KR102460843B1 - 고도로 글리코실화된 cea인 mg7에 특이적으로 결합하는 단일쇄 항체 및 검출 및 치료에서 이의 용도 - Google Patents

고도로 글리코실화된 cea인 mg7에 특이적으로 결합하는 단일쇄 항체 및 검출 및 치료에서 이의 용도 Download PDF

Info

Publication number
KR102460843B1
KR102460843B1 KR1020197006047A KR20197006047A KR102460843B1 KR 102460843 B1 KR102460843 B1 KR 102460843B1 KR 1020197006047 A KR1020197006047 A KR 1020197006047A KR 20197006047 A KR20197006047 A KR 20197006047A KR 102460843 B1 KR102460843 B1 KR 102460843B1
Authority
KR
South Korea
Prior art keywords
ser
gly
seq
thr
leu
Prior art date
Application number
KR1020197006047A
Other languages
English (en)
Other versions
KR20190034626A (ko
Inventor
다이밍 판
용잔 니에
카이천 우
위에춍 카오
위에?l 카오
지준 위안
쉐준 위
Original Assignee
더 폴쓰 밀리터리 메디컬 유니버시티
상하이 제네켐 씨오., 엘티디.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 더 폴쓰 밀리터리 메디컬 유니버시티, 상하이 제네켐 씨오., 엘티디. filed Critical 더 폴쓰 밀리터리 메디컬 유니버시티
Publication of KR20190034626A publication Critical patent/KR20190034626A/ko
Application granted granted Critical
Publication of KR102460843B1 publication Critical patent/KR102460843B1/ko

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3007—Carcino-embryonic Antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631—Chimeric Antigen Receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/46448—Cancer antigens from embryonic or fetal origin
    • A61K39/464482—Carcinoembryonic antigen [CEA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70517—CD8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70521—CD28, CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70575—NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
    • A61K2239/51—Stomach
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2510/00—Genetically modified cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Cell Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Wood Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Mycology (AREA)
  • Oncology (AREA)
  • Urology & Nephrology (AREA)
  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Food Science & Technology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)

Abstract

글리코실화된 CEA를 과발현하는 종양의 진단 또는 치료를 위한 제제 또는 약제의 제조에 이용될 수 있는, 글리코실화된 CEA를 표적하는 키메라 항원 수용체 (chimeric antigen receptor, CAR), 및 글리코실화된 CEA-특이적 단일쇄 항체가 개시된다.

Description

고도로 글리코실화된 CEA인 MG7에 특이적으로 결합하는 단일쇄 항체 및 검출 및 치료에서 이의 용도
본 발명은 종양 면역요법(tumor immunotherapy) 분야에 관한 것으로, 특히, 본 발명은 글리코실화된 CEA-특이적 단일쇄 항체, 및 글리코실화된 CEA를 과발현하는 종양에 대한 형질전환 변형 입양 T 림프구 치료(transgenic modified adoptive T lymphocyte therapy) 분야에 관한 것이다.
위암(gastric cancer) 발생률은 중국 내 소화관 악성 종양에서 1위를 차지하고, 세계에서는 2위를 차지한다. 연간 사망은 악성 종양 사망의 약 24%를 차지하고, 5년 생존율(five-year survival rate)은 단지 약 27%에 불과하다. 위암 환자의 진단은 흔히 느려서, 예후가 극도로 좋지 못하다. 위암에 대한 효과적인 표적 치료는 존재하지 않는다. 암배아 항원(carcinoembryonic antigen, CEA)은 막 결합 단백질로, 일반적으로 태아의 간, 장 및 췌장에서 발현된다. 정상적으로는, 이는 장으로 분비되고, 이의 혈청 수준은 낮다. 세포가 암성(cancerous)인 경우에, 혈청 수준은 상승하는데, 이는 췌장암 및 결장암의 조기 진단에 대한 보조적인 중요성(auxiliary significance)을 가지며, 종양 확산, 치료 효과, 재발 및 예후에 대한 특정한 참고 값(reference value)을 가진다. 제4군의대학(Fourth Military Medical University)의 판 다이밍(Fan Daiming) 교수는 글리코실화된 CEA가 다양한 소화관 암에 고감도(highly sensitive)이고 고도로 특이적(highly specific)임을 밝혀냈다. 임상 연구는 위암 조직에서 글리코실화된 CEA의 양성률(positive rate)이 80%를 초과하고, 결장암에서 양성률이 40%를 초과하며, 위의 전암성 병변(gastric precancerous lesion)에서 양성률이 30%를 초과하고, 식도암 조직에서 양성률이 18% 이상임을 제시하였다. 동시에, 임상 시험의 결과는 28명의 위암 환자에서 혈청 글리코실화된 CEA의 양성률이 수술 전의 양성률에 비해서 현저하게 감소되었다는 것을 나타냈으며, 이는 글리코실화된 CEA와 위암 사이에 밀접한 관계가 있다는 것을 제시한다 (Gadler et al., Int J Cancer 25 ( 1): 91-4, 1980).
현재, 표적된 입양 세포 치료 기술(targeted adoptive cell therapy technology)을 이용한 신생의 키메라 항원 수용체 T 세포 (chimeric antigen receptor T cell, CAR-T)는 다양한 악성 종양의 치료에서 중요한 역할을 한다. CAR-T는 단일쇄 항체와 같은 종양-관련 항원(TAA)-특이적 인식 펩티드[tumor-associated antigen (TAA)-specific recognition peptide], CD3제타와 같은 T 세포 활성화 신호를 수반한 특이적 수용체의 융합이고, 융합 단백질은 렌티바이러스(lentivirus) 등에 의해 T 세포 표면상에 특이적으로 발현되는데, 이는 변형된 T 세포가 종양 세포를 특이적으로 인식하고 사멸시키도록 하며, 주조직 적합성 항원(major histocompatibility antigen, MHC)과 독립적이고, MHC 결실로 인한 종양 면역 회피(tumor immune escape)를 피할 수 있다.
키메라 항원 수용체는 세포 외 항원 표적 및 인식 영역, 힌지 영역, 막 관통 영역, 및 세포 내 공동 자극 신호전달 영역을 포함한다. 항원 인식 영역은 대부분 단일쇄 항체 또는 특이적인 수용체로, 변형 T 세포가 표적 세포를 특이적으로 인식할 수 있고, 표적 세포를 특이적으로 사멸시키도록 활성화될 수 있는 것을 보장하며; 힌지 영역은, T 세포가 표적 세포에 접촉하고 T 세포 작용에 영향을 미치는 것을 보장하는 CD8α, CD28ECD, IgG Fc 단편 등을 일반적으로 채용하고(adopting); 세포 내 신호 영역은 면역수용체 티로신 활성화 모티프 (immunoreceptor tyrosine activation motif, ITAM), 예를 들어, CD3제타 및 CD28, CD137, CD27, ICOS, OX40, DAP10 등과 같은 공동 자극 신호를 채용한다 (Sadelain et al., Cancer Discov 3(4): 388-98, 2013).
CAR-T가 혈액 악성 종양(hematological malignancy)의 치료에서 좋은 응용 가치를 보였으나, CAR-T는 흔히 고형 종양(solid tumor)의 치료에서 기대되는 결과를 달성하지 못한다. 일부 임상 연구에서조차, CAR-T는 비표적 효과(off-target effect)로 인한 독성을 보일 수 있다. 고형 종양에서, 효과적이지 않으며 특이적이지 않은 표적이 종종 존재하는 것이 중요한 이유다. 많은 종양-관련 항원의 경우에, 정상 조직 내 특정한 발현 정도(degree of expression)가 흔히 존재한다. 예를 들어, HER2는 악성 교종(malignant glioma) 및 유방암과 같은 악성 종양에 대한 중요한 표적이나, HER2 표적에 대한 CAR-T 임상 시험에서, 환자는 CAR-T 재주입(re-infusion) 후에, 폐부전(pulmonary failure)을 겪었고, "사이토카인 폭풍(cytokine storm)"이 촉발되어, 단시간에 환자의 죽음을 야기했다. 그러므로, 고형 종양의 고도로 특이적이며 고감도인 표적을 발견하는 것은 고형 종양에서 CAR-T 치료 적용의 중요한 요점이다 (Morgan et al., Mol Ther 18(4): 843-51, 2010).
NK 세포는 CD16와 CD56을 발현하는 림프구 및 선천성 면역(innate immunity)의 중요한 구성요소이다. NK 세포는 MHC-결실 표적 세포를 사멸시킬 수 있다. T 세포에 비해, NK 세포는 T-세포 수용체를 발현하지 않고, 따라서 이식편대 숙주반응(graft versus host response, GVHD)을 겪지 않는다. NK 세포 활성화는 살해 활성화 수용체(Killer Activation Receptor, KAR) 및 살해 저해 수용체(Killer Inhibition Receptor, KIR)에 대한 신호의 평형 상태에 있다. 생체 내 주요 KIR 리간드는 MHC이다. KIR 리간드의 불일치나 결실의 경우, 이는 NK 세포의 활성화를 야기할 것이다. CAR-NK 기술은, 암치료를 위한 NK 세포 또는 NK 세포주 (NK92와 같은) 표면상의 CAR 구조 발현(CAR structure expression)을 이용하는 신생 기술로, 이의 이점은 NK 세포가 IL6를 분비하지 않고, NK 세포가 말초 혈액에서 매우 짧은 순환 반감기(circulating half-life)를 가지며, NK 세포가 높은 형질주입 효율 (비-바이러스성 벡터)을 가지고, NK 세포주가 GMP 수준의 거대한 규모에서 배양될 수 있다는 것이다. NK 세포 또는 NK 세포주의 표면 상에서 CAR 구조 발현은 NK 세포에게 표적화 능력(targeting ability)을 부여할 수 있다. 동시에, CAR-NK 동종이식(allograft)에서, KIR 수용체의 불일치는 NK 세포의 활성화를 강화시켜 더 나은 종양 제거를 달성할 수 있다. 생체 내 NK 세포주의 순환 시간은 매우 짧고, 따라서 안전 고려사항(safety consideration)을 제공한다 (Han et al., Sci Rep 5: 11483, 2015).
