KR20110106826A - Screening method of human papillomavirus antibody using fusion polypeptide hpv antigen - Google Patents
Screening method of human papillomavirus antibody using fusion polypeptide hpv antigen Download PDFInfo
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- KR20110106826A KR20110106826A KR1020110026033A KR20110026033A KR20110106826A KR 20110106826 A KR20110106826 A KR 20110106826A KR 1020110026033 A KR1020110026033 A KR 1020110026033A KR 20110026033 A KR20110026033 A KR 20110026033A KR 20110106826 A KR20110106826 A KR 20110106826A
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- Enzymes And Modification Thereof (AREA)
Abstract
본 발명은 융합 폴리펩타이드 HPV 항원을 이용한 HPV 항체 스크리닝 방법으로서, N 말단에 글루타티온 S-트랜스퍼라제(Glutathione S-transferase, GST)의 아미노산 서열 또는 이의 활성단편 C 말단에 시미안 바이러스 40 대형 T 항원(simian virus 40 large T-antigen)의 아미노산 서열 또는 이의 활성단편 및 HPV 6 L1 항원, HPV11 L1 항원, HPV16 L1 항원 및 HPV18 L1 항원으로 구성된 군으로부터 선택된 HPV L1 항원의 아미노산 서열 또는 이의 활성단편을 포함하는 융합 폴리펩타이드, 상기 융합 폴리펩타이드 HPV 항원을 이용하여 시료 내 HPV 항체를 검출하는 방법 및 상기 융합 폴리펩타이드 HPV 항원을 포함하는 비드 어레이용 HPV 항체 검출 키트에 관한 것이다. 본 발명을 이용하면 HPV 항체에 특이적으로 결합할 수 있는 활성에 영향을 미치지 않으면서도 재조합 HPV 항원을 고순도로 분리, 정제하고 비드 어레이용 비드에 효과적으로 균일하게 부착시킬 수 있어 높은 민감도 및 정확도로 시료 내 HPV 6, 11, 16 및 18 항체를 복합적으로 검출할 수 있다. 항체 역가를 측정하여 HPV 백신의 접종시기를 결정하는데 활용될 수 있고, 백신 접종 후 방어 기간의 측정 등에 활용 가능하다.The present invention relates to an HP antibody screening method using a fusion polypeptide HPV antigen, wherein the amino acid sequence of glutathione S-transferase (GST) at the N-terminus or Simian virus 40 large T antigen ( simian virus 40 large T-antigen) or an active fragment thereof and the amino acid sequence of HPV L1 antigen selected from the group consisting of HPV 6 L1 antigen, HPV11 L1 antigen, HPV16 L1 antigen and HPV18 L1 antigen or active fragment thereof A fusion polypeptide, a method for detecting an HPV antibody in a sample using the fusion polypeptide HPV antigen, and a HPV antibody detection kit for a bead array containing the fusion polypeptide HPV antigen. Using the present invention, it is possible to isolate and purify recombinant HPV antigens with high purity and effectively and uniformly attach them to beads for beads array without affecting the activity that can specifically bind to HPV antibodies. Internal HPV 6, 11, 16 and 18 antibodies can be detected in combination. The antibody titer can be used to determine the inoculation time of the HPV vaccine, and can be used to measure the duration of defense after vaccination.
Description
본 발명은 융합 폴리펩타이드 HPV 항원을 이용한 HPV 항체 스크리닝 방법으로서, N 말단에 글루타티온 S-트랜스퍼라제(Glutathione S-transferase, GST)의 아미노산 서열 또는 이의 활성단편; C 말단에 시미안 바이러스 40 대형 T 항원(SV 40 large T-antigen)의 아미노산 서열 또는 이의 활성단편; 및 HPV 6 L1 항원, HPV11 L1 항원, HPV16 L1 항원 및 HPV18 L1 항원으로 구성된 군으로부터 선택된 HPV L1 항원의 아미노산 서열 또는 이의 활성단편을 포함하는 융합 폴리펩타이드, 상기 융합 폴리펩타이드 HPV 항원을 이용하여 시료 내 HPV 항체를 검출하는 방법 및 상기 융합 폴리펩타이드 HPV 항원을 포함하는 비드 어레이용 HPV 항체 검출 키트에 관한 것이다.The present invention provides an antibody screening method for HPV using a fusion polypeptide HPV antigen, comprising: an amino acid sequence of glutathione S-transferase (GST) at its N-terminus or an active fragment thereof; The amino acid sequence of an
전세계적으로 매 2분마다 한 명의 여성이 자궁경부암으로 사망한다. 세계적으로 매년 발생하고 있는 자궁경부암은 전세계 여성에게 2번째로 빈번히 발생하는 암이며, 해마다 약 50만 명에게 발병하며 특히 여성에게는 유방암과 폐암에 이어 세 번째로 주된 암 사망의 원인이다. 자궁경부암의 99% 이상에서 HPV (Human Papillomavirus) 감염이 발견되는데, 이러한 HPV는 100종이 넘으며 그 중 30 - 40 종은 점막조직(mucosal tissue) 감염을 유발하며 저위험성 HPV (low-risk HPV)와 발암성 HPV로 나뉜다. 무엇보다 중요한 것은, 자궁경부암과 직접 관련이 있는 15종 이상의 발암성 HPV이다. 이러한 발암성 HPV 중 16번, 18번이 가장 중요한데 이는 전세계적으로 70% 이상의 자궁경부암에서 발견된다. 대부분의 HPV 감염은 보통 6개월에서 2년 내에 자연 치유되지만 발암성 HPV에 지속적으로 감염되면 자궁경부암으로 발전할 수 있다.
Every two minutes, one woman dies of cervical cancer worldwide. Cervical cancer, which occurs worldwide annually, is the second most common cancer among women worldwide, affecting about half a million people each year, and among women, the third leading cause of cancer deaths after breast and lung cancer. Human Papillomavirus (HPV) infections are found in more than 99% of cervical cancers, including more than 100 HPVs, 30-40 of which cause mucosal tissue infections, and low-risk HPVs. And carcinogenic HPV. Most importantly, there are more than 15 carcinogenic HPVs that are directly linked to cervical cancer. Of these carcinogenic HPVs, 16 and 18 are the most important and are found in more than 70% of cervical cancers worldwide. Most HPV infections usually heal naturally within six months to two years, but persistent infection with carcinogenic HPV can lead to cervical cancer.
HPV의 아형의 종류는 인종적, 지형적, 환경적 특징을 갖기 때문에 백신개발에 있어 그 나라 고유의 아형 실정을 바로 알아야 하며, 한국에서 많이 발생하는 아형을 이용한 한국 고유의 백신 개발이 필요하며 나아가 이러한 백신의 개발시 필수적으로 백신의 면역원성(immunity)을 측정할 수 있는 기술 시스템이 확립되어야 한다. 현재까지 개발된 Gardasil (Merck사)와 Cervarix (GSK사)와 같은 HPV 예방백신 접종 후 항체의 유지기간과 효능 나아가 백신의 투여시기를 조사하기 위해서는 혈청 내 이들 HPV 아형에 대해 생성된 항체의 역가를 측정하는 것이 무엇보다 중요하다. 그러나 이러한 백신에 대한 면역원성을 동시에 측정할 수 있는 기법이 아직 확립되지 못했다. Since the types of HPV subtypes have racial, geographical and environmental characteristics, it is necessary to know the specific subtype status of the country in developing vaccines, and it is necessary to develop Korea's own vaccines using many subtypes that occur in Korea. In the development of the system, it is essential that a technical system be established to measure the immunogenicity of the vaccine. To investigate the maintenance and efficacy of antibodies after HPV vaccinations, such as Gardasil (Merck) and Cervarix (GSK), which have been developed to date, and the timing of vaccine administration, the titers of antibodies produced against these HPV subtypes in serum are measured. It is important to measure. However, no technique has yet been established to simultaneously measure immunogenicity against these vaccines.
이에, 본 발명자들은 백신의 면역원성을 측정할 수 있는 HPV 항체 스크리닝 기술을 확립하기 위해 노력한 결과, HPV 항원을 N 말단에 글루타티온 S-트랜스퍼라제(Glutathione S-transferase, GST)의 아미노산 서열 또는 이의 활성단편, C 말단에 시미안 바이러스 40 대형 T 항원(simian virus 40 large T-antigen)의 아미노산 서열 또는 이의 활성단편과 융합함으로써, HPV 항체에 특이적으로 결합할 수 있는 활성에 영향을 미치지 않으면서도 재조합 HPV 항원을 고순도로 분리, 정제하고 비드 어레이용 비드에 효과적으로 균일하게 부착시킬 수 있어 높은 민감도 및 정확도로 시료 내 HPV 항체를 스크리닝할 수 있다는 것을 발견하고 본 발명을 완성하였다.
Accordingly, the present inventors have endeavored to establish an HPV antibody screening technique capable of measuring the immunogenicity of the vaccine. As a result, the amino acid sequence of glutathione S-transferase (GST) at the N-terminus of HPV antigen or its activity By fusion with the fragment, the amino acid sequence of the
본 발명의 목적은 N 말단에 글루타티온 S-트랜스퍼라제(Glutathione S-transferase, GST)의 아미노산 서열 또는 이의 활성단편; C 말단에 시미안 바이러스 40 대형 T 항원(simian virus 40 large T-antigen)의 아미노산 서열 또는 이의 활성단편; 및 HPV 6 L1 항원, HPV11 L1 항원, HPV16 L1 항원 및 HPV18 L1 항원으로 구성된 군으로부터 선택된 HPV L1 항원의 아미노산 서열 또는 이의 활성단편을 포함하는 융합 폴리펩타이드를 제공하는 것이다.An object of the present invention is an amino acid sequence of glutathione S-transferase (GST) at its N terminus or an active fragment thereof; The amino acid sequence of the
본 발명의 다른 목적은 상기 융합 폴리펩타이드를 암호화하는 폴리뉴클레오티드, 상기 폴리뉴클레오티드를 포함하는 발현벡터 및 상기 발현벡터로 형질전환된 형질전환체를 제공하는 것이다.Another object of the present invention is to provide a polynucleotide encoding the fusion polypeptide, an expression vector comprising the polynucleotide, and a transformant transformed with the expression vector.
본 발명의 또다른 목적은 상기 융합 폴리펩타이드를 비드 어레이용 비드에 결합시키는 단계; 상기 융합 폴리펩타이드가 결합된 비드를 시료와 반응시키는 단계; 상기 시료를 표지자 표지된 2차 항체와 반응시키는 단계; 상기 2차 항체를 형광물질이 부착된 상기 표지자의 특이적 결합제와 반응시키는 단계; 및 비드 유래의 형광값과 표지자의 특이적 결합제 유래의 형광값을 측정하여 시료 내 HPV 항체를 검출하는 단계를 포함하는 시료 내 HPV 항체 검출 방법을 제공하는 것이다. 또한, 상기 융합 폴리펩타이드를 포함하는 비드 어레이용 HPV 항체 검출 키트를 제공하는 것이다.
Another object of the present invention is to bind the fusion polypeptide to the beads for beads array; Reacting the beads to which the fusion polypeptide is bound with a sample; Reacting the sample with a marker labeled secondary antibody; Reacting the secondary antibody with a specific binding agent of the marker to which a fluorescent substance is attached; And detecting the HPV antibody in the sample by measuring the fluorescence value derived from the bead and the fluorescence value derived from the specific binding agent of the marker. In addition, to provide a bead array HPV antibody detection kit comprising the fusion polypeptide.
하나의 양태로서 본 발명은 N 말단에 글루타티온 S-트랜스퍼라제(Glutathione S-transferase, GST)의 아미노산 서열 또는 이의 활성단편; C 말단에 시미안 바이러스 40 대형 T 항원(simian virus 40 large T-antigen)의 아미노산 서열 또는 이의 활성단편; 및 HPV 6 L1 항원, HPV11 L1 항원, HPV16 L1 항원 및 HPV18 L1 항원으로 구성된 군으로부터 선택된 HPV L1 항원의 아미노산 서열 또는 이의 활성단편을 포함하는 융합 폴리펩타이드를 제공한다. 상기 융합 폴리펩타이드의 아미노산 서열은 서열번호 11 내지 14로 구성된 군으로부터 선택된 아미노산 서열일 수 있다. 상기 활성단편의 길이는 제한되지 않으나 본 발명의 구체적인 실시예에 따르면 시미안 바이러스 40 대형 T 항원 활성단편 길이는 11개 아미노산일 수 있다.
In one embodiment, the invention provides an amino acid sequence of glutathione S-transferase (GST) at its N terminus or an active fragment thereof; The amino acid sequence of the
HPV 항원을 N 말단에 글루타티온 S-트랜스퍼라제(Glutathione S-transferase, GST)의 아미노산 서열 또는 이의 활성단편, C 말단에 시미안 바이러스 40 대형 T 항원(simian virus 40 large T-antigen)의 아미노산 서열 또는 이의 활성단편과 융합함으로써, HPV 항체에 특이적으로 결합할 수 있는 활성에 영향을 미치지 않으면서도, 재조합 HPV 항원을 고순도로 분리, 정제하고 비드 어레이용 비드에 효과적으로 균일하게 부착시킬 수 있으며, 시미안 바이러스 40 대형 T 항원을 통하여 재조합 HPV 항원이 비드에 잘 부착되었는지, 부착시킨 양이 항상 동일한지, HPV 항원 4종간에 비드에 부착된 정도가 균일한지 등을 판정할 수 있어, 높은 민감도 및 정확도로 시료 내 HPV 항체를 스크리닝할 수 있다.
The amino acid sequence of glutathione S-transferase (GST) at its N terminus or an active fragment thereof, the amino acid sequence of
또한, 상기 아미노산 서열과 하나 이상의 아미노산 잔기가 상이한 서열을 가지는 폴리펩타이드를 포함할 수 있다. 분자의 활성을 전체적으로 변경시키지 않는 단백질 및 폴리펩타이드에서의 아미노산 교환은 당해 분야에 공지되어 있다. 가장 통상적으로 일어나는 교환은 아미노산 잔기 Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr, Ser/Asn, Ala/Val, Ser/Gly, Thy/Phe, Ala/Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Ala/Glu, Asp/Gly 간의 교환이다. 또한, 아미노산 서열상의 변이 또는 수식에 의해서 단백질의 열, pH등에 대한 구조적 안정성이 증가하거나 단백질 활성이 증가한 단백질을 포함할 수 있다.
In addition, the amino acid sequence and one or more amino acid residues may include a polypeptide having a different sequence. Amino acid exchanges in proteins and polypeptides that do not alter the activity of the molecule as a whole are known in the art. The most commonly occurring exchanges are amino acid residues Ala / Ser, Val / Ile, Asp / Glu, Thr / Ser, Ala / Gly, Ala / Thr, Ser / Asn, Ala / Val, Ser / Gly, Thy / Phe, Ala / Exchange between Pro, Lys / Arg, Asp / Asn, Leu / Ile, Leu / Val, Ala / Glu, Asp / Gly. In addition, the protein may include a protein having increased structural stability or increased protein activity against heat, pH, etc. of the protein by variation or modification on the amino acid sequence.
본 발명의 융합 폴리펩타이드는 당해 분야에 공지된 화학적 펩타이드 합성방법으로 제조하거나, 각 부위를 암호화하는 유전자를PCR (polymerase chain reaction) 에 의해 증폭하거나 공지된 방법으로 합성한 후 인프레임(in frame)으로 연결하여 발현벡터에 작동 가능하게 연결하여 클로닝하여발현시킬 수 있다.
The fusion polypeptides of the present invention may be prepared by chemical peptide synthesis methods known in the art, or may be synthesized in a frame after amplifying genes encoding respective sites by PCR (polymerase chain reaction) or by known methods. It can be linked to the expression vector operatively linked to the clone can be expressed.
