KR101002791B1 - Ｈｃｖ ｅ2 당단백질을 표적하고 시험관내 중화 활성을보유하는 사람 단클론항체 ｆａｂ 단편 - Google Patents
Ｈｃｖ ｅ2 당단백질을 표적하고 시험관내 중화 활성을보유하는 사람 단클론항체 ｆａｂ 단편 Download PDFInfo
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Abstract
본 발명은 HCV E2 당단백질을 표적하고 생체내 중화 활성을 보유하는 사람 항체 또는 이의 기능적 단편; 상기 항체의 치료요법적 효과량을 함유하는 항-HCV 요법용 조성물; 겔, 크림, 연고, 소란 제제로서 국소용 조성물; 항-HCV 백신을 검증하기 위한 상기 항체의 용도에 관한다.
Description
본 발명은 HCV E2 당단백질을 표적하고 시험관내 중화 활성을 보유하는 사람 단클론항체 Fab 단편에 관한다. C형 간염 바이러스(VCV)는 세계 인구의 4% 정도를 감염시킨다. 상기 병원균과 접촉한 개체의 80% 이상은 숙주 면역 반응으로 이런 감염을 극복할 수 없기 때문에 만성 감염이 발생하고, 심각한 간 질환, 예를 들면 만성 간염, 간경변증, 간세포 암종의 위험에 노출된다[1, 2].
만성 감염의 치료는 인터페론 및 리바비린(rivavirin)과의 복합 요법에 기초하는데, 이런 복합 요법은 비용 측면에서 상당한 부담을 유발하고 효과가 경미하다(4명중 1명만 장기적인 결과를 얻는다)[3,4]. 이런 바이러스 감염은 면역 보호를 제공하지 않는다. 면역계에 의해 인식되는 항원 구조에서 상기 바이러스의 높은 변이성과 함께, 이런 사실은 HCV 감염으로부터 개체를 보호하는데 효과적인 혈청 요법과 백신의 개발을 방해한다. 이런 이유로, 새로운 항바이러스 전략이 강하게 요구되고 있다.
본 발명자는 면역 보호 반응의 가장 중요한 표적으로 간주되는 외부 E2 당단 백질인 HCV 단백질중 하나를 표적하는 다수의 사람 Fab 항체 단편을 코딩하는 유전자를 클론하였다[5]. 하지만, HCV에 대한 중화 활성을 결정하는데 이용가능한 신뢰성 있는 시험관내 시스템이 없기 때문에, 이들 항체 단편의 생물학적 활성 평가가 간단하지 않다. 따라서, 본 발명자는 이런 활성과 혈청의 중화 활성간의 상관관계를 입증하지 않고, 표적 세포에 대한 단백질 E2의 결합을 저해하는 서로 다른 Fab의 가변적 능력만을 평가하고 기술하였다[5].
기존 문헌에서 Burioni 등(2001)[6]은 HCV-감염된 환자에 의해 생산된 일부 항-E2 항체가 부정적인 효과를 나타내고, 상기 바이러스가 아마도 E2 항원에 대한 결합 및 이의 형태 변화로 인하여 숙주 면역 반응에 덜 민감해진다고 밝혔다[6]. 이는 높은 항-E2 항체 역가가 HCV 감염에 대한 보호와 직접적으로 상관하지 않는 이유를 설명한다.
Bugli 등(2001)[7]은 항-E2 사람 Fab에 시험관내에서 결합할 수 있는 E2 단백질 에피토프의 지도를 만들고, 면역 반응이 표적하는 4개의 구별된 영역을 보였다(도 2)[7]. 만성적으로 감염된 환자의 혈청에서 하나이상의 이들 영역을 표적하는 항체의 존재는 합병증, 감소된 치료 효능, 상이한 예후와 연관할 수 있다. 이런 이유로, HCV E2 단백질의 서로 다른 에피토프를 표적하는 항체를 생물 유체에서 확인하는 방법이 필요하다. 본 발명의 한 구체예서는 이런 방법을 제시한다.
또한, 본 발명자는 바이러스 가유형(viral pesudotype), 다시 말하면 HCV와 외적으로 동일하지만 표적 세포에 들어간 이후 형광을 발생시키는 단백질을 생산할 수 있는 바이러스 시스템에서 다양한 항-E2 항체의 중화 활성을 평가하였다[8]. 세 포에서 형광의 존부를 확인으로써, 상기 방법은 서로 다른 에피토프를 표적하는 항-E2 항체의 생체내 중화 활성을 직접적으로 측정할 수 있다.
예상치 않게, 본 발명자는 분석된 항체중 2가지, e137과 e301이 항체 제형의 단일 장관외 투여로 획득가능한 농도에서 상기 바이러스를 중화시킬 수 있다는 것을 발견하였다; 다른 2개의 항체는 중화 활성을 보유하지 않았고, 한 항체는 바이러스 감염을 오히려 촉진하였다.
환자에서 서로 다른 항체 집단을 적정하는 방법의 개발은 심각한 합병증이 발생할 위험이 있는 감염 개체와 좀더 긍정적인 예후를 보이는 감염 개체를 구별할 수 있는 귀중한 진단과 예측 도구를 제공한다. 후자 군에서, 상기 방법은 심각한 부작용과 연관하는 거의 무효한 치료제를 투여하는 필요를 배제하면서 비용을 현저하게 감소시킨다.
이렇게 동정된 E2 에피토프는 합성 펩티드를 합성하면 재현되지 않기 때문에[5], 상기 방법은 상관된 임상과 역학(疫學) 데이터로 단백질 E2의 서로 다른 단편에 대한 항체의 양을 확인할 수 있는 유일한 방법이다.
우수한 중화 활성을 보유하는 사람 Fab형 항-E2 항체의 동정은 이들의 대규모 생산 및 항-HCV 치료에서 약물로서 또는 위험 개체(HCV 상태가 부조화된 부부, 직업적으로 노출된 개체 등)에 바이러스 전파를 저해하는 국소형 예방제로서 이용을 가능하게 한다.
광범위한 범위의 바이러스를 인식할 수 있는 중화 사람 항체의 유효성은 인공 백신의 생산에 결정적이다. 본원에 기술된 중화 항체는 중화 교차-반응을 촉진 할 수 있는 백신(펩티드 또는 항-이디오타입 항체로부터) 개발의 주형으로 이용될 수 있다.
본 발명의 목적은 HCV E2 단백질을 표적하고 생체내 중화 활성을 보유하는 사람 항체 또는 이의 기능적 단편이다.
특정 구체예에서, 본 발명의 항체는 아래의 중쇄와 경쇄 가변 영역의 아미노산 서열로 특성화되는 항체 e137이다:
e137 중쇄(HC)
LLEQSGSEVKVPGSSLKVSCKTSGGTFSTYTFSWVRQAPGQGLEWMG
GITPIIGIANYARNFQDRVTITADESTSTVYMEVRRLRSEDTAVYYCAKTS
EVTATRGRTFFYSAMDVWGQGT
e137 경쇄(LC)
MAELTQSPSFLSASVGDRVTITCRASQGISNYLAWYQQKPGKAPKLLIYA
ASTLQSGVPSRFSGSGSWTEFTLTISRLQPEDFATYYCQHLNTYPWTFG
QGT
다른 구체예에서, 본 발명의 항체는 아래의 중쇄와 경쇄 가변 영역의 아미노산 서열로 특성화되는 항체 e301이다:
e301 중쇄(HC)
LLEQSGSEVKKPGSSVRVSCTTSGGTLSDYGFNWLRQAPGQGPEWMG
GIIPLFRRTTYGQKFQGRLTITADESTGATYMELSSLRSDDTAVYYCARE
KVSVLTGGKSLHYFEYWGKGT
e301 경쇄(LC)
MAELTQSPATLSVSPGERATLSCRASQSVSSRLAWYQQKRGQAPSLLIY
DTSSRATGVPARFSASGSGTQFTLTISSLQSEDFALYYCQQYNDWPSTF
GQGT
본 발명의 또 다른 목적은 항-HCV 요법용 조성물인데, 상기 조성물은 본 발명에 따른 적어도 한가지 항체의 치료 효과량을 함유한다. 적절하게는, 상기 조성물은 당업자에 공지된 부형제와 함께, 장관외 투여용으로 정제된 형태, 또는 다른 국소용 제제, 예를 들면 겔, 크림, 연고, 소란(ovule)으로 제공된다.
본 발명의 또 다른 목적은 본 발명의 항체 각각을 코딩하는 핵산이다. 적절하게는, 핵산은 진핵세포 또는 원핵세포에서 본 발명의 항체를 효과적으로 발현할 수 있는 발현 벡터에 포함된다. 바람직한 형태에서, 재조합 벡터는 본 발명의 항체에 대한 코딩 서열이 실질적으로 연속되는 단일 펩티드를 코딩하는 뉴클레오티드 서열을 포함하고, 상기 항체를 세포 환경 외부로 내보낼 수 있다.