제1 측면에 있어서, 본 발명은
i) 글리코실화된 CEA를 표적하는 항원-결합 도메인;
ii) 막 관통 도메인; 및
iii) 공동자극 도메인(costimulatory domain)을 포함하는 세포 내 신호전달 도메인;을 포함하는 키메라 항원 수용체 (chimeric antigen receptor, CAR)로서,
상기 글리코실화된 CEA를 표적하는 항원-결합 도메인은, 하기 조합 중 어느 하나로부터 선택되는 것을 특징으로 하는 중쇄 가변영역 및 경쇄 가변영역을 포함하는 것인, 키메라 항원 수용체를 제공한다:
a. SEQ ID NO: 1에 제시된 CDR-H1, SEQ ID NO: 2에 제시된 CDR-H2, 또는 SEQ ID NO: 3에 제시된 CDR-H3로 기술된 하나 이상의 CDR을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 4에 제시된 CDR-L1, SEQ ID NO: 5에 제시된 CDR-L2, 또는 SEQ ID NO: 6에 제시된 CDR-L3로 기술된 하나 이상의 CDR을 포함하는 경쇄 가변영역;
b. SEQ ID NO:7에 제시된 CDR-H1, SEQ ID NO:8에 제시된 CDR-H2, 또는 SEQ ID NO:9에 제시된 CDR-H3로 기술된 하나 이상의 CDR을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 10에 제시된 CDR-L1, SEQ ID NO: 11에 제시된 CDR-L2, 또는 SEQ ID NO: 12에 제시된 CDR-L3으로 기술된 하나 이상의 CDR을 포함하는 경쇄 가변영역;
c. SEQ ID NO: 13에 제시된 CDR-H1, SEQ ID NO: 14에 제시된 CDR-H2, 또는 SEQ ID NO: 15에 제시된 CDR-H3으로 기술된 하나 이상의 CDR을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 16에 제시된 CDR-L1, SEQ ID NO: 17에 제시된 CDR-L2, 또는 SEQ ID NO: 18에 제시된 CDR-L3으로 기술된 하나 이상의 CDR을 포함하는 경쇄 가변영역;
d. SEQ ID NO: 19에 제시된 CDR-H1, SEQ ID NO: 20에 제시된 CDR-H2, 또는 SEQ ID NO: 21에 제시된 CDR-H3으로 기술된 하나 이상의 CDR을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 22에 제시된 CDR-L1, SEQ ID NO: 23에 제시된 CDR-L2, 또는 SEQ ID NO: 24에 제시된 CDR-L3으로 기술된 하나 이상의 CDR을 포함하는 경쇄 가변영역; 또는
e. SEQ ID NO: 25에 제시된 CDR-H1, SEQ ID NO: 26에 제시된 CDR-H2, 또는 SEQ ID NO: 27에 제시된 CDR-H3으로 기술된 하나 이상의 CDR을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 28에 제시된 CDR-L1, SEQ ID NO: 29에 제시된 CDR-L2, 또는 SEQ ID NO:30에 제시된 CDR-L3으로 기술된 하나 이상의 CDR을 포함하는 경쇄 가변영역.
특정 양태에서, 상기 중쇄 가변영역 및 경쇄 가변영역은 하기 조합 중 어느 하나로부터 선택된다: a) SEQ ID NO: 31에 제시된 폴리펩티드 단편을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 32에 제시된 폴리펩티드 단편을 포함하는 경쇄 가변영역; b) SEQ ID NO: 33에 제시된 폴리펩티드 단편을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 34에 제시된 폴리펩티드 단편을 포함하는 경쇄 가변영역; c) SEQ ID NO: 35에 제시된 폴리펩티드 단편을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 36에 제시된 폴리펩티드 단편을 포함하는 경쇄 가변영역; d) SEQ ID NO: 37에 제시된 폴리펩티드 단편을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 38에 제시된 폴리펩티드 단편을 포함하는 경쇄 가변영역; 또는 e) SEQ ID NO: 39에 제시된 폴리펩티드 단편을 포함하는 중쇄 가변영역, 및 SEQ ID NO:40에 제시된 폴리펩티드 단편을 포함하는 경쇄 가변영역.
다른 양태에서, 본 발명의 항원-결합 도메인은 글리코실화된 CEA(glycosylated CEA)를 특이적으로 인식하는 단일쇄 항체(single-chain antibody)이고, 상기 단일쇄 항체의 아미노산 서열은 SEQ ID NO: 171-180 중 어느 하나에 제시되며, 가장 바람직하게는 상기 단일쇄 항체의 아미노산 서열은 SEQ ID NO: 173 또는 SEQ ID NO: 178이다.
바람직하게는, 본 발명의 키메라 항원 수용체에서, 상기 막 관통 도메인은 CD8α 및/또는 CD28을 포함하고, 상기 세포 내 신호전달 도메인은 CD28, CD137, 및 CD3제타 중 하나 이상을 포함하나, CD8α 힌지 영역은 SEQ ID NO: 52에 제시된 서열에 의해 암호화되고, CD8α 막 관통 영역은 SEQ ID NO:54에 제시된 서열에 의해 암호화되며, CD28 힌지 영역은 SEQ ID NO:53에 제시된 서열에 의해 암호화되고, CD28 막 관통 영역은 SEQ ID NO: 55에 제시된 서열에 의해 암호화되며, CD28 공동자극 도메인은 SEQ ID NO:56에 제시된 서열에 의해 암호화되고, CD137 공동자극 도메인은 SEQ ID NO:57에 제시된 서열에 의해 암호화되며, 상기 CD3제타는 SEQ ID NO:58에 제시된 서열에 의해 암호화된다.
다른 측면에서, 본 발명은 본 발명의 키메라 항원 수용체를 암호화하는 핵산 분자를 제공한다.
다른 측면에서, 본 발명은 본 발명의 키메라 항원 수용체를 발현하는 세포를 제공하고, 바람직하게는 상기 세포는 T 세포, NK 세포 및 B 세포로 이루어진 군으로부터 선택되고, 더욱 바람직하게는 상기 세포는 T 세포이다.
다른 측면에서, 본 발명은 순서대로 연결되어 있는 세포 외 표적된 인식 항원 서열, 힌지 영역 서열, 막 관통 영역 서열, 및 세포 내 신호 서열을 포함하는; 키메라 항원 수용체를 발현하는 림프구를 제공한다. 세포 외 인식 항원 서열은 상기와 같이 정의된 본 발명에서 기술된 글리코실화된 CEA를 특이적으로 인식하는 단일쇄 항체이다. 힌지 영역은 CD8α, CD28ECD, 및 IgG Fc 단편으로 이루어진 군으로부터 선택된다. 세포 내 신호 영역은 CD3제타와 같은 면역수용체 티로신 활성화 모티프(immunoreceptor tyrosine activation motif, ITAM) 및 CD28, CD137, CD27, ICOS, OX40, DAP10과 같은 공동자극 신호를 이용할 수 있다. 한 양태에서, 키메라 항원 수용체 내 힌지 영역 서열은 SEQ ID NO: 52 또는 SEQ ID NO: 53에 각각 제시된 서열에 의해 암호화되는 CD8α 또는 CD28를 포함하고; 키메라 항원 수용체 내 막 관통 영역 서열은 SEQ ID NO: 54 또는 SEQ ID NO: 55에 각각 제시된 서열에 의해 암호화되는 CD8α 또는 CD28를 포함하며; 키메라 항원 수용체 내 세포 내 신호 서열은 CD28, CD137, CD3제타 및 이의 조합을 포함하고, CD28은 SEQ ID NO: 56에 제시된 서열에 의해 암호화되며, CD137은 SEQ ID NO: 57에 제시된 서열에 의해 암호화되고, CD3제타는 SEQ ID NO:58에 제시된 서열에 의해 암호화된다. 한 양태에서, 백혈구는 T 세포, B 세포 또는 NK 세포 등 일 수 있다. 특정 양태에서, 백혈구는 T 세포이고, 키메라 항원수용체는 하기와 같이 발현된다:
scFv-CD8α-CD137-CD3제타,
scFv-CD28-CD28-CD137-CD3제타, 및
scFv-CD28-CD28-CD3제타.
바람직한 양태에서, 본 발명에서 제작된 키메라 항원 수용체는 SEQ ID NO: 69-128에 제시된 서열을 가진다.
키메라 항원 수용체의 항원-결합 도메인이 이의 대응하는 항원에 결합하는 경우에, 키메라 항원 수용체를 포함하는 세포는 항-종양 면역을 보인다.
본 발명은 일련의 글리코실화된 CEA에 대한 단일쇄 항체를 제작한다. 본 발명의 단일쇄 항체는 위암, 대장암, 및 식도암과 같은 종양의 검출 및 치료에 이용될 수 있다. 이러한 단일쇄 항체는 T 세포 및 NK 세포와 같은 백혈구의 표면 상에 발현되어, 글리코실화된 CEA 발현-양성 세포 및 조직을 특이적으로 사멸시키기 위한 글리코실화된 CEA에 대한 키메라 항원 수용체 T 세포 또는 키메라 항원 수용체 NK 세포를 제작 및 형성할 수 있다.
제2 측면에서, 본 발명은 각각 FM2, FM3, FM4, FM5, FM6인, 글리코실화된 CEA에 대한 단일쇄 항체를 제공하며, 이들의 중쇄 가변 영역 및 경쇄 가변 영역의 CDR 서열은 SEQ ID NO : 1~30이고, 이들의 암호화 뉴클레오티드는 각각 SEQ ID NO: 129-158인데, 서열 목록을 참고한다.
본 발명은 각각 FM2, FM3, FM4, FM5, FM6인 글리코실화된 CEA에 대한 단일쇄 항체를 제공하고, 이들의 중쇄 가변 영역은 각각 SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35. SEQ ID NO: 37 또는 SEQ ID NO: 39이며; 이들의 경쇄 가변 영역은 각각 SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38 또는 SEQ ID NO: 40이다. 한 양태에서, 본 발명은 VH-링커-VL 또는 VL-링커-VH의 형태로 배열된 글리코실화된 CEA에 대한 단일쇄 항체를 제공하며, VH는 상기 기술된 중쇄 가변 영역 서열로부터 선택되고, VL은 상기 기술된 경쇄 가변 영역 서열로부터 선택된다. 바람직한 양태에서, 링커, 즉, 링커 펩티드는 SEQ ID NO:41에 제시된 서열이다.
본 발명은 본 발명의 단일쇄 항체를 암호화하는 분리된 핵산 분자를 제공한다. 한 양태에서, 단일쇄 항체의 중쇄 가변 영역을 암호화하는 뉴클레오티드 서열은 SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48 또는 SEQ ID NO: 50이다. 한 양태에서, 단일쇄 항체의 경쇄 가변 영역을 암호화하는 핵산 서열은 SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49 또는 SEQ ID NO: 51이다.
본 발명은 키메라 항원 수용체를 암호화하는 핵산 서열을 포함하는 벡터를 또한 제공한다. 특정 양태에서, 벡터는 pGC-EIF1α-MCS (CV185, 진켐) 및 pGC-EIF1α-MCS-2A-EGFP (CV178, 진켐)이다.
종양의 진단을 위한 시약 또는 종양의 치료를 위한 약제의 제조에서, 바람직하게는 상기 종양은 소화관 종양, 더욱 바람직하게는 위암, 대장암, 및 식도암으로 이루어진 군으로부터 선택되는 것인, 본 발명에 따른 키메라 항원 수용체 및 단일쇄 항체의 용도.
본 발명은 포유류에서 항-종양 면역을 제공하는 방법을 또한 제공한다. 한 양태에서, 이 방법은 포유류에게 본 발명의 키메라 항원 수용체 T 세포의 유효량을 투여하여, 포유류에서 항-종양 면역을 제공하는 단계를 포함한다.
본 발명은 증가된 종양 항원 발현과 관련 있는 질병, 질환 또는 병태를 가지는 포유류의 치료방법, 예를 들어, CEA의 고발현(high expression)이 있는 위장관 종양의 치료를 또한 포함한다. 한 양태에서, 상기 방법은 포유류에게 본 발명의 키메라 항원 수용체 T 세포의 유효량을 투여하여, 포유류에서 종양을 치료하는 단계를 포함한다.
