KR101718509B1 - Antibody of specific binding to HA protein of influenza viruses - Google Patents
Antibody of specific binding to HA protein of influenza viruses Download PDFInfo
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- KR101718509B1 KR101718509B1 KR1020120052732A KR20120052732A KR101718509B1 KR 101718509 B1 KR101718509 B1 KR 101718509B1 KR 1020120052732 A KR1020120052732 A KR 1020120052732A KR 20120052732 A KR20120052732 A KR 20120052732A KR 101718509 B1 KR101718509 B1 KR 101718509B1
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Abstract
본 발명은 신종 인플루엔자 바이러스에 특이적으로 결합하는 결합 분자에 관한 것으로, 본 발명의 신종 인플루엔자 바이러스에 특이적인 결합 분자는 신종 인플루엔자 바이러스 유래 질환의 예방 및 치료에 유용하며, 본 발명의 결합 분자를 이용하여 신종 인플루엔자 바이러스의 진단에도 유용하게 이용될 수 있다.The present invention relates to a binding molecule specifically binding to a swine influenza virus. The binding molecule specific to the swine influenza virus of the present invention is useful for the prevention and treatment of a disease derived from a swine influenza virus, And can be used to diagnose a new influenza virus.
Description
본 발명은 신종 인플루엔자 바이러스 HA 단백질에 대하여 특이적으로 결합하는 항체에 관한 것이다.
The present invention relates to an antibody that specifically binds to a swine influenza virus HA protein.
인플루엔자의 원인바이러스는 Orthomyxoviridae 패밀리에 속하는 단일 가닥 RNA (ssRNA) 바이러스이다. 인플루엔자 바이러스는 통상 A, B, C형으로 구분한다. A 형 인플루엔자는 사람뿐만 아니라 조류 및 돼지도 감염시킨다. C형 인플루엔자는 사람에서 경미한 질병만 일으킨다. A형 인플루엔자는 다시 표면항원인 헤마글루타닌 (H) 항원과 뉴라미다아제 (N) 항원에 의해 아형이 결정된다. H 항원은 H1-H16까지 알려져 있으며, N 항원은 N1-N9까지 알려져 있다. A형 인플루엔자의 유전자는 8개의 유전자 조각으로 구성되어 있으며, 이러한 이유로 유전자 재조합이 일어날 수 있다.The causative virus of influenza is Orthomyxoviridae Family < / RTI > RNA (ssRNA) virus. Influenza viruses are usually divided into A, B, and C types. Influenza A virus infects not only humans but also birds and swine. Influenza C causes only mild illness in humans. Influenza A is subtyped again by surface antigens hemagglutanin (H) and neuramidase (N) antigens. H antigens are known to H1-H16, and N antigens are known to N1-N9. The gene for type A influenza is composed of 8 gene fragments, and for this reason, genetic recombination can occur.
조류 인플루엔자 바이러스나 돼지 인플루엔자 바이러스는 사람을 잘 감염시키지 못하며, 그 이유는 종간 장벽이 있기 때문이다. 하지만 드물게 종간 장벽을 넘어서는 감염병이 발생하기도 하는데, 1976년 미국의 뉴저지주에서 돼지 인플루엔자 (H1N1)가 일으킨 감염사례가 발생하였다. 모두 13명의 감염환자가 발생하였으며 이 중 1명이 사망하였다. 1997년 홍콩에서는 조류 인플루엔자 H5N1가 일으킨 감염병이 발생하였으며, H5N1 인플루엔자 바이러스에 의한 감염은 현재까지도 산발적으로 발생하고 있다. 2009년 6월 1일까지 세계적으로 모두 432명의 조류 인플루엔자 환자가 발생하였으며 이중 262명 (60%)이 사망하였다.Avian influenza viruses and swine influenza viruses do not infect humans well because of interspecies barriers. However, in rare cases infectious diseases exceed species barriers. In 1976, a case of infection with swine influenza (H1N1) occurred in New Jersey, USA. There were 13 infected patients and one of them died. In 1997 in Hong Kong, an infectious disease caused by avian influenza H5N1 occurred, and infection by the H5N1 influenza virus is still sporadic. By June 1, 2009, there were 432 cases of avian influenza in all over the world, of which 262 (60%) died.
신종 인플루엔자[A(H1N1)pdm09]의 원인 미생물은 인플루엔자 A H1N1임이 밝혀졌다. 하지만 신종 인플루엔자[A(H1N1)pdm09]의 원인 바이러스는 계절 인플루엔자를 일으켰던 인플루엔자 A (H1N1)과 달리 돼지로부터 기인한 것임이 밝혀져서 S-OIV (돼지 기원 인플루엔자 바이러스)로 불리게 되었으며, 다시 A(H1N1)pdm09 바이러스로 이름이 바뀌게 되었다. 분자 생물학적 연구 결과 A(H1N1)pdm09 바이러스는 4가지 인플루엔자 바이러스 유전자가 재조합된 것임이 밝혀졌다. 4가지 인플루엔자 바이러스는 각각 북아메리카 돼지 인플루엔자 바이러스, 북아메리카 조류 인플루엔자 바이러스, 사람 인플루엔자 바이러스, 유라시아 돼지 인플루엔자 바이러스이다.Influenza A H1N1 has been identified as the causative microorganism of the new influenza A (H1N1) pdm09. However, unlike Influenza A (H1N1), which caused seasonal influenza, it became known that the causative virus of swine influenza [A (H1N1) pdm09] was caused by pigs and became known as S-OIV (swine influenza virus) ) The name changed to pdm09 virus. Molecular biology research has shown that the A (H1N1) pdm09 virus is a recombination of four influenza virus genes. The four influenza viruses are the North American swine influenza virus, the North American avian influenza virus, the human influenza virus and the Eurasian swine influenza virus, respectively.
현재 인플루엔자 바이러스 진단 방법은 바이러스 배양이며, 시기를 잘 맞추어 배양하면 진단의 민감도도 좋다고 알려져 있다(Reina, 1997). 그러나 바이러스 배양법은 실험실적으로 비용이 많이 들고 실험실까지의 바이러스의 배송과 확진까지 많은 시간이 소요되는 단점이 있다.Currently, the influenza virus diagnosis method is viral culture, and it is known that the sensitivity of the diagnosis is good when the culture is well matched (Reina, 1997). However, the virus culture method has a disadvantage in that it is costly in terms of experimental results, and it takes much time to deliver and confirm the virus to the laboratory.
상용화된 신속진단 시약으로는 인체용의 경우, A 항원형 및 B 항원형 동시 검출 키트가 있으며 동물용의 경우에는 A 항원형만 검출하는 키트가 있다. 그러나, 현재 상용화된 인플루엔자 신속 진단 키트는 최근 유행하고 있는 신종 인플루엔자[A(H1N1)pdm09] 바이러스와 계절형 독감을 구별할 수 없는 단점이 있다. 현재 신종 인플루엔자[A(H1N1)pdm09] 바이러스와 계절형 독감을 구별할 수 있는 방법은 RT-PCR(real time polymerase chain reaction)법으로 많은 병원에서 신종인플루엔자[A(H1N1)pdm09] 바이러스 확진 검사로 사용되고 있으나 고가의 장비와 높은 기술력을 요해 사용 편리성이 떨어지는 단점이 있다.
As a commercialized rapid diagnosis reagent, there is a simultaneous detection kit of A-type circular and B-type rounds for human body, and a kit for detecting only A-type rounds in case of animals. However, the current commercialized influenza rapid diagnostic kit has a disadvantage that it can not distinguish the seasonal flu from the swine flu [A (H1N1) pdm09] virus which is currently popular. The current method for distinguishing between seasonal influenza and the new influenza A (H1N1) pdm09 virus is the real-time polymerase chain reaction (RT-PCR) However, it has expensive equipment and high technical power, which makes it less convenient to use.
본 발명은 신종 인플루엔자 바이러스에 대하여 특이적으로 결합하는 결합분자를 제공하는 것을 목적으로 한다.
It is an object of the present invention to provide a binding molecule specifically binding to a swine influenza virus.