본 발명의 또 다른 목적은 유전자 요법에서 앞서 기술된 재조합 벡터의 실용이다.
본 발명은 아래의 도면을 참고로 하여 실험적 실시예를 기술하지만, 이들 실시예는 본 발명을 제한하지 않는다.
도 1 FIT: 이론적 기준. 패널 A는 경쟁 상대가 없는 상태에서 Fab-FLAG의 에 피토프 결합을 보여준다. (A)에 존재하는 동일 농도의 Fab를 사용하여 환자의 혈청과 항원을 사전배양하면, 혈청에서 Fab에 의해 인식되는 에피토프를 표적하는 항체의 정량적 분석이 가능하다. 패널 B와 C에서, Fab와 경쟁하는 결합 항체는 패널 A와 비교하여 결합량이 비례적으로 감소한다. 패널 D와 E에서, 특정 에피토프를 표적하지 않는 항체의 존재는 Fab 결합에 최소한의 영향도 주지 않는다.
도 2A와 B: 공지된 농도의 e8-IgG1과 e509-IgG1(Fab에 의해 인식되는 에피토프를 표적하는 전체 항체)을 함유하는 혈청에 의한 HCV/E2에 대한 e8-FLAG(A)와 e5O9-FLAG(B)의 결합 저해. 분명하게, Fab 결합의 저해는 동일 특이성을 갖는 전체 항체의 존재하에서만 관찰될 수 있고 항체 농도에 좌우된다.
도 3A, B, C: 서로 다른 농도의 정제된 항-HCV/E2 사람 재조합 Fab에 의한 VSV/HCV와 VSV/G 가유형의 감염 저해. Fab-처리된 가유형으로 감염된 HepG2 세포는 16시간동안 배양하고, 녹색 형광 단백질-발현 세포의 수는 형광 검경으로 측정하였다. 데이터는 대조 웰(Fab 첨가되지 않음)에서 탐지된 감염의 %로 나타낸다. 도시된 결과는 이중으로 실시된 독립 분석의 평균이다.
도 4: 본 연구에 이용된 단클론 항체에 의해 인식되고 HCV/E2의 표면에 존재하는 사람 B 세포 에피토프의 2차원 표면-유사 지도. 부분적으로 겹쳐진 원은 상호 저해를 표시한다. VSV/HCV 가유형 중화 활성을 보유하는 Fab는 밑줄로 표시한다. 세포 표적과 HCV/E2의 상호작용을 매개하는 추정 영역은 점선으로 표시한다. 중화 항체에 의해 인식되는 추정 영역은 검은색 원으로 표시한다. 항원-항체 상호작용에 의해 유도되는 변형으로 인하여, 이런 다이어그램은 실제 물리 지도와 일치하지 않 는다.
실시예 1
재료와 방법
항-HCV Fab와 전장 IgG1 생산
항-HCV/E2 Fab의 생산, 정제, 특성화는 기존 문헌에서 기술하였다[5]. FLAG-Fab(펜타펩티드 가교로 중쇄 단편의 카르복시 말단에 융합된 FLAG 에피토프로 표지된 Fab)는 기존 문헌에서 밝힌 바와 같이 작제하고 정제하였다[6]. 분석의 검증과 표준화는 전장 사람 단클론 항체(HuMab)를 작제하기 위한 Fab-코딩 유전자를 이용하여 실시하였는데, 상기 유전자는 트랜스펙션된 세포에서 후속 생산에 적합한 진핵 벡터에 삽입되었다[9]. 배양 상층액에 존재하는 HuMab는 기존 문헌에서 밝힌 바와 같이 면역친화성 정제하고 PAGE로 순도-확인하였다[10]. 사람 항체의 양은 샌드위치 면역분석법으로 분석하였다. 모든 항체와 Fab는 사용 때까지 -70℃에 보관하였다.
혈청과 시료
건강한 공여자와 HCV-양성 환자로부터 얻은 혈청은 표준 절차에 따라 상용 진단 키트(Ortho, Raritan, NJ)를 이용하여 분석하였다. 일정한 에피토프를 표적하는 공지된 함량의 항체로 가짜 시료를 제조하기 위하여, HCV-음성 혈청은 PBS에서 농축되고 정제된 HuMab를 조금 첨가하고 양성과 음성 혈청에서와 동일하게 처리하였다.
Fab 저해 역가(FIT) 분석법의 설계
본 분석법의 목적은 에피토프에 대한 표지된 Fab의 결합을 저해하는 혈청의 능력을 평가하고, 따라서 혈청에서 에피토프-결합 항체의 함량을 간접적으로 측정하는 것이다(도 1).
FLAG-Fab는 정제하고[10], FLAG-Fab-특이적 ELISA에서 분석하여 저해 실험에 이용되는 정확한 농도를 결정하였다. 간단히 말하면, 공지된 농도의 FLAG-Fab 제형은 ELISA로 적정하는데[11], 여기서 항원-피복된 평판은 PBS/1%BSA로 37℃에서 1시간동안 차단하였다. 차단 용액을 제거한 이후, PBS/BSA 1%에서 만들어진 FLAG-Fab 의 50 ㎕ 점진적 희석액을 웰에 첨가하고 37℃에서 2시간동안 배양하였다. 평판은 자동화 평판 세척기(DiaSorin, Saluggia, Italy)에서 PBS/0.05% Tween-20으로 10회 세척하고, 이후 PBS/BSA 1%에 녹인 항-FLAG 생쥐 단클론 항체 M2(Sigma, St. Louis, MO; PBS에서 10 ㎍/㎖)의 10 ㎍/㎖ 용액 50 ㎕를 첨가하였다. 37℃에서 1시간 배양한 이후, 웰은 전술한 바와 같이 PBS/Tween-20으로 10회 세척하고, 생쥐 단클론 항체 결합은 양고추냉이 과산화효소-공액된 염소 항-생쥐 IgG(Pierce; PBS에서 1:8,000)으로 확인하였다. 기질을 첨가하고, 실온의 암실에서 30분동안 배양한 이후 자동화 평판 판독기에서 OD450에서 평판을 판독하였다. 모든 분석은 적어도 2회 실시하였다. 음성 대조 항원(BSA)은 항상 포함시키고, OD 시도(reading)는 기준값(background)으로서 감하였다.
혈청의 Fab 저해 역가(FIT) 측정에서, 표준 조건에서 최대값의 50%에 상응하 는 OD450 시도(reading)를 산출하는 농도의 정제된 FLAG-Fab는 Fab 저해 ELISA의 추후 실험에 사용하였다. 이들 실험에서, 평판은 전술한 바와 같이 피복하고 차단하였다. PBS/BSA 1%에서 점진적 1:4 혈청 희석액을 ELISA 웰당 50 ㎕ 양으로 첨가하였다. 37℃에서 2시간 배양후, 정제된 FLAG-Fab는 최종 농도에 도달할 때까지 혈청 희석액에 직접 첨가하였다. 평판은 추가로 30분동안 배양하고, 이후 FLAG-Fab ELISA에서 앞서 밝힌 바와 같이 처리하였다. 100% 저해에 해당하고 20:1의 과다 정제된 표지되지 않은 Fab를 함유하는 양성 대조 시료를 포함시킨다. 0% 저해에 해당하고 과량의 대조 무관한 Fab[12]를 함유하는 음성 대조 시료 역시 포함시킨다. 최종 결과는 아래의 공식에 따라 저해 %로 나타낸다: 100 x (프로브 FLAG-Fab 단독의 OD450 - 경쟁 혈청과 함께 프로브 FLAG-Fab의 OD450)/프로브 FLAG-Fab 단독의 OD450
.
FLAG-Fab 결합의 70% 초과 저해를 제공하는 최대 혈청 희석은 상기 에피토프와 혈청에 대한 Fab 저해 역가(FIT)로 간주된다.