본 발명은 증가된 종양 항원 발현과 관련 있는 질병, 질환, 또는 병태의 진단방법, 예를 들어, 높은 CEA 발현이 있는 소화관 종양을 진단하는 것을 또한 포함한다. 한 양태에서, 상기 방법은 종양 및 종양의 주변 조직을 검출하기 위한 상당한 양의 글리코실화된 CEA의 발현을 포함한다.
도 1. 유세포 분석에 의한 SW620-CEA 내 CEA 발현의 검출.
도 2. FM2(VL→VH), FM4( VL → VH ), FM5( VL → VH ), FM6( VL → VH )는 구조 scFv-CD8α-CD137-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620-CEA, LOVO, KATO3)와 함께 16시간 동안 배양되었고, IL2 방출이 측정되었다.
도 3. FM2(VL→VH), FM4( VL → VH ), FM5( VL → VH ), FM6( VL → VH )는 구조 scFv-CD8α-CD137-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620-CEA, LOVO, KATO3)와 함께 16시간 동안 배양되었고, TNFα 방출이 측정되었다.
도 4. FM2(VL→VH), FM4( VL → VH ), FM5( VL → VH ), FM6( VL → VH )는 구조 scFv-CD8α-CD137-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620-CEA, LOVO, KATO3)와 함께 16시간 동안 배양되었고, INFγ 방출이 측정되었다.
도 5. FM2( VL → VH ), FM4( VL → VH )는 구조 scFv-CD28-CD28-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620, SW620-CEA, LOVO, KATO3, CRYPT)와 함께 16시간 동안 배양되었고, IL2 방출이 측정되었다.
도 6. FM2(VL→VH), FM4( VL → VH )는 구조 scFv-CD28-CD28-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620, SW620-CEA, LOVO, KATO3, CRYPT)와 함께 16시간 동안 배양되었고, TNFα 방출이 측정되었다.
도 7. FM2(VL→VH), FM4( VL → VH )는 구조 scFv-CD28-CD28-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620, SW620-CEA, LOVO, KATO3, CRYPT)와 함께 16시간 동안 배양되었고, INFγ 방출이 측정되었다.
도 8. FM2(VL→VH)-BBz가 표적 세포와 E:T 비율로 4시간 동안 혼합되었고, 상청액 내 LDH 방출이 측정되어 FM2( VL → VH )-BBz에 의한 표적 세포의 사멸을 측정하였다.
도 9. FM4(VL→VH)-BBz가 표적 세포와 E:T 비율로 4시간 동안 혼합되었고, 상청액 내 LDH 방출이 측정되어 FM4( VL → VH )-BBz에 의한 표적 세포의 사멸을 측정하였다.
도 10. PDX 모델 마우스의 말초 혈액내 IFNγ 방출의 검출.
도 11. PDX 모델의 종양 성장 곡선.
도 12. FM4(VL→VH)-BBz-NK92 사이토카인 분비 검정.
도 13. FM4(VL→VH)-BBz-NK92 세포 사멸 검정.
도 14. 종양 모델의 마우스에서 INFγ 방출의 검출.
도 15. 종양 모델의 마우스에서 종양 사멸 효과.
우선, 본 발명이 더욱 용이하게 이해될 수 있도록 특정 용어들이 정의된다. 본원에서 사용된 모든 기술적 용어 및 특정한 용어는, 달리 명시되지 않는 한, 본 발명이 속하는 기술분야의 통상적인 기술자에 의해 통상적으로 이해된 것과 동일한 의미를 가진다. 본원에서 기술된 방법 및 재료와 유사하거나 등가적인 것이 본 발명의 실행 또는 테스트에서 이용될 수 있으나, 적합한 방법 및 재료가 하기에 기술된다. 본원에 인용된 모든 출판물, 특허 명세서, 특허, 및 다른 참고문헌은 이들의 전체 기재내용이 참고로 본원에 포함된다. 상충의 경우에, 본 명세서 (정의를 포함하는)가 우위에 있을 것이다. 또한, 재료, 방법, 및 예시는 단지 설명적인 것이며 제한적인 것이 아니다.
단일쇄 항체 (single-chain antibody)
본 명세서에서 사용되는 "단일쇄 항체 (단일쇄 Fv, scFv)"는 면역글로불린의 중쇄 가변영역 (heavy chain variable region, VH)과 경쇄 가변영역 (light chain variable region, VL)을 라이게이션 펩티드(ligation peptide)를 통해 연결하여 형성된 재조합 단백질로, 완전한 항원 결합 부위를 갖는 가장 작은 항체 단편이다. 인간 면역글로불린 (Ig)은 IgA, IgD, IgM, IgE 및 IgG의 5개의 하위 유형을 포함하는데, 이 중 IgG가 인간 면역글로불린의 75%를 차지한다; IgG는 두 개의 중쇄 IgH 및 두 개의 경쇄 IgL이 사슬 간 이황화결합(interchain disulfide bond)을 통해 형성된 "Y"형 항체 구조이고; 여기서, IgH는 중쇄 가변영역 (VH) 및 불변영역 (Constant Region)을 포함하며; IgL은 경쇄 가변영역 (VL) 및 불변 영역 (Constant Region)을 포함한다. VH 및 VL의 다양성은 면역글로불린이 항원에 결합하는 것에 대한 근거가 된다. VH 및 VL은 프레임 영역(frame region, FR)과 상보성 결정 영역(complementary determining region, CDR)으로 구성되고, CDR 영역은 고도로 가변적인(highly variable)며 항원 및 항체의 특이적인 결합을 결정한다; 여기서, VH는 CDRH1, CDRH2, CDRH3로 표기된 세 개의 CDR 영역을 포함하고; VL은 CDRL1, CDRL2, CDRL3로 표기된 CDR 영역을 포함한다.
본 발명은 단일쇄 항체의 변이체, 유도체, 및 유사체를 또한 포함한다. 본문에서 사용된 용어 "변이체", "유도체" 및" "유사체"는 본 발명의 단일쇄 항체의 동일한 생물학적 기능 또는 활성을 실질적으로 보유하는 폴리펩티드를 의미한다. 본 발명의 폴리펩티드 변이체, 유도체 또는 유사체는 (i) 하나 이상의 보존적이거나 비-보전적인 아미노산 잔기 (바람직하게는 보존적 아미노산 잔기)가 치환되고, 이러한 치환된 아미노산 잔기가 유전적 암호에 의해 암호화되거나 암호화되지 않을 수 있는 폴리펩티드, 또는 (ii) 하나 이상의 아미노산 잔기가 치환 그룹(substituent group)을 갖는 폴리펩티드, 또는 (iii) 추가의 아미노산 서열을 폴리펩티드 서열 (선도 서열 또는 분비서열 또는 폴리펩티드의 정제에 이용되는 서열 또는 폴리펩티드 서열, 또는 융합 폴리펩티드와 같은)을 융합하여 형성된 폴리펩티드일 수 있다. 이러한 변이체, 유도체 및 유사체는 본원의 정의에 따라서 통상적인 기술자의 이해의 범위 내에 있다.
본 발명의 "단일쇄 항체"는 글리코실화된 CEA에 특이적으로 결합하는 폴리펩티드를 의미한다. 용어는 글리코실화된 CEA에 특이적으로 결합할 수 있는 폴리펩티드 서열을 가지는 변이체 형태를 또한 포함할 수 있다. 이러한 변이체는 C-말단 및/또는 N-말단에서 일부(대개 1-50, 바람직하게는 1-30, 더욱 바람직하게는 1-20, 가장 바람직하게는 1-10, 더욱 더 바람직하게는 1-8 또는 1-5) 아미노산의 결실, 삽입 및/또는 치환, 및 하나 이상의 (대개 20 이내, 바람직하게는 10 이내, 더욱 바람직하게는 5 이하) 아미노산의 삽입 또는 결실을 포함한다 (그러나, 이에 제한되는 것은 아님). 예를 들어, 기술분야에서, 가깝거나 유사한 특성의 아미노산과의 치환은 대개 단백질의 기능을 변화시키지 않는다. 다른 예로서, C-말단 및/또는 N-말단에서 하나 이상의 아미노산의 삽입 또는 결실도 또한 일반적으로 단백질의 기능을 변화시키지 않는다.
본 발명은 단일쇄 항체의 유사체를 또한 제공한다. 이러한 유사체와 자연적인 단일쇄 항체 사이의 차이점은 아미노산 서열의 차이, 서열에 영향을 끼치지 않는 변형 형태의 차이, 또는 이의 조합일 수 있다. 이러한 폴리펩티드는 자연적이거나 유도된 유전적 변이체를 포함한다. 유도된 변이체는 방사선 조사 또는 돌연변이원에 대한 노출에 의한 무작위 돌연변이 유발(random mutagenesis), 또는 부위-지정 돌연변이 유발(site-directed mutagenesis) 또는 분자 생물학의 다른 공지된 기법과 같은 다양한 기법에 의해 수득될 수 있다. 유사체는 자연적인 L-아미노산 (예, D-아미노산) 외의 잔기를 갖는 유사체 뿐만 아니라 비-자연적으로 발생하거나 합성인 아미노산(예를 들어, β-아미노산, γ-아미노산)을 갖는 유사체를 또한 포함한다. 본 발명의 폴리펩티드가 상기 예시된 대표적인 폴리펩티드에 한정되는 것이 나이라는 것을 이해해야 할 것이다.
또한, 본 발명의 단일쇄 항체의 활성, 발현량 및 안정성에 실질적으로 영향을 미치지 않는 다른 아미노산 서열이 단일쇄 항체의 아미노 말단 또는 카르복시 말단에 추가될 수 있다. 바람직하게는, 이러한 추가된 아미노산 서열은 발현 (예, 신호 펩티드)을 용이하게 하거나, 정제 (예, 6 x His 서열), 또는 단일쇄 항체의 활성, 발현 또는 안정성을 촉진하는 다른 서열을 용이하게 한다.
본 발명은 본 발명의 단일쇄 항체 또는 이의 변이체, 유도체를 암호화하는 DNA 분자를 또한 포함한다. DNA 분자는 모두 PCR 증폭에 의해 인공적으로 합성될 수 있거나 수득될 수 있다.
숙주 세포의 발현 수준을 더 증가시키기 위해, 본 발명의 단일쇄 항체의 암호화 서열을, 예를 들어, 숙주 세포-선호 코돈(host cell-preferred codon)을 이용해 조작하여 유전자 전사 및 번역에 도움이 되지 않는 서열을 제거할 수 있다.
단일쇄 항체의 발현
본 발명의 신규한 단일쇄 항체 또는 이의 변이체 또는 유도체를 암호화하는 DNA 서열을 수득한 후에, 이는 적합한 발현 벡터로 클로닝되고, 적합한 숙주 세포로 도입된다. 마침내, 형질전환된 숙주 세포가 배양되고, 본 발명의 신규한 단일쇄 항체는 분리 및 정제에 의해 수득된다.
본원에 사용된 용어 "벡터"는 플라스미드, 코스미드, 발현 벡터, 클로닝 벡터, 바이러스 벡터 등을 포함한다.