본 발명은 신종 인플루엔자 바이러스의 HA 단백질에 특이적으로 결합하는 결합 분자에 있어서, 상기 결합 분자가 결합하는 에피토프는 HA 단백질의 아미노산 서열 중 G56, G172 P176 또는 K180 중 적어도 하나를 포함하는 결합 분자를 제공한다. 본 발명의 일 실시예에 있어서, 상기 에피토프는 서열번호 1 내지 서열번호 3 중 하나이고, 본 발명의 일 실시예에 있어서, 상기 HA 단백질은 서열번호 4이다.The present invention relates to a binding molecule specifically binding to a HA protein of a swine influenza virus, wherein an epitope to which the binding molecule binds comprises a binding molecule comprising at least one of G56, G172 P176 or K180 in the amino acid sequence of the HA protein do. In one embodiment of the present invention, the epitope is one of SEQ ID NO: 1 to SEQ ID NO: 3, and in one embodiment of the present invention, the HA protein is SEQ ID NO: 4.
본 발명의 일 실시예에 있어서, 결합 분자가 결합하는 에피토프는 HA 단백질의 아미노산 서열 중 G56, G172 P176 또는 K180 중 적어도 하나를 포함하는 신종 인플루엔자 바이러스의 HA 단백질에 특이적으로 결합하는 결합 분자; 및 신종 인플루엔자 바이러스 치료제를 포함하는 항체-약물 접합체를 제공하고, 본 발명의 일 실시예에 있어서, 상기 에피토프는 서열번호 1 내지 서열번호 3 중 하나를 포함하며, 본 발명의 일 실시예에 있어서, 상기 HA 단백질은 서열번호 4이다.In one embodiment of the present invention, the epitope to which the binding molecule binds is a binding molecule that specifically binds to the HA protein of the swine influenza virus comprising at least one of G56, G172 P176 or K180 in the amino acid sequence of the HA protein; And an antibody-drug conjugate comprising a novel influenza virus therapeutic agent. In one embodiment of the present invention, the epitope comprises one of SEQ ID NOS: 1 to 3, and in one embodiment of the present invention, The HA protein is SEQ ID NO: 4.
본 발명의 일 실시예에 있어서, 상기의 결합 분자를 코딩하는 유전자를 포함하는 벡터를 제공한다.In one embodiment of the present invention, there is provided a vector comprising a gene encoding said binding molecule.
본 발명의 일 실시예에 있어서, 상기의 벡터를 포함하는 세포주를 제공하고, 본 발명의 일 실시예에 있어서, 상기 세포주는 F2N, HEK293, CHOK1, DG44, DXB11, CHO-S, BHK, Sp2/0, 또는 NS이다.In one embodiment of the present invention, there is provided a cell line comprising the vector, wherein the cell line is selected from the group consisting of F2N, HEK293, CHOK1, DG44, DXB11, CHO-S, BHK, Sp2 / 0, or NS.
본 발명의 일 실시예에 있어서, 상기의 벡터를 세포주에 형질 감염시켜 결합 분자를 생산하는 방법을 제공하고, 본 발명의 일 실시예에 있어서, 상기 세포주는 F2N, HEK293, CHOK1, DG44, DXB11, CHO-S, BHK, Sp2/0, 또는 NS이다.In one embodiment of the present invention, there is provided a method for producing a binding molecule by transfecting the vector into a cell line, wherein the cell line is selected from the group consisting of F2N, HEK293, CHOK1, DG44, DXB11, CHO-S, BHK, Sp2 / 0, or NS.
본 발명의 일 실시예에 있어서, 상기의 결합분자를 포함하는 신종 인플루엔자 바이러스 예방 또는 치료용 조성물을 제공하고, 본 발명의 일 실시예에 있어서, 상기 예방 또는 치료용 조성물은 0.001~100 mg/kg을 투여하며, 본 발명의 일 실시예에 있어서, 상기 예방 또는 치료용 조성물은 쥐, 개, 돼지, 소, 말, 토끼, 라마 또는 페렛용이고, 본 발명의 일 실시예에 있어서, 상기 예방 또는 치료용 조성물은 경구형 제형, 외용제, 사전 충전식 주사(pre-filled syringe)용액제, 좌제, 멸균 주사용액 또는 동결건조(lyophilized)된 형태이다.In one embodiment of the present invention, there is provided a composition for the prevention or treatment of swine influenza virus comprising the above-mentioned binding molecule. In one embodiment of the present invention, the composition for prevention or treatment comprises 0.001 to 100 mg / kg In one embodiment of the present invention, the composition for preventing or treating is for a mouse, a dog, a pig, a cattle, a horse, a rabbit, a llama or a pellet. In one embodiment of the present invention, The therapeutic composition may be in the form of an oral preparation, an external preparation, a pre-filled syringe solution, a suppository, a sterilized injection solution or a lyophilized form.
본 발명의 일 실시예에 있어서, 상기의 결합분자를 목적하는 시료와 반응시키는 과정을 포함하는 신종 인플루엔자 바이러스의 존재 여부에 관한 정보제공 방법을 제공한다.In one embodiment of the present invention, there is provided a method for providing information on the presence or absence of a novel influenza virus, comprising the step of reacting the binding molecule with a target sample.
본 발명의 일 실시예에 있어서, 상기의 결합분자를 포함하는 신종 인플루엔자 바이러스의 진단 키트를 제공한다.
In one embodiment of the present invention, there is provided a diagnostic kit for a novel influenza virus comprising the binding molecule.
항체의 역가는, 인플루엔자바이러스의 면역 및 감염에 의해 생성된 인플루엔자바이러스의 HA 단백질의 헤드 부분인 HA1에 대한 항체들이 인플루엔자바이러스와 적혈구 사이에 헤마글루티네이션 (hemagglutination)을 저해하는 작용을 하는데, 이러한 항체의 헤마글루티네이션 저해 효과를 이용하여 측정한다.Antibody titers, antibodies against HA1, the head part of the HA protein of influenza viruses produced by the immunization and infection of influenza virus, act to inhibit hemagglutination between influenza virus and red blood cells, And measuring the hemagglutination inhibitory effect of the antibody.
회피 변이는, 헤마글루티네이션 저해 능력을 갖는 단일 클론 항체를 제작 시 사용된 인플루엔자 바이러스를 단일 클론 항체와 공배양하면, 단일 클론 항체의 저해를 피해 생존하는 변이체 인플루엔자바이러스가 생기는데, 이러한 바이러스는 주로 단일 클론 항체가 작용하는 인플루엔자바이러스 표면항원에 변이를 갖게 되어 단일 클론 항체의 작용을 회피한다고 하여 회피 변이라 한다. 이렇게 밝혀진 회피 돌연변이는 단일 클론 항체가 작용하는 에피토프에 발생하게 되므로 에피토프의 위치 결정에 이용될 수 있다. Avoidance mutation is caused by co-culturing the influenza virus used in the production of a monoclonal antibody having hemagglutination inhibiting ability with a monoclonal antibody, resulting in the surviving mutant influenza virus, which prevents the inhibition of the monoclonal antibody. It is said to avoid the action of the monoclonal antibody because it has a mutation on the surface antigen of the influenza virus on which the monoclonal antibody acts. This avoidance mutation can be used to locate an epitope because it occurs in an epitope on which a monoclonal antibody acts.
본 발명에서 사용하는 형질 전황 방법은 당업계에 공지된 방법, 예를 들어 이에 한정되지는 않으나, CaCl2 완충액을 사용한 컴피턴트 세포를 만든 후 열충격(42℃) 방법에 의해 발현벡터를 숙주세포 내로 넣는 방법, 전기 충격에 의한 형질전환 방법, 일시적 형질감염(transient transfection), 미세주사, 세포융합, 칼슘 포스페이트 침전법, 전기침공법(electroporation) 등에 의해 숙주 세포 내로 도입할 수 있다.The transforming growth method used in the present invention can be carried out by a method known in the art, for example, but not limited to, by making a competent cell using CaCl 2 buffer, and then introducing the expression vector into a host cell The transfection may be introduced into the host cell by transfection, transfection, transient transfection, microinjection, cell fusion, calcium phosphate precipitation, electroporation, or the like.
본 발명에서 사용하는 신종 인플루엔자 치료제는, 이에 제한되는 것은 아니나, 타미플루 또는 리렌자일 수 있다.