결과
본 분석에 이용하기 적합한 FLAG-Fab 농도는 각 FLAG-Fab에서 측정하는데, 10 ㎍/㎖(e8, e2O, e137, e301, e5O9) 내지 0.1 ㎍/㎖(e1O-B)이다. 다양한 항체의 경쇄와 중쇄의 아미노산 서열은 아래에 제시한다:.
e8 HC
LLEQSGAEVKMPGATVKVSCQSSRYTFTSYGIGWVRQAPGQGLEWMG
WISGYTHETKYAQSFQGRVTMTAETSTGTAYMELRSLRSDDTATYYCA
RDGGGRVVVPPTHLRAFDVWGQGT
e8 LC
MAELTQSPGTLSLSPGERATLSCRASHRVNNNFLAWYQQKPGQAPRLLI
SGASTRATGIPDRFSGSGSGTDFTLTISRLEPDDFAVYYCQQYGDSPLY
SFGQGT
e1O HC
LLESGPGLVKPSQTLSLTCTVSGVSISYGGRGVSYWGWVRQSPGKGLE
WIGHIYYFGDTFYNPSLNNRATISIDSSKNQFSLKLKSVTASDTALYFCAR
STLQYFDWLLTREAAYSIDFWGQGI
e1O LC
MAELTQSPSFLSASVGDRVTITCRASQGVTILLAWYQQKPGKPPKALIYA
ASSLQSGVPSRFSGSGSDTDFTLTISSLQPEDSATYYCQQLNTYPWTFG
QGT
e2O HC
LLEQSGAEVKKPGSSVKVSCKASGDHYGINWVRQAPGQGLEWMGGIIP
VFGTTTYAQKFQGRATITADDSTGTAFLELTRLTFDDTAVYFCATPHQLH
VLRGGKALSPWDYWGQGT
e2O LC
MAELTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKRGQAPSLLIY
GTSTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNDWPSTF
GQGT
e137 HC
LLEQSGSEVKVPGSSLKVSCKTSGGTFSTYTFSWVRQAPGQGLEWMG
GITPIIGIANYARNFQDRVTITADESTSTVYMEVRRLRSEDTAVYYCAKTS
EVTATRGRTFFYSAMDVWGQGT
e137 LC
MAELTQSPSFLSASVGDRVTITCRASQGISNYLAWYQQKPGKAPKLLIYA
ASTLQSGVPSRFSGSGSWTEFTLTISRLQPEDFATYYCQHLNTYPWTFG
QGT
e301 HC
LLEQSGSEVKKPGSSVRVSCTTSGGTLSDYGFNWLRQAPGQGPEWMG
GIIPLFRRTTYGQKFQGRLTITADESTGATYMELSSLRSDDTAVYYCARE
KVSVLTGGKSLHYFEYWGKGT
e301 LC
MAELTQSPATL8VSPGERATLSCRASQSVSSRLAWYQQKRGQAPSLLIY
DTSSRATGVPARFSASGSGTQFTLTISSLQSEDFALYYCQQYNDWPSTF
GQGT
e5O9 HC
LLEESGAEVKKPGSSVKVSCKTSGDTFRYGITWVRQAPGQGLEWMGQI
MPTFATATYAQRFQGRVTISADESTSTAYLEVRSLRSEDTAVYYCATPR
QVTILRGPKALSPWDYWGQGT
e5O9 LC
MAELTQSPATLSASPGERASLSCRASQSVSSNLAWYQQKPGQAPRLLIS
GASTRATGVPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPH
FGQGT
앞서 밝힌 Fab 단편을 코딩하는 뉴클레오티드 서열은 아래와 같이 표시된다:
e8 HC
CTGCTCGAGCAGTCTGGAGCTGAGGTGAAGATGCCTGGGGCCACAG
TGAAGGTCTCCTGCCAGTCTTCCCGTTACACCTTCACCAGTTACGGT
ATCGGCTGGGTGCGACAGGCCCCTGGACAGGGGCTTGAGTGGATG
GGATGGATCAGCGGATACACCCATGAGACAAAATATGCACAGAGTTT
CCAGGGCAGAGTCACCATGACCGCAGAGACATCCACGGGCACAGCG
TATATGGAGTTGAGGAGCCTGCGGTCTGACGACACGGCCACATATTA
CTGCGCGAGAGATGGAGGAGGGAGGGTGGTAGTGCCGCCTACTCAT
CTACGTGCTTTTGATGTCTGGGGTCAAGGGACG
e8 LC
ATGGCCGAGCTCACCCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGG
GGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCACAGAGTCAATAACA
ACTTCTTAGCCTGGTATCAGCAGAAACCTGGCCAGGCTCCCAGGCTC
CTCATCTCTGGTGCATCTACCAGGGCCACTGGCATCCCAGACAGGTT
CAGTGGCAGTGGGTCTGGAACAGACTTCACTCTCACCATCAGCAGAC
TGGAGCCTGATGATTTTGCAGTTTATTATTGTCAGCAGTATGGTGACT
CACCTCTTTATTCTTTTGGCCAGGGGACC
e1O HC
CTGCTCGAGTCTGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGT
CCCTCACCTGCACCGTCTCCGGTGTCTCCATCAGTTACGGTGGTCGT
GGCGTTTCCTACTGGGGTTGGGTCCGCCAGTCCCCAGGGAAGGGCC
TGGAGTGGATTGGCCACATCTACTACTTTGGAGACACCTTCTACAAC
CCGTCCCTCAACAATCGAGCTACCATATCAATAGACTCATCCAAAAAC
CAGTTCTCCCTCAAGCTCAAGTCTGTGACTGCCTCAGACACGGCCCT
GTATTTCTGTGCCAGGAGCACCCTACAGTATTTTGACTGGTTATTGAC
ACGGGAGGCTGCCTACTCCATTGACTTCTGGGGCCAGGGAATA
e1O LC
ATGGCCGAGCTCACCCAGTCTCCATCCTTCCTGTCTGCATCTGTTGG
AGACCGAGTCACCATCACTTGCCGGGCCAGTCAGGGCGTCACCATT
CTTTTAGCCTGGTATCAGCAAAAGCCAGGGAAACCCCCTAAGGCCCT
GATTTATGCTGCATCGTCTTTGCAAAGTGGGGTCCCATCAAGGTTCA
GCGGCAGTGGTTCTGACACAGATTTCACTCTCACAATCAGCAGCCTA
CAGCCTGAAGATTCTGCAACTTATTACTGTCAACAACTTAACACTTAC
CCGTGGACGTTCGGCCAGGGGACC
e2O HC
CTGCTCGAGCAGTCAGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGG
TGAAGGTCTCCTGCAAGGCTTCTGGAGACCACTATGGTATCAACTGG
GTGCGACAGGCCCCTGGACAAGGGCTGGAGTGGATGGGCGGTATCA
TCCCTGTCTTTGGCACAACTACCTACGCACAGAAGTTCCAGGGCAGA
GCCACCATTACCGCGGACGACTCCACGGGGACGGCCTTTTTGGAGC
TGACCAGACTGACATTTGACGACACGGCCGTCTATTTCTGTGCGACA
CCTCACCAACTGCATGTCCTCCGGGGCGGTAAAGCCCTCTCCCCCT
GGGACTACTGGGGCCAGGGAACC
e2O LC
ATGGCCGAGCTCACCCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGG
GGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGT
AACTTAGCCTGGTACCAGCAGAAACGTGGCCAGGCTCCCAGTCTCCT
CATCTACGGAACATCTACCAGGGCCACTGGTATCCCAGCCAGGTTCA
GTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCT
GCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATGATTG
GCCCTCCACCTTCGGCCAAGGGACA
e137 HC
CTGCTCGAGCAGTCTGGGTCTGAAGTAAAAGTGCCCGGGTCCTCGTT
GAAGGTCTCCTGCAAGACTTCTGGAGGCACCTTCAGCACCTATACTT
TCAGCTGGGTGCGACAGGCCCCTGGACAGGGACTTGAGTGGATGGG
GGGGATCACCCCTATCATTGGCATCGCAAACTACGCACGGAACTTCC
AGGACAGAGTCACCATCACCGCGGACGAATCCACGAGCACGGTCTA
CATGGAGGTGAGGAGGCTGAGATCTGAGGACACGGCCGTATATTATT
GTGCGAAAACTTCGGAAGTAACAGCCACTAGAGGGCGGACTTTCTTC
TACTCCGCTATGGACGTCTGGGGTCAAGGGACC
e137 LC
ATGGCCGAGCTCACCCAGTCTCCATCCTTCCTGTCTGCATCTGTAGG
AGACAGAGTCACCATCACTTGCCGGGCCAGTCAGGGCATAAGCAATT
ATTTAGCCTGGTATCAGCAAAAACCAGGGAAAGCCCCTAAGCTCCTG
ATCTATGCTGCATCCACTTTGCAAAGTGGGGTCCCATCGAGGTTCAG
CGGCAGTGGATCTTGGACAGAATTCACTCTCACAATCAGCCGCCTCC
AGCCTGAAGATTTTGCAACTTATTACTGTCAACACCTTAATACTTACCC
GTGGACGTTCGGCCAAGGGACC
e301 HC
CTGCTCGAGCAGTCTGGGTCTGAGGTGAAGAAACCTGGGTCCTCGG
TGAGGGTCTCGTGCACGACTTCTGGAGGCACCTTGAGCGACTATGGT
TTCAACTGGTTACGACAGGCCCCTGGACAAGGGCCTGAGTGGATGG
GAGGGATCATCCCTTTGTTTCGAAGAACAACCTACGGACAGAAGTTC
CAGGGCAGACTCACCATTACCGCGGACGAGTCCACGGGCGCAACCT
ACATGGAGCTGAGCAGCCTGAGATCTGACGACACGGCCGTCTATTAC
TGTGCGAGAGAGAAAGTTTCGGTCCTCACAGGCGGAAAGTCACTCCA
TTACTTTGAATATTGGGGCAAGGGAACC
e301 LC
ATGGCCGAGCTCACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAG
GGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAG
CAGGTTAGCCTGGTACCAGCAGAAACGTGGCCAGGCTCCCAGTCTC
CTCATCTATGACACATCTTCCAGGGCCACTGGTGTCCCAGCCAGGTT
CAGTGCCAGTGGGTCTGGGACGCAGTTCACTCTCACCATCAGCAGC
CTGCAGTCTGAAGATTTTGCACTTTATTACTGTCAGCAGTATAATGATT
GGCCCTCCACCTTCGGCCAAGGGACA
e5O9 HC
CTGCTCGAGGAGTCTGGGGCTGAGGTGAAGAAGCCAGGGTCCTCGG
TGAAGGTCTCCTGCAAGACTTCTGGAGACACCTTCAGATATGGTATC
ACGTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAC
AGATCATGCCTACGTTTGCGACAGCAACCTACGCACAGAGGTTCCAG
GGCAGAGTCACGATTTCCGCGGACGAATCCACGAGCACAGCCTACTT
GGAGGTGCGCAGCCTGAGATCTGAAGACACGGCCGTCTATTACTGT
GCGACACCTCGCCAAGTTACTATACTTCGGGGACCTAAAGCCCTCTC
CCCTTGGGACTACTGGGGCCAGGGAACC
e5O9 LC
ATGGCCGAGCTCACCCAGTCTCCAGCCACCCTGTCTGCGTCTCCAG
GGGAAAGAGCCTCCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGTAG
CAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTC
CTCATCTCTGGTGCATCCACCAGGGCCACTGGTGTCCCGGCCAGGT
TCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGTAGC
CTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAAC
TGGCCTCCCCACTTTGGCCAGGGGACC
정제된 표지된 Fab 분자에서 FLAG-Fab ELISA는 매우 특이적이고 재현가능한 결과를 산출한다. FIT 측정은 10개의 HCV-음성 혈청에서 실시한다; 역가는 검사의 탐지 상한선인 >1:20으로 일관하는데, 이는 특이적인 항-HCV 항체가 부재하는 경우에 저해가 발생하지 않음을 시사한다.