본 발명에서, 기술분야에 공지된 다양한 벡터가 이용될 수 있다. 예를 들어, 시판 벡터가 선택된 다음, 본 발명의 신규한 단일쇄 항체를 암호화하는 뉴클레오티드 서열이 발현 조절 서열에 작동 가능하게(operably) 연결되어 발현 벡터를 형성한다.
본 발명에서, 용어 "숙주 세포"는 원핵 세포 및 진핵 세포를 포함한다. 통상적으로 이용되는 원핵 숙주 세포의 예시는 에스체리치아 콜라이 ( Escherichia coli), 바실러스 서브틸리스 (Bacillus subtilis ) 등을 포함한다. 단일쇄 항체를 발현하기 위한 숙주 세포는 에스체리치아 콜라이, 효모 세포, 곤충 세포, COS 세포, CHO 세포 등을 포함한다. 바람직하게는, 숙주 세포는 원핵 세포, 더욱 바람직하게는 E. coli 세포이다.
형질전환된 숙주 세포를 수득한 후에, 상기 세포는 본 발명의 단일쇄 항체의 발현에 적합한 조건 하에서 배양되어 단일쇄 항체를 발현할 수 있고; 이어서, 발현된 단일쇄 항체는 분리될 수 있다.
링커 펩티드(Linker peptide)
본원에서 사용된 용어 "링커 펩티드" (링커)는 항체(또는 이의 변이체)의 중쇄 가변영역 및 항체(또는 이의 변이체)의 경쇄 가변영역 사이의 짧은 펩티드를 의미하는데, 이는 링커로 작용하고, 중쇄 및 경쇄 가변영역이 자유롭게 폴딩(folding)하도록 하며, 이로써 항원 결합 부위를 분자 동력학(molecular dynamics)의 변화를 야기하지 않고, 적절한 구성에 둘 수 있다. 일반적으로, 링커 펩티드는 중쇄 가변영역 (VH) 및 경쇄 가변영역 (VL)의 아미노산 서열의 올바른 폴딩 및 공간적 구조의 형성에 영향을 끼치지 않거나 현저하게 영향을 끼치지 않는다; 대안적으로는, 링커 펩티드는 중쇄 가변영역 (VH)과 경쇄 가변영역 (VL) 사이의 유연한 연결부를 구성하며, 이는 이들의 정상적인 폴딩을 용이하게 한다. 링커 펩티드의 길이는, 길이가 중쇄 및 경쇄 가변영역이 자유롭게 폴딩되도록 허용되고, 항원 결합 부위가 분자 동력학의 변화를 야기하지 않고 적절한 구성에 있는 것이 허용되는 한, 특별히 제한되지 않는다. 예를 들어, 링커 펩티드의 길이는 4-30 aa일 수도 있다. 바람직하게는, 본 발명의 링커 펩티드의 서열은 SEQ ID NO: 1에 제시된다.
키메라 항원 수용체 (Chimeric antigen receptor, CAR)
본 발명의 단일쇄 항체는 위암(gastric cancer), 대장암(colorectal cancer), 및 식도암(esophageal cancer)과 같은 종양의 검출 및 치료에 이용될 수 있다. 본 발명의 단일쇄 항체는 T 세포의 표면상에 특이적으로 발현되어 글리코실화된 CEA에 대한 키메라 항원 수용체 T 세포를 제작할 수 있고, 글리코실화된 CEA 발현-양성 세포 및 조직을 특이적으로 사멸시킬 수 있다. 본 발명의 단일쇄 항체 각각에 대하여, 세 구조의 CAR-T가 별도로 제작될 수 있고, 각 항체하에서 이 세 구조의 기능적 차이를 비교하여, 적절한 CAR-T 구조를 적합한 표적 세포로 채용한다. 세 구조의 CAR-T는 각각 하기와 같다:
scFv-CD8α-CD137-CD3제타,
scFv-CD28-CD28-CD137-CD3제타, 및
scFv-CD28-CD28-CD3제타.
본 발명의 키메라 항원 수용체 구조에서:
힌지 영역은 CD8α, CD28, 인간 IgG1 Fc, 인간 IgG4 Fc, DAP10 등으로 이루어진 군으로부터 선택된 세포 외 영역일 수 있다.
막 관통 영역은 CD8α, CD28, DAP10 등으로 이루어진 군으로부터 선택된 막 관통 영역일 수 있다.
공동자극 도메인은 CD28, CD134 (OX40), CD137 (4-1BB), ICOS, DAP10 등으로 이루어진 군으로부터 선택된 세포 내 영역일 수 있다.
필수적인 신호 도메인은 CD3제타로부터 선택될 수 있다.
실시예
본 발명은 특정 실시예 및 첨부한 도면과 함께 아래에서 더 기술되나, 이는 본 발명을 제한하려는 의도는 아니다. 조건이 특정하게 기술되지 않은 하기 실시예의 실험방법은 J. Sambrook et al., Molecular Cloning Experiment Guide, Science Press, 2002에 의해 기술된 조건과 같은 통상의 조건 또는 제조자의 추천 조건에 따라서 수행한다. 다르게 명시되지 않는 한, 퍼센트(percentage) 및 파트(part)는 중량 퍼센트 및 중량부이다.
[ 실시예 1: 단일쇄 항체의 제작]
[표 1]
Figure 112019020880710-pct00001
단일쇄 항체의 발현 방법
각각의 합성된 뉴클레오티드 서열 FM2, 3, 4, 5, 및 6을 3'-말단의 8개의 His (CACCATCACCATCACCATCACCAT)와 함께 추가하였고, 증폭된 단편은 이의 양 말단의 sfiI 및 NotI 제한 부위와 함께 추가한 다음에, pCANTAB5E 벡터 (GE 헬스케어)에 삽입하였다. 제작된 pCANTAB5E (GE) 벡터는 E. coli-HB2151 균주로 형질전환하였고, IPTG에 의해 유도하여 밤새 발현시켰다. 세포를 PBS 완충액에서 재현탁하였고, 얼음 위에서 10분 동안 초음파 분쇄하였다(sonicated). 원심분리 후에, 상청액을 히스 트랩 컬럼(His Trap Column) (GE)으로 정제하였고, 20 mM 이미다졸을 함유한 PBS 완충액을 이용하여 5-10 컬럼 부피(column volume) 동안 세척한 다음에, 500 mM 이미다졸을 함유하는 PBS를 이용하여 용출시켰다; 그 후의 이미다졸은 탈염 G25 컬럼(Desalting G25 column) (GE)을 이용하여 탈염시켜 PBS에 용해된 단일쇄 항체를 수득하였다.
[ 실시예 2: CAR 재조합 렌티바이러스 벡터의 제작]
본 발명에서 제작된 바이러스는 표 2에 제시된다.
[표 2]
Figure 112019020880710-pct00002
Figure 112019020880710-pct00003
Figure 112019020880710-pct00004
Figure 112019020880710-pct00005
Figure 112019020880710-pct00006
1. 렌티바이러스 플라스미드 벡터의 제작
1) 유전자 서열의 전장 유전자 합성(Whole gene synthesis)
표 2의 렌티바이러스를 제작하기 위해, 표 2에 제시된 구조에 따라서, 필수 유전자 서열을 전장 유전자 합성하였다.
2) 핵산 단편의 증폭
SEQ ID NO. 69-78, 89-98, 109-118으로 넘버링한(numbering) 합성된 유전자 생성물을 상류 프라이머 (SEQ ID NO. 159-168) 및 하류 프라이머 (SEQ ID NO. 169)를 이용하여 증폭시켰다. PCR 증폭 조건은 다음과 같다: 전-변성: 95°C, 5분; 변성: 95°C, 30초; 어닐링: 55°C, 30초; 신장: 72°C, 1분, 35 사이클; 마지막 신장: 72°C, 10분.
SEQ ID NO. 79-88, 99-108, 119-128로 넘버링된 합성된 유전자 생성물을 상류 프라이머 (SEQ ID NO. 159-168) 및 하류 프라이머 (SEQ ID NO. 170)를 이용하여 증폭시켰다. PCR 증폭 조건은 상기 조건과 같다.
3) 바이러스 플라스미드 벡터의 제작
a) SEQ ID NO. 79-88, 99-108, 119-128의 증폭된 단편을 제한 내부핵산 가수분해효소 절단(restriction endonuclease digestion)하였다. 이용된 제한효소는 BamHI과 EcoRI이었고, 절단 시스템은 다음과 같았다: 20 μl까지 멸균수가 보충된, BamHI 0.5 μl, EcoRI 0.5 μl, 완충액 2 μl, BSA 2 μl, 및 증폭된 단편 2 μg. 37°C에서 2시간 동안 인큐베이팅(incubating) 시킨 후에, 효소 절단 시스템을 DNA 클리닝 및 회수(DNA cleaning and recovery)하였다. 회수 방법은 다음과 같았다: 80 μl의 완충액 PCR-A를 절단 시스템에 추가한 후에, 혼합물을 준비 튜브(preparation tube)로 옮겼고, 준비 튜브를 2 ml 원심분리 튜브(centrifuge tube)에 꽂았으며, 12,000 Х g에서 1분 동안 원심분리하였고, 여과물을 버렸다. 준비 튜브를 2 ml 원심분리 튜브에 다시 꽂았고, 700 μl의 완충액 W2를 추가하였으며, 12,000 Х g에서 1분 동안 원심분리하였고, 여과물을 버렸다. 준비 튜브를 깨끗한 1.5 ml 원심분리 튜브에 꽂았고, 25-30 μl의 용출액 또는 탈이온화수(deionized water)를 준비 튜브의 멤브레인 중앙에 추가하였고, 1분 동안 실온에 두었다. DNA를 12,000 Х g에서 1분 동안 원심분리에 의해 용출시켰다.