The novel influenza therapeutic agent used in the present invention may be, but is not limited to, Tamiflu or Relenza.
본 발명의 항체는 신종 인플루엔자 바이러스의 HA 단백질에 대하여 특이적으로 결합하므로, 상기 신종 인플루엔자 바이러스의 치료 및 감염 여부를 진단하는 방법으로 유용하다.
Since the antibody of the present invention specifically binds to the HA protein of the swine influenza virus, it is useful as a method for diagnosing treatment and infection of the influenza virus.
도 1 A)는 본 발명의 일 실시예에 따른 결합 분자 mAbD383의 ELISA 실험 결과, 도 1 B)는 본 발명의 일 실시예에 따른 결합 분자 mAbI38의 ELISA 실험 결과이다.
도 2는 본 발명의 일 실시예에 따른 결합 분자 mAbD383 및 mAbI38의 면역형광어세이 결과이다.
도 3은 본 발명의 일 실시예에 따른 결합 분자 mAbD383 및 mAbI38의 각종 바이러스에 대한 결합 여부를 확인하기 위한 면역형광 염색법에 따른 결과이다.
도 4는 본 발명의 일 실시예에 따른 결합 분자 mAbD383 및 mAbI38가 결합하는 항원의 에피토프이다.FIG. 1A) shows ELISA results of a binding molecule mAbI383 according to an embodiment of the present invention, and FIG. 1B shows ELISA results of a binding molecule mAbI38 according to an embodiment of the present invention.
2 is a result of immunofluorescence analysis of binding molecules mAbD383 and mAbI38 according to an embodiment of the present invention.
FIG. 3 shows results of immunofluorescence staining for confirming binding of the binding molecules mAbD383 and mAbI38 to various viruses according to an embodiment of the present invention.
4 is an epitope of an antigen to which the binding molecule mAbD383 and mAbI38 bind according to an embodiment of the present invention.
이하 본 발명의 단어를 다음과 같이 정의한다.
Hereinafter, the word of the present invention will be defined as follows.
본 발명에서 사용되는 "헤마글루티닌 (hemaggutinin, 이하 "HA"라 칭함)"은 인플루엔자 바이러스의 외피 (envelope) 당단백질을 나타낸다. HA는 인플루엔자 바이러스가 숙주 세포에 흡착하여 관통하는 것을 매개한다. 현재까지 16 종류의 서브타입이 보고되어 있다. As used herein, "hemagglutinin (HA)" refers to the envelope glycoprotein of influenza virus. HA mediates the passage of influenza virus through the host cell. So far 16 types of subtypes have been reported.
본 발명에서 사용되는 “결합 분자”는 키메라, 인간화 또는 인간 단일클론 항체와 같은 단일클론 항체를 포함하는 온전한(intact) 이뮤노글로블린(immunoglobulin), 또는 항원에 결합하는 이뮤노글로믈린, 예를 들면 인플루엔자 A 바이러스의 단량체 HA 또는 삼량체 HA와의 결합을 위해 온전한(intact) 이뮤노글로블린과 경쟁하는 이뮤노글로블린 단편을 포함하는 가변성 도메인 또는 기질과 결합 가능한 효소, 수용체, 단백질을 뜻한다. 구조와는 상관없이 항원-결합 단편은 온전한(intact) 이뮤노글로블린에 의해 인식된 동일한 항원과 결합된다. 항원-결합 단편은 결합 분자의 아미노산 서열의 2개 이상의 연속기, 20개 이상의 연속 아미노산 잔기, 25개 이상의 연속 아미노산 잔기, 30개 이상의 연속 아미노산 잔기, 35개 이상의 연속 아미노산 잔기, 40개 이상의 연속 아미노산 잔기, 50개 이상의 연속 아미노산 잔기, 60개 이상의 연속 아미노산 잔기, 70개 이상의 연속 아미노산 잔기, 80개 이상의 연속 아미노산 잔기, 90개 이상의 연속 아미노산 잔기, 100개 이상의 연속 아미노산 잔기, 125개 이상의 연속 아미노산 잔기, 150개 이상의 연속 아미노산 잔기, 175개 이상 연속 아미노산 잔기, 200개 이상의 연속 아미노산 잔기, 또는 250개 이상의 연속 아미노산 잔기의 아미노산 서열을 포함하는 펩티드 또는 폴리펩티드를 포함할 수 있다. “항원-결합 단편”은 특히 Fab, F(ab') F(ab')2, Fv, dAb, Fd, 상보성 결정 영역(CDR) 단편, 단일-쇄 항체(scFv), 2가(bivalent) 단일-쇄 항체, 단일-쇄 파지 항체, 디아바디(diabody), 트리아바디, 테트라바디, 폴리펩티드로의 특정 항원에 결합하기에 충분한 이뮤노글로브린의 하나 이상의 단편을 함유하는 폴리펩티드 등을 포함한다. 상기 단편은 합성으로 또는 완전한 이뮤노글로블린의 효소적 또는 화학적 분해에 의해 생성되거나, 재조합 DNA 기술에 의해 유전공학적으로 생성될 수 있다. 생성 방법은 당업계에 잘 알려져 있다. Binding molecule " as used herein refers to an intact immunoglobulin comprising a monoclonal antibody, such as a chimeric, humanized or human monoclonal antibody, or an immunoglobulin that binds to an antigen, for example, Receptor or protein capable of binding to a variable domain or substrate comprising an immunoglobulin fragment competing with intact immunoglobulin for binding to influenza A virus monomer HA or trimer HA. Regardless of structure, the antigen-binding fragments bind to the same antigen recognized by the intact immunoglobulin. The antigen-binding fragment may comprise two or more contiguous amino acid sequences of the binding molecule, at least 20 contiguous amino acid residues, at least 25 contiguous amino acid residues, at least 30 contiguous amino acid residues, at least 35 contiguous amino acid residues, , At least 50 contiguous amino acid residues, at least 60 contiguous amino acid residues, at least 70 contiguous amino acid residues, at least 80 contiguous amino acid residues, at least 90 contiguous amino acid residues, at least 100 contiguous amino acid residues, A peptide or polypeptide comprising an amino acid sequence of at least 150 consecutive amino acid residues, at least 175 consecutive amino acid residues, at least 200 consecutive amino acid residues, or at least 250 consecutive amino acid residues. &Quot; Antigen-binding fragments " specifically include Fab, F (ab ') F (ab') 2 , Fv, dAb, Fd, complementarity determining region (CDR) fragments, single- A polypeptide containing one or more fragments of an immunoglobulin sufficient to bind to a particular antigen to a single chain phage antibody, a diabody, a triabody, a tetrabody, a polypeptide, and the like. The fragment may be produced synthetically or by enzymatic or chemical degradation of the complete immunoglobulin, or may be genetically engineered by recombinant DNA technology. Methods of generation are well known in the art.
본 발명에서 사용되는 “약제학적으로 허용가능한 부형제”라는 용어는 용인가능한 또는 편리한 투약 형태를 제조하기 위한 약물, 제제 또는 결합 분자와 같은 활성 분자로 조합되는 불활성 물질을 의미한다. 약제학적으로 허용가능한 부형제는 비독성이거나, 적어도 독성이 사용된 용량 및 농도에서 수용자에게 이의 의도된 용도를 위해 허용될 수 있는 부형제이고, 약물, 제제 또는 결합 분제를 포함하는 제형화의 다른 성분과 양립할 수 있다.As used herein, the term " pharmaceutically acceptable excipient " means an inert material combined with an active molecule, such as a drug, agent, or binding molecule to produce an acceptable or convenient dosage form. Pharmaceutically acceptable excipients are non-toxic or at least those excipients which are acceptable for their intended use in the recipient at the dosages and concentrations for which they are used and include other components of the formulation including drugs, Can be compatible.
본 발명에서 사용되는 “치료학적으로 유효한 양”이라는 용어는 인플루엔자 A 바이러스의 노출 전 또는 노출 후에 예방 또는 치료에 유효한 본 발명의 결합 분자의 양을 나타낸다.As used herein, the term " therapeutically effective amount " refers to the amount of the binding molecule of the present invention effective for prevention or treatment before or after exposure of influenza A virus.