FIT가 본 발명의 FLAG-Fab에 의해 인식되는 에피토프를 표적하는 항체를 효과적으로 계량함을 입증하기 위하여, 음성 혈청과 일정한 특이성의 사람 단클론 항체를 혼합하고 본 발명의 Fab에 의해 인식되는 HCV E2 에피토프를 표적하는 공지된 함량의 IgG를 함유하는 가성 시료를 수득하여 준비한 가짜 시료에서 동일한 분석을 실시한다. 결과(도 2A와 B)는 FIT와 항체 함량간의 유효한 상관관계를 보여주는데, 이는 FIT가 환자의 혈청에서 에피토프-특이적 항체의 함량에 관한 신뢰성 있는 정보를 제공할 수 있음을 시사한다.
최종적으로, FIT는 HCV-양성 혈청에서 항상 양성이고, 수치는 광범위한 희석 을 포괄한다. FIT는 동일한 혈청 시료에서 서로 다른 Fab에 대하여 극히 상이하고, 환자간 이질성(heterogeneity)이 상당하다.
실시예 2
재료와 방법
사람 항체 단편
본 실시예에서 사람 재조합 항체 단편은 Bugli et al. (2001)[7]에서 상세히 기술하는데, 실시예 1에 사용된 항체 단편과 일치한다. 간단히 말하면, Fab를 코딩하는 유전자는 혈액에 1b 유전형의 HCV RNA가 지속적으로 존재하는 58세의 만성 간염 여성의 IgG1/카파 레퍼토리를 보유하는 파지 전시 조합 라이브러리로부터 얻었다. 선택된 유전자는 적합한 박테리아 발현 벡터에 삽입하고[13], 이후 형질전환된 세포는 재조합 Fab의 공급원으로 사용하는데, 상기 재조합 Fab는 기존 문헌에서 밝힌 바와 같이 생산하고 정제한다[14]. 세포에 대한 E2 결합 중화(NOB) 활성[5, 15] 및 이들 분자의 상호작용[7]이 기존 문헌에서 기술되었다. HCV-감염된 환자의 혈청에서 유사한 항체의 존재는 저해 ELISA로 확인한다[7].
가유형과 중화 분석
본 실시예에 이용된 가유형은 완전하게 특성화되었고 Matsuura et al., 2001[8]에서 기술한다. 간단히 말하면, VSV△G*/HCVE1-E2 가유형(VSV/HCV)은 수포성 구내염 바이러스로 구성되는데, 여기서 G 외피 단백질은 VSV G 단백질의 막통과 세포질 도메인으로 N-말단 신호 서열에 융합된 1b형 HCV cDNA 클론(NIH-J1)의 E1과 E2 단백질의 엑토도메인(ectodomain)으로 구성되는 키메라 E1과 E2 HCV 외피 당단백질로 치환된다. 플라스미드[16]와 진핵 발현 벡터의 작제는 기존 문헌에서 기술하였다[8, 17]. VSV/HCV는 G 단백질-코딩 영역이 녹색 형광 단백질 유전자(GFP)로 치환된 재조합 VSV로 키메라 E1과 E2 cDNA를 구성적으로 발현하는 CHO 세포를 감염시켜 준비한다[18]. VSV/HCV 가유형을 생산하는데 이용되는 VSV△G*/HCVE1-E2(VSV/G) 가유형(대조)은 G 단백질을 일시적으로 발현하는 세포주를 VSV△G*로 감염시켜 생산한다. 중화 분석은 기존 문헌에서 밝힌 바와 같이 실시한다[8]. 정제된 사람 재조합 Fab의 희석액은 가유형 VSV/HCV 또는 VSV/G의 2.4 X 103 감염 단위(Infection Unit)(IU)로 37℃에서 30분동안 배양하고, 96-웰 평판에 준비된 HepG2 세포(4 x 104 세포)에 접종한다. 37℃에서 60분동안 흡수이후, 세포는 10% FBS를 함유하는 DMEM으로 3회 세척하고 37℃에서 16시간동안 배양한다. 바이러스의 IU는 형광 검경으로 GFP-발현 세포의 수를 계산하여 측정한다. 데이터는 항체가 첨가되지 않은 대조 웰과 비교하여 저해 %로 나타낸다. 데이터는 이중으로 실시된 3회 실험의 평균이다.
결과
항-HCV/E2 사람 단클론 항체 패널 발생과 서열 특성화
사람 단클론 항체 Fab 단편의 패널은 1b 유전형의 HCV로 만성적으로 감염된 한 환자의 항-HCV/E2 면역 레퍼토리를 나타낸다[5, 19]. CHO 세포에서 발현되는 1a 유전형(균주 H)[20]의 정제된 재조합 HCV/E2로 선별된 항체 단편은 완전하게 특성화되었고 HCV/E2에 대한 공유된 동등한 친화성으로 만성 감염된 환자들의 혈청에 존재하는 클론과 일치한다. 5가지 항체 각각은 상기 환자의 항-E2 항체 레퍼토리가 분류되는 5가지 계통군중 하나를 대표한다. 동일 계통군에 속하는 Fab는 유사한 생물학적 활성을 공유하고 DNA 서열의 강한 상동성을 보유한다[5]. 5가지 Fab 각각은 E2의 표면에서 서로 다른 에피토프를 인식한다[7]. 관련된 생식세포 서열로부터 분기(divergence)는 항원-유도된 친화력 증진을 대표하고(표 1a와 1b), 항원에 대한 장기간 노출을 암시한다.
표 1A, B. 항-HCVE2 사람 단클론 항체의 가변 영역에서 생식세포와 V 유전자 돌연변이.
서열은 Burioni et al., 1998[5]에서 밝힌 바와 같이 확인하고 IMGT 데이터베이스에서 생식세포 서열과 정렬시킨다[21]. 뉴클레오티드와 아미노산 돌연변이의 비율은 중쇄와 경쇄의 골격 영역(FR) 1, FR 2, FR 3; 중쇄의 상보성 결정 영역(CDR) 1과 CDR 2; 경쇄의 CDR 1, CDR 2, CDR 3을 고려하여, Kabat와 Wu 정렬 방법[22]에 따라 산정한다.