또 하나의 양태로서 본 발명은 상기 융합 폴리펩타이드를 암호화하는 폴리뉴클레오티드, 상기 폴리뉴클레오티드를 포함하는 발현벡터, 상기 발현벡터로 형질전환된 형질전환체를 제공한다.In another aspect, the present invention provides a polynucleotide encoding the fusion polypeptide, an expression vector comprising the polynucleotide, and a transformant transformed with the expression vector.
상기 시미안 바이러스 40 대형 T 항원의 아미노산 서열 또는 이의 활성단편을 암호화하는 폴리뉴클레오티드는 서열번호 1 및 서열번호 2로 구성된 이중가닥 폴리뉴클레오티드를 SalI 및 NotI 제한효소로 절단한 것일 수 있다.The polynucleotide encoding the amino acid sequence of the
상기 HPV 6 L1 항원의 아미노산 서열 또는 이의 활성단편을 암호화하는 폴리뉴클레오티드는 HPV 6 게놈으로부터 서열번호 3 및 서열번호 4의 프라이머 세트를 이용하여 증폭된 폴리뉴클레오티드를 EcoRI 및 SalI 제한효소로 절단한 것일 수 있다.The polynucleotide encoding the amino acid sequence of the
상기 HPV 11 L1 항원의 아미노산 서열 또는 이의 활성단편을 암호화하는 폴리뉴클레오티드는 HPV 11 게놈으로부터 서열번호 5 및 서열번호 6의 프라이머 세트를 이용하여 증폭된 폴리뉴클레오티드 EcoRI 및 SalI 제한효소로 절단한 것일 수 있다.The polynucleotide encoding the amino acid sequence of the HPV 11 L1 antigen or an active fragment thereof is a polynucleotide Eco RI and Sal I restriction enzyme amplified from the HPV 11 genome using a primer set of SEQ ID NO: 5 and SEQ ID NO: 6 Can be.
상기 HPV 16 L1 항원의 아미노산 서열 또는 이의 활성단편을 암호화하는 폴리뉴클레오티드는 HPV 16 게놈으로부터 서열번호 7 및 서열번호 8의 프라이머 세트를 이용하여 증폭된 폴리뉴클레오티드 BglII 및 SalI 제한효소로 절단한 것일 수 있다.The polynucleotide encoding the amino acid sequence of the
상기 HPV 18 L1 항원의 아미노산 서열 또는 이의 활성단편을 암호화하는 폴리뉴클레오티드는 HPV 18 게놈으로부터 서열번호 9 및 서열번호 10의 프라이머 세트를 이용하여 증폭된 폴리뉴클레오티드 EcoRI 및 SalI 제한효소로 절단한 것일 수 있다.
The polynucleotide encoding the amino acid sequence of the
본 발명의 구체예에서, 상기 시미안 바이러스 40 대형 T 항원의 아미노산 서열 또는 이의 활성단편을 암호화하는 폴리뉴클레오티드를 제한효소 SalI 및 NotI으로 절단된 발현벡터 pGEX 4T-3에 삽입하여 mpGEX 4T-3 벡터를 제조하는 단계, 상기 mpGEX 4T-3 벡터를 제한효소 EcoRI, SalI으로 절단하여 HPV 6 L1 항원의 아미노산 서열 또는 이의 활성단편을 암호화하는 폴리뉴클레오티드를 삽입하여 도 2에 개시된 개열지도를 가지는 mpGEX4T-3/HPV 6 L1 벡터를 제조하는 단계, 상기 mpGEX4T-3/HPV6 L1 벡터를 Escherichia coli BL21 Gen-XTM에 형질전환하는 단계 및 상기 형질전환체로부터 HPV 6 L1 항원을 포함하는 융합 폴리펩타이드를 수득하는 단계를 통해 HPV 6 L1 항원을 포함하는 융합 폴리펩타이드를 제조할 수 있다.In an embodiment of the present invention, the polynucleotide encoding the amino acid sequence of the
또한, 본 발명의 구체예에서, 상기 시미안 바이러스 40 대형 T 항원의 아미노산 서열 또는 이의 활성단편을 암호화하는 폴리뉴클레오티드를 제한효소 SalI 및 NotI으로 절단된 발현벡터 pGEX 4T-3에 삽입하여 mpGEX 4T-3 벡터를 제조하는 단계, 상기 mpGEX 4T-3 벡터를 제한효소 EcoRI, SalI으로 절단하여 HPV 11 L1 항원의 아미노산 서열 또는 이의 활성단편을 암호화하는 폴리뉴클레오티드를 삽입하여 도 3에 개시된 개열지도를 가지는 mpGEX4T-3/HPV 11 L1 벡터를 제조하는 단계, 상기 mpGEX4T-3/HPV11 L1 벡터를 Escherichia coli BL21 Gen-XTM에 형질전환하는 단계 및 상기 형질전환체로부터 HPV 11 L1 항원을 포함하는 융합 폴리펩타이드를 수득하는 단계를 통해 HPV 11 L1 항원을 포함하는 융합 폴리펩타이드를 제조할 수 있다.In addition, in an embodiment of the present invention, the polynucleotide encoding the amino acid sequence of the Simian
또한, 본 발명의 구체예에서, 상기 시미안 바이러스 40 대형 T 항원의 아미노산 서열 또는 이의 활성단편을 암호화하는 폴리뉴클레오티드를 제한효소 SalI 및 NotI으로 절단된 발현벡터 pGEX 4T-3에 삽입하여 mpGEX 4T-3 벡터를 제조하는 단계, 상기 mpGEX 4T-3 벡터를 제한효소 BamHI, SalI으로 절단하여 HPV 16 L1 항원의 아미노산 서열 또는 이의 활성단편을 암호화하는 폴리뉴클레오티드를 삽입하여 도 4에 개시된 개열지도를 가지는 mpGEX4T-3/HPV 16 L1 벡터를 제조하는 단계, 상기 mpGEX4T-3/HPV16 L1 벡터를 Escherichia coli BL21 Gen-XTM에 형질전환하는 단계 및 상기 형질전환체로부터 HPV 16 L1 항원을 포함하는 융합 폴리펩타이드를 수득하는 단계를 통해 HPV 16 L1 항원을 포함하는 융합 폴리펩타이드를 제조할 수 있다.In addition, in an embodiment of the present invention, the polynucleotide encoding the amino acid sequence of the Simian
또한, 본 발명의 구체예에서, 상기 시미안 바이러스 40 대형 T 항원의 아미노산 서열 또는 이의 활성단편을 암호화하는 폴리뉴클레오티드를 제한효소 SalI 및 NotI으로 절단된 발현벡터 pGEX 4T-3에 삽입하여 mpGEX 4T-3 벡터를 제조하는 단계, 상기 mpGEX 4T-3 벡터를 제한효소 EcoRI, SalI으로 절단하여 HPV 18 L1 항원의 아미노산 서열 또는 이의 활성단편을 암호화하는 폴리뉴클레오티드를 삽입하여 도 5에 개시된 개열지도를 가지는 mpGEX4T-3/HPV 18 L1 벡터를 제조하는 단계, 상기 mpGEX4T-3/HPV18 L1 벡터를 Escherichia coli BL21 Gen-XTM에 형질전환하는 단계 및 상기 형질전환체로부터 HPV 18 L1 항원을 포함하는 융합 폴리펩타이드를 수득하는 단계를 통해 HPV 18 L1 항원을 포함하는 융합 폴리펩타이드를 제조할 수 있다.
In addition, in an embodiment of the present invention, the polynucleotide encoding the amino acid sequence of the Simian
HPV 항원의 N 말단에 글루타티온 S-트랜스퍼라제(Glutathione S-transferase, GST)의 아미노산 서열 또는 이의 활성단편, C 말단에 시미안 바이러스 40 대형 T 항원(simian virus 40 large T-antigen)의 아미노산 서열 또는 이의 활성단편과 융합함으로써, 재조합 HPV 항원을 고순도로 분리, 정제하고 비드 어레이용 비드에 효과적으로 균일하게 부착시킬 수 있으며, 시미안 바이러스 40 대형 T 항원을 통하여 재조합 HPV 항원이 비드에 잘 부착되었는지, 부착시킨 양이 항상 동일한지, HPV 항원 4종간에 비드에 부착된 정도가 균일한지 등을 판정할 수 있는데, HPV 항체에 특이적으로 결합할 수 있는 항원성에 영향을 미치지 않기 위해서는 HPV 항원 부위의 선택, 결합 방향, 결합 위치가 모두 고려되어야 한다. 양 말단의 융합 부분의 존재로 인하여 항원성을 나타내는 부위가 분자 내부로 몰입되어 항원성이 감소하는 경우도 발생할 수 있기 때문이다. 본 발명의 융합 폴리펩타이드가 시료 내 HPV 항체를 높은 민감도 및 정확도로 스크리닝할 수 있다는 것은 전혀 유추할 수 없는 효과이다.
Amino acid sequence of glutathione S-transferase (GST) at its N terminus of HPV antigen or active fragment thereof, amino acid sequence of
상기 폴리뉴클레오티드 서열은 하나 이상의 염기가 치환, 결실, 삽입 또는 이들의 조합에 의해 변이될 수 있다. 뉴클레오티드 서열을 화학적으로 합성하여 제조하는 경우, 당업계에 널리 공지된 합성법, 예를 들어 문헌(Engels and Uhlmann, Angew Chem IntEd Engl., 37:73-127, 1988)에 기술된 방법을 이용할 수 있으며, 트리에스테르, 포스파이트, 포스포르아미다이트 및 H-포스페이트 방법, PCR 및 기타 오토프라이머 방법, 고체 지지체상의올리고뉴클레오티드 합성법 등을 들 수 있다.
The polynucleotide sequence may be mutated by one or more bases substituted, deleted, inserted, or a combination thereof. When chemically synthesizing nucleotide sequences, synthetic methods well known in the art may be used, for example, those described in Engels and Uhlmann, Angew Chem Int Ed Eng., 37: 73-127, 1988. , Triester, phosphite, phosphoramidite and H-phosphate methods, PCR and other autoprimer methods, oligonucleotide synthesis on a solid support, and the like.
본 발명에서 "작동가능하게 연결(operably linked)"은 일반적 기능을 수행하도록 핵산 발현조절 서열과 목적하는 단백질 또는 RNA를 암호화하는 핵산 서열이 기능적으로 연결(functional linkage)되어 있는 것을 말한다. 예를 들어 프로모터와 단백질 또는 RNA를 암호화하는 핵산 서열이 작동가능하게 연결되어 코딩서열의 발현에 영향을 미칠 수 있다. 발현 벡터와의 작동적 연결은 당해 기술분야에서 잘 알려진 유전자 재조합 기술을 이용하여 제조할 수 있으며, 부위-특이적 DNA 절단 및 연결은 당해 기술 분야에서 일반적으로 알려진 효소 등을 사용한다. In the present invention, "operably linked" refers to a functional linkage of a nucleic acid expression control sequence and a nucleic acid sequence encoding a protein or RNA of interest to perform a general function. For example, promoters and nucleic acid sequences encoding proteins or RNAs can be operably linked to affect expression of coding sequences. Operative linkage with expression vectors can be prepared using genetic recombination techniques well known in the art, and site-specific DNA cleavage and ligation employs enzymes and the like generally known in the art.
본 발명에서 "발현벡터"란 적당한 숙주세포에서 목적 단백질을 발현할 수 있는 재조합 벡터로서, 유전자 삽입물이 발현되도록 작동하게 연결된 필수적인 조절 요소를 포함하는 유전자 제작물을 말한다. 본 발명의 발현벡터는 적합한 발현벡터가 일반적으로 가지고 있는 요소로서 프로모터, 오퍼레이터, 개시코돈 같은 발현 조절 요소들을 포함한다. 개시 코돈 및 종결 코돈은 일반적으로 폴리펩타이드를 암호화하는 뉴클레오티드 서열의 일부로 간주되며, 유전자 제작물이 투여되었을 때 개체에서 반드시 작용을 나타내야 하며 코딩 서열과 인프레임(in frame)에 있어야 한다. 벡터의 프로모터는 구성적 또는 유도성일 수 있다. As used herein, an "expression vector" refers to a gene construct that is a recombinant vector capable of expressing a protein of interest in a suitable host cell and includes essential regulatory elements operably linked to express a gene insert. The expression vectors of the present invention include expression control elements such as promoters, operators, initiation codons as elements generally possessed by suitable expression vectors. Initiation and termination codons are generally considered to be part of a nucleotide sequence encoding a polypeptide and must be functional in the individual when the gene construct is administered and must be in frame with the coding sequence. The promoter of the vector may be constitutive or inducible.
또한, 세포 배양액으로부터 단백질의 분리를 촉진하기 위하여 융합 폴리펩타이드의 배출을 위한 시그널 서열을 포함할 수 있다. 특이적인 개시 시그널은 또한 삽입된 핵산 서열의 효율적인 번역에 필요할 수도 있다. 이들 시그널은 ATG 개시 코돈 및 인접한 서열들을 포함한다. 어떤 경우에는, ATG 개시 코돈을 포함할 수 있는 외인성 번역 조절 시그널이 제공되어야 한다. 이들 외인성 번역 조절 시그널들 및 개시 코돈들은 다양한 천연 및 합성 공급원일 수 있다. 발현 효율은 적당한 전사 또는 번역 강화 인자의 도입에 의하여 증가될 수 있다.
It may also include a signal sequence for the release of the fusion polypeptide to facilitate the separation of the protein from the cell culture. Specific initiation signals may also be required for efficient translation of inserted nucleic acid sequences. These signals include ATG start codons and contiguous sequences. In some cases, an exogenous translational control signal must be provided that can include an ATG start codon. These exogenous translational control signals and initiation codons can be various natural and synthetic sources. Expression efficiency can be increased by the introduction of appropriate transcriptional or translation enhancing factors.
발현벡터는 통상의 모든 발현 벡터를 다 사용할 수 있다. 숙주 세포에 따라서 단백질의 발현량과 수식 등이 다르게 나타나므로, 목적에 가장 적합한 숙주세포를 선택하여 사용하면 된다. 본 발명의 구체예에서, 본 발명의 융합 폴리펩타이드를 암호화하는 폴리뉴클레오티드를 포함한 발현 벡터로서 mpGEX4T-3/HPV6 L1 벡터, mpGEX4T-3/HPV11 L1 벡터, mpGEX4T-3/HPV16 L1 벡터, mpGEX4T-3/HPV18 L1 벡터를 제조하였다. As the expression vector, all conventional expression vectors can be used. Depending on the host cell, the expression level and expression of the protein are different. Therefore, the host cell may be selected and used according to the purpose. In an embodiment of the invention, an expression vector comprising a polynucleotide encoding the fusion polypeptide of the invention is an mpGEX4T-3 / HPV6 L1 vector, an mpGEX4T-3 / HPV11 L1 vector, an mpGEX4T-3 / HPV16 L1 vector, mpGEX4T-3 / HPV18 L1 vector was prepared.