본 발명에 따른 물질을 포함하는 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 멸균 주사용액, 사전 충전식 주사(pre-filled syringe)용액제의 형태 또는 동결건조(lyophilized)된 형태로 제형화할 수 있다. 상세하게는, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose), 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween)61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.The composition containing the substance according to the present invention can be administered orally or parenterally in the form of powders, granules, tablets, capsules, oral liquid preparations such as suspensions, emulsions, syrups and aerosols, external preparations, pre-filled syringe solution, or lyophilized form. In detail, when formulating the composition, it can be prepared using a diluent or an excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant and the like which are usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose ), Lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. in addition to commonly used diluents such as water and liquid paraffin . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
본 발명의 화합물, 특히 본 발명의 결합 분자들은 신종 인플루엔자 바이러스를 검출하는데 있어서 진단 시약으로서 특히 유용하다.The compounds of the present invention, particularly the binding molecules of the present invention, are particularly useful as diagnostic reagents in the detection of swine influenza virus.
진단 조성물에 사용되는 본 발명의 상기 화합물들은 검출가능하게 표식되는 것이 바람직하다. 생분자들을 표식시키는데 사용가능한 다양한 방법들이 당업자에게 잘 알려져 있고, 본 발명의 범주내에서 고려된다. 상기 방법들은 Tijssen, 'Practice and theory of enzyme immuno assays', Burden, RH and von Knippenburg (Eds), Volume 15 (1985), 'Basic methods in molecular biology'; Davis LG, Dibmer MD; Battey Elsevier (1990), Mayer et al., (Eds) 'Immunochemical methods in cell and molecular biology' Academic Press, London (1987), or in the series 'Methods in Enzymology', Academic Press, Inc에 기술되어 있다.Preferably, the compounds of the present invention used in the diagnostic composition are detectably labeled. Various methods that can be used to label biomolecules are well known to those skilled in the art and are contemplated within the scope of the present invention. These methods are described in Tijssen, 'Practice and theory of enzyme immunoassays', Burden, RH and von Knippenburg (Eds), Volume 15 (1985), 'Basic methods in molecular biology'; Davis LG, Dibmer MD; Acad. Press, London (1987), or in the series 'Methods in Enzymology', Academic Press, Inc .; Battey Elsevier (1990), Mayer et al., (Eds.) Immunochemical methods in cell and molecular biology.
당업자에게 공지되어 있는 표식 방법과 많은 다른 표식들이 있다. 본 발명에서 사용될 수 있는 표식 종류의 예로는 효소, 방사성 동위원소, 콜로이드 금속, 형광 화합물, 화학발광 화합물 및 생발광 화합물이 있다.There are many other markings and marking methods known to those skilled in the art. Examples of marking classes that can be used in the present invention include enzymes, radioactive isotopes, colloidal metals, fluorescent compounds, chemiluminescent compounds and bioluminescent compounds.
통상적으로 사용되는 표식들은 형광물질(가령, 플루레신, 로다민, 텍사스 레드 등), 효소(가령, 고추냉이 퍼옥시다아제, β-갈락토시다아제, 알칼리 포스파타 아제), 방사성 동위원소(가령, 32 P 또는 125I), 바이오틴, 디곡시게닌, 콜로이드 금속, 화학발광 또는 생발광 화합물(가령, 디옥세탄, 루미놀 또는 아크리디늄)을 포함한다. 효소 또는 바이오티닐기의 공유 결합법, 요오드화법, 인산화법, 바이오틴화법 등과 같은 표식 방법들이 당 분야에 잘 알려져 있다.Commonly used markers include fluorescent substances (e.g., fluorescein, rhodamine, Texas red, etc.), enzymes (such as horseradish peroxidase,? -Galactosidase, alkaline phosphatase), radioactive isotopes 32 P or 125 I), biotin, digoxigenin, colloidal metals, chemiluminescent or bioluminescent compounds (such as dioxetane, luminol or acridinium). Methods of labeling enzymes or biotinyl groups such as covalent bonding, iodination, phosphorylation, biotinylation, and the like are well known in the art.
검출 방법들로는 오토라디오그래피, 형광 현미경, 직접 및 간접 효소반응 등이 있으며, 이에 제한되지는 않는다. 통상적으로 사용되는 검출 분석법으로는 방사성 동위원소 또는 비-방사성 동위원소 방법이 있다. 이들은 그중에서도 웨스턴블롯팅, 오버레이-분석법, RIA(Radioimmuno Assay) 및 IRMA(Immune Radioimmunometric Assay), EIA(Enzyme Immuno Assay), ELISA(Enzyme Linked Immuno Sorbent Assay), FIA(Fluorescent Immuno Assay) 및 CLIA(Chemioluminescent Immune Assay)이 있다.Detection methods include, but are not limited to, autoradiography, fluorescence microscopy, direct and indirect enzyme reactions, and the like. Detection assays commonly used include radioisotope or non-radioisotope methods. Among them, they include Western blotting, overlay-analysis, RIA (Radioimmunoassay) and IRMA (Immune Radioimmunoassay), EIA (Enzyme Immuno Assay), ELISA (Enzyme Linked Immuno Sorbent Assay), FIA (Fluorescent Immuno Assay) Assay).
본 발명에 따른 항체는 약제가 결합된 항체-약물 접합체의 형태로 사용될 수 있다. 약물을 국소 전달하기위해 항체-약물 접합체 (ADC), 즉 면역접합체를 사용하게 되면 상기 약물 모이어티를 감염된 세포에 표적화 전달할 수 있는데, 상기 약물 작용제를 접합시키지 않은 채로 투여하게 되면, 정상 세포에 대해서도 허용될 수 없는 수준의 독성이 야기될 수 있기 때문이다. 약물-연결성 및 약물-방출성 뿐만 아니라 폴리클로날 및 모노클로날 항체 (mAb)의 선택성을 높임으로써 ADC의 최대 효능과 최소 독성을 개선할 수 있다.The antibody according to the present invention can be used in the form of a drug-conjugated antibody-drug conjugate. When an antibody-drug conjugate (ADC), that is, an immunoconjugate, is used for local delivery of a drug, the drug moiety can be targeted to the infected cells. If the drug is administered without conjugation, This can lead to unacceptable levels of toxicity. By increasing the selectivity of polyclonal and monoclonal antibodies (mAbs) as well as drug-linking and drug-releasing properties, the maximum efficacy and minimal toxicity of the ADC can be improved.
약물 모이어티를 항체에 부착시키는, 즉 공유 결합을 통하여 연결시키는 통상적인 수단으로는, 일반적으로 약물 모이어티가 항체 상의 수 많은 부위에 부착되는 불균질한 분자 혼합물이 유발된다. 예를 들어, 세포독성 약물을 전형적으로, 종종 항체의 수 많은 리신 잔기를 통하여 항체와 접합시켜 불균질한 항체-약물 접합체 혼합물을 생성킬 수 있다. 반응 조건에 따라서, 이러한 불균질한 혼합물은 전형적으로, 약물 모이어티에 부착된 항체 분포도가 0 내지 약 8 이상이다. 또한, 특별한 정수 비의 약물 모이어티 대 항체를 수반한 접합체의 각 아군은, 약물 모이어티가 항체 상의 각종 부위에 부착되는 잠재적으로 불균질한 혼합물이다. 항체는 크고, 복잡하며 구조적으로 다양한 생체 분자이고, 종종 많은 반응성 관능기를 갖고 있다. 링커 시약 및 약물-링커 중간체와의 반응성은 pH, 농도, 염 농도 및 조용매와 같은 요인들에 의해 좌우된다.
Conventional means of attaching a drug moiety to an antibody, i. E., Through covalent bonds, generally result in a heterogeneous molecular mixture in which the drug moiety is attached to numerous sites on the antibody. For example, a cytotoxic drug can typically be conjugated to an antibody, often through numerous lysine residues of the antibody, to produce a heterogeneous antibody-drug conjugate mixture. Depending on the reaction conditions, such a heterogeneous mixture typically has an antibody distribution of 0 to about 8 or more attached to the drug moiety. In addition, each aliquot of the conjugate with a specific integer ratio drug moiety-to-antibody is a potentially heterogeneous mixture in which the drug moiety is attached to various sites on the antibody. Antibodies are large, complex and structurally diverse biomolecules, often with many reactive functional groups. Reactivity with linker reagents and drug-linker intermediates is dependent on such factors as pH, concentration, salt concentration and cosolvent.