표 1 a - 중쇄
| 항체 | V 유전자 | 돌연변이된 뉴클레오티드 % | 돌연변이된 아미노산 % | ||
| FR | CDR | FR | CDR | ||
| e8 | VH1-18 | 9.5 | 22.2 | 14.9 | 33.3 |
| e20 | VH1-69 | 9.4 | 16.9 | 19 | 38 |
| e137 | VH1-69 | 11.5 | 15.3 | 14 | 41.7 |
| e301 | VH1-69 | 8.9 | 19.4 | 15.6 | 45.8 |
| e509 | VH1-69 | 5.2 | 15.9 | 10.9 | 33.3 |
표 1 b - 경쇄
| 항체 | V 유전자 | 돌연변이된 뉴클레오티드 % | 돌연변이된 아미노산 % | ||
| FR | CDR | FR | CDR | ||
| e8 | KV 3-20 | 2.7 | 16 | 2.6 | 33.3 |
| e20 | KV 1-9 | 4.3 | 7.7 | 9.7 | 22.2 |
| e137 | KV 1-8 | 2.2 | 9 | 3.2 | 15.4 |
| e301 | KV 3-15 | 3.8 | 14.3 | 9.7 | 23 |
| e509 | KV 3-15 | 3.2 | 1.3 | 6.5 | 0 |
각 Fab의 결합 중화(NOB) 활성을 또한 측정하였는데[5], 일부 클론(e137과 e8)은 세포에 대한 HCV/E2 결합을 저해할 수 없고 다른 클론은 매우 낮은 농도에서도 HCV/E2 결합을 저해하는 것으로 밝혀졌다.
사람 재조합 Fab에 의한 가유형 바이러스의 중화
HCV/E2의 표면에서 서로 다른 에피토프를 인식하는 2가지 Fab, e8과 e2O[7]은 높은 농도(80 ㎍/㎖)에서도 VSV/HCV 가유형 감염을 중화시키지 않는다. 이들 2가지 Fab중에서 e2O은 강한 NOB 활성을 보유하는데[5], 이는 E2 결합을 저해하는 항체도 바이러스 감염을 예방하지 못할 수 있음을 확증한다.
2가지 다른 Fab, e137과 e301은 10 ㎍/㎖ 농도에서 VSV/HCV를 효과적으로 중화시키지만, VSV G 외피 단백질을 보유하는 VSV 가유형(VSV/G 가유형)은 영향을 받지 않는다(도 3a와 3b). 이들 데이터는 HCV/E2에서 사람 에피토프의 2차원 표면 지도(도 4)에 지시된 바와 같이, 이들 2가지 클론이 중화 활성을 보유하는 사람 항체에 의해 인식되는 것으로 생각되는 동일한 E2 영역에 대하여 경쟁한다는 이전의 조사 결과와 일치한다.
Fab 509는 NOB 활성의 측면에서 현재 가장 강한 항체이며, 매우 낮은 농도에 서 E2와 세포 표적간 결합을 저해할 수 있다(표 2). VSV/HCV 가유형과 상기 Fab를 함께 배양하면, 간암 세포로 바이러스 유입이 1 ㎍/㎖ 농도로 강화된다. VSV/G 가유형을 사용하는 경우에는 감염도(infectivity) 증가가 나타나지 않기 때문에, 상기 Fab와 세포막의 비-특이적인 상호작용이 바이러스의 세포 유입을 촉진할 가능성은 배제된다(도 3C).
표 2 - 항-HCV/E2 항체 특징
NOB 활성은 정제된 HCV/E2 제형의 세포 표적 결합의 50% 중화를 달성하는 농도(㎍/㎖)로 산정한다.
| Fab 클론 | 50% NOB 농도(㎍/㎖) | VSV/HCV 감염에 대한 효과 |
| e8 | >40(없음) | 없음 |
| e20 | 3(높음) | 없음 |
| e137 | 40(낮음) | 저해 |
| e301 | 3(높음) | 강한 저해 |
| e509 | <0.035(최대) | 강화 |
대조 항체[23]은 VSV/HCV와 VSV/G 가유형 모두를 중화시키지 않기 때문에, 가유형 시스템에 영향을 주지 않는다. VSV/G 가유형은 이들 실험에서 중화 대조로 이용되고 VSV/HCV에 영향을 주지 않는 다클론 항-VSV 항혈청의 최대 1:1000 희석액에 의해 적절히 중화된다[8]. 여러 숙주에서 발생된 다클론과 단클론 항-E1과 항-E2 항체는 VSV/HCV 가유형에 중화 효과를 보이지 않는다.
일가(monovalent) Fab의 중화 활성은 HCV 유입이 바이러스 응집 또는 가교-결합 없이도 저해될 수 있음을 보여준다; 더 나아가, 바이러스와 세포 표적간 상호작용의 차단은 HCV 중화에서 핵심 인자가 아닌 것으로 생각된다. 이들 데이터는 혈 청에서 NOB 활성과 질병으로부터 보호간 상관관계의 부재를 분자 수준에서 설명할 수 있다.
1a 유전형의 E2로 선별된 항-E2 항체가 1b 유전형의 E2를 보유하는 가유형을 중화시킬 수 있기 때문에, 항-HCV 항체에 의해 상당한 교차-보호가 제공된다.
이런 결과는 VSV/G 구조체에 대한 효과가 명확하지는 않지만, Fab 509가 VSV/HCV 가유형 바이러스의 감염도를 강화시킬 수 있음을 보여준다. e5O9가 바이러스 유입을 촉진하는 능력을 설명할 수 있는 해답은 상기 항체가 바이러스의 세포 부착에 관여하는 세포 구조인 CD81에 결합하는 E2의 영역에 특이적이고 매우 효과적으로 결합한다는 관찰 결과에서 찾을 수 있다[24]. E2에 대한 e509의 결합은 세포 표적중 하나에 대한 E2의 결합을 모방하고 CD81에 의해 유도되는 것과 유사한 E2 형태 변화를 촉진한다. E2는 적어도 2가지 구조 형태로 존재하는데, 상기 단백질에 항체를 결합시키면 결합 경쟁없이 사람 Fab의 NOB 활성을 조절함으로써 상기 단백질의 입체 상태를 변화시킬 수 있다[6]. 따라서, Fab 509는 HCV와 세포 표면간 상호작용을 연구하기 위한 핵심 도구로 생각되며, 백신용 분자를 평가하는 시험관내 모델에 사용될 수 있다.
참고문헌
1. Hoofnagle, Hepatitis C: the clinical spectrum of disease. Hepatology, 1997. 26(3 Suppl 1): p. 15S-20S.
2. Cerny and Chisari, Pathogenesis of chronic hepatitis C: immunological features of hepatic injury and viral persistence. Hepatology, 1999. 30(3): p. 595-601.
3. Fried and Hoofnagle, Therapy of hepatitis C. Semin Liver Dis, 1995. 15(1): p. 82-91.
4. Hoofnagle and di Bisceglie, The treatment of chronic viral hepatitis. N Engl J Med, 1997. 336(5): p. 347-56.
5. Burioni, et al., Dissection of human humoral immune response against hepatitis C virus E2 glycoprotein by repertoire cloning and generation of recombinant Fab fragments. Hepatology, 1998. 28(3): p. 810-4.
6. Burioni, et al., Non-neutralizing human antibody fragments against Hepatitis C Virus E2 Glycoprotein Modulate Neutralization of Binding Activity of Human Recombinant Fabs. Virology, 2001. 288: p. 29-35.
7. Bugli, et al., Mapping B cell epitopes of Hepatitis C Virus E2 glycoprotein using human monoclonal antibodies from phage display libraries. J Virol, 2001. 75(20): p. 9986-9990.
8. Matsuura, et al., Characterization of Pseudotype VSV possessing HCV envelope proteins. Virology, 2001. 286(2): p. 263-75.
9. Bender, et al., Recombinant human antibodies: linkage of an Fab fragment from a combinatorial library to an Fc fragment for expression in mammalian cell culture. Hum Antibodies Hybridomas, 1993. 4(2): p.74-9.
10. Barbas, et al., Human monoclonal Fab fragments derived from a combinatorial library bind to respiratory syncytial virus F glycoprotein and neutralize infectivity. Proc Natl Acad Sci U S A, 1992. 89(21): p. 1016-8.
11. Williamson, et al., Human monoclonal antibodies against a plethora of viral pathogens from single combinatorial libraries [published erratum appears in Proc Natl Acad Sci U S A 1994 Feb 1; 91(3):1193]. Proc Natl Acad Sci U S A, 1993. 90(9): p. 4141-5.
12. Burioni, et al., Recombinant human Fab to glycoprotein D neutralizes infectivity and prevents cell-to-cell transmission of herpes simplex viruses 1 and 2 in vitro. Proc Natl Acad Sci U S A, 1994. 91(1): p. 355-9.