상기 벡터가 발현되는 형질전환체를 영양배지에서 배양하면 유용한 단백질을 대량으로 제조, 분리 가능하다. 배지와 배양조건은 숙주 세포에 따라 관용되는 것을 적당히 선택하여 이용할 수 있다. 배양시 세포의 생육과 단백질의 대량 생산에 적합하도록 온도, 배지의 pH 및 배양시간 등의 조건들을 적절하게 조절하여야 한다. 본 발명에 따른 발현 벡터로 형질전환될 수 있는 숙주 세포는 원핵 세포를 포함하며, DNA의 도입효율이 높고, 도입된 DNA의 발현효율이 높은 숙주가 통상 사용된다. 세균, 예를 들어 에쉐리키아, 슈도모나스, 바실러스, 스트렙토마이세스와 같은 주지의 원핵 숙주들이 사용될 수 있는 숙주 세포의 예이다. 바람직하게는 대장균이 사용될 수 있다. 펩타이드의 발현은 유도인자 IPTG를사용하여 발현을 유도할 수 있고, 유도시간은 단백질의 양을 최대화되게 조절할 수 있다. 본 발명에서, 재조합적으로 생산된 펩타이드는 배지 또는 세포 분해물로부터 회수될 수 있다. 펩타이드 발현에 사용된 세포는 동결-해동 반복, 음파처리, 기계적 파괴 또는 세포 분해제와 같은 다양한 물질적 또는 화학적 수단에 의해 파괴될 수 있으며, 통상적인 생화학 분리 기술에 의해서 분리. 정제 가능하다(Sambrook et al., Molecular Cloning: A laborarory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, 1989; Deuscher, M., Guide to Protein Purification Methods Enzymology, Vol. 182. Academic Press. Inc., San Diego, CA, 1990). 전기영동, 원심분리, 겔여과, 침전, 투석, 크로마토그래피(이온교화크로마토그래피, 친화력 크로마토그래피, 면역흡착 친화력 크로마토그래피, 역상 HPLC, 겔 침투 HPLC), 등전성 포커스 및 이의 다양한 변화 및 복합 방법을 포함하나 이에 국한되지 않는다. When the transformant expressing the vector is cultured in a nutrient medium, a large amount of useful protein can be prepared and separated. The medium and culture conditions may be appropriately selected depending on the host cell. In culture, conditions such as temperature, pH of the medium, and incubation time should be appropriately adjusted to be suitable for cell growth and mass production of proteins. Host cells that can be transformed with the expression vector according to the present invention include prokaryotic cells, and a host with high expression efficiency of introduced DNA and a high expression efficiency of introduced DNA is usually used. Bacteria, for example, known prokaryotic hosts such as Escherichia, Pseudomonas, Bacillus, Streptomyces, are examples of host cells that can be used. Preferably E. coli can be used. Expression of the peptide can be induced using inducer IPTG, and induction time can be controlled to maximize the amount of protein. In the present invention, recombinantly produced peptides can be recovered from medium or cell lysate. Cells used for peptide expression can be disrupted by a variety of physical or chemical means, such as freeze-thaw repeats, sonication, mechanical disruption or cell digestion, and are isolated by conventional biochemical separation techniques. Purification is possible (Sambrook et al., Molecular Cloning: A laborarory Manual, 2nd Ed., Cold Spring Harbor Laboratory Press, 1989; Deuscher, M., Guide to Protein Purification Methods Enzymology, Vol. 182. Academic Press. Inc., San Diego, CA, 1990). Electrophoresis, centrifugation, gel filtration, precipitation, dialysis, chromatography (ion exchange chromatography, affinity chromatography, immunosorbent affinity chromatography, reverse phase HPLC, gel permeation HPLC), isoelectric focus and various variations and combinations thereof Including but not limited to.
또다른 양태로서, 본 발명은 상기 융합 폴리펩타이드를 비드 어레이용 비드에 결합시키는 단계; 상기 융합 폴리펩타이드가 결합된 비드를 시료와 반응시키는 단계; 상기 시료를 표지자 표지된 2차 항체와 반응시키는 단계; 상기 2차 항체를 형광물질이 부착된 상기 표지자의 특이적 결합제와 반응시키는 단계 및 비드 유래의 형광값과 표지자의 특이적 결합제 유래의 형광값을 측정하여 시료 내 HPV 항체를 검출하는 방법을 제공한다. 상기 비드 어레이용 비드는 글루타치온-카세인(Glutathione-casein ;GC) 비드일 수 있고, 상기 표지자는 비오틴이고 상기 표지자의 특이적 결합제는 스트렙타비딘일 수 있으며, 상기 형광물질은 플루오레신, 이소티오시아네이트, 로다민, 피코에리트린, 피코시아닌, 알로피코시아닌, o-프탈데히드 또는 플루오레스카민일 수 있다. 상기 비드 어레이는 다중 비드 어레이일 수 있고, 본 발명의 구체적인 실시예에서는 루미넥스 분석법을 이용하였다.
In another aspect, the present invention provides a method for preparing a bead array comprising: binding the fusion polypeptide to beads for beads array; Reacting the beads to which the fusion polypeptide is bound with a sample; Reacting the sample with a marker labeled secondary antibody; A method of detecting HPV antibodies in a sample by reacting the secondary antibody with a specific binding agent of the marker to which a fluorescent substance is attached and measuring a fluorescence value derived from a bead and a fluorescence value derived from a specific binding agent of a marker are provided. . The bead array beads may be glutathione-casein (GC) beads, the marker may be biotin and the specific binding agent of the marker may be streptavidin, and the fluorescent material may be fluorescein, isothiocia. Nate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthalaldehyde or fluorescarmine. The bead array may be a multi-bead array, in the specific embodiment of the present invention was used luminex analysis.
본 발명에 따른 방법은 N 말단에 글루타티온 S-트랜스퍼라제(Glutathione S-transferase, GST)의 아미노산 서열 또는 이의 활성단편; C 말단에 시미안 바이러스 40 대형 T 항원(simian virus 40 large T-antigen)의 아미노산 서열 또는 이의 활성단편; 및 HPV 6 L1 항원, HPV11 L1 항원, HPV16 L1 항원 및 HPV18 L1 항원으로 구성된 군으로부터 선택된 HPV L1 항원의 아미노산 서열 또는 이의 활성단편을 포함하는 융합 폴리펩타이드인 재조합 HPV 항원을 비드 어레이용 비드에 결합시키는 단계를 포함한다.
The method according to the present invention comprises an amino acid sequence of glutathione S-transferase (GST) at its N terminus or an active fragment thereof; The amino acid sequence of the
상기 비드 어레이용 비드로 루미넥스 비드 (Luminex bead)를 사용할 수 있다. 상기 비드는 다중 비드 어레이 방법에 사용될 수 있는 것이면 특별히 제한되지 않고 비드에 추가적으로 글루타치온-카세인(Glutathione-casein; GC)을 결합시킨 글루타치온-카세인(Glutathione-casein; GC) 비드를 사용할 수도 있다. 글루타치온-카세인 비드는 당업계 공지된 다양한 방법으로 제작할 수 있으며 또는 구입하여 사용할 수도 있다. 본 발명의 구체적인 실시예 따르면, N-ethylmaleimide(NEM)로 카세인의 시스테인(cysteine) 잔기를 블로킹(blocking) 시킨 후 heterobifunctional cross-linker인 sulfo-succinimidyl-4-(P-maleimidophenyl)-butyrate(sulfo-SMPB)를 첨가하여 티올(thiol)기와 반응할 수 있는 casein-maleimidophenyl-butyrate을 형성시키고 글루타치온(glutathione)의 cystain의 티올 잔기와 반응하여 글루타치온-카세인(Glutathione-casein ;GC)이 형성되도록 하였다. 글루타치온-카세인(Glutathione-casein ;GC)의 말단 아민(terminal amines)과 비드의 카볼실 그룹(carboxyl groups)을 결합시켜 글루타치온-카세인 비드를 제작하였다.
Luminex beads may be used as beads for the bead array. The beads are not particularly limited as long as they can be used in a multi-bead array method, and glutathione-casein (GC) beads in which glutathione-casein (GC) is additionally bound to the beads may be used. Glutathione-casein beads can be prepared by a variety of methods known in the art or can be purchased and used. According to a specific embodiment of the present invention, after blocking the cysteine residue of casein with N-ethylmaleimide (NEM), a heterobifunctional cross-linker sulfo-succinimidyl-4- (P-maleimidophenyl) -butyrate (sulfo- SMPB) was added to form casein-maleimidophenyl-butyrate, which can react with thiol groups, and to form glutathione-casein (GC) by reacting with thiol residues of glutathione cystain. Glutathione-casein beads were prepared by combining terminal amines of glutathione-casein (GC) with carboxyl groups of the beads.
상기 다중 비드 어레이용 비드는 색으로 100종류까지 구별할 수 있으므로 특정 색(번호)의 비드에 특정 항원을 붙여주고 여러 비드 세트를 섞어서 반응을 진행한 후 다중 비드 어레이 분석기(예를 들어, 루미넥스 분석기)로 각 비드의 색과 그 비드 표면의 항원 항체 반응량을 동시에 측정하면, HPV 6 L1 항체, HPV11 L1 항체, HPV16 L1 항체 또는 HPV18 L1 항체를 포함하여 여러 항체를 동시에 측정할 수 있다. 따라서 소량의 시료만으로 분석이 가능할 뿐만 아니라 1회 실험으로 여러 번의 실험을 대신할 수 있으므로 시간과 노동력이 절약된다.
Since the beads for the multiple bead array can be distinguished up to 100 types by color, a specific antigen is attached to the beads of a specific color (number), and a plurality of bead mixtures are mixed to perform a reaction, and then a multiple bead array analyzer (for example, Luminex By measuring the color of each bead and the reaction amount of the antigenic antibody on the surface of the bead simultaneously, several antibodies can be measured simultaneously, including
또한, 본 발명에 따른 방법은 상기 융합 폴리펩타이드가 결합된 비드를 시료와 반응시키는 단계를 포함한다. 상기 시료는 HPV에 의하여 감염될 수 있는 개체들[예, 포유 동물 예컨대, 인간, 가축(예, 소, 말, 돼지, 양 및 염소) 및 애완 동물(예, 고양이 및 개)]등을 포함하는 개체에서 유래한다. 시료는 혈청, 세포 등 HPV 항체를 포함할 수 있는 것이면 모두 포함된다. 융합 폴리펩타이드 항원은 시료 내 HPV 6 L1 항체, HPV11 L1 항체, HPV16 L1 항체 및 HPV18 L1 항체와 항원-항체 반응을 한다.
In addition, the method according to the invention comprises the step of reacting the beads with the fusion polypeptide is bound to the sample. The sample may include individuals that may be infected by HPV (eg mammals such as humans, livestock (eg cattle, horses, pigs, sheep and goats) and pets (eg cats and dogs)). It comes from an individual. Samples are included as long as they can contain HPV antibodies, such as serum and cells. The fusion polypeptide antigens undergo antigen-antibody reactions with
또한 본 발명은 상기 시료를 표지자 표지된 2차 항체와 반응시키는 단계 상기 2차 항체를 형광물질이 부착된 상기 표지자의 특이적 결합제와 반응시키는 단계 및 비드 유래의 형광값과 표지자의 특이적 결합제 유래의 형광값을 측정하여 시료 내 HPV 항체를 검출하는 단계를 포함한다. 상기 표지자는 비오틴(biotin)일 수 있고, 표지자의 특이적 결합제는 스트렙타비딘일 수 있다.
In another aspect, the present invention is the step of reacting the sample with a marker-labeled secondary antibody reacting the secondary antibody with a specific binding agent of the marker to which the fluorescent material is attached and the fluorescence value from the beads and the specific binding agent of the marker Detecting the HPV antibody in the sample by measuring the fluorescence value of the sample. The marker may be biotin and the specific binding agent of the marker may be streptavidin.
상기 2차 항체는 시료 내 HPV 6 L1 항체, HPV11 L1 항체, HPV16 L1 항체 및 HPV18 L1 항체와 특이적으로 결합하며 2차 항체에 결합된 비오틴은 스트렙타비딘(또는 아비딘)과 특이적으로 결합하므로 스트렙타비딘에 결합된 형광물질에서 형광을 발현하게 된다. 상기 형광물질은 예를 들어 플루오레신, 이소티오시아네이트, 로다민, 피코에리트린, 피코시아닌, 알로피코시아닌, o-프탈데히드 또는 플루오레스카민일 수 있으나 이에 제한되지 않으며 당업계에 공지된 다양한 형광물질을 사용할 수 있다.
The secondary antibody specifically binds
비드 유래의 형광값(각 비드의 색)과 표지자의 특이적 결합제 유래의 형광값을 함께 측정하여 항원 항체 반응량을 결정함으로써 시료 내 HPV 6 L1 항체, HPV11 L1 항체, HPV16 L1 항체 또는 HPV18 L1 항체의 존부 및 항체의 역가를 정확히 검출할 수 있다. 항체의 역가는 형광값의 판정 기준치(cutoff value) 설정하여 측정한다.
The fluorescence value derived from the beads (color of each bead) and the fluorescence value derived from the specific binding agent of the marker were measured together to determine the reaction amount of the antigen antibody. The presence of and the titer of the antibody can be detected accurately. The titer of an antibody is measured by setting the cutoff value of a fluorescence value.
본 발명의 구체적 실시예에서, 상기 HPV 항원을 N 말단에 글루타티온 S-트랜스퍼라제(Glutathione S-transferase, GST)의 아미노산 서열 또는 이의 활성단편, C 말단에 시미안 바이러스 40 대형 T 항원(simian virus 40 large T-antigen)의 아미노산 서열 또는 이의 활성단편과 융합함으로써, HPV 항체에 특이적으로 결합할 수 있는 활성에 영향을 미치지 않으면서도, 재조합 HPV 항원을 고순도로 분리, 정제하고 비드 어레이용 비드에 효과적으로 균일하게 부착시킬 수 있으며, 시미안 바이러스 40 대형 T 항원을 통하여 재조합 HPV 항원이 비드에 잘 부착되었는지, 부착시킨 양이 항상 동일한지, HPV 항원 4종간에 비드에 부착된 정도가 균일한지 등을 판정할 수 있어, 높은 민감도 및 정확도로 시료 내 HPV 6 L1 항체, HPV11 L1 항체, HPV16 L1 항체 또는 HPV18 L1 항체를 포함하는 HPV 항체를 스크리닝할 수 있었다.
In a specific embodiment of the present invention, the HPV antigen is the amino acid sequence of glutathione S-transferase (GST) at the N terminus or an active fragment thereof,
다른 양태로 본 발명은 N 말단에 글루타티온 S-트랜스퍼라제(Glutathione S-transferase, GST)의 아미노산 서열 또는 이의 활성단편 C 말단에 시미안 바이러스 40 대형 T 항원(simian virus 40 large T-antigen)의 아미노산 서열 또는 이의 활성단편 및 HPV 6 L1 항원, HPV11 L1 항원, HPV16 L1 항원 및HPV18 L1 항원으로 구성된 군으로부터 선택된 HPV L1 항원의 아미노산 서열 또는 이의 활성단편을 포함하는 융합 폴리펩타이드를 포함하는 비드 어레이용 HPV 항체 검출 키트를 제공한다.
In another aspect, the present invention provides an amino acid sequence of glutathione S-transferase (GST) at the N-terminus or an amino acid of
본 발명을 이용하면 HPV 항체에 특이적으로 결합할 수 있는 활성에 영향을 미치지 않으면서도 재조합 HPV 항원을 고순도로 분리, 정제하고 비드 어레이용 비드에 효과적으로 균일하게 부착시킬 수 있어 높은 민감도 및 정확도로 시료 내 HPV 6, 11, 16 및 18 항체를 복합적으로 검출할 수 있다. 항체 역가를 측정하여 HPV 백신의 접종시기를 결정하는데 활용될 수 있고, 백신 접종 후 방어 기간의 측정 등에 활용 가능하다.
Using the present invention, it is possible to isolate and purify recombinant HPV antigens with high purity and effectively and uniformly attach them to beads for beads array without affecting the activity that can specifically bind to HPV antibodies.