이하 본 발명을 상세히 설명한다. 그러나 하기 실시예들은 본 발명의 내용을 예시하는 것일 뿐 발명의 범위가 실시예에 의해 한정되는 것은 아니다. 본 발명에서 인용된 문헌은 본 발명의 명세서에 참조로서 통합된다.Hereinafter, the present invention will be described in detail. However, the following examples are intended to illustrate the contents of the present invention and are not intended to limit the scope of the invention. The documents cited in the present invention are incorporated herein by reference.
본원에 기재된 다양한 구체예가 도면을 참조로 기재된다. 하기 설명에서, 본 발명의 완전한 이해를 위해서, 다양한 특이적 상세사항, 예컨대, 특이적 형태, 조성물, 및 공정 등이 기재되어 있다. 그러나, 특정의 구체예는 이들 특이적 상세 사항 중 하나 이상 없이, 또는 다른 공지된 방법 및 형태와 함께 실행될 수 있다. 다른 예에서, 공지된 공정 및 제조 기술은, 본 발명을 불필요하게 모호하게 하지 않게 하기 위해서, 특정의 상세사항으로 기재되지 않는다.
Various embodiments described herein are described with reference to the drawings. In the following description, for purposes of complete understanding of the present invention, various specific details are set forth, such as specific forms, compositions, and processes, and the like. However, certain embodiments may be practiced without one or more of these specific details, or with other known methods and forms. In other instances, well-known processes and techniques of manufacture are not described in any detail, in order not to unnecessarily obscure the present invention.
실시예Example
실시예Example 1. 바이러스 농축 및 정제 1. Virus Concentration and Purification
불활화된 신종 인플루엔자 바이러스 배양액 (A/Korea/01/2009)을 제공받았다. 국내에서 분리된 신종 인플루엔자 바이러스(A/Korea/01/2009, A(H1N1)pdm09)로부터 항원을 농축 및 정제하기 위하여, S. Kodiballi 등 (1993)의 방법을 이용하였다. Inactivated swine influenza virus culture (A / Korea / 01/2009) was provided. The method of S. Kodiballi et al. (1993) was used to concentrate and purify antigens from the newly isolated influenza virus (A / Korea / 01/2009, A (H1N1) pdm09).
구체적으로, 약 25 HA activity가 되도록 배양된 신종 인플루엔자 바이러스를 β-프로피오락톤 (propiolactone)으로 불활화시키고, 4,000 x g에서 30분간 1차 원심분리한 후, 상층액을 2차로 70,000 x g에서 3시간 동안 초원심분리 (L8-70M, Beckman, USA)하였다. 원심분리된 펠렛 (pellet)을 수크로오즈 (sucrose)에 재부유시키고 (수크로오즈 양의 1/25배), 수크로오즈 밀도 구배 초원심분리 (sucrose density gradient ultracentrifugation, 100,000 x g, 90분)를 수행한 다음, 혈구응집능을 보이는 분획을 분리하였다. 이렇게 농축된 바이러스 분획에 5% (w/v) n-옥틸-b-D-글루코피라노시드 (n-octyl-b-D-gluco pyranoside)를 첨가하고 22℃에서 2시간 처리하여 바이러스를 파괴 (disruption)시켰다. 그 후, 70,000 x g에서 90분간 원심분리하고, 얻어진 펠렛을 0.1M NaCl로 용해시킨 후, 다시 10,000 x g에서 30분간 원심분리하여, 신종 인플루엔자 바이러스를 분리하였다.Specifically, the swine influenza virus cultured to about 25 HA activity was inactivated with β-propiolactone and subjected to primary centrifugation at 4,000 × g for 30 minutes. The supernatant was then centrifuged at 70,000 xg (L8-70M, Beckman, USA). The centrifuged pellet was resuspended in sucrose (1/25 times the amount of sucrose), sucrose density gradient ultracentrifugation (100,000 xg, 90 min) And then the fraction showing hemagglutination activity was isolated. To this concentrated virus fraction, 5% (w / v) n-octyl-bD-gluco pyranoside was added and the virus was disrupted by treatment at 22 ° C for 2 hours . Thereafter, the pellet was centrifuged at 70,000 xg for 90 minutes, the pellet was dissolved in 0.1 M NaCl, and centrifuged again at 10,000 xg for 30 minutes to isolate the influenza virus.
실시예Example
2. 단일클론 항체 제작 2. Monoclonal antibody production
2.1 면역원 준비2.1 Immunogen preparation
면역원을 완전 프로인트 항원 보강제(complete Freund's adjuvant)(sigma사)와 혼합하여 충분히 유화시켜 마우스에 1주 간격으로 3회를, 200 ㎍씩 각각 접종하고, 꼬리 정맥 주사를 3회 실시하였다.
The immunogen was mixed with complete Freund's adjuvant (Sigma) and emulsified sufficiently. The mice were inoculated 3 times at 1 week intervals with 200 ㎍ each, and the tail vein injection was performed 3 times.
2.2 혈청 채취, 2.2 Serum collection, 역가Potency 측정 및 세포 융합 Measurement and cell fusion
면역된 마우스 (Balb/c)의 꼬리에서 소량 채혈을 하여 혈청을 분리 한 후 효소면역측정법으로 역가를 측정 하였다. 역가 측정은 면역원을 각각 ELISA용 플레이트에 흡착시키고 항혈청을 10, 100, 1,000, 10,000배 등으로 10배 단계별 희석을 실시한 후 반응시켰다. 구입된 염소 항-마우스 IgG-과산화효소(Goat anti-mouse IgG-peroxidase)를 이용하여 2차 반응을 시키고 TMB로 발색 시켰다. 정상 마우스 혈청의 흡광도 값보다 약 3배 이상 되는 흡광도를 컷오프로 하여 항혈청 희석배수가 1,000배 이상에서 컷오프 이상의 역가를 나타내면 세포 융합을 실시하였다(표 1). A small amount of blood was collected from the tail of the immunized mouse (Balb / c), and the serum was separated, and the activity was measured by enzyme immunoassay. Antibody titers were adsorbed on an ELISA plate, and antiserum was diluted 10, 100, 1,000, and 10,000 times with 10 times dilution. Secondary reactions were performed using goat anti-mouse IgG-peroxidase (Goat anti-mouse IgG-peroxidase) and developed with TMB. Cell fusion was performed when the absorbance of the enzyme was about 3 times higher than the absorbance of normal mouse serum as a cutoff and the titer of the antiserum was more than 1,000 times and the titer was more than the cutoff (Table 1).
면역된 마우스의 비장 세포를 분리하여 골수종 세포 (SP2/0)와 접합시켜 만들어진 단클론 항체를 분비하는 잡종 세포주를 혈구 응집 반응 억제 시험법 (Hemagglutinin Inhibition Assay)를 통하여 신종 인플루엔자 특이적인 헤마글루티닌 항체를 선별하고 한계 희석 방법으로 여러 단세포군을 확립하였다. 세포주를 대량 배양하여 Balb/c 마우스의 복강에 세포를 접종하여 항체가 다량 함유된 복수를 얻고 단백질 G 겔을 이용하여 IgG 항체를 정제하였다.
The splenic cells of the immunized mouse were isolated and hybridized with myeloma cells (SP2 / 0) to produce a monoclonal antibody. The hybridoma cell line was transfected with a hemagglutinin inhibition assay (Hemagglutinin Inhibition Assay) And several monocytic cells were established by limiting dilution method. Cells were mass-cultured and cells were inoculated into the peritoneal cavity of Balb / c mice to obtain ascites containing a large amount of antibody, and the IgG antibody was purified using protein G gel.