13. Burioni, et al., A vector for the expression of recombinant monoclonal Fab fragments in bacteria. J Immunol Methods, 1998. 217(12): p. 195-9.
14. Barbas, et al., Recombinant human Fab fragments neutralize human type 1 immunodeficiency virus in vitro. Proc Natl Acad Sci U S A, 1992. 89(19): p. 9339-43.
15. Rosa, et al., A quantitative test to estimate neutralizing antibodies to the hepatitis C virus: cytofluorimetric assessment of envelope glycoprotein 2 binding to target cells. Proc Natl Acad Sci U S A, 1996. 93(5): p. 1759-63.
16. Takikawa, et al., Cell fusion activity of hepatitis C virus envelope proteins. J Virol, 2000. 74(11): p. 5066-74.
17. Ohashi, et al, Ligand-induced activation of chimeric receptors between the erythropoietin receptor and receptor tyrosine kinases. Proc Natl Acad Sci U S A, 1994. 91(1): p. 158-62.
18. Takada, et al., A system for functional analysis of Ebola virus glycoprotein. Proc Natl Acad Sci U S A, 1997. 94(26): p. 14764-9.
19. Plaisant, et al., Human monoclonal recombinant Fabs specific for HCV antigens obtained by repertoire cloning in phage display combinatorial vectors. Res Virol, 1997. 148(2): p. 165-9.
20. Lesniewski, et al., Antibody to hepatitis C virus second envelope (HCV-E2) glycoprotein: a new marker of HCV infection closely associated with viremia. J Med Virol, 1995. 45(4): p. 415-22.
21. Lefranc, et al., IMGT, the international ImMunoGeneTics database. Nucleic Acids Res, 1999. 27(1): p. 209-12.
22. Kabat, Sequences of Proteins of Immunological Interest. 5th ed. 1991, Bethesda, MD: U.S. Department of Health and Human Services.
23. Burioni, et al., A new subtraction technique for molecular cloning of rare antiviral antibody specificities from phage display libraries Res Virol, 1998. 149(5): p. 327-30.
24. Pileri, et al., Binding of hepatitis C virus to CD81. Science, 1998. 282(5390): p. 938-41.
SEQUENCE LISTING
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Leu Leu Glu Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val
1 5 10 15
Lys Val Ser Cys Lys Ala Ser Gly Asp His Tyr Gly Ile Asn Trp Val
20 25 30
Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Gly Ile Ile Pro
35 40 45
Val Phe Gly Thr Thr Thr Tyr Ala Gln Lys Phe Gln Gly Arg Ala Thr
50 55 60
Ile Thr Ala Asp Asp Ser Thr Gly Thr Ala Phe Leu Glu Leu Thr Arg
65 70 75 80
Leu Thr Phe Asp Asp Thr Ala Val Tyr Phe Cys Ala Thr Pro His Gln
85 90 95
Leu His Val Leu Arg Gly Gly Lys Ala Leu Ser Pro Trp Asp Tyr Trp
100 105 110
Gly Gln Gly Thr
115
<210> 6
<211> 102
<212> PRT
<213> Homo sapiens
<400> 6
Met Ala Glu Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Arg Gly Gln Ala Pro Ser Leu Leu Ile
35 40 45
Tyr Gly Thr Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asp Trp Pro Ser
85 90 95
Thr Phe Gly Gln Gly Thr
100
<210> 7
<211> 120
<212> PRT
<213> Homo sapiens
<400> 7
Leu Leu Glu Gln Ser Gly Ser Glu Val Lys Val Pro Gly Ser Ser Leu
1 5 10 15
Lys Val Ser Cys Lys Thr Ser Gly Gly Thr Phe Ser Thr Tyr Thr Phe
20 25 30
Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Gly
35 40 45
Ile Thr Pro Ile Ile Gly Ile Ala Asn Tyr Ala Arg Asn Phe Gln Asp
50 55 60
Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Val Tyr Met Glu
65 70 75 80
Val Arg Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys
85 90 95
Thr Ser Glu Val Thr Ala Thr Arg Gly Arg Thr Phe Phe Tyr Ser Ala
100 105 110
Met Asp Val Trp Gly Gln Gly Thr
115 120
<210> 8
<211> 102
<212> PRT
<213> Homo sapiens
<400> 8
Met Ala Glu Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Trp Thr Glu Phe Thr Leu Thr Ile Ser Arg Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Leu Asn Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr
100
<210> 9
<211> 118
<212> PRT
<213> Homo sapiens
<400> 9
Leu Leu Glu Gln Ser Gly Ser Glu Val Lys Lys Pro Gly Ser Ser Val
1 5 10 15
Arg Val Ser Cys Thr Thr Ser Gly Gly Thr Leu Ser Asp Tyr Gly Phe
20 25 30
Asn Trp Leu Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met Gly Gly
35 40 45
Ile Ile Pro Leu Phe Arg Arg Thr Thr Tyr Gly Gln Lys Phe Gln Gly
50 55 60
Arg Leu Thr Ile Thr Ala Asp Glu Ser Thr Gly Ala Thr Tyr Met Glu
65 70 75 80
Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
85 90 95
Glu Lys Val Ser Val Leu Thr Gly Gly Lys Ser Leu His Tyr Phe Glu
100 105 110
Tyr Trp Gly Lys Gly Thr
115
<210> 10
<211> 102
<212> PRT
<213> Homo sapiens
<400> 10
Met Ala Glu Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Arg
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Arg Gly Gln Ala Pro Ser Leu Leu Ile
35 40 45
Tyr Asp Thr Ser Ser Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Ala
50 55 60
Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Leu Tyr Tyr Cys Gln Gln Tyr Asn Asp Trp Pro Ser
85 90 95
Thr Phe Gly Gln Gly Thr
100
<210> 11
<211> 118
<212> PRT
<213> Homo sapiens
<400> 11
Leu Leu Glu Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val
1 5 10 15
Lys Val Ser Cys Lys Thr Ser Gly Asp Thr Phe Arg Tyr Gly Ile Thr
20 25 30
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Gln Ile
35 40 45
Met Pro Thr Phe Ala Thr Ala Thr Tyr Ala Gln Arg Phe Gln Gly Arg
50 55 60
Val Thr Ile Ser Ala Asp Glu Ser Thr Ser Thr Ala Tyr Leu Glu Val
65 70 75 80
Arg Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Thr Pro
85 90 95
Arg Gln Val Thr Ile Leu Arg Gly Pro Lys Ala Leu Ser Pro Trp Asp
100 105 110
Tyr Trp Gly Gln Gly Thr
115
<210> 12
<211> 102
<212> PRT
<213> Homo sapiens
<400> 12
Met Ala Glu Leu Thr Gln Ser Pro Ala Thr Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Ala Ser Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Ser Gly Ala Ser Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Pro
85 90 95
His Phe Gly Gln Gly Thr
100
<210> 13
<211> 357
<212> DNA
<213> Homo sapiens
<400> 13
ctgctcgagc agtctggagc tgaggtgaag atgcctgggg ccacagtgaa ggtctcctgc 60
cagtcttccc gttacacctt caccagttac ggtatcggct gggtgcgaca ggcccctgga 120