도 1은 SV40 대형 T 항원 올리고머가 발현벡터 pGEX4T-3 내에 정확히 삽입되어 있음을 확인하기 위해 SV40 대형 T 항원이 삽입된 pGEX4T-3 벡터로 형질전환한 대장균 E. coli DH5α로부터 플라스미드 DNA를 분리한 다음, 제한효소 SalI으로 절단한 후, 1% 아가로스 겔에 DNA 사이즈 마커와 SalI으로 절단된 pGEX4T-3을 함께 전기영동한 것을 도시한 것이다.
도 2는 mpGEX4T-3/HPV6 L1 벡터를 나타낸 개열지도이다.
도 3은 mpGEX4T-3/HPV11 L1 벡터를 나타낸 개열지도이다.
도 4는 mpGEX4T-3/HPV16 L1 벡터를 나타낸 개열지도이다.
도 5는 mpGEX4T-3/HPV18 L1 벡터를 나타낸 개열지도이다.
도 6은 재조합 균주 E. coli BL21 Gen-XTM / mpGEX4T-3/HPV 6L1, E. coli BL21 Gen-XTM / mpGEX4T-3/HPV11L1, E. coli BL21 Gen-XTM / mpGEX4T-3/HPV16L1 및 E. coli BL21 Gen-XTM / mpGEX4T-3/HPV18L1으로부터 발현한 HPV 6 L1 항원 포함 융합 폴리펩타이드, HPV 11 L1 항원 포함 융합 폴리펩타이드, HPV 16 L1 항원 포함 융합 폴리펩타이드, HPV 18 L1 항원 포함 융합 폴리펩타이드를rabbit anti-GST항체를 사용하여 웨스턴 블랏팅한 것을 나타낸 것이다.
도 7은 재조합 균주 E. coli BL21 Gen-XTM / mpGEX4T-3/HPV16L1 으로부터 발현한 HPV 16 L1 항원 포함 융합 폴리펩타이드를 mouse anti-HPV16 L1 항체를 사용하여 웨스턴 블랏한 것을 나타낸 것이다.
도 8은 재조합 균주 E. coli BL21 Gen-XTM / mpGEX4T-3/HPV18L1으로부터 발현한 HPV 18 L1 항원 포함 융합 폴리펩타이드를 mouse anti-HPV18 L1 항체를 사용하여 웨스턴 블랏한 것을 나타낸 것이다.
도 9 및 도 10은 HPV 16 항체와 HPV18 항체를 차례로 희석하여 HPV 16 L1 항원 및 HPV18 L1 항원을 이용한 표준 정량 곡선을 나타낸 것이다.
도 11은 2가 HPV 백신과 Placebo 백신을 접종한 그룹을 대상으로 백신 접종 후 혈액을 채취하여 혈청을 분리 한 후 본 발명의 HPV16 L1 항원 및 HPV18 L1 항원을 이용하여 실제로 혈액 내 HPV 항체의 양을 측정한 결과이다.FIG. 1 shows plasmid DNA isolated from E. coli DH5α transformed with pGEX4T-3 vector inserted with SV40 large T antigen to confirm that the SV40 large T antigen oligomer is correctly inserted into the expression vector pGEX4T-3. , After digestion with restriction enzyme Sal I, electrophoresis of pGEX4T-3 digested with Sal I with a DNA size marker on a 1% agarose gel.
2 is a cleavage map showing an mpGEX4T-3 / HPV6 L1 vector.
3 is a cleavage map showing an mpGEX4T-3 / HPV11 L1 vector.
4 is a cleavage map showing an mpGEX4T-3 / HPV16 L1 vector.
5 is a cleavage map showing an mpGEX4T-3 / HPV18 L1 vector.
6 shows recombinant
7 shows recombinant strain E. coli The blotting polypeptide expressed from BL21 Gen-X ™ / mpGEX4T-3 / HPV16L1 was expressed by Western blot using a mouse anti-HPV16 L1 antibody.
8 shows recombinant strain E. coli The blotting polypeptide of
9 and 10 show standard quantification
Figure 11 shows the actual amount of HPV antibody in the blood using the HPV16 L1 antigen and HPV18 L1 antigen of the present invention after the blood was collected after vaccination in the group vaccinated with the bivalent HPV vaccine and Placebo vaccine. It is a result of a measurement.
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.
실시예1: SV40가 태깅된 변형된 발현벡터의 구축Example 1 Construction of a Modified Expression Vector Tagged with SV40
차후 마이크로비드와 융합 폴리펩타이드의 결합을 확인하기 위하여, 항원에 SV40 대형 T 항원의 11개의 아미노산이 태깅되도록 pGEX4t-3 발현벡터를 변형하였다. To confirm the binding of the microbeads and the fusion polypeptides later, the pGEX4t-3 expression vector was modified to tag the antigen with 11 amino acids of the SV40 large T antigen.
먼저 SV40 대형 T 항원의 11개의 아미노산 서열을 암호화하는 서열번호 1 센스 DNA 올리고머 (SV40S)와 그 염기에 상보적인 서열번호 2 안티센스 DNA 올리고머 (SV40AS)를 각각 제작하였다. 서열번호 1 올리고머는 제한효소 SalI 절단부위를, 서열번호 2 올리고머는 제한효소 NotI 절단부위를 각각 포함하도록 합성하였다. 합성된 각각의 올리고머를 어닐링 완충용액 하에서 90℃에서 4분간 반응시킨 후 70℃ 10분, 10℃에서 2시간 반응시켰다. 어닐링된 SV40 대형 T 항원 올리고머를 제한효소 SalI 및 NotI으로 절단된 발현벡터 pGEX4T-3에 삽입하여 T4 DNA 연결효소를 사용하여 실온에서 3시간 동안 연결반응을 시켜 연결시킨 후, 대장균 E. coli DH5α에 형질전환시켰다 (참조: Sambrook, J. et al., 1989, Molecular cloning, a laboratory manual, 2nd ed., Cold Spring Harbor Laboratory Press).
First, SEQ ID NO: 1 sense DNA oligomer (SV40S) encoding 11 amino acid sequences of the SV40 large T antigen and SEQ ID NO: 2 antisense DNA oligomer (SV40AS) complementary to the base were prepared, respectively. The SEQ ID NO: 1 oligomer was synthesized to include restriction enzyme Sal I cleavage site, and the SEQ ID NO: 2 oligomer included restriction enzyme Not I cleavage site. Each of the synthesized oligomers was reacted at 90 ° C. for 4 minutes under annealing buffer, followed by reaction at 70 ° C. for 10 minutes and 10 ° C. for 2 hours. The annealed SV40 large T antigen oligomer was inserted into the expression vector pGEX4T-3 digested with restriction enzymes Sal I and Not I and ligated for 3 hours at room temperature using T4 DNA ligase, followed by Escherichia coli E. coli. DH5α was transformed (Sambrook, J. et al., 1989, Molecular cloning, a laboratory manual, 2nd ed., Cold Spring Harbor Laboratory Press).
서열번호 1 센스 DNA 올리고머 (SV40S) : SEQ ID NO: 1 sense DNA oligomer (SV40S):
5'-TC GAC AAA CCT CCC ACA CCT CCC CCT GAA CCT GAA ACA GC-3'
5'- TC GAC AAA CCT CCC ACA CCT CCC CCT GAA CCT GAA ACA GC -3 '
서열번호 2 안티센스 DNA 올리고머 (SV40AS) : SEQ ID NO: 2 antisense DNA oligomer (SV40AS):
5'-GGCCGC TGT TTC AGG TTC AGG GGG AGG TGT GGG AGG TTT G-3'
5'- GGCCGC TGT TTC AGG TTC AGG GGG AGG TGT GGG AGG TTT G -3 '
형질전환체들로부터 플라스미드 DNA를 분리한 다음, 제한효소 SalI으로 절단한 후, 1% 아가로스 겔에 DNA 사이즈 마커와 SalI으로 절단된 pGEX4T-3을 함께 전기영동하여 SV40 대형 T 항원 올리고머가 발현벡터 내에 정확히 삽입되어 있음을 재확인하였다(도 1). 상기와 같이 구축된 SV40 대형 T 항원을 암호화하는 DNA 서열로 변형된 pGEX4T-3를 mpGEX4T-3으로 명명하였다.
Plasmid DNA was isolated from the transformants, digested with restriction enzyme Sal I, and electrophoresed with DNA size markers and pGEX4T-3 digested with Sal I on a 1% agarose gel to obtain SV40 large T antigen oligomer. It was again confirmed that it was correctly inserted in the expression vector (FIG. 1). PGEX4T-3 modified with the DNA sequence encoding the SV40 large T antigen constructed as above was named mpGEX4T-3.
실시예 2: HPV 6 L1, HPV 11 L1, HPV 16 L1 및 HPV 18 L1 유전자의 발현을 위한 발현벡터의 구축Example 2 Construction of Expression Vectors for Expression of
독일로부터 분양 받은 recombinant plasmid harboring full genome of HPV 6, HPV 11, HPV 16 및 HPV 18 로부터 얻은 L1 유전자를 발현벡터에 삽입한 재조합 플라스미드 (mpGEX4T-3/HPV 6 L1, mpGEX4T-3/HPV11 L1, mpGEX4T-3/HPV16 L1 및mpGEX4T-3/HPV18 L1)를 하기와 같이 구축하였다.Recombinant plasmid containing L1 genes from recombinant plasmid harboring full genome of
먼저 HPV 6 L1, HPV 11 L1, HPV 16 L1 및 HPV 18 L1 유전자를 얻기 위해 HPV 6 L1 유전자의 염기서열로부터 N-말단 아미노산 서열을 암호화하는 서열번호 3 프라이머 (HPV6L1F) (5' 말단 프라이머)와 C-말단 아미노산 서열을 암호화하는 DNA 염기에 상보적인 서열번호 4 프라이머 (HPV6L1R) (3' 말단 프라이머) HPV 11 L1 유전자의 염기서열로부터 N-말단 아미노산 서열을 암호화하는 서열번호 5 프라이머 (HPV11L1F) (5' 말단 프라이머)와 C-말단 아미노산 서열을 암호화하는 DNA 염기에 상보적인 서열번호 6 프라이머 (HPV11L1R) (3' 말단 프라이머) HPV 16 L1 유전자의 염기서열로부터 N-말단 아미노산 서열을 암호화하는 서열번호 7 프라이머 (HPV16L1F) (5' 말단 프라이머)와 C-말단 아미노산 서열을 암호화하는 DNA 염기에 상보적인 서열번호 8 프라이머 (HPV16L1R) (3' 말단 프라이머) HPV 18 L1 유전자의 염기서열로부터 N-말단 아미노산 서열을 암호화하는 서열번호 9 프라이머 (HPV18L1F) (5' 말단 프라이머)와 C-말단 아미노산 서열을 암호화하는 DNA 염기에 상보적인 서열번호 10 프라이머 (HPV18L1R) (3' 말단 프라이머)를 각각 제작하였다. First, the SEQ ID NO: 3 primer (HPV6L1F) (5 'terminal primer) encoding the N-terminal amino acid sequence from the nucleotide sequence of the HPV 6 L1 gene to obtain HPV 6 L1, HPV 11 L1, HPV 16 L1 and HPV 18 L1 gene SEQ ID NO: 4 primer (HPV6L1R) complementary to the DNA base encoding the C-terminal amino acid sequence (3 'terminal primer) SEQ ID NO: 5 primer (HPV11L1F) encoding the N-terminal amino acid sequence from the nucleotide sequence of the HPV 11 L1 gene ( SEQ ID NO: 6 primer (HPV11L1R) (3 'terminal primer) sequence complementary to the DNA base encoding the C-terminal amino acid sequence) and the C-terminal amino acid sequence Salt of HPV 18 L1 gene with SEQ ID NO: 8 primer (HPV16L1R) (3 'terminal primer) complementary to 7 primer (HPV16L1F) (5' terminal primer) and DNA base encoding C-terminal amino acid sequence SEQ ID NO: 9 primer (HPV18L1F) (5 'terminal primer) encoding the N-terminal amino acid sequence from the sequence and SEQ ID NO: 10 primer (HPV18L1R) (3' terminal primer) complementary to the DNA base encoding the C-terminal amino acid sequence Were produced respectively.
제작한 프라이머를 이용하여 각각의 HPV L1 유전자를 증폭시켰다. 서열번호 3, 5, 7, 9 프라이머는 제한효소 EcoRI 또는 BglII 절단부위를, 서열번호 4, 6, 8, 10 프라이머는 제한효소 SalI 절단부위를 각각 포함하도록 합성하였다. Each HPV L1 gene was amplified using the prepared primers. The primers SEQ ID NO: 3, 5, 7, 9 were synthesized to include restriction enzyme Eco RI or Bgl II cleavage sites, and SEQ ID NO: 4, 6, 8, 10 primers containing restriction enzyme Sal I cleavage sites.
각각의 PCR은 0.2 ㎍ HPV 플라스미드 DNA와 10 pmole의 5'-말단 프라이머 및 3'-말단 프라이머, 200 μM dNTPs, 10X Accuprime DNA 중합효소 완충용액 및 2.5 U Accuprime DNA 중합효소 (invitrogen)로 이루어진 혼합 조성액을 95℃에서 3분간 반응시킨 후 95℃ 30초, 60℃에서 30초, 68℃에서 90초의 조건으로 30회 반복한 후, 마지막 68℃에서 5분간 반응시켰다.