SEQ ID NO. 69-78, 89-98, 109-118의 증폭된 단편을 제한 내부핵산 가수분해효소 절단하였다. 사용된 제한 내부핵산 가수분해 효소는 BamHI이었다. 절단 시스템은 다음과 같았다: 20 μl까지 멸균수가 보충된 0.5 μl의 BamHI, 0.5 μl의 EcoRI, 2 μl의 완충액, 2 μl의 BSA, 및 2 μg의 증폭 단편. 2시간 동안 37°C에서 인큐베이팅(incubating) 시킨 후에, 효소 절단 시스템을 DNA 클리닝 및 회수(DNA cleaning and recovery)하였다. 회수 방법은 상기 회수 방법과 같았다.
b) 벡터 단편을 제한 내부핵산 가수분해효소 절단했고, 효소 절단 시스템 및 방법은 상기에 제시된 것과 같았다. 절단 후에, 시스템을 DNA 아가로오스 겔 전기영동(DNA agarose gel electrophoresis)하였고, 벡터 단편 (약 8 Kb)를 겔에 의해 회수하였다. 회수 시스템은 다음과 같다: 관심 있는 DNA 단편을 아가로오스 전기영동에 의해 다른 DNA 밴드로부터 분리한 다음에, 회수될 DNA를 함유하는 아가로오스 겔 블록을 깨끗한 메스로 절제하였고, 미리 넘버링된 1.5 ml EP 튜브에 넣었다. 아가로오스 겔 블록은 가능한 한 얇게 절제되어야 하고, 자외선 조사 시간은 가능한 한 짧아야 한다. 500 μl의 겔 용액(gel solution)을 각 튜브에 추가하였고, 65°C의 웜 배쓰(warm bath)에서, 5분 내지 10분 동안 인큐베이팅(incubating)시켰는데, 이 시간 동안에 혼합물을 2분 마다 인버팅(inverting)시켜서 겔을 완전히 녹였다. 용해된 겔을 수조(water bath)에서 꺼내서, 겔이 실온으로 식을 때까지 2분 동안 실온에 두었다. A UNIQ-10 회수 컬럼(UNIQ-10 recovery column)을 500 μl의 평형 용액(equilibration solution)과 함께 추가하였고, 12,000 rpm에서 1분 동안 원심분리 하였으며, 수집 용액(collection solution)을 제거하였고, 따로 보관하였다(set aside). 이 액체를 UNIQ-10 컬럼으로 옮기고, 1분 동안 실온에 두었으며, 8,000 rpm에서 1분 동안 원심분리했다. UNIQ-10 컬럼을 내렸고(get down), 수집 튜브(collection tube) 내 폐액(waste liquid)을 버렸고 (표적 스트립이 매우 가벼운 경우에, 수집 튜브의 용액을 UNIQ-10 컬럼에 다시 통과시킬 수 있다), UNIQ-10 컬럼을 동일한 수집 튜브에 꽂고, 700 μl의 세척 완충액(Wash buffer)을 추가하였으며, 10,000 rpm에서 30초 동안 원심분리시켰는데, 이 과정을 한번 더 반복하였다. UNIQ-10 컬럼을 내렸고, 수집 튜브 내 폐액을 제거하였고, UNIQ-10 컬럼을 동일한 수집 튜브에 꽂았으며, 12,000 rpm에서 2분 동안 원심분리시켰다. UNIQ-10 컬럼을 새 1.5 ml EP 튜브에 꽂았고, UNIQ-10 컬럼의 뚜껑을 열어서, 65°C의 오븐에 10분 동안 두어, 에탄올을 충분히 증발시켰다. 40 μl의 용출 완충액을 컬럼 멤브레인 중앙에 추가하였고 (주의: 팁(tip)을 교체하여 오염을 피해야한다), UNIQ-10 컬럼의 뚜껑을 닫아서, 65°C의 오븐에 2분 동안 두었다. 관심 있는 DNA를 12,000 rpm에서 1분 동안 원심분리시켜 회수하였다.
EGFP 발현 벡터를 제한 내부핵산 가수분해효소 절단하였는데, 사용한 제한 효소는 BamHI이었고, 효소 절단 시스템 및 겔 회수 방법은 상기 기술된 것과 같았다.
c) 관심 있는 플라스미드 벡터 및 단편의 라이게이션
SEQ ID NO. 79-88, 99-108, 119-128의 절단 생성물을 EGFP 발현-프리 벡터 (CV185, 진켐)[EGFP expression-free vector (CV185, Genechem)]에 라이게이션하였고; SEQ ID NO. 69-78, 89-98, 109-118의 증폭된 절단 생성물을 EGFP 발현 벡터 (CV178, 진켐)으로 라이게이션하였다.
라이게이션 시스템은 다음과 같았다: 20 μl까지 멸균수가 보충된, 25 ng의 삽입 단편, 100 ng의 벡터 단편, 2 μl의 T4 리가아제 완충액, 1 μl의 T4 리가아제, 및 22°C에서 1시간 동안 라이게이션.
2. 렌티바이러스 패키징(Lentiviral packaging)
3세대 렌티바이러스 패키징 시스템(third generation of lentiviral packaging system)을 이용하였다: 전달 플라스미드(transfer plasmid): CV178 또는 CV185 (진켐), 엔벨롭 플라스미드(Envelop plasmid): H1 (진켐), 패키징 플라스미드: H2 (진켐) (Zufferey et al., J Virol 72 ( 12): 9873-80, 1998).
HEK-293T 세포를 24시간 계대 주기(24h passage period)에 따라 보충했고, 배지를 형질주입 전에 교체하였다. 각 플레이트의 세포를 전자 피펫(electric pipette)을 이용하여 2% FBS를 함유한 DMEM 배지 5 ml로 교체하였다. HBW, H1 (12μg/플레이트, 이 플레이트는 10cm 세포 배양 접시(dish)를 의미하며, 이하 마찬가지임), 재조합 H2 (10μg/플레이트), 벡터 (24μg/플레이트), CaCl2 (50μl/플레이트)를 차례로 추가하였고, 2 x HBS (500 μl/디스크)를 적가하여, 마지막으로 볼텍스 오실레이터(vortex oscillator) 상에서 진동을 가했으며(oscillated), 형질주입 시스템은 1 ml/플레이트였다. 이들 중, 벡터는 단계 1에서 제작된 벡터였다. 혼합 후에, 형질주입 시스템을 조심스럽게 피페팅하였고, 1000 μl의 혼합물을 취해 293T 세포에 적가하였으며, 작업을 계속 안정하게 유지하였고, 형질전환 시스템을 10 cm 플레이트 상에 균등하게 분배하였다. 이 플레이트를 평평하게(level) 유지하여 플레이트 내 액체를 각각의 전, 후, 좌, 우 방향에서 10회 교반시킨 다음에-이 혼합 과정은 충분해야 하나, 플레이트 밖으로 엎지르거나 넘치는 액체는 없어야 한다-37°C, 5% CO2 배양기에 두었다. 형질전환 후 8시간 후에, 상청액을 버리고, DMEM 배지를 전자 피펫을 이용하여 교체하였다. 형질전환의 종료 후 28시간 내지 30시간 사이에, 상청액을 처음으로 수집하였고, 10 ml의 DMEM 배지를 보충을 위해 추가하였다. 형질전환의 종료 후 48시간 내지 50시간 사이에, 상청액을 두번째로 수집하였다. 초원심분리 후에, 나중에 사용하기 위해, 이를 100 μl의 DMEM에 재현탁하였다.
[ 실시예 3: 재조합 렌티바이러스를 이용한 T 림프구의 감염]
감염 실험을 통상적인 기술자에게 공지된 통상의 방법에 따라 수행하였다. 감염 단계를 다음과 같이 간단히 기술하였다:
1. 말초 혈액 단핵 림프구(Peripheral blood mononuclear lymphocyte, PBMC)를 수득하였고, >1 x 107 세포를 성분 수혈 시스템(blood apheresis system)에 의해 수득하였다.
2. 세포 배양 접시의 실험 항-인간 CD3/CD28 항체 처리.
항-인간 CD3 항체 (OKT3 클론, MACS) 및 항-인간 CD28 항체 (15E8 클론, MACS)를 최종 농도 1 μg/ml으로 PBS로 희석하였고, 희석된 항체 혼합물을 세포 배양 접시로 추가하여, 접시 내 배양물을 도말하였다. 실온에서 2시간 동안의 배양 후에, 접시를 PBS로 1회 세척하였고, 따로 보관하였다.
3. T 림프구의 활성화
분리된 PBMC를 T 림프구 배양 배지 (TexMACS medium + 10% FBS + 30 IU/재조합 인간 IL-2)에서 1*106 세포/ml의 최종 농도로 재현탁하였고, 단계 2에서 처리된 접시에 놓고 배양시켰다. 배양 조건은 37°C + 5% CO2였고, 배양 시간은 24시간이었다.
4. 활성화된 T 림프구의 감염
1) 감염 시약의 준비
특정 양의 T 세포 배양 배지를 취하여, 신퍼로닉(synperonic) F108과 함께 추가하여 최종 농도 1 mg/ml에 도달시켰고, 충분히 혼합하였으며, 수조에서 37°C로 가열시켰고, 따로 보관하였다.
2) 배양 플레이트의 처리
1 mg/ml CD3 및 0.5 mg/ml CD28 항체를 취하여, 적합한 양의 PBS 완충액에 대한 1:1000 부피비로 희석시켰고, 레트로넥틴 시약 (다카라, Cat. No. T100A)을 취하여, PBS 완충액에 대해 1:40의 부피비로 희석시켰다. 충분히 혼합한 후에, 완충액을 균등하게 세포 접시에 도말하였고 실온에서 2시간 동안 배양시켰다. 2시간 후에, 접시를 PBS로 세척하였고, 따로 보관하였다.
3) 렌티바이러스를 이용한 T 림프구의 감염 및 T 림프구 유지(maintaining)
1)에서 준비된 감염 시약을 이용하여 활성화된 T림프구를 희석하였고, 렌티바이러스를 MOI=3에 따라서 추가하였으며, 혼합하였다. 혼합물을 2)에서 처리된 접시에 균등하게 도말하였다.
감염 후에, 세포 밀도를 모니터링하여, 세포를 1*106 세포/ml로 유지시켰고; 통상적으로, 14일 후에, 세포는 30-100배 증폭되었다.
[ 실시예 4: 소화관 공급원의 암 세포주 내 글리코실화된 C EA 발현의 검출]
유세포 분석을 이용하여 다양한 표적 세포에서의 글리코실화된 CEA의 발현 수준을 검출하였다. 특이적인 검출 방법은 다음과 같았다:
1. 표 3에 제시된 6*105 세포/그룹을 취해서 200g에서 5분 동안 원심분리하였고, 상청액을 버렸다;
2. 200 μl PBS에서 재현탁한 후에, 재현탁된 세포를 두 개의 그룹으로 나누었는데, 이 중 한 그룹을 본 발명의 글리코실화된 CEA에 대한 단일쇄 항체 1 μg과 함께 추가하였고, 4°C에서 2시간 동안 배양시켰다;
3. 1 ml의 PBS를 각 그룹에 추가하였고, 혼합하였으며, 200 g에서 5 분 동안 원심분리하였고, 상청액은 버렸다; 세포를 100 μl의 PBS로 재현탁하였고, 5 μl의 고트(goat) 항-마우스 IgG1 FITC-표지 2차 항체를 세포 현탁액에 추가하였으며, 4 °C에서 1시간 동안 배양시켰다;
4. 세포를 PBS로 3회 세척하였고, 유세포 분석으로 측정 및 분석하였다.
결과는 표 3에 제시된다. 글리코실화된 CEA 항원의 발현은 SW620에서는 검출되지 않으나, CEA를 과발현하는 LOVO 세포주 및 SW620-CEA 뿐만 아니라, KATO3, CRYPT에서도 상이한 정도의 글리코실화된 CEA 발현이 검출되었다.
SW620-CEA 세포주의 제작 방법: 10% FBS와 함께 추가된 1640 배지에서 SW620 세포를 유지 및 배양시켰다; 전체 길이의 CEA 유전자 (CEACAM5, NM-004363)를 전장 유전자 합성에 의해 수득하였다; GV348 벡터(진켐)에 클로닝한 후에, 두 헬퍼 플라스미드(helper plasmid)와 함께 유전자를 인산 칼슘을 이용하여 293T 세포로 형질주입하였고, 패키징하여 렌티바이러스를 구성하였다. SW620 세포를 24-웰 플레이트로, 105/웰 접종하였고, 밤새 배양시켰다; SW620를 CEA-발현 렌티바이러스를 이용해 MOI=3에 따라서 감염시켰고, 푸로마이신(puromycin)을 추가하여, 감염 후 24 시간 후에 최종 농도를 1 μg/ml에 도달시켰다; 세포를 푸로마이신을 이용해 스크리닝하여, 단일항체를 수득하였다. CEA 발현을 FACS로 검출하였다. 결과는 도 1에 제시된다.