흡광도(Absorbance (
ODOD
450450
) )
흡광도(Absorbance (
ODOD
450450
) )
2.3 마우스 단일 클론 신종 인플루엔자 바이러스 2.3 Mouse monoclonal swine influenza virus 헤미글루티닌Hemiglutinin 항체 선별 Antibody screening
U-plated의 각 웰(well) 당 PBS(phosphate buffered saline) 30 ㎕를 분주하고, 검체를 첫 웰에 30 ㎕를 섞은 후 다음 웰로 1/2씩 희석하고, 마지막 웰에서는 30 ㎕를 희석 후 덜어냈으며, 대조군에는 검체를 넣지 않았다. 여러 아형(subtype)의 바이러스를 22 HAU(Hemagglutination unit)가 되도록 희석하여 검체를 넣은 웰에 30 ㎕씩 넣었으며, 대조군에는 22 HA 바이러스를 첫 웰에 넣고 1/2씩 3번 희석하여 준비하였다.30 μl of PBS (phosphate buffered saline) was added to each well of the U-plated. 30 μl of the sample was mixed with the first well and diluted by 1/2 with the next well. After diluting 30 μl with the final well, And the control group did not contain any specimen. Subtypes of viruses were diluted to 2 2 HAU (Hemagglutination unit), and 30 μl of each sample was added to the wells. In the control group, 2 2 HA virus was added to the first well and diluted 3 times with 1/2 Respectively.
그 후 상온에서 30분간 정치시키고, 각 웰에 1% 닭 적혈구 30 ㎕를 분주하였으며, 대조군에도 동일하게 적혈구를 분주하였다. 다시 상온에서 40분간 정치시키고, 대조군과 비교하여 적혈구의 침전이 일어나는 세포 주를 선별하였다.
Thereafter, the cells were allowed to stand at room temperature for 30 minutes, and 30 쨉 l of 1% chicken erythrocytes were dispensed into each well, and red blood cells were similarly dispensed into the control group. The cells were allowed to stand at room temperature again for 40 minutes, and cell lines in which erythrocyte sedimentation occurred were selected as compared with the control group.
2.4 마우스 2.4 Mouse 단클론Monoclonal 항체 정제 Antibody purification
상기 실시예 2.3에서 선별된 세포주를 대량 배양하여 Balb/c 마우스의 복강에 접종하여 항체가 다량 함유된 복수를 얻은 후, 상기 복수를 2500 rpm에서 10분 동안 원심하고 침전을 제거하였다. 상기 복수의 4배 부피의 결합 완충액(binding buffer)으로 복수를 희석하고 상온에서 1시간 정치하였다. A large number of cell strains selected in Example 2.3 were cultured and inoculated into peritoneal cavity of Balb / c mice to obtain a plurality of antibodies containing a large amount of antibody, and then the plurality was centrifuged at 2500 rpm for 10 minutes and the precipitate was removed. The plurality was diluted with the above-mentioned 4-fold volumes of binding buffer and allowed to stand at room temperature for 1 hour.
상기 희석액을 12000 rpm으로, 4℃에서, 5분 (High speed 원심기) 동안 원심하고 침전을 제거하고, 단백질 G 겔을1.5M 내지 3M NaSCN으로 OD280 값이 0.000될 때까지 세척하였다. 세척된 단백질 G 겔을 결합 완충액으로 평형이 되도록 하였다. 준비된 상기 검체를 로딩(loading) 하고, 세척액의 OD280값이 0.05 이하 될 때까지 결합 완충액으로 세척하였다. 용출 완충액(Elution buffer)으로 용출(2반복)하고, 10분 정치한 후, 각 분획의 OD280값을 측정하였다. The diluted solution was centrifuged at 12000 rpm at 4 캜 for 5 minutes (High speed centrifugation) and the precipitate was removed and the protein G gel was washed with 1.5M to 3M NaSCN in OD 280 Lt; RTI ID = 0.0 > 0. < / RTI > The washed protein G gel was allowed to equilibrate with binding buffer. The prepared specimen was loaded and washed with binding buffer until the OD 280 value of the washing solution was less than 0.05. Elution was carried out by elution buffer (2 times repeated), and after standing for 10 minutes, OD 280 value of each fraction was measured.
측정된 OD280 값이 0.9 이상인 튜브만 PBS (pH7.2) 0.1% NaN3로 PD-10 투석한 후, 투석된 항체를 0.2 ㎛ 포어 사이즈를 가지는 필터로 거르고, OD280를 측정하여 농도 값을 결정하였다.
A The measured OD 280 value of 0.9 or more tubes only PD-10 in PBS (pH7.2) 0.1% NaN 3 after dialysis, filtering the dialyzed antibody as a filter having a pore size of 0.2 ㎛, by measuring the OD 280 value of the concentration .
실시예Example
3. 신종 인플루엔자 바이러스 [A( 3. Swine influenza virus [A (
H1N1H1N1
))
pdm09pdm09
] 특이 항체의 결합 특성] Binding characteristics of specific antibodies
신종 인플루엔자 바이러스의 헤마클루티닌 단백질을 마우스에 접종하였고 신종 인플루엔자 바이러스에 대한 항체를 혈구응집 억제반응을 통해 선별(이하 선별된 2개의 항체를 D383 및 I38이라 함)하였으며, 이와 같이 선별된 2가지 항체의 결합 특성을 확인하였다.
The mouse was inoculated with the hemagglutinin protein of the new influenza virus and the antibody against the new influenza virus was selected through hemagglutination inhibition reaction (hereinafter, two selected antibodies were designated as D383 and I38) The binding characteristics of the antibodies were confirmed.
3.1 3.1 ELISAELISA
신종 인플루엔자 바이러스에 특이성이 있는지 여부를 확인하기 위하여 ELISA를 실시하였으며, 구체적인 방법은 공지의 기술과 같다.An ELISA was conducted to confirm whether or not the swine influenza virus was specific. Specific methods are the same as known techniques.
그 결과, 도 1에 도시된 바와 같이, mAb D383 및 mAb I38 두 가지 모두의 경우, A(H1N1)pdm09에만 특이적으로 결합하는 것으로 나타났으며, 대조군인A/H1N1, A/H3N2, B/Wisconsin/1/2010-like (Yamagata lineage) 및 B/Brisbane/60/2008-like (Victoria lineage) 에서는 결합이 거의 일어나지 않는 것으로 나타났다.
As a result, as shown in Fig. 1, both of mAb D383 and mAb I38 specifically bind to A (H1N1) pdm09, and the control groups A / H1N1, A / H3N2, B / In the Wisconsin / 1/2010-like (Yamagata lineage) and B / Brisbane / 60/2008-like (Victoria lineage)
3.2 면역 형광법(3.2 Immunofluorescence IFAIFA ; ; ImmunofluorescenceImmunofluorescence assayassay ))
MDPK 세포를 A(H1N1)pdm09, A/H1N1, A/H3N2, B/Wisconsin/1/2010-like (Yamagata lineage) 및 B/Brisbane/60/2008-like (Victoria lineage) 바이러스로 감염시키고, 상기 D383 및 I38 항체 및 항-NP(neucleoprotein) 항체로 각각 반응시킨 후, FITC로 라벨링된 항-마우스 IgG로 염색하였다. 파랑색은 DAPI에 의해 염색된 MDCK핵이고, 녹색은 각각의 mAbI38, D383과 항-NP에 의해 염색된 것이다. 여기에서 H1N1pdm09, H1N1, H1N1, H3N2 및 influenza B는 각각 A/Korea/01/2009, A/Brisbane/59/2007, A/Solomon Islands/3/2006 및 B/Brisbane/60/2008를 나타낸다.MDPK cells were infected with A (H1N1) pdm09, A / H1N1, A / H3N2, B / Wisconsin / 1 / 2010- like (Yamagata lineage) and B / Brisbane / 60 / D383 and I38 antibodies and anti-NP (neucleoprotein) antibodies, respectively, and then stained with anti-mouse IgG labeled with FITC. The blue color is the MDCK nucleus stained by DAPI and the green is stained by the respective mAbI38, D383 and anti-NP. Here, H1N1 pdm09, H1N1, H1N1, H3N2 and influenza B represent A / Korea / 01/2009, A / Brisbane / 59/2007, A / Solomon Islands / 3/2006 and B / Brisbane / 60/2008, respectively.
그 결과, 도 2에 도시된 바와 같이, D383 및 I38 항체는 A(H1N1)pdm09가 감염된 세포에만 특이적으로 결합하였으며, 이는 ELISA의 결과와 일치함을 알 수 있었다.