caggggcttg agtggatggg atggatcagc ggatacaccc atgagacaaa atatgcacag 180
agtttccagg gcagagtcac catgaccgca gagacatcca cgggcacagc gtatatggag 240
ttgaggagcc tgcggtctga cgacacggcc acatattact gcgcgagaga tggaggaggg 300
agggtggtag tgccgcctac tcatctacgt gcttttgatg tctggggtca agggacg 357
<210> 14
<211> 312
<212> DNA
<213> Homo sapiens
<400> 14
atggccgagc tcacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca cagagtcaat aacaacttct tagcctggta tcagcagaaa 120
cctggccagg ctcccaggct cctcatctct ggtgcatcta ccagggccac tggcatccca 180
gacaggttca gtggcagtgg gtctggaaca gacttcactc tcaccatcag cagactggag 240
cctgatgatt ttgcagttta ttattgtcag cagtatggtg actcacctct ttattctttt 300
ggccagggga cc 312
<210> 15
<211> 372
<212> DNA
<213> Homo sapiens
<400> 15
ctgctcgagt ctggcccagg actggtgaag ccttcacaga ccctgtccct cacctgcacc 60
gtctccggtg tctccatcag ttacggtggt cgtggcgttt cctactgggg ttgggtccgc 120
cagtccccag ggaagggcct ggagtggatt ggccacatct actactttgg agacaccttc 180
tacaacccgt ccctcaacaa tcgagctacc atatcaatag actcatccaa aaaccagttc 240
tccctcaagc tcaagtctgt gactgcctca gacacggccc tgtatttctg tgccaggagc 300
accctacagt attttgactg gttattgaca cgggaggctg cctactccat tgacttctgg 360
ggccagggaa ta 372
<210> 16
<211> 306
<212> DNA
<213> Homo sapiens
<400> 16
atggccgagc tcacccagtc tccatccttc ctgtctgcat ctgttggaga ccgagtcacc 60
atcacttgcc gggccagtca gggcgtcacc attcttttag cctggtatca gcaaaagcca 120
gggaaacccc ctaaggccct gatttatgct gcatcgtctt tgcaaagtgg ggtcccatca 180
aggttcagcg gcagtggttc tgacacagat ttcactctca caatcagcag cctacagcct 240
gaagattctg caacttatta ctgtcaacaa cttaacactt acccgtggac gttcggccag 300
gggacc 306
<210> 17
<211> 348
<212> DNA
<213> Homo sapiens
<400> 17
ctgctcgagc agtcaggggc tgaggtgaag aagcctgggt cctcggtgaa ggtctcctgc 60
aaggcttctg gagaccacta tggtatcaac tgggtgcgac aggcccctgg acaagggctg 120
gagtggatgg gcggtatcat ccctgtcttt ggcacaacta cctacgcaca gaagttccag 180
ggcagagcca ccattaccgc ggacgactcc acggggacgg cctttttgga gctgaccaga 240
ctgacatttg acgacacggc cgtctatttc tgtgcgacac ctcaccaact gcatgtcctc 300
cggggcggta aagccctctc cccctgggac tactggggcc agggaacc 348
<210> 18
<211> 306
<212> DNA
<213> Homo sapiens
<400> 18
atggccgagc tcacccagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agtaacttag cctggtacca gcagaaacgt 120
ggccaggctc ccagtctcct catctacgga acatctacca gggccactgg tatcccagcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tataatgatt ggccctccac cttcggccaa 300
gggaca 306
<210> 19
<211> 360
<212> DNA
<213> Homo sapiens
<400> 19
ctgctcgagc agtctgggtc tgaagtaaaa gtgcccgggt cctcgttgaa ggtctcctgc 60
aagacttctg gaggcacctt cagcacctat actttcagct gggtgcgaca ggcccctgga 120
cagggacttg agtggatggg ggggatcacc cctatcattg gcatcgcaaa ctacgcacgg 180
aacttccagg acagagtcac catcaccgcg gacgaatcca cgagcacggt ctacatggag 240
gtgaggaggc tgagatctga ggacacggcc gtatattatt gtgcgaaaac ttcggaagta 300
acagccacta gagggcggac tttcttctac tccgctatgg acgtctgggg tcaagggacc 360
<210> 20
<211> 306
<212> DNA
<213> Homo sapiens
<400> 20
atggccgagc tcacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gggcataagc aattatttag cctggtatca gcaaaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatcg 180
aggttcagcg gcagtggatc ttggacagaa ttcactctca caatcagccg cctccagcct 240
gaagattttg caacttatta ctgtcaacac cttaatactt acccgtggac gttcggccaa 300
gggacc 306
<210> 21
<211> 354
<212> DNA
<213> Homo sapiens
<400> 21
ctgctcgagc agtctgggtc tgaggtgaag aaacctgggt cctcggtgag ggtctcgtgc 60
acgacttctg gaggcacctt gagcgactat ggtttcaact ggttacgaca ggcccctgga 120
caagggcctg agtggatggg agggatcatc cctttgtttc gaagaacaac ctacggacag 180
aagttccagg gcagactcac cattaccgcg gacgagtcca cgggcgcaac ctacatggag 240
ctgagcagcc tgagatctga cgacacggcc gtctattact gtgcgagaga gaaagtttcg 300
gtcctcacag gcggaaagtc actccattac tttgaatatt ggggcaaggg aacc 354
<210> 22
<211> 306
<212> DNA
<213> Homo sapiens
<400> 22
atggccgagc tcacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
ctctcctgca gggccagtca gagtgttagc agcaggttag cctggtacca gcagaaacgt 120
ggccaggctc ccagtctcct catctatgac acatcttcca gggccactgg tgtcccagcc 180
aggttcagtg ccagtgggtc tgggacgcag ttcactctca ccatcagcag cctgcagtct 240
gaagattttg cactttatta ctgtcagcag tataatgatt ggccctccac cttcggccaa 300
gggaca 306
<210> 23
<211> 354
<212> DNA
<213> Homo sapiens
<400> 23
ctgctcgagg agtctggggc tgaggtgaag aagccagggt cctcggtgaa ggtctcctgc 60
aagacttctg gagacacctt cagatatggt atcacgtggg tgcgacaggc ccctggacaa 120
gggcttgagt ggatgggaca gatcatgcct acgtttgcga cagcaaccta cgcacagagg 180
ttccagggca gagtcacgat ttccgcggac gaatccacga gcacagccta cttggaggtg 240
cgcagcctga gatctgaaga cacggccgtc tattactgtg cgacacctcg ccaagttact 300
atacttcggg gacctaaagc cctctcccct tgggactact ggggccaggg aacc 354
<210> 24
<211> 306
<212> DNA
<213> Homo sapiens
<400> 24
atggccgagc tcacccagtc tccagccacc ctgtctgcgt ctccagggga aagagcctcc 60
ctctcctgca gggccagtca gagtgttagt agcaacttag cctggtacca gcagaaacct 120
ggccaggctc ccaggctcct catctctggt gcatccacca gggccactgg tgtcccggcc 180
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagtag cctgcagtct 240
gaagattttg cagtttatta ctgtcagcag tataataact ggcctcccca ctttggccag 300
gggacc 306
Claims (11)
- 서열번호 7의 아미노산 서열을 중쇄 가변 영역으로 포함하고 서열번호 8의 아미노산 서열을 경쇄 가변 영역으로 포함하는 항체 또는 기능적 단편을 유효성분으로 포함하는 HCV 감염 억제용 조성물.
- 제 1항에 있어서, 상기 항체는 인간 단클론 항체인 것을 특징으로 HCV 감염 억제용 조성물.
- 제 1항에 있어서, 상기 항체는 IgG1 분자인 것을 특징으로 하는 HCV 감염 억제용 조성물.
- 제 1항에 있어서, 상기 기능적 단편은 인간 단클론 항체의 FAb 단편인 것을 특징으로 하는 HCV 감염 억제용 조성물.
- 제 1항 내지 제 4항 중 어느 한 항에 있어서, 상기 조성물은 비경구용 형태 또는 국소용 형태인 것을 특징으로 하는 HCV 감염 억제용 조성물.
- 서열번호 9의 아미노산 서열을 중쇄 가변 영역으로 포함하고 서열번호 10의 아미노산 서열을 경쇄 가변 영역으로 포함하는 항체 또는 기능적 단편을 유효성분으로 포함하는 HCV 감염 억제용 조성물.
- 제 6항에 있어서, 상기 항체는 인간 단클론 항체인 것을 특징으로 HCV 감염 억제용 조성물.
- 제 6항에 있어서, 상기 항체는 IgG1 분자인 것을 특징으로 하는 HCV 감염 억제용 조성물.
- 제 6항에 있어서, 상기 기능적 단편은 인간 단클론 항체의 FAb 단편인 것을 특징으로 하는 HCV 감염 억제용 조성물.
- 제 6항 내지 제 9항 중 어느 한 항에 있어서, 상기 조성물은 비경구용 형태 또는 국소용 형태인 것을 특징으로 하는 HCV 감염 억제용 조성물.