[표 3]
Figure 112019020880710-pct00007
[ 실시예 4a: FM4 단일쇄 항체 및 CEA 항체를 이용한 종양 시료에서 CEA 발현의 검출]
환자의 위암 종양 조직 시료를 액체 파라핀에 포매시켰고 동결하였으며, 절편(section)을 유리 슬라이드에 고정시켰다; 크실렌을 이용해 탈랍(dewaxing)시킨 후에, 시트르산 완충액을 이용하여 항원 회수를 수행하였다; 회수된 시료를 5% FBS를 이용하여 PBS 완충액에서 30분 동안 블로킹시켰고, 2 μg/ml의 본 발명의 FM4 단일쇄 항체 또는 CEA 항체 (클론 CB30) [이바이오사이어스(ebioscience), Cat. No. 14-0669-82]를 4°C의 냉장고에서 밤새 추가하였다; 조직 슬라이드를 PBS로 3회 세척하였고, 2차 항체와 함께 추가하였으며, 발색 전개시켰다(color development).
FM4 단일쇄 항체는 더 높은 감도 및 조직 특이성을 보였다 (표 4에 제시됨).
[표 4]
Figure 112019020880710-pct00008
[ 실시예 5: 글리코실화된 C EA 양성 세포 상의 CAR-T의 특이성에 대한 연구 ]
CAR-T가 글리코실화된 CEA-양성 세포 (항원의 낮은 수준의 발현이 있는 SW620-CEA, CRYPT, KATO3, 및 LoVo)내 특이적 기능을 특이적으로 인식 및 생성하는지에 대한 여부를 조사하기 위해, 본 발명의 실험실은, 4개의 제작된 CAR-T, 즉, FM2(VL→VH)-BBz, FM4( VL → VH )-BBz, FM5( VL → VH )-BBz, 및 FM6( VL → VH )-BBz (SEQ ID NO. 80, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88)의 표적 세포-특이적인 사멸 및 특이적인 사이토카인 방출을, 표적 세포와 공동 배양한 후에, 유사한 감염 효율(infection efficiency) 하에서, CAR 바이러스로 감염되지 않은 T 림프구를 대조군으로 이용하여 검출하였다.
1. CAR-T 감염 효율의 플로우 검출(Flow detection)
EGFP 단백질 및 CAR 단백질이 CAR-T 세포에서 공동 발현(co-expressed)되기 때문에, 유세포 분석에 의해 검출된 EGFP-양성 세포의 백분율은 CAR-양성 세포를 나타낼 수 있다. CAR 바이러스로 감염되지 않은 T세포를 대조군으로 이용하였고, 테스트 결과를 하기 표(표 5)에 제시하였다.
[표 5]
Figure 112019020880710-pct00009
2. 표적 세포와 CAR-T의 상호작용 후, 사이토카인 분비 수준
표적 세포는 SW620, SW620-CEA, LoVo, 및 KATO3 세포였다. 이펙터 세포는 표 5에서 언급된 5개의 세포였고, 사이토카인 분비를 CAR 바이러스 감염 후 10일 째에서 검출하였다.
방법은 다음과 같았다: 1*105 표적 세포를 이펙터 세포와 1:1의 비율로 100 μl의 RPMI 1640+2% FBS 배지에서 별도로 혼합하였고, 약 16 시간 동안 37°C의 5% CO2 배양기에서 배양시켰다. 16시간 후에, 원심분리를 5분 동안 200 g에서 수행하였고, 상청액을 취해 상청액 내 사이토카인의 분비 수준을 측정하였다. 사이토카인 함량을 BD 컴퍼니가 생산한 HU TH1-TH2 CBA 키트로 측정하였다. 측정 메커니즘은, 반응 용액 내 사이토카인이 대응하는 비드 상의 항체와 결합할 수 있고, 각 사이토카인에 대응하는 비드는 상이한 강도의 APC 형광수준을 가지며; 사이토카인이 비드에 결합된 후에, 비드에 결합된 사이토카인은 다른 PE 형광 표지 항체로 더 표지되었고, 사이토카인 함량은 PE의 형광 강도를 측정함으로써 측정되었으며, 상이한 사이토카인 종류가 APC 형광 광도의 차이에 의해 구별되었다는 것이다. 이 연구에서, 세 사이토카인, 즉, IL-2, IFN-γ 및 TNF-α의 분비 수준을 측정하였다. 특이적인 테스트 방법은 키트 지시사항을 의미했다. 테스트 결과를 FCAP 어레이 v3 소프트웨어에 의해 분석하였고, 결과는 도 2, 도 3, 도 4, 도 5, 도 6, 및 도 7에 제시된다.
결과는 FM2( VL → VH )-BBz 및 FM4( VL → VH )-BBz가 표적 세포와 상호작용한 후에, IL-2, TNF-α, IFN-γ 및 다른 사이토카인이 현저히 증가한 것을 제시하였다.
3. CAR-T와 표적 세포의 상호작용 후에 표적 세포에 대한 시험관 내 사멸 독성(killing toxicity)
글리코실화된 CEA-양성 표적 세포에 대한 CAR-T의 사멸 효과를 확인하기 위해, 낮은 수준의 항원 발현이 있는 SW620-CEA 뿐만 아니라, 항원 발현-양성 세포 LoVo, KATO3 및 CRYPT도 이 연구에서 이용되었다. 사용된 키트는 사이토톡스96 비-방사성 세포독성 검정 키트(프로메가) [Cytotox96 non-radioactive cytotoxicity assay kit (Promega)]였다. 이 방법의 메커니즘은 통상의 방사성 원소가 세포에서 안정적으로 발현되고 분비되지 않는 젖산 탈수소효소(lactate dehydrogenase, LDH)로 대체되고; 세포의 세포사멸(apoptosis)이 발생되는 경우에, LDH가 세포 외로 방출되면, LDH에 산화된 포르마잔(formazan)의 함량이 검출되어 상청액 내 효소의 수준을 측정함으로써, 세포사멸의 수준을 측정하는 것이다. 이펙터 세포는 FM4( VL → VH )-28z였고, 이펙터 세포의 표적 세포에 대한 비율은 각각 1:2, 1:5, 1:10, 1:20, 1:30이었다. 표적 세포의 수는 10,000 세포/웰이었고, 두 개의 부수적인 웰(accessory well)이 각 그룹에 설정되었으며, 검출 시간은 상호작용 후 4시간이었다.
이들 중에서, 각각의 실험 그룹 및 대조 그룹은 다음과 같이 설정하였다:
실험 그룹: 표적 세포 및 상이한 표적 세포에 대한 이펙터 세포의 상이한 비율의 CAR-T 세포;
대조 그룹 1: 표적 세포의 LDH의 방출 중 LDH의 최대 방출이 있는 그룹;
대조 그룹 2: 표적 세포의 LDH의 방출 중 자발적인 LDH의 방출이 있는 그룹; 및
대조 그룹 3: 이펙터 세포의 방출에서 자발적인 방출이 있는 그룹.
특정한 실험 방법은 키트 지시사항을 의미했다. 세포독성은 하기의 식에 의해 산출되었다:
특이적 용해(Specific lysis) = (실험 그룹 - 대조 그룹 2 - 대조 그룹 3) / (대조 그룹 1 - 대조 그룹 2).
결과는 FM4( VL → VH )-28z가 LoVo, KATO3 및 CRYPT 세포에 대한 강한 사멸 효과를 가지나, SW620-CEA에 대해서는 사멸 효과를 거의 가지지 않는 것을 제시하였다. 관련 결과는 도 8 및 도 9에 제시된다.
이 연구는 FM4( VL → VH )-28z가 글리코실화된 CEA 항원을 특이적으로 인식하고, 낮은 정도의 글리코실화가 있는 CEA 항원에 대해서는 감도가 낮은 것을 입증하였다.
[ 실시예 6: 글리코실화된 C EA -양성 PDX 종양 모델에 대한 CAR-T의 효과]
NCG 마우스 [난징 대학교의 모델 생물학 연구소(Institute of Model Biology)로부터 구입함]에게 글리코실화된 CEA 항원-양성 환자-유래의 종양 세포를 피하로 주사하였다. 환자의 종양 조직을 제거한 후에, 표면상의 결합 조직 및 혈관을 제거하였고; 종양 덩어리를 정중선(midline)을 따라 절제하였으며, 괴사 조직(necrotic tissue), 큰 석회화 지점(large calcification point) 및 분비물(secretion)을 제거하였고, 조심스러운 세척(cleaning) 후에, 양질(good quality) 및 좋은 단단함(good toughness)을 가진 종양 조직을 신선한, 아주 차가운(ice-cold) RPMI-1640 배지로 옮겼다. 종양 조직을 약 3Х3 mm2의 작은 종양 덩어리로 절제하여 NSG 마우스에 일측으로 이식하였다(transplanted unilaterally). 평균적인 종양 부피가 160-180 mm3에 도달되는 경우에, 모델 동물에게 이펙터 세포를 종양내로(intratumorally) 주사하였다.
이 연구에 이용된 이펙터 세포는 FM4( VL → VH )-BBz였고, 대조 그룹은 CAR로 형질주입되지 않은 T 세포 및 동일한 양의 동일한 양의 PBS였다. 주사 전에, 이펙터 세포를 PBS로 2회 세척하였고, PBS에서 재현탁하여 각각 3E7/ml 및 1E8/ml에 달하게 했고, 각각 저용량 그룹(low dose group) 및 고용량 그룹(high dose group)으로 기록하였다. 각 마우스에게 30 μl의 이펙터 세포/PBS를 종양내로 주사하였다.
이 연구의 연구 내용(research content)은 다음을 포함하였다:
마우스 체중 및 종양 부피 / 3 일 / 시간;
마우스 말초 혈액 사이토카인 검출 / 7 일 / 시간; 및
마우스 말초 혈액 CAR 카피 수(copy number) / 7 일 / 시간.
종양 부피 결과는 도 11에 제시된다. CAR-T의 주사 후 4일째부터, FM4( VL →VH)-BBz 고용량 그룹의 종양 부피는 감소하기 시작 한 반면, 공 T-세포 그룹(empty T-cell group) 및 PBS 그룹은 하락세를 보이지 않았다. 이는 CAR-T가 글리코실화된 CEA-양성 종양에 대한 현저한 저해 효과를 가지는 것을 나타낸다. CAR-T의 주사 후에, 공 T 세포 그룹 및 PBS 대조 그룹에 비해서, CAR-T가 주사된 마우스의 현저한 체중 변화는 없었다.
말초 혈액 내 사이토카인 분비 경향은 도 10에 제시된다. CAR-T 주입 그룹에서, 다양한 인간 사이토카인(IL-2, TNF-α, IFN-γ)의 분비는 말초 혈액에서 검출되었고, 사이토카인의 분비량은 종양 부피의 감소와 함께 점진적으로 감소되었는데, 이는 CAR-T이 종양 세포에 대한 현저한 활성화 반응을 생성하는 것을 증명하였다.