As a result, as shown in Fig. 2, the antibodies D383 and I38 specifically bind only to cells infected with A (H1N1) pdm09, which is consistent with the result of ELISA.
실시예Example
4. 항원의 4. Antigen
에피토프(Epitope)의Epitope
특정 certain
4.1 회피 돌연변이4.1 Avoid mutation
MDCK세포에 각각의 인플루엔자바이러스를 감염시킨 후, mAbI38, mAbD383및 인플루엔자바이러스 핵단백질에 특이적인 항-NP 항체를 사용하여 염색한 결과, 도 3에 나타난 바와 같이, 단일 클론 항체 mAbI33 또는 mAbD383의 처리배양에 의해 생성된 mI38(2-1), mD383 (2-8) 인플루엔자 바이러스의 경우, mAbI38 또는 mAbD383와는 결합하지 않았다. 파랑색은 DAPI에 의해 염색된 MDCK핵이고, 녹색은 각각의 mAbI38, mAbD383과 항-NP에 의해 염색된 것이다.MDCK cells were infected with respective influenza viruses and then stained with anti-NP antibodies specific to mAbI38, mAbD383 and influenza virus nucleoprotein. As a result, as shown in Fig. 3, the treated monoclonal antibody mAbI33 or mAbD383 In the case of mI38 (2-1), mD383 (2-8) influenza viruses produced by M. tuberculosis, but not with mAbI38 or mAbD383. The blue color is the MDCK nucleus stained with DAPI, and the green is stained with the respective mAbI38, mAbD383 and anti-NP.
이를 통하여 볼 때, 단일 클론 항체 mAbI38 또는 mAbD383이 결합하는 부위에 회피 돌연변이(escape mutant)가 발생하였음을 알 수 있었으며, mI38(2-1), mD383 (2-8) 의 표면항원(NA, HA, M2)의 염기서열을 분석하여 야생형(KR02)과 비교하여 회피 돌연변이 부위를 찾아내었다. 회피 변이가 일어난 부위가 mAbI38 및 mAb 에피토프임을 알 수 있다. 시퀀스 확인 결과는 하기 표 2와 같다.
As a result, it was found that escape mutant occurred at the site where monoclonal antibody mAbI38 or mAbD383 binds, and surface antigens of mI38 (2-1) and mD383 (2-8) (NA, HA , M2) was analyzed to identify a mutation site in comparison with the wild type (KR02). It can be seen that the site where the avoidance mutation occurred is mAbI38 and mAb epitope. Sequence confirmation results are shown in Table 2 below.
D383D383
I38I38
회피 돌연변이들의 염기 서열을 분석하고 야생형 바이러스의 서열과 비교해본 결과, HA 56, 172, 176 및 180번 아미노산이 에피토프임을 알 수 있었다.
The nucleotide sequences of the avoidance mutations were analyzed and compared with the wild type virus sequences, and it was found that the amino acids HA 56, 172, 176 and 180 were epitopes.
4.2 단일클론 항체의 4.2 Monoclonal Antibodies 에피토프Epitope 매핑Mapping
에피토프 매핑을 하기 위하여 A(H1N1)pdm09의 헤마글루티닌 단백질에서 F 서브도메인 및 Sa 항원성 부위를 함유하는 20개의 펩타이드로 덮인 ELISA가 사용되었다. mAb에 의해 인식된 펩타이드는 도 4 A) 및 도 4 B)의 표에서 붉은색 및 녹색으로 표시되었다. P*는 양성 대조군으로써 A(H1N1)pdm09의 불활성 바이러스 항원이 ELISA에 사용된 경우이다. 또한, ELISA 결과를 통해 도출한 에피토프를 도 4 C)에서 붉은색 및 녹색으로 나타냈으며, 상기 실시예 4.1에서 기재된 G56E 및 G172E는 노란색으로 표시하였다. 도 4 C)의 붉은 색 및 녹색은 4 A) 및 도 4 B)의 표에의 붉은색 및 녹색과 일치한다. 도 4 D)는 A(H1N1)pdm09의 3차 구조에서 Sa 항원성 부위 및 F' 서브도메인을 각각 파란색 및 보라색으로 표시했다. Sa 항원성 부위에서 G172E, P176Q 및 K180E 변이는 노란색으로 표시되었다. F'서브도메인에서 G56E 변이는 녹색으로 표시하였다. 도 4 C) 및 도 4 D)의 왼쪽 및 오른쪽 도면은 각각 HA 단백질 3차 구조의 측면도 및 상면도이다.
ELISA covered with 20 peptides containing the F subdomain and the Sa antigenic site in the hemagglutinin protein of A (H1N1) pdm09 was used for epitope mapping. The peptides recognized by the mAbs were indicated in red and green in the table of FIG. 4 A) and FIG. 4 B). P * is the case when an inactive viral antigen of A (H1N1) pdm09 was used for ELISA as a positive control. In addition, epitopes derived from the ELISA results are shown in red and green in FIG. 4C, and G56E and G172E described in Example 4.1 are shown in yellow. The red and green of FIG. 4C correspond to the red and green in the table of 4A) and FIG. 4B). 4D) shows the Sa antigenic site and the F 'subdomain in blue and purple in the tertiary structure of A (H1N1) pdm09, respectively. The G172E, P176Q and K180E mutations in the Sa antigenic site are shown in yellow. The G56E mutation in the F 'subdomain is shown in green. 4C) and FIG. 4D) are side and top views, respectively, of the HA protein tertiary structure.
<110> Republic of Korea <120> Antibody of specific binding to HA protein of influenza viruses <130> IPDB-46124 <160> 4 <170> KopatentIn 2.0 <210> 1 <211> 15 <212> PRT <213> A/Korea/01/2009 <400> 1 Ser Val Asn Leu Leu Glu Asp Lys His Asn Gly Lys Leu Cys Lys 1 5 10 15 <210> 2 <211> 15 <212> PRT <213> A/Korea/01/2009 <400> 2 His Asn Gly Lys Leu Cys Lys Leu Arg Gly Val Ala Pro Leu His 1 5 10 15 <210> 3 <211> 15 <212> PRT <213> A/Korea/01/2009 <400> 3 Lys Ser Phe Tyr Lys Asn Leu Ile Trp Leu Val Lys Lys Gly Asn 1 5 10 15 <210> 4 <211> 566 <212> PRT <213> A/Korea/01/2009 <400> 4 Met Lys Ala Ile Leu Val Val Leu Leu Tyr Thr Phe Ala Thr Ala Asn 1 5 10 15 Ala Asp Thr Leu Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr 20 25 30 Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn 35 40 45 Leu Leu Glu Asp Lys His Asn Gly Lys Leu Cys Lys Leu Arg Gly Val 50 55 60 Ala Pro Leu His Leu Gly Lys Cys Asn Ile Ala Gly Trp Ile Leu Gly 65 70 75 80 Asn Pro Glu Cys Glu Ser Leu Ser Thr Ala Ser Ser Trp Ser Tyr Ile 85 90 95 Val Glu Thr Ser Ser Ser Asp Asn Gly Thr Cys Tyr Pro Gly Asp Phe 100 105 110 Ile Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe 115 120 125 Glu Arg Phe Glu Ile Phe Pro Lys Thr Ser Ser Trp Pro Asn His Asp 130 135 140 Ser Asn Lys Gly Val Thr Ala Ala Cys Pro His Ala Gly Ala Lys Ser 145 150 155 160 Phe Tyr Lys Asn Leu Ile Trp Leu Val Lys Lys Gly Asn Ser Tyr Pro 165 170 175 Lys Leu Ser Lys Ser Tyr Ile Asn Asp Lys Gly Lys Glu Val Leu Val 180 185 190 Leu Trp Gly Ile His His Pro Ser Thr Ser Ala Asp Gln Gln Ser Leu 195 200 205 Tyr Gln Asn Ala Asp Ala Tyr Val Phe Val Gly Ser Ser Arg Tyr Ser 210 215 220 Lys Lys Phe Lys Pro Glu Ile Ala Ile Arg Pro Lys Val Arg Asp Gln 225 230 235 240 Glu Gly Arg Met Asn Tyr Tyr Trp Thr Leu Val Glu Pro Gly Asp Lys 245 250 255 Ile Thr Phe Glu Ala Thr Gly Asn Leu Val Val Pro Arg Tyr Ala Phe 260 265 270 Ala Met Glu Arg Asn Ala Gly Ser Gly Ile Ile Ile