and allergic contact dermatitis. < RTI ID = 0.0 > 21. < / RTI >
상기 단량체는 변형된 Fc 영역을 포함하며,
상기 변형된 Fc 영역과 FcεRIa-ECD는 힌지를 통해 결합된, 식품 조성물.1. A food composition for improving and alleviating an allergic symptom comprising as an active ingredient a polypeptide dimer comprising two monomers comprising an extracellular domain of an alpha subunit of an IgE Fc receptor (Fc? RIa-ECD)
Wherein the monomer comprises a modified Fc region,
Wherein the modified Fc region and the Fc [epsilon] RIA-ECD are joined through a hinge.
2) 폴리펩티드 이량체를 회수하는 단계를 통해 수득된,
IgE Fc 수용체의 알파 서브유닛의 세포외 도메인(FcεRIa-ECD)을 포함하는 단량체 두 개를 포함하는 폴리펩티드 이량체를 유효성분으로 포함하는 알러지성 질환 치료용 또는 예방용 약학적 조성물로서,
상기 단량체는 변형된 Fc 영역을 포함하며,
상기 변형된 Fc 영역과 FcεRIa-ECD는 힌지를 통해 결합된, 약학적 조성물.1) culturing a cell into which a polynucleotide encoding a polypeptide monomer and a sialic acid transferase gene have been introduced; And
2) recovering the polypeptide dimer,
A pharmaceutical composition for treating or preventing an allergic disease comprising as an active ingredient a polypeptide dimer comprising two monomers comprising an extracellular domain of an alpha subunit of an IgE Fc receptor (Fc? RIA-ECD)
Wherein the monomer comprises a modified Fc region,
Wherein said modified Fc region and Fc < RTI ID = 0.0 > RIa-ECD < / RTI > are joined via a hinge.
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KR20210006293A (en) * | 2019-07-08 | 2021-01-18 | (주)지아이이노베이션 | POLYPEPTIDE DIMER COMPRISING EXTRACELLULAR DOMAIN OF ALPHA SUBUNIT OF IgE Fc RECEPTOR WITH HIGH CONTENT OF SIALIC ACID AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME |
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