Each PCR was a mixed composition consisting of 0.2 μg HPV plasmid DNA, 10 pmole 5'-terminal and 3'-terminal primers, 200 μM dNTPs, 10X Accuprime DNA polymerase buffer and 2.5 U Accuprime DNA polymerase (invitrogen). After reacting for 3 minutes at 95
서열번호 3 프라이머 (HPV6L1F) :SEQ ID NO: 3 Primer (HPV6L1F):
5'-NNNNN GAATTC AATGTGGCGGCCTAGCGACAG-3'(EcoRI 절단부위 포함)5'-NNNNN GAATTC AATGTGGCGGCCTAGCGACAG-3 '(includes Eco RI cut)
서열번호 4 프라이머 (HPV6L1R) :SEQ ID NO: 4 Primer (HPV6L1R):
5'-GCATGA GTCGAC CCTTTTAGTTTTGGCGCGC-3'(SalI 절단부위 포함)5'-GCATGA GTCGAC CCTTTTAGTTTTGGCGCGC-3 'with Sal I cut
서열번호 5 프라이머 (HPV11L1F) :SEQ ID NO: 5 Primer (HPV11L1F):
5'-GCAGTC GAATTC GTGGCGGCCTAGCGACAGCACA-3' (EcoRI 절단부위 포함)5'-GCAGTC GAATTC GTGGCGGCCTAGCGACAGCACA-3 '(includes Eco RI cut)
서열번호 6 프라이머 (HPV11L1R) :SEQ ID NO: 6 Primer (HPV11L1R):
5'-NNNNN GTCGAC CTTTTTGGTTTTGGTACGTTTTCGTTT-3' (SalI 절단부위 포함)
5'-NNNNN GTCGAC CTTTTTGGTTTTGGTACGTTTTCGTTT-3 '(including Sal I cut)
서열번호 7 프라이머 (HPV16L1F) :SEQ ID NO: 7 Primer (HPV16L1F):
5'-NNNNN AGATCT ATGCAGGTGACTTTTATTTACATCCTA-3' (BglII 절단부위 포함)
5'-NNNNN AGATCT ATGCAGGTGACTTTTATTTACATCCTA-3 '(including Bgl II cleavage site)
서열번호 8 프라이머 (HPV16L1R) :SEQ ID NO: 8 Primer (HPV16L1R):
5'-GCATGA GTCGAC CAGCTTACGTTTTTTGCGTTTAGC-3' (SalI 절단부위 포함)
5'-GCATGA GTCGAC CAGCTTACGTTTTTTGCGTTTAGC-3 '(Including Sal I cut)
서열번호 9 프라이머 (HPV18L1F) :SEQ ID NO: 9 Primer (HPV18L1F):
5'-NNNNN GAATTC AATGTGCCTGTATACACGGGTCCTG-3' (EcoRI 절단부위 포함)
5'-NNNNN GAATTC AATGTGCCTGTATACACGGGTCCTG-3 '(includes Eco RI cut)
서열번호 10 프라이머 (HPV18L1R) :SEQ ID NO: 10 Primer (HPV18L1R):
5'-GCATGA GTCGAC CTTCCTGGCACGTACACGGAC-3' (SalI 절단부위 포함)
5'-GCATGA GTCGAC CTTCCTGGCACGTACACGGAC-3 '(includes Sal I cleavage)
DNA 사이즈 마커 (size marker)와 함께 1% 아가로스 겔에 전기영동하여 약 1.5 kb 위치에 각각의 밴드가 존재하는 것을 확인하였다. PCR이 끝난 반응 혼합물을 1% 아가로스 겔에 전기영동하여, PCR을 통해 증폭된 약 1.5 kb의 DNA 산물을 PCR quick-spinTM PCR Product Purification Kit (Intron, Korea)을 사용하여 정제하여 회수하였다. 회수된 HPV 6, HPV 11, HPV 18 DNA를 제한효소 EcoRI 및 SalI으로, HPV 16 DNA를 제한효소 BglII 및 SalI으로 각각 절단한 다음, 유전자 절편을 각각 정제하고 회수하였다. 정제된 유전자 절편을 동일한 제한효소로 절단된 발현벡터 mpGEX4T-3에 각각 삽입하여 T4 DNA 연결효소를 사용하여 실온에서 3시간 동안 연결반응을 시켜 연결시킨 후, E. coli BL21 Gen-XTM 에 형질전환시켰다. (mpGEX4T-3/HPV16 L1을 제작하기 위하여 제한효소 BglII 와 BamHI은 annealing 서열이 동일함으로 mpGEX4T-3을 BamHI으로, HPV 16 L1을 BglII 로 절단하여 연결하였다.) 형질전환체들로부터 플라스미드 DNA를 분리한 다음, 상기의 제한효소로 절단한 후, 1% 아가로스 겔에 DNA 사이즈 마커와 함께 전기영동하여 각각의 유전자가 발현벡터 내에 정확히 삽입되어 있음을 재확인하였다. 상기와 같이 구축된 HPV 6 L1 유전자의 발현을 위해 구축된 발현벡터를 mpGEX4T-3/HPV6L1으로 (도 2), HPV 11 L1 유전자의 발현을 위해 구축된 발현벡터를 mpGEX4T-3/HPV11L1으로 (도 3), HPV 16 L1 유전자의 발현을 위해 구축된 발현벡터를 mpGEX4T-3/HPV16L1으로(도 4) HPV 18 L1 유전자의 발현을 위해 구축된 발현벡터를 mpGEX4T-3/HPV18L1으로 명명하였다 (도 5).
Electrophoresis on 1% agarose gels with DNA size markers confirmed the presence of each band at about 1.5 kb. After the PCR reaction mixture was electrophoresed on a 1% agarose gel, the DNA product of about 1.5 kb amplified by PCR was recovered by using a PCR quick-spin TM PCR Product Purification Kit (Intron, Korea). The recovered
실시예 3: HPV 6 L1, HPV 11 L1, HPV 16 L1, HPV 18 L1 포함 융합 폴리펩타이드의 발현과 정제Example 3: Expression and Purification of Fusion
대장균에 형질전환 시킨 재조합 균주 E. coli BL21 Gen-XTM / mpGEX4T-3/HPV 6L1, E. coli BL21 Gen-XTM / mpGEX4T-3/HPV11L1, E. coli BL21 Gen-XTM / mpGEX4T-3/HPV16L1 및 E. coli BL21 Gen-XTM / mpGEX4T-3/HPV18L1으로부터 N 말단에 GST가, C말단에 SV40이 융합된 HPV 6 L1항원, HPV11 L1항원, HPV16 L1항원과 HPV18 L1항원으로 각각 발현시킨 후, rabbit anti-GST 항체, mouse anti-HPV6 L1 항체, mouse anti-HPV11 L1 항체, mouse anti-HPV16 L1 항체 또는 mouse anti-HPV18 L1 항체, KT3항체 각각을 첫번째 항체로 사용한 웨스턴 블랏을 시행하여 발현 여부를 확인하였다. 그 결과를 도 6 내지 8을 통하여 확인하였다. 그 다음 발현된 단백질을 아래와 같이 정제하였다. E. coli BL21 Gen-X TM / mpGEX4T-3 / HPV 6L1, E. coli BL21 Gen-X TM / mpGEX4T-3 / HPV11L1, E. coli BL21 Gen-X TM / mpGEX4T-3 / HPV16L1 and E. coli BL21 Gen-X TM / mpGEX4T-3 / from the GST at the N-terminal HPV18L1,
재조합 플라스미드를 가지고 있는 E. coli BL21 Gen-XTM 을 100 ㎍/㎕ 암피실린이 첨가된 LB 액체 배지에 접종하여 37℃에서 16시간 동안 배양한 다음 500ul를 100 ㎍/㎕ 암피실린이 첨가된 LB 액체 배지에 접종하여 100㎖에 접종하여 37℃에서 배양하였다. 600 nm에서의 흡광도가 0.4정도가 되었을 때, IPTG (isopropyl β-D-galactopyranoside)를 최종농도가 1.0 mM이 되도록 첨가하고 3시간 배양하여 단백발현을 유도하였다. 6,000 rpm으로 15분간 원심 분리하여 균체 (1.4 g/ wet weight)를 회수한 다음 CompleteTM Protease Inhibitor Cocktail (Santa Cruz Biotechnology)이 포함된 5 ml의 초음파처리 완충액 (sonication buffer) (50 mM Tris-HCl [pH8.0], 150 mM NaCl, 5 mM EDTA)에 현탁 한 다음 최종농도 0.1㎎/㎖ lysozyme을 첨가하고 4℃에서 1시간 lysis 시킨다. 초음파로 파쇄한 후1% triton x-100을 첨가하고 4℃에서 1시간 반응시킨 다음 14,000 rpm으로 15분간 원심 분리하여 대장균 세포 파편(cell debris)을 제거하였다. 다음으로 상기 상층액을 Glutathione SepharoseTM 4B (GE Healthcare)를 이용한 친화성 크로마토그래피를 통해 최종적으로 정제하였다.
E. coli BL21 Gen-X TM with recombinant plasmid was inoculated in LB liquid medium with 100 μg / μl ampicillin and incubated at 37 ° C. for 16 hours, followed by 500ul of LB liquid medium with 100 μg / μl Ampicillin. Inoculated in 100ml and incubated at 37 ℃. When the absorbance at 600 nm was about 0.4, IPTG (isopropyl β-D-galactopyranoside) was added to a final concentration of 1.0 mM and incubated for 3 hours to induce protein expression. Cells (1.4 g / wet weight) were recovered by centrifugation at 6,000 rpm for 15 minutes and then 5 ml of sonication buffer (50 mM Tris-HCl [1] containing Complete TM Protease Inhibitor Cocktail (Santa Cruz Biotechnology) [ pH8.0], 150 mM NaCl, 5 mM EDTA), and then the final concentration of 0.1mg / ml lysozyme is added and lysed at 4 ° C for 1 hour. After crushing by ultrasound, 1% triton x-100 was added and reacted at 4 ° C. for 1 hour, and centrifuged at 14,000 rpm for 15 minutes to remove E. coli cell debris. Next, the supernatant was finally purified by affinity chromatography using Glutathione Sepharose ™ 4B (GE Healthcare).
실시예 4: 정제된 융합 폴리펩타이드를 카세인(casein)이 커플링(coupling) 된 비드(bead)에 결합Example 4 Binding the Purified Fusion Polypeptide to Casein-Coupled Beads
4-1.Glutathione-casein (GC) 제조4-1.Glutathione-casein (GC) manufacture
N-ethylmaleimide(NEM)로 카세인의 시스테인(cysteine) 잔기를 블로킹(blocking) 시킨 후 heterobifunctional cross-linker인sulfo-succinimidyl-4-(P-maleimidophenyl)-butyrate(sulfo-SMPB)를 첨가하여 티올(thiol)기와 반응할 수 있는 casein-maleimidophenyl-butyrate을 형성시켰다. PD10 column을 이용하여 잔여 NEM과 sulfo-SMPB를 제거한 후, 글루타치온(glutathione)의 cystain의 티올 잔기와 반응하여 glutathione-casein이 형성되도록 하였다. 다시 PD10 column을 이용하여 잔여 glutathione을 제거하였다.
Blocking cysteine residues of casein with N-ethylmaleimide (NEM) and then adding thiol by adding sulfo-succinimidyl-4- (P-maleimidophenyl) -butyrate (sulfo-SMPB), a heterobifunctional cross-linker. ) Casein-maleimidophenyl-butyrate was formed. After removing residual NEM and sulfo-SMPB using PD10 column, glutathione-casein was formed by reaction with thiol residue of glutathione cystain. The remaining glutathione was removed using the PD10 column again.
4-2. 루미넥스 비드(Luminex bead)와 GC와의 결합4-2. Luminex bead with GC
GC의 말단 아민(terminal amines)과 비드의 카볼실 그룹(carboxyl groups)이 결합된 Glutathione-casein (GC) beads를 생산하기 위해서, 1.25ㅧ106 개의 비드를 200 ㎕의 활성화(activation) 완충용액 [0.1 mol/L sodium phosphate, pH 6.2]로 2번 씻은 후, 50 mg/mL의 N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) 와 N-hydroxysuccinimide(NHS)를 각각 25㎕씩 첨가하여 차광된 실온에서 20분간 비드를 활성 시켰다. 활성화된 비드는 1 ㎖의 커플링 완충용액 [2-morpholinoethanesulfonic acid, 50 mmol/L, pH 5.0]로 2 번 씻은 후, 상층을 제거한 후 250㎖의 250 ㎎/L, GC 용액으로 현탁시켜 차광한 후 실온에서 2 시간 동안 커플링하였다. 그 후 1㎖의 세척 완충용액[phosphate-buffered saline (PBS), 50 mmol/L Tris, 0.5 mL/L Tween 20, pH 7.4]으로 2번 씻은 후, 보관용액 [PBS, pH 7.4, containing 1 g/L casein and 0.5 g/L sodium azide]에 담아 4℃에서 차광하여 보관하였다.
In order to produce Glutathione-casein (GC) beads combined with the terminal amines of GC and the carboxyl groups of beads, 200 μl activation buffer [0.1] was used. mol / L sodium phosphate, pH 6.2] twice, and then shaded with 25 μl of 50 mg / mL of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC) and N-hydroxysuccinimide (NHS). The beads were activated for 20 minutes at room temperature. Activated beads were washed twice with 1 ml of coupling buffer [2-morpholinoethanesulfonic acid, 50 mmol / L, pH 5.0], the upper layer was removed, and then suspended with 250 ml of 250 mg / L, GC solution. After coupling at room temperature for 2 hours. Then, washed twice with 1 ml of washing buffer [phosphate-buffered saline (PBS), 50 mmol / L Tris, 0.5 mL /
4-3. 융합 폴리펩타이드와 GC 비드와의 결합4-3. Binding Polypeptides to GC Beads
생산된 융합 폴리펩타이드는 1g/L로 카세인 완충용액 [1g/L casein in PBS, pH 7.4]로 희석한 후, 3000개의 GC 비드와 실온에서 차광하여 반응시켰다. 1시간 후 카세인 완충용액으로 3번 씻어서 보관하였다.
The produced fusion polypeptide was diluted with 1 g / L of casein buffer [1 g / L casein in PBS, pH 7.4] and then reacted by shielding 3,000 GC beads at room temperature. After 1 hour, washed three times with casein buffer solution.
실시예 5 : 멀티플렉스 루미넥스 분석Example 5 Multiplex Luminex Analysis
HPV 16 항체(Abnova, MAB1616)와 HPV18 항체 (Ab31492)를 각각 4,000 - 500 배까지 차례로 희석하여 HPV 16 L1 항원 및 HPV18 L1 항원을 이용한 표준 정량 곡선을 우선 확인하였다(도 9 및 도 10).
그 후, 2가 HPV 백신(서바릭스, GSK) 과 Placebo 백신을 접종한 그룹을 대상으로백신 접종 후 3개월 후에 혈액을 채취하여혈청을 분리 한 후 개발된 HPV16 L1 항원 및 HPV18 L1 항원을 이용하여 실제로 혈액 내 HPV 항체의 양을 측정하였다. 융합 폴리펩타이드가 결합된 비드 혼합액을 희석된 혈청과 96 웰 플레이트에서 2시간 동안 차광하여 실온에서 반응시켰다. 100 ㎕ 카세인 완충용액으로 3번 씻어주고 비오틴(biotin)이 결합된 2차 항체[goat anti-human IgA, IgM, IgG (H+L)]를 1:1,000으로 희석하여 30분간 반응시킨다. 마지막으로 발색 시약인 스트렙타비딘-알-피코에리트린(streptavidin-R-phycoerythrin)을 첨가하여 30분간 반응시키고, Luminex analyzer로 median fluorescence intensity (MFI)를 측정하였다. Subsequently, blood was collected three months after vaccination in the group vaccinated with the bivalent HPV vaccine (Serbarix, GSK) and Placebo vaccine, and the serum was isolated using the developed HPV16 L1 antigen and HPV18 L1 antigen. The amount of HPV antibody in the blood was measured. The bead mixture to which the fusion polypeptide was bound was shielded for 2 hours in diluted wells and 96 well plates and reacted at room temperature. Wash three times with 100 μl casein buffer and dilute biotin-bound secondary antibody (goat anti-human IgA, IgM, IgG (H + L)) to 1: 1,000 for 30 minutes. Finally, the reaction was performed for 30 minutes by the addition of streptavidin-R-phycoerythrin, a color developing reagent, and median fluorescence intensity (MFI) was measured by a Luminex analyzer.