Ser Asp Thr Pro 275 280 285 Val His Asp Cys Asn Thr Thr Cys Gln Thr Pro Lys Gly Ala Ile Asn 290 295 300 Thr Ser Leu Pro Phe Gln Asn Ile His Pro Ile Thr Ile Gly Lys Cys 305 310 315 320 Pro Lys Tyr Val Lys Ser Thr Lys Leu Arg Leu Ala Thr Gly Leu Arg 325 330 335 Asn Val Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly 340 345 350 Phe Ile Glu Gly Gly Trp Thr Gly Met Val Asp Gly Trp Tyr Gly Tyr 355 360 365 His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Leu Lys Ser 370 375 380 Thr Gln Asn Ala Ile Asp Glu Ile Thr Asn Lys Val Asn Ser Val Ile 385 390 395 400 Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn His 405 410 415 Leu Glu Lys Arg Ile Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe 420 425 430 Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn 435 440 445 Glu Arg Thr Leu Asp Tyr His Asp Ser Asn Val Lys Asn Leu Tyr Glu 450 455 460 Lys Val Arg Ser Gln Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly 465 470 475 480 Cys Phe Glu Phe Tyr His Lys Cys Asp Asn Thr Cys Met Glu Ser Val 485 490 495 Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ala Lys Leu 500 505 510 Asn Arg Glu Glu Ile Asp Gly Val Lys Leu Glu Ser Thr Arg Ile Tyr 515 520 525 Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Val 530 535 540 Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu 545 550 555 560 Gln Cys Arg Ile Cys Ile 565 <110> Republic of Korea <120> Antibody of specific binding to HA protein of influenza viruses <130> IPDB-46124 <160> 4 <170> Kopatentin 2.0 <210> 1 <211> 15 <212> PRT <213> A / Korea / 01/2009 <400> 1 Ser Val Asn Leu Leu Glu Asp Lys His Asn Gly Lys Leu Cys Lys 1 5 10 15 <210> 2 <211> 15 <212> PRT <213> A / Korea / 01/2009 <400> 2 His Asn Gly Lys Leu Cys Lys Leu Arg Gly Val Ala Pro Leu His 1 5 10 15 <210> 3 <211> 15 <212> PRT <213> A / Korea / 01/2009 <400> 3 Lys Ser Phe Tyr Lys Asn Leu Ile Trp Leu Val Lys Lys Gly Asn 1 5 10 15 <210> 4 <211> 566 <212> PRT <213> A / Korea / 01/2009 <400> 4 Met Lys Ala Ile Leu Val Val Leu Leu Tyr Thr Phe Ala Thr Ala Asn 1 5 10 15 Ala Asp Thr Leu Cys Ile Gly Tyr His Ala Asn Asn Ser Thr Asp Thr 20 25 30 Val Asp Thr Val Leu Glu Lys Asn Val Thr Val Thr His Ser Val Asn 35 40 45 Leu Leu Glu Asp Lys His Asn Gly Lys Leu Cys Lys Leu Arg Gly Val 50 55 60 Ala Pro Leu His Leu Gly Lys Cys Asn Ile Ala Gly Trp Ile Leu Gly 65 70 75 80 Asn Pro Glu Cys Glu Ser Leu Ser Thr Ala Ser Ser Trp Ser Tyr Ile 85 90 95 Val Glu Thr Ser Ser Asp Asn Gly Thr Cys Tyr Pro Gly Asp Phe 100 105 110 Ile Asp Tyr Glu Glu Leu Arg Glu Gln Leu Ser Ser Val Ser Ser Phe 115 120 125 Glu Arg Phe Glu Ile Phe Pro Lys Thr Ser Ser Trp Pro Asn His Asp 130 135 140 Ser Asn Lys Gly Val Thr Ala Ala Cys Pro His Ala Gly Ala Lys Ser 145 150 155 160 Phe Tyr Lys Asn Leu Ile Trp Leu Val Lys Lys Gly Asn Ser Tyr Pro 165 170 175 Lys Leu Ser Lys Ser Tyr Ile Asn Asp Lys Gly Lys Glu Val Leu Val 180 185 190 Leu Trp Gly Ile His His Pro Ser Thr Ser Ala Asp Gln Gln Ser Leu 195 200 205 Tyr Gln Asn Ala Asp Ala Tyr Val Phe Val Gly Ser Ser Arg Tyr Ser 210 215 220 Lys Lys Phe Lys Pro Glu Ile Ala Ile Arg Pro Lys Val Arg Asp Gln 225 230 235 240 Glu Gly Arg Met Met Asn Tyr Tyr Trp Thr Leu Val Glu Pro Gly Asp Lys 245 250 255 Ile Thr Phe Glu Ala Thr Gly Asn Leu Val Val Pro Arg Tyr Ala Phe 260 265 270 Ala Met Glu Arg Asn Ala Gly Ser Gly Ile Ile Ile Ser Asp Thr Pro 275 280 285 Val His Asp Cys Asn Thr Thr Cys Gln Thr Pro Lys Gly Ala Ile Asn 290 295 300 Thr Ser Leu Pro Phe Gln Asn Ile His Pro Ile Thr Ile Gly Lys Cys 305 310 315 320 Pro Lys Tyr Val Lys Ser Thr Lys Leu Arg Leu Ala Thr Gly Leu Arg 325 330 335 Asn Val Pro Ser Ile Gln Ser Arg Gly Leu Phe Gly Ala Ile Ala Gly 340 345 350 Phe Ile Glu Gly Gly Trp Thr Gly Met Val Asp Gly Trp Tyr Gly Tyr 355 360 365 His His Gln Asn Glu Gln Gly Ser Gly Tyr Ala Ala Asp Leu Lys Ser 370 375 380 Thr Gln Asn Ala Ile Asp Glu Ile Thr Asn Lys Val Asn Ser Val Ile 385 390 395 400 Glu Lys Met Asn Thr Gln Phe Thr Ala Val Gly Lys Glu Phe Asn His 405 410 415 Leu Glu Lys Arg Ile Glu Asn Leu Asn Lys Lys Val Asp Asp Gly Phe 420 425 430 Leu Asp Ile Trp Thr Tyr Asn Ala Glu Leu Leu Val Leu Leu Glu Asn 435 440 445 Glu Arg Thr Leu Asp Tyr His Asp Ser Asn Val Lys Asn Leu Tyr Glu 450 455 460 Lys Val Arg Ser Glu Leu Lys Asn Asn Ala Lys Glu Ile Gly Asn Gly 465 470 475 480 Cys Phe Glu Phe Tyr His Lys Cys Asp Asn Thr Cys Met Glu Ser Val 485 490 495 Lys Asn Gly Thr Tyr Asp Tyr Pro Lys Tyr Ser Glu Glu Ala Lys Leu 500 505 510 Asn Arg Glu Glu Ile Asp Gly Val Lys Leu Glu Ser Thr Arg Ile Tyr 515 520 525 Gln Ile Leu Ala Ile Tyr Ser Thr Val Ala Ser Ser Leu Val Leu Val 530 535 540 Val Ser Leu Gly Ala Ile Ser Phe Trp Met Cys Ser Asn Gly Ser Leu 545 550 555 560 Gln Cys Arg Ile Cys Ile 565
Claims (17)
A monoclonal antibody that specifically binds to a hemagglutinin (HA) protein of A / Korea / 01/2009 virus, wherein the epitope to which the monoclonal antibody binds is a hemagglutinin A / Korea / 01/2009 virus hemagglutinin which reacts with a desired sample and at least one of G56, G172, P176 or K180 among the amino acid sequence of the protein is reacted with a desired sample and avoidance mutation does not bind to the antibody A method for providing information on the presence or absence of A / Korea / 01/2009 virus, comprising the step of analyzing the nucleotide sequence of lutinin (HA) and comparing with the wild type.
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| KR101329344B1 (en) * | 2010-09-15 | 2013-11-15 | 대한민국 | Antibody for Detecting Hemagglutinin of Swine Influenza and Use Thereof |
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