- (a) 서열번호 7의 아미노산 서열을 중쇄 가변 영역으로 포함하고 서열번호 8의 아미노산 서열을 경쇄 가변 영역으로 포함하는 항체 또는 기능적 단편; 및(b) 서열번호 9의 아미노산 서열을 중쇄 가변 영역으로 포함하고 서열번호 10의 아미노산 서열을 경쇄 가변 영역으로 포함하는 항체 또는 기능적 단편;을 유효성분으로 포함하는 HCV 감염 억제용 조성물.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2002RM000049A ITRM20020049A1 (it) | 2002-01-30 | 2002-01-30 | Frammenti fab di anticorpi monoclonali umani diretti contro la glicoproteina e2 di hcv e dotati di potere neutralizzante in vitro. |
| ITRM2002A000049 | 2002-01-30 | ||
| PCT/IT2003/000032 WO2003064473A2 (en) | 2002-01-30 | 2003-01-29 | Human monoclonal antibody fab fragments directed against hcv e2 glycoprotein and endowed with in vitro neutralizing activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20040077745A KR20040077745A (ko) | 2004-09-06 |
| KR101002791B1 true KR101002791B1 (ko) | 2010-12-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020047011208A KR101002791B1 (ko) | 2002-01-30 | 2003-01-29 | Ｈｃｖ ｅ2 당단백질을 표적하고 시험관내 중화 활성을보유하는 사람 단클론항체 ｆａｂ 단편 |
Country Status (17)
| Country | Link |
|---|---|
| US (2) | US20050084845A1 (ko) |
| EP (1) | EP1476468B9 (ko) |
| JP (1) | JP4287280B2 (ko) |
| KR (1) | KR101002791B1 (ko) |
| CN (1) | CN1856508A (ko) |
| AT (1) | ATE407147T1 (ko) |
| AU (1) | AU2003208000B2 (ko) |
| CA (1) | CA2474801C (ko) |
| DE (1) | DE60323333D1 (ko) |
| DK (1) | DK1476468T3 (ko) |
| EA (1) | EA009861B1 (ko) |
| ES (1) | ES2314179T3 (ko) |
| IT (1) | ITRM20020049A1 (ko) |
| NZ (1) | NZ534922A (ko) |
| RU (1) | RU2004126238A (ko) |
| WO (1) | WO2003064473A2 (ko) |
| ZA (1) | ZA200406187B (ko) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7727962B2 (en) | 2004-05-10 | 2010-06-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Powder comprising new compositions of oligosaccharides and methods for their preparation |
| US7611709B2 (en) * | 2004-05-10 | 2009-11-03 | Boehringer Ingelheim Pharma Gmbh And Co. Kg | 1,4 O-linked saccharose derivatives for stabilization of antibodies or antibody derivatives |
| US7723306B2 (en) | 2004-05-10 | 2010-05-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Spray-dried powder comprising at least one 1,4 O-linked saccharose-derivative and methods for their preparation |
| ITTO20070066A1 (it) | 2007-01-30 | 2008-07-31 | Pomona Biotechnologies Llc | Anticorpi monoclonali anti-idiotipo mimotopi dell'antigene gp 120 di hiv |
| WO2008107187A1 (en) * | 2007-03-06 | 2008-09-12 | Ribovax Biotechnologies S.A. | Antibodies specific for rubella virus |
| CN101809033A (zh) | 2007-07-25 | 2010-08-18 | 日本国立感染症研究所 | 对丙型肝炎病毒(hcv)感染具有抑制活性的抗体和其用途 |
| TW200940090A (en) * | 2007-12-17 | 2009-10-01 | Medical Res Council Technology | Hepatitis C virus antibodies |
| ITTO20080204A1 (it) | 2008-03-17 | 2009-09-18 | Pomona Biotechnologies Llc | Anticorpi monoclonali atti a reagire con una pluralita di sottotipi del virus influenzale a |
| ITTO20080398A1 (it) | 2008-05-27 | 2009-11-28 | Pomona Biotechnologies Llc | Anticorpi monoclonali aventi proprieta' di cross-neutralizzazione omosubtipica per virus influenzali di tipo a sottotipo h1 |
| WO2010035292A1 (en) * | 2008-09-24 | 2010-04-01 | Natimab Therapeutics S.R.L. | The use of a human monoclonal anti-hcv antibody as a medicament for the therapeutic treatment and prevention of hcv infections |
| US20100104555A1 (en) * | 2008-10-24 | 2010-04-29 | The Scripps Research Institute | HCV neutralizing epitopes |
| ITTO20080964A1 (it) * | 2008-12-22 | 2010-06-23 | Natimab Therapeutics S R L | Anticorpo monoclonale anti-hcv come medicamento per il trattamento terapeutico e la prevenzione di infezioni da hcv |
| IT1395961B1 (it) | 2009-06-01 | 2012-11-02 | Pomona Biotechnologies Llc | Anticorpi monoclonali come medicamento per il trattamento terapeutico e/o profilattico delle infezioni da virus influenzale a (h1n1) di origine suina (s-oiv) |
| CN102596996B (zh) | 2009-10-30 | 2014-06-18 | 东丽株式会社 | 对丙型肝炎病毒(hcv)具有感染抑制活性的抗体及其用途 |
| US9719141B2 (en) | 2010-03-01 | 2017-08-01 | Vincent Agnello | Prognostic marker for cryoglobulinemic vasculitis and B cell malignancies in HCV infected patients |
| CN104119436B (zh) * | 2013-04-27 | 2016-12-28 | 中国科学院上海生命科学研究院 | 抗丙型肝炎病毒的中和性全人单克隆抗体 |
| GB201415714D0 (en) * | 2014-09-05 | 2014-10-22 | Medical Res Council | Antibodies and antigen binding fragments thereof |
| CN105254756B (zh) * | 2015-11-27 | 2018-09-07 | 武汉大学 | 一种针对丙型肝炎病毒包膜蛋白e2的单克隆抗体及应用 |
| KR20180001380U (ko) | 2016-10-31 | 2018-05-10 | 대우조선해양 주식회사 | 해양구조물의 발로 작동시키는 캡스탄 |
| CN118440202A (zh) | 2019-12-27 | 2024-08-06 | 凯奥目生物科学株式会社 | 抗cdcp1抗体 |
| WO2022049867A1 (ja) | 2020-09-02 | 2022-03-10 | 国立大学法人東京大学 | がん免疫微小環境の調節物質およびそれによる予防・診断・治療的利用 |
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|---|---|---|---|---|
| CN1325517C (zh) * | 1998-07-21 | 2007-07-11 | 展马博联合股份有限公司 | 抗丙型肝炎病毒抗体及其用途 |
| US7091324B2 (en) * | 1998-11-05 | 2006-08-15 | Board Of Trustees Of Leland Stanford Junior University | Prevention and treatment of HCV infection employing antibodies directed against conformational epitopes |
| AU2001273363A1 (en) | 2000-07-12 | 2002-01-21 | General Instrument Corporation | Method and apparatus for downloading objects via an inband channel with minimal subscriber impact |
| JP2004524829A (ja) * | 2000-12-01 | 2004-08-19 | アメリカ合衆国 | Ｃ型肝炎ウイルスのｅ２糖タンパク質に特異的なモノクローナル抗体、ならびにｃ型肝炎の診断、治療、および予防におけるそれらの使用 |
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2002
- 2002-01-30 IT IT2002RM000049A patent/ITRM20020049A1/it unknown
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2003
- 2003-01-29 AU AU2003208000A patent/AU2003208000B2/en not_active Ceased
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- 2003-01-29 JP JP2003564093A patent/JP4287280B2/ja not_active Expired - Fee Related
- 2003-01-29 RU RU2004126238/13A patent/RU2004126238A/ru not_active Application Discontinuation
- 2003-01-29 EA EA200401081A patent/EA009861B1/ru not_active IP Right Cessation
- 2003-01-29 DK DK03705004T patent/DK1476468T3/da active
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- 2003-01-29 CA CA2474801A patent/CA2474801C/en not_active Expired - Lifetime
- 2003-01-29 ES ES03705004T patent/ES2314179T3/es not_active Expired - Lifetime
- 2003-01-29 US US10/502,307 patent/US20050084845A1/en not_active Abandoned
- 2003-01-29 KR KR1020047011208A patent/KR101002791B1/ko active IP Right Grant
- 2003-01-29 WO PCT/IT2003/000032 patent/WO2003064473A2/en active IP Right Grant
- 2003-01-29 CN CNA038030926A patent/CN1856508A/zh active Pending
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Non-Patent Citations (2)
| Title |
|---|
| Journal of General Virology, Vol.81, pp.2451-2459(2000)* |
| Virology, Vol.288, pp.29-35(2001.09.15.)* |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2474801A1 (en) | 2003-08-07 |
| RU2004126238A (ru) | 2005-04-20 |
| ATE407147T1 (de) | 2008-09-15 |
| US7727529B2 (en) | 2010-06-01 |
| EA200401081A1 (ru) | 2005-10-27 |
| AU2003208000B2 (en) | 2010-05-20 |
| EA009861B1 (ru) | 2008-04-28 |
| ES2314179T3 (es) | 2009-03-16 |
| CN1856508A (zh) | 2006-11-01 |
| EP1476468B1 (en) | 2008-09-03 |
| WO2003064473A2 (en) | 2003-08-07 |
| JP4287280B2 (ja) | 2009-07-01 |
| ITRM20020049A0 (it) | 2002-01-30 |
| KR20040077745A (ko) | 2004-09-06 |
| EP1476468A2 (en) | 2004-11-17 |
| DE60323333D1 (de) | 2008-10-16 |
| CA2474801C (en) | 2012-03-20 |
| US20050084845A1 (en) | 2005-04-21 |
| NZ534922A (en) | 2008-07-31 |
| EP1476468B9 (en) | 2009-04-08 |
| ITRM20020049A1 (it) | 2003-07-30 |
| ZA200406187B (en) | 2006-06-28 |
| DK1476468T3 (da) | 2009-01-19 |
| WO2003064473A3 (en) | 2003-12-24 |
| JP2005531286A (ja) | 2005-10-20 |
| US20080241162A1 (en) | 2008-10-02 |
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