그 결과를 도 11에 나타내었다. 총 12명 (2가 HPV 백신접종자 7명, Placebo 백신 접종자 5명)을 대상으로실시하였으며, 접종자 모두 HPV 16 타입에 대한 항체가 형성되었으나 HPV 18에 대한 항체는 7명중 5명에서만 검출된 것을 확인할 수 있었다.The results are shown in FIG. A total of 12 subjects (7 bivalent HPV vaccinates and 5 Placebo vaccinates) were tested. All of the vaccinated antibodies formed
<110> Gyngen Bio CO., LTD. DIATECH KOREA CO., LTD. <120> Screening method of Human Papillomavirus antibody using fusion polypeptide HPV antigen <130> PA110192/KR <150> KR10-2010-0025690 <151> 2010-03-23 <160> 14 <170> KopatentIn 1.71 <210> 1 <211> 40 <212> DNA <213> Artificial Sequence <220> <223> SV40 Large T antigen sense <400> 1 tcgacaaacc tcccacacct ccccctgaac ctgaaacagc 40 <210> 2 <211> 39 <212> DNA <213> Artificial Sequence <220> <223> SV40 Large T antigen antisense <400> 2 ggccgctgtt tcaggttcag ggggaggtgt gggaggttt 39 <210> 3 <211> 32 <212> DNA <213> Artificial Sequence <220> <223> primer HPV6L1F <400> 3 nnnnngaatt caatgtggcg gcctagcgac ag 32 <210> 4 <211> 31 <212> DNA <213> Artificial Sequence <220> <223> primer HPV6L1R <400> 4 gcatgagtcg acccttttag ttttggcgcg c 31 <210> 5 <211> 34 <212> DNA <213> Artificial Sequence <220> <223> primer HPV11L1F <400> 5 gcagtcgaat tcgtggcggc ctagcgacag caca 34 <210> 6 <211> 38 <212> DNA <213> Artificial Sequence <220> <223> primer HPV11L1R <400> 6 nnnnngtcga cctttttggt tttggtacgt tttcgttt 38 <210> 7 <211> 38 <212> DNA <213> Artificial Sequence <220> <223> primer HPV16L1F <400> 7 nnnnnagatc tatgcaggtg acttttattt acatccta 38 <210> 8 <211> 36 <212> DNA <213> Artificial Sequence <220> <223> primer HPV16L1R <400> 8 gcatgagtcg accagcttac gttttttgcg tttagc 36 <210> 9 <211> 36 <212> DNA <213> Artificial Sequence <220> <223> primer HPV18L1F <400> 9 nnnnngaatt caatgtgcct gtatacacgg gtcctg 36 <210> 10 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> primer HPV18L1R <400> 10 gcatgagtcg accttcctgg cacgtacacg gac 33 <210> 11 <211> 746 <212> PRT <213> Artificial Sequence <220> <223> fusion polypeptide HPV 6 L1 <400> 11 Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro 1 5 10 15 Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu 20 25 30 Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu 35 40 45 Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys 50 55 60 Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn 65 70 75 80 Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu 85 90 95 Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser 100 105 110 Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu 115 120 125 Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn 130 135 140 Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp 145 150 155 160 Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu 165 170 175 Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr 180 185 190 Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala 195 200 205 Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Val Pro Arg 210 215 220 Gly Ser Pro Asn Ser Met Trp Arg Pro Ser Asp Ser Thr Val Tyr Val 225 230 235 240 Pro Pro Pro Asn Pro Val Ser Lys Val Val Ala Thr Asp Ala Tyr Val 245 250 255 Thr Arg Thr Asn Ile Phe Tyr His Ala Ser Ser Ser Arg Leu Leu Ala 260 265 270 Val Gly His Pro Tyr Phe Ser Ile Lys Arg Ala Asn Lys Thr Val Val 275 280 285 Pro Lys Val Ser Gly Tyr Gln Tyr Arg Val Phe Lys Val Val Leu Pro 290 295 300 Asp Pro Asn Lys Phe Ala Leu Pro Asp Ser Ser Leu Phe Asp Pro Thr 305 310 315 320 Thr Gln Arg Leu Val Trp Ala Cys Thr Gly Leu Glu Val Gly Arg Gly 325 330 335 Gln Pro Leu Gly Val Gly Val Ser Gly His Pro Phe Leu Asn Lys Tyr 340 345 350 Asp Asp Val Glu Asn Ser Gly Ser Gly Gly Asn Pro Gly Gln Asp Asn 355 360 365 Arg Val Asn Val Gly Met Asp Tyr Lys Gln Thr Gln Leu Cys Met Val 370 375 380 Gly Cys Ala Pro Pro Leu Gly Glu His Trp Gly Lys Gly Lys Gln Cys 385 390 395 400 Thr Asn Thr Pro Val Gln Ala Gly Asp Cys Pro Pro Leu Glu Leu Ile 405 410 415 Thr Ser Val Ile Gln Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala 420 425 430 Met Asn Phe Ala Asp Leu Gln Thr Asn Lys Ser Asp Val Pro Ile Asp 435 440 445 Ile Cys Gly Thr Thr Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ala Ala 450 455 460 Asp Pro Tyr Gly Asp Arg Leu Phe Phe Phe Leu Arg Lys Glu Gln Met 465 470 475 480 Phe Ala Arg His Phe Phe Asn Arg Ala Gly Glu Val Gly Glu Pro Val 485 490 495 Pro Asp Thr Leu Ile Ile Lys Gly Ser Gly Asn Arg Thr Ser Val Gly 500 505 510 Ser Ser Ile Tyr Val Asn Thr Pro Ser Gly Ser Leu Val Ser Ser Glu 515 520 525 Ala Gln Leu Phe Asn Lys Pro Tyr Trp Leu Gln Lys Ala Gln Gly His 530 535 540 Asn Asn Gly Ile Cys Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp 545 550 555 560 Thr Thr Arg Ser Thr Asn Met Thr Leu Cys Ala Ser Val Thr Thr Ser 565 570 575 Ser Thr Tyr Thr Asn Ser Asp Tyr Lys Glu Tyr Met Arg His Val Glu 580 585 590 Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Ser Ile Thr Leu Ser 595 600 605 Ala Glu Val Met Ala Tyr Ile His Thr Met Asn Pro Ser Val Leu Glu 610 615 620 Asp Trp Asn Phe Gly Leu Ser Pro Pro Pro Asn Gly Thr Leu Glu Asp 625 630 635 640 Thr Tyr Arg Tyr Val Gln Ser Gln Ala Ile Thr Cys Gln Lys Pro Thr 645 650 655 Pro Glu Lys Glu Lys Pro Asp Pro Tyr Lys Asn Leu Ser Phe Trp Glu 660 665 670 Val Asn Leu Lys Glu Lys Phe Ser Ser Glu Leu Asp Gln Tyr Pro Leu 675 680 685 Gly Arg Lys Phe Leu Leu Gln Ser Gly Tyr Arg Gly Arg Ser Ser Ile 690 695 700 Arg Thr Gly Val Lys Arg Pro Ala Val Ser Lys Ala Ser Ala Ala Pro 705 710 715 720 Lys Arg Lys Arg Ala Lys Thr Lys Arg Val Asp Lys Pro Pro Thr Pro 725 730 735 Pro Pro Glu Pro Glu Thr Ala Ala Ala Ser 740 745 <210> 12 <211> 746 <212> PRT <213> Artificial Sequence <220> <223> fusion polypeptide HPV 11 L1 <400> 12 Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro 1 5 10 15 Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu 20 25 30 Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu 35 40 45 Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys 50 55 60 Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn 65 70 75 80 Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu 85 90 95 Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser 100 105 110 Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu 115 120 125 Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn 130 135 140 Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp 145 150 155 160 Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu 165 170 175 Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr 180 185 190 Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala 195 200 205 Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Val Pro Arg 210 215 220 Gly Ser Pro Asn Ser Trp Arg Pro Ser Asp Ser Thr Val Tyr Val Pro 225 230 235 240 Pro Pro Asn Pro Val Ser Lys Val Val Ala Thr Asp Ala Tyr Val Lys 245 250 255 Arg Thr Asn Ile Phe Tyr His Ala Ser Ser Ser Arg Leu Leu Ala Val 260 265 270 Gly His Pro Tyr Tyr Ser Ile Lys Lys Val Asn Lys Thr Val Val Pro 275 280 285 Lys Val Ser Gly Tyr Gln Tyr Arg Val Phe Lys Val Val Leu Pro Asp 290 295 300 Pro Asn Lys Phe Ala Leu Pro Asp Ser Ser Leu Phe Asp Pro Thr Thr 305 310 315 320 Gln Arg Leu Val Trp Ala Cys Thr Gly Leu Glu Val Gly Arg Gly Gln 325 330 335 Pro Leu Gly Val Gly Val Ser Gly His Pro Leu Leu Asn Lys Tyr Asp 340 345 350 Asp Val Glu Asn Ser Gly Gly Tyr Gly Gly Asn Pro Gly Gln Asp Asn 355 360 365 Arg Val Asn Val Gly Met Asp Tyr Lys Gln Thr Gln Leu Cys Met Val 370 375 380 Gly Cys Ala Pro Pro Leu Gly Glu His Trp Gly Lys Gly Thr Gln Cys 385 390 395 400 Ser Asn Thr Ser Val Gln Asn Gly Asp Cys Pro Pro Leu Glu Leu Ile 405 410 415 Thr Ser Val Ile Gln Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala 420 425 430 Met Asn Phe Ala Asp Leu Gln Thr Asn Lys Ser Asp Val Pro Leu Asp 435 440 445 Ile Cys Gly Thr Val Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ala Ala 450 455 460 Asp Pro Tyr Gly Asp Arg Leu Phe Phe Tyr Leu Arg Lys Glu Gln Met 465 470 475 480 Phe Ala Arg His Phe Phe Asn Arg Ala Gly Thr Val Gly Glu Pro Val 485 490 495 Pro Asp Asp Leu Leu Val Lys Gly Gly Asn Asn Arg Ser Ser Val Ala 500 505 510 Ser Ser Ile Tyr Val His Thr Pro Ser Gly Ser Leu Val Ser Ser Glu 515 520 525 Ala Gln Leu Phe Asn Lys Pro Tyr Trp Leu Gln Lys Ala Gln Gly His 530 535 540 Asn Asn Gly Ile Cys Trp Gly Asn His Leu Phe Val Thr Val Val Asp 545 550 555 560 Thr Thr Arg Ser Thr Asn Met Thr Leu Cys Ala Ser Val Ser Lys Ser 565 570 575 Ala Thr Tyr Thr Asn Ser Asp Tyr Lys Glu Tyr Met Arg His Val Glu 580 585 590 Glu Phe Asp Leu Gln Phe Ile Phe Gln Leu Cys Ser Ile Thr Leu Ser 595 600 605 Ala Glu Val Met Ala Tyr Ile His Thr Met Asn Pro Ser Val Leu Glu 610 615 620 Asp Trp Asn Phe Gly Leu Ser Pro Pro Pro Asn Gly Thr Leu Glu Asp 625 630 635 640 Thr Tyr Arg Tyr Val Gln Ser Gln Ala Ile Thr Cys Gln Lys Pro Thr 645 650 655 Pro Glu Lys Glu Lys Gln Asp Pro Tyr Lys Asp Met Ser Phe Trp Glu 660 665 670 Val Asn Leu Lys Glu Lys Phe Ser Ser Glu Leu Asp Gln Phe Pro Leu 675 680 685 Gly Arg Lys Phe Leu Leu Gln Ser Gly Tyr Arg Gly Arg Thr Ser Ala 690 695 700 Arg Thr Gly Ile Lys Arg Pro Ala Val Ser Lys Pro Ser Thr Ala Pro 705 710 715 720 Lys Arg Lys Arg Thr Lys Thr Lys Lys Val Asp Lys Pro Pro Thr Pro 725 730 735 Pro Pro Glu Pro Glu Thr Ala Ala Ala Ser 740 745 <210> 13 <211> 774 <212> PRT <213> Artificial Sequence <220> <223> fusion polypeptide HPV 16 L1 <400> 13 Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro 1 5 10 15 Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu 20 25 30 Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu 35 40 45 Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys 50 55 60 Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn 65 70 75 80 Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu 85 90 95 Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser 100 105 110 Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu 115 120 125 Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn 130 135 140 Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp 145 150 155 160 Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu 165 170 175 Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr 180 185 190 Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala 195 200 205 Thr Phe Gly Gly Gly Asp His Xaa Pro Lys Ser Asp Leu Val Pro Arg 210 215 220 Gly Ser Met Gln Val Thr Phe Ile Tyr Ile Leu Val Ile Thr Cys Tyr 225 230 235 240 Glu Asn Asp Val Asn Val Tyr His Ile Phe Phe Gln Met Ser Leu Trp 245 250 255 Leu Pro Ser Glu Ala Thr Val Tyr Leu Pro Pro Val Pro Val Ser Lys 260 265 270 Val Val Ser Thr Asp Glu Tyr Val Ala Arg Thr Asn Ile Tyr Tyr His 275 280 285 Ala Gly Thr Ser Arg Leu Leu Ala Val Gly His Pro Tyr Phe Pro Ile 290 295 300 Lys Lys Pro Asn Asn Asn Lys Ile Leu Val Pro Lys Val Ser Gly Leu 305 310 315 320 Gln Tyr Arg Val Phe Arg Ile His Leu Pro Asp Pro Asn Lys Phe Gly 325 330 335 Phe Pro Asp Thr Ser Phe Tyr Asn Pro Asp Thr Gln Arg Leu Val Trp 340 345 350 Ala Cys Val Gly Val Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly 355 360 365 Ile Ser Gly His Pro Leu Leu Asn Lys Leu Asp Asp Thr Glu Asn Ala 370 375 380 Ser Ala Tyr Ala Ala Asn Ala Gly Val Asp Asn Arg Glu Cys Ile Ser 385 390 395 400 Met Asp Tyr Lys Gln Thr Gln Leu Cys Leu Ile Gly Cys Lys Pro Pro 405 410 415 Ile Gly Glu His Trp Gly Lys Gly Ser Pro Cys Thr Asn Val Ala Val 420 425 430 Asn Pro Gly Asp Cys Pro Pro Leu Glu Leu Ile Asn Thr Val Ile Gln 435 440 445 Asp Gly Asp Met Val His Thr Gly Phe Gly Ala Met Asp Phe Thr Thr 450 455 460 Leu Gln Ala Asn Lys Ser Glu Val Pro Leu Asp Ile Cys Thr Ser Ile 465 470 475 480 Cys Lys Tyr Pro Asp Tyr Ile Lys Met Val Ser Glu Pro Tyr Gly Asp 485 490 495 Ser Leu Phe Phe Tyr Leu Arg Arg Glu Gln Met Phe Val Arg His Leu 500 505 510 Phe Asn Arg Ala Gly Thr Val Gly Glu Asn Val Pro Asp Asp Leu Tyr 515 520 525 Ile Lys Gly Ser Gly Ser Thr Ala Asn Leu Ala Ser Ser Asn Tyr Phe 530 535 540 Pro Thr Pro Ser Gly Ser Met Val Thr Ser Asp Ala Gln Ile Phe Asn 545 550 555 560 Lys Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn Asn Gly Ile Cys 565 570 575 Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp Thr Thr Arg Ser Thr 580 585 590 Asn Met Ser Leu Cys Ala Ala Ile Ser Thr Ser Glu Thr Thr Tyr Lys 595 600 605 Asn Thr Asn Phe Lys Glu Tyr Leu Arg His Gly Glu Glu Tyr Asp Leu 610 615 620 Gln Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr Ala Asp Val Met 625 630 635 640 Thr Tyr Ile His Ser Met Asn Ser Thr Ile Leu Glu Asp Trp Asn Phe 645 650 655 Gly Leu Gln Pro Pro Pro Gly Gly Thr Leu Glu Asp Thr Tyr Arg Phe 660 665 670 Val Thr Ser Gln Ala Ile Ala Cys Gln Lys His Thr Pro Pro Ala Pro 675 680 685 Lys Glu Asp Pro Leu Lys Lys Tyr Thr Phe Trp Glu Val Asn Leu Lys 690 695 700 Glu Lys Phe Ser Ala Asp Leu Asp Gln Phe Pro Leu Gly Arg Lys Phe 705 710 715 720 Leu