[ 실시예 6a: 마우스 종양 모델]
NSG 마우스 (NOD scid IL2Rγnull)에게 1E7/마우스의 Lovo 세포 (CCL229, ATCC)를 피하로 접종하여 200mm3-300mm3 부피의 종양을 형성시켰다. 종양을 대조군으로서 PBMC와 함께 주사하였고, FM4(VL→VH)-BBz, 및 특이적 그룹은 다음과 같다:
Figure 112019020880710-pct00010
PBMC 또는 FM4BBz T 세포로 수혈된 NSG 마우스를 꼬리 혈관(tail vein)을 통해 40 μl (3일째 및 7일째)를 채혈했고, 시료를 동일한 부피의 PBS에 재현탁 및 원심분리하였고, 상청액을 사이토카인 방출 검정 [BD 사이토메트릭 비드 검정(BD Cytometric Bead Array)]에 이용하였다. 결과는 도 14에 제시된다.
도 14에 제시된 바와 같이, 고용량 또는 저용량 FM4BBz-수혈 그룹 모두에서, IFNγ가 말초 혈액에서 검출되었는데, 이는 FM4BBz가 종양 세포를 접촉하였고, 사이토카인의 방출을 야기한 반면, 대조 그룹에서는 PBMC가 사이토 카인의 방출을 유도하지 않았다는 것을 제시하였다(FM4BBzH/L vs. PBMC 그룹, p 값 <0.001). 종양 부피를 35일 동안 주 2회 측정하였고, 종양 성장 곡선이 도 15에 제시된다.
도 15에 제시된 바와 같이, 고용량 및 저용량 FM4BBz 그룹 모두가 종양 성장에 대한 현저한 저해를 보이는데, 이는 FM4BBz가 종양을 사멸시키는 효과를 가지는 것을 제시한다.
[ 실시예 7: FM4 ( VL → VH ) - BBz 렌티바이러스를 이용한 NK92 세포의 감염]
NK92 세포를 20% FBS, 150 IU/ml hIL-2를 함유한 1640 배지에서 배양시켰다. 실시예 3의 방법에 따라서, NK92 세포주를 FM4( VL → VH )-BBz CAR 바이러스로 감염시켰고, 10일 동안 지속해서 배양시켰다. FM4(VL→VH)-BBz-NK92 세포를 사멸 실험(killing experiment) 및 사이토카인 방출 검정에 이용하였고, 결과를 도 12 및 도 13에 제시하였다.
[ 실시예 8: 항체-세포 결합 검정]
항체 FM2, FM4, FM5, 및 FM6를 1% BSA를 함유하는 PBS 완충액으로 희석시켰고, SW620-CEA 또는 CRYPT 세포와 1시간 동안 실온에서 배양시켰고 (최종 농도: 50 μg/ml, 5 μg/ml, 0.5 μg/ml, 0.05 μg/ml, 0.005 μg/ml, 0.0005 μg/ml); 세포를 1% BSA를 함유하는 PBS 완충액으로 2회 세척한 다음, 고트 항 마우스 IgG-APC(Goat Anti Mouse IgG-APC)와 함께 1시간 동안 배양시켰으며; 세포를 1% BSA를 함유하는 PBS 완충액으로 2회 세척하였고, PBS 완충액에서 재현탁하였으며; 세포의 APC 형광 값(fluorescence value)을 BD Accuri C6 FACS를 이용하여 판독하였다.
중간 형광 값(median fluorescence value, MFI)을 세로 좌표로 이용하고 항체 농도를 (μg/ml) 가로 좌표로 이용하여, S-곡선을 로지스틱 방정식(logistic equation)을 이용해 피팅하여 항체 결합 EC50를 계산하였다, 결과는 하기 표에 제시된다:
[표 6]
Figure 112019020880710-pct00011
[결론]
SW620-CEA는 SW620 세포주 (CEACAM5)에서 과발현된 CEA이고, 이의 표면 CEA는 비-글리코실화 상태이다; CRYPT는 글리코실화된 CEA를 발현하는 종양 세포주이다.
항체-세포 결합 검정에 따라 계산된 항체의 EC50값으로부터, 항체 FM4가 글리코실화된 CEA에 특이적으로 결합하고, 높은 특이성 [선택성있음(selective) > 100배)]을 가진다는 것을 결론 내릴 수 있다.
SEQUENCE LISTING <110> The fourth military medical university; Shanghai Genechem CO., LTD <120> Single-chain antibody specifically binding MG7, highly glycosylated CEA and use thereof in detection and therapy <130> IEC160056PCT <160> 180 <170> PatentIn version 3.5 <210> 1 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 1 Gly Phe Thr Phe Ser Arg Tyr 1 5 <210> 2 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 2 Ser Asn Ser Gly Ser Tyr 1 5 <210> 3 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 3 Gly Ser Pro 1 <210> 4 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 4 Gly Ala Ser Glu Asn Ile Tyr Gly Ala Leu Asn 1 5 10 <210> 5 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 5 Gly Ala Thr Lys Leu Ala Asp 1 5 <210> 6 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 6 Gln Asn Val Leu Ser Lys Pro Tyr Ala 1 5 <210> 7 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 7 Gly Tyr Thr Phe Ser Thr Tyr 1 5 <210> 8 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 8 Tyr Pro Gly Asp Gly Asp 1 5 <210> 9 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 9 Gly Gly Leu Tyr Tyr Gly Tyr Asp Ile Ala Tyr 1 5 10 <210> 10 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 10 Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu 1 5 10 15 <210> 11 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 11 Lys Val Ser Asn Arg Phe Ser 1 5 <210> 12 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 12 Phe Gln Gly Ser His Val Pro Phe Thr 1 5 <210> 13 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 13 Gly Phe Thr Phe Thr Asp Tyr 1 5 <210> 14 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 14 Arg Asn Lys Val Asn Gly Asp Thr 1 5 <210> 15 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 15 Asp Lys Gly Ile Ala Tyr Tyr Phe Asp Tyr 1 5 10 <210> 16 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 16 Arg Ala Ser Ser Ser Val Ser Tyr Ile His 1 5 10 <210> 17 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 17 Gly Thr Ser Asn Leu Ala Ser 1 5 <210> 18 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 18 Gln Gln Trp Ser Ser Asn Leu Ser Thr 1 5 <210> 19 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 19 Gly Phe Ser Leu Thr Ser Tyr 1 5 <210> 20 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 20 Trp Thr Gly Gly Gly 1 5 <210> 21 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 21 Gly Val Tyr Tyr Phe Asp Tyr 1 5 <210> 22 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 22 Lys Ala Ser Gln Asp Val Thr Thr Ala Val Ala 1 5 10 <210> 23 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 23 Trp Ala Ser Thr Arg His Thr 1 5 <210> 24 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 24 Gln Gln Tyr Tyr Arg Thr Pro Arg Thr 1 5 <210> 25 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 25 Gly Tyr Thr Phe Asn Asp Tyr Asn Met Asp Tyr 1 5 10 <210> 26 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 26 Asn Pro Asn Tyr Asp Ser 1 5 <210> 27 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 27 Arg Asp Tyr Asp Gly Arg Arg Gly Ala Trp Phe Ser Tyr 1 5 10 <210> 28 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 28 Thr Ala Ser Ser Ser Val Ser Tyr Met Tyr Trp Tyr 1 5 10 <210> 29 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 29 Leu Thr Ser Asn Leu Ala Ser 1 5 <210> 30 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 30 Gln Gln Trp Asp Ser Asn Pro Leu Thr 1 5 <210> 31 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 31 Gly Val Gln Cys Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val 1 5 10 15 Lys Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr 20 25 30 Phe Ser Arg Tyr Thr Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg 35 40 45 Leu Glu Trp Val Ala Thr Ile Ser Asn Ser Gly Ser Tyr Thr Tyr Tyr 50 55 60 Arg Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys 65 70 75 80 Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala 85 90 95 Met Tyr Tyr Cys Thr Arg Gly Ser Pro Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ala 115 <210> 32 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 32 Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Ala 20 25 30 Leu Asn Trp Tyr Gln Arg Lys Gln Gly Lys Ser Pro Gln Leu Leu Ile 35 40 45 Tyr Gly Ala Thr Lys Leu Ala Asp Gly Met Ser Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Asn Arg Gln Tyr Ser Leu Lys Ile Ser Ser Leu His Pro 65 70 75 80 Asp Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Lys Pro Tyr 85 90 95 Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 33 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 33 Glu Val Lys Leu Gln Gln Ser Gly Ala Asp Leu Ala Thr Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Thr Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Thr Ile Tyr Pro Gly Asp Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala His 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Leu Tyr Tyr Gly Tyr Asp Ile Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ala 115 120 <210> 34 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 34 Asp Ile Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Pro Leu Ile Lys Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 35 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 35 Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ile Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Asn Trp Val Arg Gln Ser Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Val Asn Gly Asp Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Thr Leu Arg Thr Glu Asp Ser Ala Thr Tyr 85 90 95 Tyr Cys Ala Arg Asp Lys Gly Ile Ala Tyr Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Leu Thr Val Ser Ser 115 120 <210> 36 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 36 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Phe Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile His 35 40 45 Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Leu Ser Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 37 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 37 Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Asn Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr 20 25 30 Ala Ile Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Ile Ile Trp Thr Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Arg Tyr Tyr Cys Ala 85 90 95 Ser Gly Val Tyr Tyr Phe Asp Tyr Trp Gly Leu Gly Thr Thr Leu Thr 100 105 110 Val Ser Ser 115 <210> 38 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 38 Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Thr Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Val Leu Ile 35 40 45 Phe Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln Tyr Tyr Arg Thr Pro Arg 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 39 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 39 Glu Val Lys Leu Gln Glu Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Asn Asp Tyr 20 25 30 Asn Met Asp Tyr Leu Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asp Ile Asn Pro Asn Tyr Asp Ser Thr Ile Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Asp Tyr Asp Gly Arg Arg Gly Ala Trp Phe Ser Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ala 115 120 <210> 40 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 40 Gln Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Val Thr Cys Thr Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Tyr Trp Tyr Gln Gln Lys Pro Arg Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Thr Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Asp Ser Asn Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 41 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 41 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> 42 <211> 348 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 42 ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60 tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120 gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180 tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240 aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300 acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgca 348 <210> 43 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 43 gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60 atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120 ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180 aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240 gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300 gggaccaaac tggaaataaa a 321 <210> 44 <211> 360 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 44 gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120 cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180 actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240 atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300 ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360 <210> 45 <211> 336 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 45 gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60 atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120 tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240 agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300 ttcacgttcg gctcggggac aaagttggaa ataaaa 336 <210> 46 <211> 363 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 46 gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60 tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120 ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180 gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240 ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300 gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360 tca 363 <210> 47 <211> 318 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 47 caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60 atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120 tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180 ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240 gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300 accaagctgg aaataaaa 318 <210> 48 <211> 345 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 48 caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60 acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120 ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180 tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240 aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300 tactttgact actggggcct aggcaccact ctcacagtct cctca 345 <210> 49 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 49 gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60 atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120 gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180 cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240 gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300 ggcaccaaac tggaaatcaa a 321 <210> 50 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 50 gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60 tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120 catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180 aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240 atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300 tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360 tctgca 366 <210> 51 <211> 318 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 51 caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60 gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120 tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180 ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240 gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300 accaaactgg agctgaaa 318 <210> 52 <211> 135 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 52 accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60 tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120 gacttcgcct gtgat 135 <210> 53 <211> 117 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 53 attgaagtta tgtatcctcc tccttaccta gacaatgaga agagcaatgg aaccattatc 60 catgtgaaag ggaaacacct ttgtccaagt cccctatttc ccggaccttc taagccc 117 <210> 54 <211> 72 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 54 atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 60 accctttact gc 72 <210> 55 <211> 81 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 55 ttttgggtgc tggtggtggt tgggggagtc ctggcttgct atagcttgct agtaacagtg 60 gcctttatta ttttctgggt g 81 <210> 56 <211> 123 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 56 aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 60 gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 120 tcc 123 <210> 57 <211> 123 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 57 aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 60 actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120 gaa 123 <210> 58 <211> 342 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 58 ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 60 ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga caagagacgt 120 ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga aggcctgtac 180 aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 240 cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 300 acctacgacg cccttcacat gcaggccctg ccccctcgct aa 342 <210> 59 <211> 714 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 59 ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60 tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120 gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180 tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240 aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300 acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360 tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420 tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480 tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540 ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600 cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660 aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaa 714 <210> 60 <211> 741 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 