Leu Gln Ala Gly Leu Lys Ala Lys Pro Lys Phe Thr Leu Gly Lys 725 730 735 Arg Lys Ala Thr Pro Thr Thr Ser Ser Thr Ser Thr Thr Ala Lys Arg 740 745 750 Lys Lys Arg Lys Leu Val Asp Lys Pro Pro Thr Pro Pro Pro Glu Pro 755 760 765 Glu Thr Ala Ala Ala Ser 770 <210> 14 <211> 814 <212> PRT <213> Artificial Sequence <220> <223> fusion polypeptide HPV 18 L1 <400> 14 Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro 1 5 10 15 Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu 20 25 30 Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu 35 40 45 Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys 50 55 60 Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn 65 70 75 80 Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu 85 90 95 Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser 100 105 110 Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu 115 120 125 Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn 130 135 140 Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp 145 150 155 160 Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu 165 170 175 Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr 180 185 190 Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala 195 200 205 Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Val Pro Arg 210 215 220 Gly Ser Pro Asn Ser Met Cys Leu Tyr Thr Arg Val Leu Ile Leu His 225 230 235 240 Tyr His Leu Leu Pro Leu Tyr Gly Pro Leu Tyr His Pro Arg Pro Leu 245 250 255 Pro Leu His Ser Ile Leu Val Tyr Met Val His Ile Ile Ile Cys Gly 260 265 270 His Tyr Ile Ile Leu Phe Leu Arg Asn Val Asn Val Phe Pro Ile Phe 275 280 285 Leu Gln Met Ala Leu Trp Arg Pro Ser Asp Asn Thr Val Tyr Leu Pro 290 295 300 Pro Pro Ser Val Ala Arg Val Val Asn Thr Asp Asp Tyr Val Thr Arg 305 310 315 320 Thr Ser Ile Phe Tyr His Ala Gly Ser Ser Arg Leu Leu Thr Val Gly 325 330 335 Asn Pro Tyr Phe Arg Val Pro Ala Gly Gly Gly Asn Lys Gln Asp Ile 340 345 350 Pro Lys Val Ser Ala Tyr Gln Tyr Arg Val Phe Arg Val Gln Leu Pro 355 360 365 Asp Pro Asn Lys Phe Gly Leu Pro Asp Thr Ser Ile Tyr Asn Pro Glu 370 375 380 Thr Gln Arg Leu Val Trp Ala Cys Ala Gly Val Glu Ile Gly Arg Gly 385 390 395 400 Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro Phe Tyr Asn Lys Leu 405 410 415 Asp Asp Thr Glu Ser Ser His Ala Ala Thr Ser Asn Val Ser Glu Asp 420 425 430 Val Arg Asp Asn Val Ser Val Asp Tyr Lys Gln Thr Gln Leu Cys Ile 435 440 445 Leu Gly Cys Ala Pro Ala Ile Gly Glu His Trp Ala Lys Gly Thr Ala 450 455 460 Cys Lys Ser Arg Pro Leu Ser Gln Gly Asp Cys Pro Pro Leu Glu Leu 465 470 475 480 Lys Asn Thr Val Leu Glu Asp Gly Asp Met Val Asp Thr Gly Tyr Gly 485 490 495 Ala Met Asp Phe Ser Thr Leu Gln Asp Thr Lys Cys Glu Val Pro Leu 500 505 510 Asp Ile Cys Gln Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ser 515 520 525 Ala Asp Pro Tyr Gly Asp Ser Met Phe Phe Cys Leu Arg Arg Glu Gln 530 535 540 Leu Phe Ala Arg His Phe Trp Asn Arg Ala Gly Thr Met Gly Asp Thr 545 550 555 560 Val Pro Gln Ser Leu Tyr Ile Lys Gly Thr Gly Met Arg Ala Ser Pro 565 570 575 Gly Ser Cys Val Tyr Ser Pro Ser Pro Ser Gly Ser Ile Val Thr Ser 580 585 590 Asp Ser Gln Leu Phe Asn Lys Pro Tyr Trp Leu His Lys Ala Gln Gly 595 600 605 His Asn Asn Gly Val Cys Trp His Asn Gln Leu Phe Val Thr Val Val 610 615 620 Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile Cys Ala Ser Thr Gln Ser 625 630 635 640 Pro Val Pro Gly Gln Tyr Asp Ala Thr Lys Phe Lys Gln Tyr Ser Arg 645 650 655 His Val Glu Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Thr Ile 660 665 670 Thr Leu Thr Ala Asp Val Met Ser Tyr Ile His Ser Met Asn Ser Ser 675 680 685 Ile Leu Glu Asp Trp Asn Phe Gly Val Pro Pro Pro Pro Thr Thr Ser 690 695 700 Leu Val Asp Thr Tyr Arg Phe Val Gln Ser Val Ala Ile Thr Cys Gln 705 710 715 720 Lys Asp Ala Ala Pro Ala Glu Asn Lys Asp Pro Tyr Asp Lys Leu Lys 725 730 735 Phe Trp Asn Val Asp Leu Lys Glu Lys Phe Ser Leu Asp Leu Asp Gln 740 745 750 Tyr Pro Leu Gly Arg Lys Phe Leu Val Gln Ala Gly Leu Arg Arg Lys 755 760 765 Pro Thr Ile Gly Pro Arg Lys Arg Ser Ala Pro Ser Ala Thr Thr Ser 770 775 780 Ser Lys Pro Ala Lys Arg Val Arg Val Arg Ala Arg Lys Val Asp Lys 785 790 795 800 Pro Pro Thr Pro Pro Pro Glu Pro Glu Thr Ala Ala Ala Ser 805 810 <110> Gyngen Bio CO., LTD. DIATECH KOREA CO., LTD. <120> Screening method of Human Papillomavirus antibody using fusion polypeptide HPV antigen <130> PA110192 / KR <150> KR10-2010-0025690 <151> 2010-03-23 <160> 14 <170> KopatentIn 1.71 <210> 1 <211> 40 <212> DNA <213> Artificial Sequence <220> <223> SV40 Large T antigen sense <400> 1 tcgacaaacc tcccacacct ccccctgaac ctgaaacagc 40 <210> 2 <211> 39 <212> DNA <213> Artificial Sequence <220> <223> SV40 Large T antigen antisense <400> 2 ggccgctgtt tcaggttcag ggggaggtgt gggaggttt 39 <210> 3 <211> 32 <212> DNA <213> Artificial Sequence <220> <223> primer HPV6L1F <400> 3 nnnnngaatt caatgtggcg gcctagcgac ag 32 <210> 4 <211> 31 <212> DNA <213> Artificial Sequence <220> <223> primer HPV6L1R <400> 4 gcatgagtcg acccttttag ttttggcgcg c 31 <210> 5 <211> 34 <212> DNA <213> Artificial Sequence <220> <223> primer HPV11L1F <400> 5 gcagtcgaat tcgtggcggc ctagcgacag caca 34 <210> 6 <211> 38 <212> DNA <213> Artificial Sequence <220> <223> primer HPV11L1R <400> 6 nnnnngtcga cctttttggt tttggtacgt tttcgttt 38 <210> 7 <211> 38 <212> DNA <213> Artificial Sequence <220> <223> primer HPV16L1F <400> 7 nnnnnagatc tatgcaggtg acttttattt acatccta 38 <210> 8 <211> 36 <212> DNA <213> Artificial Sequence <220> <223> primer HPV16L1R <400> 8 gcatgagtcg accagcttac gttttttgcg tttagc 36 <210> 9 <211> 36 <212> DNA <213> Artificial Sequence <220> <223> primer HPV18L1F <400> 9 nnnnngaatt caatgtgcct gtatacacgg gtcctg 36 <210> 10 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> primer HPV18L1R <400> 10 gcatgagtcg accttcctgg cacgtacacg gac 33 <210> 11 <211> 746 <212> PRT <213> Artificial Sequence <220> 223 fusion polypeptide HPV 6 L1 <400> 11 Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro 1 5 10 15 Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu 20 25 30 Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu 35 40 45 Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys 50 55 60 Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn 65 70 75 80 Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu 85 90 95 Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser 100 105 110 Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu 115 120 125 Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn 130 135 140 Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp 145 150 155 160 Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu 165 170 175 Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr 180 185 190 Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala 195 200 205 Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Val Pro Arg 210 215 220 Gly Ser Pro Asn Ser Met Trp Arg Pro Ser Asp Ser Thr Val Tyr Val 225 230 235 240 Pro Pro Pro Asn Pro Val Ser Lys Val Val Ala Thr Asp Ala Tyr Val 245 250 255 Thr Arg Thr Asn Ile Phe Tyr His Ala Ser Ser Ser Arg Leu Leu Ala 260 265 270 Val Gly His Pro Tyr Phe Ser Ile Lys Arg Ala Asn Lys Thr Val Val 275 280 285 Pro Lys Val Ser Gly Tyr Gln Tyr Arg Val Phe Lys Val Val Leu Pro 290 295 300 Asp Pro Asn Lys Phe Ala Leu Pro Asp Ser Ser Leu Phe Asp Pro Thr 305 310 315 320 Thr Gln Arg Leu Val Trp Ala Cys Thr Gly Leu Glu Val Gly Arg Gly 325 330 335 Gln Pro Leu Gly Val Gly Val Ser Gly His Pro Phe Leu Asn Lys Tyr 340 345 350 Asp Asp Val Glu Asn Ser Gly Ser Gly Gly Asn Pro Gly Gln Asp Asn 355 360 365 Arg Val Asn Val Gly Met Asp Tyr Lys Gln Thr Gln Leu Cys Met Val 370 375 380 Gly Cys Ala Pro Pro Leu Gly Glu His Trp Gly Lys Gly Lys Gln Cys 385 390 395 400 Thr Asn Thr Pro Val Gln Ala Gly Asp Cys Pro Pro Leu Glu Leu Ile 405 410 415 Thr Ser Val Ile Gln Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala 420 425 430 Met Asn Phe Ala Asp Leu Gln Thr Asn Lys Ser Asp Val Pro Ile Asp 435 440 445 Ile Cys Gly Thr Thr Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ala Ala 450 455 460 Asp Pro Tyr Gly Asp Arg Leu Phe Phe Phe Leu Arg Lys Glu Gln Met 465 470 475 480 Phe Ala Arg His Phe Phe Asn Arg Ala Gly Glu Val Gly Glu Pro Val 485 490 495 Pro Asp Thr Leu Ile Ile Lys Gly Ser Gly Asn Arg Thr Ser Val Gly 500 505 510 Ser Ser Ile Tyr Val Asn Thr Pro Ser Gly Ser Leu Val Ser Ser Glu 515 520 525 Ala Gln Leu Phe Asn Lys Pro Tyr Trp Leu Gln Lys Ala Gln Gly His 530 535 540 Asn Asn Gly Ile Cys Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp 545 550 555 560 Thr Thr Arg Ser Thr Asn Met Thr Leu Cys Ala Ser Val Thr Thr Ser 565 570 575 Ser Thr Tyr Thr Asn Ser Asp Tyr Lys Glu Tyr Met Arg His Val Glu 580 585 590 Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Ser Ile Thr Leu Ser 595 600 605 Ala Glu Val Met Ala Tyr Ile His Thr Met Asn Pro Ser Val Leu Glu 610 615 620 Asp Trp Asn Phe Gly Leu Ser Pro Pro Pro Asn Gly Thr Leu Glu Asp 625 630 635 640 Thr Tyr Arg Tyr Val Gln Ser Gln Ala Ile Thr Cys Gln Lys Pro Thr 645 650 655 Pro Glu Lys Glu Lys Pro Asp Pro Tyr Lys Asn Leu Ser Phe Trp Glu 660 665 670 Val Asn Leu Lys Glu Lys Phe Ser Ser Glu Leu Asp Gln Tyr Pro Leu 675 680 685 Gly Arg Lys Phe Leu Leu Gln Ser Gly Tyr Arg Gly Arg Ser Ser Ile 690 695 700 Arg Thr Gly Val Lys Arg Pro Ala Val Ser Lys Ala Ser Ala Ala Pro 705 710 715 720 Lys Arg Lys Arg Ala Lys Thr Lys Arg Val Asp Lys Pro Pro Thr Pro 725 730 735 Pro Pro Glu Pro Glu Thr Ala Ala Ala Ser 740 745 <210> 12 <211> 746 <212> PRT <213> Artificial Sequence <220> <223> fusion polypeptide HPV 11 L1 <400> 12 Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro 1 5 10 15 Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu 20 25 30 Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu 35 40 45 Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys 50 55 60 Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn 65 70 75 80 Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu 85 90 95 Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser 100 105 110 Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu 115 120 125 Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn 130 135 140 Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp 145 150 155 160 Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu 165 170 175 Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr 180 185 190 Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala 195 200 205 Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Val Pro Arg 210 215 220 Gly Ser Pro Asn Ser Trp Arg Pro Ser Asp Ser Thr Val Tyr Val Pro 225 230 235 240 Pro Pro Asn Pro Val Ser Lys Val Val Ala Thr Asp Ala Tyr Val Lys 245 250 255 Arg Thr Asn Ile Phe Tyr His Ala Ser Ser Ser Arg Leu Leu Ala Val 260 265 270 Gly His Pro Tyr Tyr Ser Ile Lys Lys Val Asn Lys Thr Val Val Pro 275 280 285 Lys Val Ser Gly Tyr Gln Tyr Arg Val Phe Lys Val Val Leu Pro Asp 290 295 300 Pro Asn Lys Phe Ala Leu Pro Asp Ser Ser Leu Phe Asp Pro Thr Thr 305 310 315 320 Gln Arg Leu Val Trp Ala Cys Thr Gly Leu Glu Val Gly Arg Gly Gln 325 330 335 Pro Leu Gly Val Gly Val Ser Gly His Pro Leu Leu Asn Lys Tyr Asp 340 345 350 Asp Val Glu Asn Ser Gly Gly Tyr Gly Gly Asn Pro Gly Gln Asp Asn 355 360 365 Arg Val Asn Val Gly Met Asp Tyr Lys Gln Thr Gln Leu Cys Met Val 370 375 380 Gly Cys Ala Pro Pro Leu Gly Glu His Trp Gly Lys Gly Thr Gln Cys 385 390 395 400 Ser Asn Thr Ser Val Gln Asn Gly Asp Cys Pro Pro Leu Glu Leu Ile 405 410 415 Thr Ser Val Ile Gln Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala 420 425 430 Met Asn Phe Ala Asp Leu Gln Thr Asn Lys Ser Asp Val Pro Leu Asp 435 440 445 Ile Cys Gly Thr Val Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ala Ala 450 455 460 Asp Pro Tyr Gly Asp Arg Leu Phe Phe Tyr Leu Arg Lys Glu Gln Met 465 470 475 480 Phe Ala Arg His Phe Phe Asn Arg Ala Gly Thr Val Gly Glu Pro Val 485 490 495 Pro Asp Asp Leu Leu Val Lys Gly Gly Asn Asn Arg Ser Ser Val Ala 500 505 510 Ser Ser Ile Tyr Val His Thr Pro Ser Gly Ser Leu Val Ser Ser Glu 515 520 525 Ala Gln Leu Phe Asn Lys Pro Tyr Trp Leu Gln Lys Ala Gln Gly His 530 535 540 Asn Asn Gly Ile Cys Trp Gly Asn His Leu Phe Val Thr Val Val Asp 545 550 555 560 Thr Thr Arg Ser Thr Asn Met Thr Leu Cys Ala Ser Val Ser Lys Ser 565 570 575 Ala Thr Tyr Thr Asn Ser Asp Tyr Lys Glu Tyr Met Arg His Val Glu 580 585 590 Glu Phe Asp Leu Gln Phe Ile Phe Gln Leu Cys Ser Ile Thr Leu Ser 595 600 605 Ala Glu Val Met Ala Tyr Ile His Thr Met Asn Pro Ser Val Leu Glu 610 615 620 Asp Trp Asn Phe Gly Leu Ser Pro Pro Pro Asn Gly Thr Leu Glu Asp 625 630 635 640 Thr Tyr Arg Tyr Val Gln Ser Gln Ala Ile Thr Cys Gln Lys Pro Thr 645 650 655 Pro Glu Lys Glu Lys Gln Asp Pro Tyr Lys Asp Met Ser Phe Trp Glu 660 665 670 Val Asn Leu Lys Glu Lys Phe Ser Ser Glu Leu Asp Gln Phe Pro Leu 675 680 685 Gly Arg Lys Phe Leu Leu Gln Ser Gly Tyr Arg Gly Arg Thr Ser Ala 690 695 700 Arg Thr Gly Ile Lys Arg Pro Ala Val Ser Lys Pro Ser Thr Ala Pro 705 710 715 720 Lys Arg Lys Arg Thr Lys Thr Lys Lys Val Asp Lys Pro Pro Thr Pro 725 730 735 Pro Pro Glu Pro Glu Thr Ala Ala Ala Ser 740 745 <210> 13 <211> 774 <212> PRT <213> Artificial Sequence <220> 223 fusion polypeptide HPV 16 L1 <400> 13 Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro 1 5 10 15 Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu 20 25 30 Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu 35 40 45 Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys 50 55 60 Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn 65 70 75 80 Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu 85 90 95 Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser 100 105 110 Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu 115 120 125 Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn 130 135 140 Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp 145 150 155 160 Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu 165 170 175 Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr 180 185 190 Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala 195 200 205 Thr Phe Gly Gly Gly Asp His Xaa Pro Lys Ser Asp Leu Val Pro Arg 210 215 220 Gly Ser Met Gln Val Thr Phe Ile Tyr Ile Leu Val Ile Thr Cys Tyr 225 230 235 240 Glu Asn Asp Val Asn Val Tyr His Ile Phe Phe Gln Met Ser Leu Trp 245 250 255 Leu Pro Ser Glu Ala Thr Val Tyr Leu Pro Pro Val Pro Val Ser Lys 260 265 270 Val Val Ser Thr Asp Glu Tyr Val Ala Arg Thr Asn Ile Tyr Tyr His 275 280 285 Ala Gly Thr Ser Arg Leu Leu Ala Val Gly His Pro Tyr Phe Pro Ile 290 295 300 Lys Lys Pro Asn Asn Asn Lys Ile Leu Val Pro Lys Val Ser Gly Leu 305 310 315 320 Gln Tyr Arg Val Phe Arg Ile His Leu Pro Asp Pro Asn Lys Phe Gly 325 330 335 Phe Pro Asp Thr Ser Phe Tyr Asn Pro Asp Thr Gln Arg Leu Val Trp 340 345 350 Ala Cys Val Gly Val Glu Val Gly Arg Gly Gln Pro Leu Gly Val Gly 355 360 365 Ile Ser Gly His Pro Leu Leu Asn Lys Leu Asp Asp Thr Glu Asn Ala 370 375 380 Ser Ala Tyr Ala Ala Asn Ala Gly Val Asp Asn Arg Glu Cys Ile Ser 385 390 395 400 Met Asp Tyr Lys Gln Thr Gln Leu Cys Leu Ile Gly Cys Lys Pro Pro 405 410 415 Ile Gly Glu His Trp Gly Lys Gly Ser Pro Cys Thr Asn Val Ala Val 420 425 430 Asn Pro Gly Asp Cys Pro Pro Leu Glu Leu Ile Asn Thr Val Ile Gln 435 440 445 Asp Gly Asp Met Val His Thr Gly Phe Gly Ala Met Asp Phe Thr Thr 450 455 460 Leu Gln Ala Asn Lys Ser Glu Val Pro Leu Asp Ile Cys Thr Ser Ile 465 470 475 480 Cys Lys Tyr Pro Asp Tyr Ile Lys Met Val Ser Glu Pro Tyr Gly Asp 485 490 495 Ser Leu Phe Phe Tyr Leu Arg Arg Glu Gln Met Phe Val Arg His Leu 500 505 510 Phe Asn Arg Ala Gly Thr Val Gly Glu Asn Val Pro Asp Asp Leu Tyr 515 520 525 Ile Lys Gly Ser Gly Ser Thr Ala Asn Leu Ala Ser Ser Asn Tyr Phe 530 535 540 Pro Thr Pro Ser Gly Ser Met Val Thr Ser Asp Ala Gln Ile Phe Asn 545 550 555 560 Lys Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn Asn Gly Ile Cys 565 570 575 Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp Thr Thr Arg Ser Thr 580 585 590 Asn Met Ser Leu Cys Ala Ala Ile Ser Thr Ser Glu Thr Thr Tyr Lys 595 600 605 Asn Thr Asn Phe Lys Glu Tyr Leu Arg His Gly Glu Glu Tyr Asp Leu 610 615 620 Gln Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr Ala Asp Val Met 625 630 635 640 Thr Tyr Ile His Ser Met Asn Ser Thr Ile Leu Glu Asp Trp Asn Phe 645 650 655 Gly Leu Gln Pro Pro Pro Gly Gly Thr Leu Glu Asp Thr Tyr Arg Phe 660 665 670 Val Thr Ser Gln Ala Ile Ala Cys Gln Lys His Thr Pro Pro Ala Pro 675 680 685 Lys Glu Asp Pro Leu Lys Lys Tyr Thr Phe Trp Glu Val Asn Leu Lys 690 695 700 Glu Lys Phe Ser Ala Asp Leu Asp Gln Phe Pro Leu Gly Arg Lys Phe 705 710 715 720 Leu Leu Gln Ala Gly Leu Lys Ala Lys Pro Lys Phe Thr Leu Gly Lys 725 730 735 Arg Lys Ala Thr Pro Thr Thr Ser Ser Thr Ser Thr Thr Ala Lys Arg 740 745 750 Lys Lys Arg Lys Leu Val Asp Lys Pro Pro Thr Pro Pro Pro Glu Pro 755 760 765 Glu Thr Ala Ala Ala Ser 770 <210> 14 <211> 814 <212> PRT <213> Artificial Sequence <220> 223 fusion polypeptide HPV 18 L1 <400> 14 Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro 1 5 10 15 Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu 20 25 30 Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu 35 40 45 Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys 50 55 60 Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn 65 70 75 80 Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu 85 90 95 Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser 100 105 110 Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu 115 120 125 Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn 130 135 140 Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp 145 150 155 160 Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu 165 170 175 Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr 180 185 190 Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala 195 200 205 Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Val Pro Arg 210 215 220 Gly Ser Pro Asn Ser Met Cys Leu Tyr Thr Arg Val Leu Ile Leu His 225 230 235 240 Tyr His Leu Leu Pro Leu Tyr Gly Pro Leu Tyr His Pro Arg Pro Leu 245 250 255 Pro Leu His Ser Ile Leu Val Tyr Met Val His Ile Ile Ile Cys Gly 260 265 270 His Tyr Ile Ile Leu Phe Leu Arg Asn Val Asn Val Phe Pro Ile Phe 275 280 285 Leu Gln Met Ala Leu Trp Arg Pro Ser Asp Asn Thr Val Tyr Leu Pro 290 295 300 Pro Pro Ser Val Ala Arg Val Val Asn Thr Asp Asp Tyr Val Thr Arg 305 310 315 320 Thr Ser Ile Phe Tyr His Ala Gly Ser Ser Arg Leu Leu Thr Val Gly 325 330 335 Asn Pro Tyr Phe Arg Val Pro Ala Gly Gly Gly Asn Lys Gln Asp Ile 340 345 350 Pro Lys Val Ser Ala Tyr Gln Tyr Arg Val Phe Arg Val Gln Leu Pro 355 360 365 Asp Pro Asn Lys Phe Gly Leu Pro Asp Thr Ser Ile Tyr Asn Pro Glu 370 375 380 Thr Gln Arg Leu Val Trp Ala Cys Ala Gly Val Glu Ile Gly Arg Gly 385 390 395 400 Gln Pro Leu Gly Val Gly Leu Ser Gly His Pro Phe Tyr Asn Lys Leu 405 410 415 Asp Asp Thr Glu Ser Ser His Ala Ala Thr Ser Asn Val Ser Glu Asp 420 425 430 Val Arg Asp Asn Val Ser Val Asp Tyr Lys Gln Thr Gln Leu Cys Ile 435 440 445 Leu Gly Cys Ala Pro Ala Ile Gly Glu His Trp Ala Lys Gly Thr Ala 450 455 460 Cys Lys Ser Arg Pro Leu Ser Gln Gly Asp Cys Pro Pro Leu Glu Leu 465 470 475 480 Lys Asn Thr Val Leu Glu Asp Gly Asp Met Val Asp Thr Gly Tyr Gly 485 490 495 Ala Met Asp Phe Ser Thr Leu Gln Asp Thr Lys Cys Glu Val Pro Leu 500 505 510 Asp Ile Cys Gln Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ser 515 520 525 Ala Asp Pro Tyr Gly Asp Ser Met Phe Phe Cys Leu Arg Arg Glu Gln 530 535 540 Leu Phe Ala Arg His Phe Trp Asn Arg Ala Gly Thr Met Gly Asp Thr 545 550 555 560 Val Pro Gln Ser Leu Tyr Ile Lys Gly Thr Gly Met Arg Ala Ser Pro 565 570 575 Gly Ser Cys Val Tyr Ser Pro Ser Pro Ser Gly Ser Ile Val Thr Ser 580 585 590 Asp Ser Gln Leu Phe Asn Lys Pro Tyr Trp Leu His Lys Ala Gln Gly 595 600 605 His Asn Asn Gly Val Cys Trp His Asn Gln Leu Phe Val Thr Val Val 610 615 620 Asp Thr Thr Arg Ser Thr Asn Leu Thr Ile Cys Ala Ser Thr Gln Ser 625 630 635 640 Pro Val Pro Gly Gln Tyr Asp Ala Thr Lys Phe Lys Gln Tyr Ser Arg 645 650 655 His Val Glu Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Thr Ile 660 665 670 Thr Leu Thr Ala Asp Val Met Ser Tyr Ile His Ser Met Asn Ser Ser 675 680 685 Ile Leu Glu Asp Trp Asn Phe Gly Val Pro Pro Pro Thr Thr Ser 690 695 700 Leu Val Asp Thr Tyr Arg Phe Val Gln Ser Val Ala Ile Thr Cys Gln 705 710 715 720 Lys Asp Ala Ala Pro Ala Glu Asn Lys Asp Pro Tyr Asp Lys Leu Lys 725 730 735 Phe Trp Asn Val Asp Leu Lys Glu Lys Phe Ser Leu Asp Leu Asp Gln 740 745 750 Tyr Pro Leu Gly Arg Lys Phe Leu Val Gln Ala Gly Leu Arg Arg Lys 755 760 765 Pro Thr Ile Gly Pro Arg Lys Arg Ser Ala Pro Ser Ala Thr Thr Ser 770 775 780 Ser Lys Pro Ala Lys Arg Val Arg Val Arg Ala Arg Lys Val Asp Lys 785 790 795 800 Pro Pro Thr Pro Pro Pro Glu Pro Glu Thr Ala Ala Ala Ser 805 810
Claims (15)
C 말단에 시미안 바이러스 40 대형 T 항원(simian virus 40 large T-antigen)의 아미노산 서열 또는 이의 활성단편 및
HPV 6 L1 항원, HPV11 L1 항원, HPV16 L1 항원 및 HPV18 L1 항원으로 구성된 군으로부터 선택된 HPV L1 항원의 아미노산 서열 또는 이의 활성단편을 포함하는 융합 폴리펩타이드.
Amino acid sequence of glutathione S-transferase (GST) at its N-terminus or active fragment thereof
The amino acid sequence of the simian virus 40 large T-antigen at its C terminus or an active fragment thereof; and
A fusion polypeptide comprising the amino acid sequence of an HPV L1 antigen selected from the group consisting of HPV 6 L1 antigen, HPV11 L1 antigen, HPV16 L1 antigen and HPV18 L1 antigen or active fragment thereof.
The fusion polypeptide of claim 1, wherein the amino acid sequence of the fusion polypeptide is an amino acid sequence selected from the group consisting of SEQ ID NOs: 11-14.
N 말단에 글루타티온 S-트랜스퍼라제(Glutathione S-transferase, GST)의 아미노산 서열 또는 이의 활성단편
C 말단에 시미안 바이러스 40 대형 T 항원(simian virus 40 large T-antigen)의 아미노산 서열 또는 이의 활성단편 및
HPV 6 L1 항원, HPV11 L1 항원, HPV16 L1 항원 및 HPV18 L1 항원으로 구성된 군으로부터 선택된 HPV L1 항원의 아미노산 서열 또는 이의 활성단편을 포함하는 융합 폴리펩타이드.
Polynucleotides encoding the following fusion polypeptides:
Amino acid sequence of glutathione S-transferase (GST) at its N-terminus or active fragment thereof
The amino acid sequence of the simian virus 40 large T-antigen at its C terminus or an active fragment thereof; and
A fusion polypeptide comprising the amino acid sequence of an HPV L1 antigen selected from the group consisting of HPV 6 L1 antigen, HPV11 L1 antigen, HPV16 L1 antigen and HPV18 L1 antigen or active fragment thereof.
The polynucleotide encoding the amino acid sequence of the Simian virus 40 large T antigen or an active fragment thereof according to claim 3, wherein the double-stranded polynucleotide consisting of SEQ ID NO: 1 and SEQ ID NO: 2 is cleaved with Sal I and Not I restriction enzymes. One, polynucleotide.
The polynucleotide encoding the amino acid sequence of the HPV 6 L1 antigen or an active fragment thereof according to claim 3, wherein the polynucleotide amplified from the HPV 6 genome using a primer set of SEQ ID NO: 3 and SEQ ID NO: 4 is determined by Eco RI and Sal. A polynucleotide cut by I restriction enzyme.
According to claim 3, wherein the polynucleotide encoding the amino acid sequence of the HPV 11 L1 antigen or active fragments thereof are polynucleotides Eco RI and Sal I amplified from the HPV 11 genome using a primer set of SEQ ID NO: 5 and SEQ ID NO: 6 Polynucleotide cut by restriction enzyme.
The polynucleotide Bgl II and Sal I of claim 3, wherein the polynucleotide encoding the amino acid sequence of the HPV 16 L1 antigen or an active fragment thereof is amplified from the HPV 16 genome using a primer set of SEQ ID NO: 7 and SEQ ID NO: 8 Polynucleotide cut by restriction enzyme.
According to claim 3, wherein the polynucleotide encoding the amino acid sequence of the HPV 18 L1 antigen or active fragments thereof are polynucleotides Eco RI and Sal I amplified from the HPV 18 genome using a primer set of SEQ ID NO: 9 and SEQ ID NO: 10 Polynucleotide cut by restriction enzyme.
An expression vector comprising the polynucleotide of any one of claims 3 to 8.
A transformant transformed with the expression vector of claim 9.
상기 융합 폴리펩타이드가 결합된 비드를 시료와 반응시키는 단계;
상기 시료를 표지자 표지된 2차 항체와 반응시키는 단계;
상기 2차 항체를 형광물질이 부착된 상기 표지자의 특이적 결합제와 반응시키는 단계; 및
비드 유래의 형광값과 표지자의 특이적 결합제 유래의 형광값을 측정하여 시료 내 HPV 항체를 검출하는 단계를 포함하는 시료 내 HPV 항체 검출 방법.
Binding the fusion polypeptide of claim 1 to the beads for beads array;
Reacting the beads to which the fusion polypeptide is bound with a sample;
Reacting the sample with a marker labeled secondary antibody;
Reacting the secondary antibody with a specific binding agent of the marker to which a fluorescent substance is attached; And
A method for detecting HPV antibodies in a sample comprising measuring a fluorescence value derived from a bead and a fluorescence value derived from a specific binder of a marker.
The method of claim 1, wherein the beads for the bead array are glutathione-casein (GC) beads.
The method of claim 11, wherein the marker is biotin and the specific binding agent of the marker is streptavidin.
The method of claim 1, wherein the fluorescent material is fluorescein, isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthalaldehyde or fluorescamine.
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CN108872596A (en) * | 2018-07-05 | 2018-11-23 | 重庆巴而思生物科技有限公司 | A kind of ELISA detection kit of HPV16 L1 antibody |
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