60 gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120 cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180 actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240 atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300 ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360 ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420 caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480 agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540 ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600 aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660 gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720 gggacaaagt tggaaataaa a 741 <210> 61 <211> 726 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 61 gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60 tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120 ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180 gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240 ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300 gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360 tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420 tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480 gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540 ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600 gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660 tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720 ataaaa 726 <210> 62 <211> 711 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 62 caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60 acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120 ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180 tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240 aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300 tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360 ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420 atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480 actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540 gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600 tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660 tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa a 711 <210> 63 <211> 729 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 63 gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60 tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120 catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180 aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240 atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300 tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360 tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420 ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480 actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540 aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600 agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660 acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720 gagctgaaa 729 <210> 64 <211> 714 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 64 gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60 atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120 ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180 aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240 gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300 gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420 ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480 tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540 ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600 gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660 tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgca 714 <210> 65 <211> 741 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 65 gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60 atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120 tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240 agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300 ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360 gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420 cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480 atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540 ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600 aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660 tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720 actctggtca ctgtctctgc a 741 <210> 66 <211> 726 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 66 caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60 atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120 tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180 ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240 gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300 accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420 ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480 tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540 acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600 atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660 agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720 tcctca 726 <210> 67 <211> 711 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 67 gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60 atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120 gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180 cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240 gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300 ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420 tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480 cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540 tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600 ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660 gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc a 711 <210> 68 <211> 729 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 68 caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60 gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120 tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180 ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240 gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300 accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420 atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480 agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540 tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600 tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660 gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720 gtctctgca 729 <210> 69 <211> 2169 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 69 ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60 tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120 gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180 tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240 aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300 acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360 tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420 tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480 tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540 ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600 cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660 aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaaaccacg 720 acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 780 cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 840 gcctgtgata tctacatctg ggcgcccttg gccgggactt gtggggtcct tctcctgtca 900 ctggttatca ccctttactg caaacggggc agaaagaaac tcctgtatat attcaaacaa 960 ccatttatga gaccagtaca aactactcaa gaggaagatg gctgtagctg ccgatttcca 1020 gaagaagaag aaggaggatg tgaactgaga gtgaagttca gcaggagcgc agacgccccc 1080 gcgtaccagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1140 tacgatgttt tggacaagag acgtggccgg gaccctgaga tggggggaaa gccgagaagg 1200 aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1260 agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1320 ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1380 cgcggatctg gcgccaccaa cttctctctg ctgaagcagg ccggcgacgt ggaggagaac 1440 ccaggcccaa tggtgagcaa gggcgaggag ctgttcaccg gggtggtgcc catcctggtc 1500 gagctggacg gcgacgtaaa cggccacaag ttcagcgtgt ccggcgaggg cgagggcgat 1560 gccacctacg gcaagctgac cctgaagttc atctgcacca ccggcaagct gcccgtgccc 1620 tggcccaccc tcgtgaccac cctgacctac ggcgtgcagt gcttcagccg ctaccccgac 1680 cacatgaagc agcacgactt cttcaagtcc gccatgcccg aaggctacgt ccaggagcgc 1740 accatcttct tcaaggacga cggcaactac aagacccgcg ccgaggtgaa gttcgagggc 1800 gacaccctgg tgaaccgcat cgagctgaag ggcatcgact tcaaggagga cggcaacatc 1860 ctggggcaca agctggagta caactacaac agccacaacg tctatatcat ggccgacaag 1920 cagaagaacg gcatcaaggt gaacttcaag atccgccaca acatcgagga cggcagcgtg 1980 cagctcgccg accactacca gcagaacacc cccatcggcg acggccccgt gctgctgccc 2040 gacaaccact acctgagcac ccagtccgcc ctgagcaaag accccaacga gaagcgcgat 2100 cacatggtcc tgctggagtt cgtgaccgcc gccgggatca ctctcggcat ggacgagctg 2160 tacaagtaa 2169 <210> 70 <211> 2169 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 70 gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60 atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120 ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180 aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240 gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300 gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420 ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480 tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540 ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600 gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660 tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgcaaccacg 720 acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 780 cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 840 gcctgtgata tctacatctg ggcgcccttg gccgggactt gtggggtcct tctcctgtca 900 ctggttatca ccctttactg caaacggggc agaaagaaac tcctgtatat attcaaacaa 960 ccatttatga gaccagtaca aactactcaa gaggaagatg gctgtagctg ccgatttcca 1020 gaagaagaag aaggaggatg tgaactgaga gtgaagttca gcaggagcgc agacgccccc 1080 gcgtaccagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1140 tacgatgttt tggacaagag acgtggccgg gaccctgaga tggggggaaa gccgagaagg 1200 aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1260 agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1320 ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1380 cgcggatctg gcgccaccaa cttctctctg ctgaagcagg ccggcgacgt ggaggagaac 1440 ccaggcccaa tggtgagcaa gggcgaggag ctgttcaccg gggtggtgcc catcctggtc 1500 gagctggacg gcgacgtaaa cggccacaag ttcagcgtgt ccggcgaggg cgagggcgat 1560 gccacctacg gcaagctgac cctgaagttc atctgcacca ccggcaagct gcccgtgccc 1620 tggcccaccc tcgtgaccac cctgacctac ggcgtgcagt gcttcagccg ctaccccgac 1680 cacatgaagc agcacgactt cttcaagtcc gccatgcccg aaggctacgt ccaggagcgc 1740 accatcttct tcaaggacga cggcaactac aagacccgcg ccgaggtgaa gttcgagggc 1800 gacaccctgg tgaaccgcat cgagctgaag ggcatcgact tcaaggagga cggcaacatc 1860 ctggggcaca agctggagta caactacaac agccacaacg tctatatcat ggccgacaag 1920 cagaagaacg gcatcaaggt gaacttcaag atccgccaca acatcgagga cggcagcgtg 1980 cagctcgccg accactacca gcagaacacc cccatcggcg acggccccgt gctgctgccc 2040 gacaaccact acctgagcac ccagtccgcc ctgagcaaag accccaacga gaagcgcgat 2100 cacatggtcc tgctggagtt cgtgaccgcc gccgggatca ctctcggcat ggacgagctg 2160 tacaagtaa 2169 <210> 71 <211> 2196 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 71 gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120 cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180 actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240 atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300 ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360 ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420 caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480 agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540 ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600 aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660 gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720 gggacaaagt tggaaataaa aaccacgacg ccagcgccgc gaccaccaac accggcgccc 780 accatcgcgt cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcggggggc 840 gcagtgcaca cgagggggct ggacttcgcc tgtgatatct acatctgggc gcccttggcc 900 gggacttgtg gggtccttct cctgtcactg gttatcaccc tttactgcaa acggggcaga 960 aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 1020 gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 1080 aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 1140 gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 1200 cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 1260 cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1320 ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1380 gcccttcaca tgcaggccct gccccctcgc ggatctggcg ccaccaactt ctctctgctg 1440 aagcaggccg gcgacgtgga ggagaaccca ggcccaatgg tgagcaaggg cgaggagctg 1500 ttcaccgggg tggtgcccat cctggtcgag ctggacggcg acgtaaacgg ccacaagttc 1560 agcgtgtccg gcgagggcga gggcgatgcc acctacggca agctgaccct gaagttcatc 1620 tgcaccaccg gcaagctgcc cgtgccctgg cccaccctcg tgaccaccct gacctacggc 1680 gtgcagtgct tcagccgcta ccccgaccac atgaagcagc acgacttctt caagtccgcc 1740 atgcccgaag gctacgtcca ggagcgcacc atcttcttca aggacgacgg caactacaag 1800 acccgcgccg aggtgaagtt cgagggcgac accctggtga accgcatcga gctgaagggc 1860 atcgacttca aggaggacgg caacatcctg gggcacaagc tggagtacaa ctacaacagc 1920 cacaacgtct atatcatggc cgacaagcag aagaacggca tcaaggtgaa cttcaagatc 1980 cgccacaaca tcgaggacgg cagcgtgcag ctcgccgacc actaccagca gaacaccccc 2040 atcggcgacg gccccgtgct gctgcccgac aaccactacc tgagcaccca gtccgccctg 2100 agcaaagacc ccaacgagaa gcgcgatcac atggtcctgc tggagttcgt gaccgccgcc 2160 gggatcactc tcggcatgga cgagctgtac aagtaa 2196 <210> 72 <211> 2196 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 72 gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60 atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120 tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240 agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300 ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360 gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420 cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480 atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540 ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600 aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660 tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720 actctggtca ctgtctctgc aaccacgacg ccagcgccgc gaccaccaac accggcgccc 780 accatcgcgt cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcggggggc 840 gcagtgcaca cgagggggct ggacttcgcc tgtgatatct acatctgggc gcccttggcc 900 gggacttgtg gggtccttct cctgtcactg gttatcaccc tttactgcaa acggggcaga 960 aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 1020 gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 1080 aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 1140 gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 1200 cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 1260 cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1320 ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1380 gcccttcaca tgcaggccct gccccctcgc ggatctggcg ccaccaactt ctctctgctg 1440 aagcaggccg gcgacgtgga ggagaaccca ggcccaatgg tgagcaaggg cgaggagctg 1500 ttcaccgggg tggtgcccat cctggtcgag ctggacggcg acgtaaacgg ccacaagttc 1560 agcgtgtccg gcgagggcga gggcgatgcc acctacggca agctgaccct gaagttcatc 1620 tgcaccaccg gcaagctgcc cgtgccctgg cccaccctcg tgaccaccct gacctacggc 1680 gtgcagtgct tcagccgcta ccccgaccac atgaagcagc acgacttctt caagtccgcc 1740 atgcccgaag gctacgtcca ggagcgcacc atcttcttca aggacgacgg caactacaag 1800 acccgcgccg aggtgaagtt cgagggcgac accctggtga accgcatcga gctgaagggc 1860 atcgacttca aggaggacgg caacatcctg gggcacaagc tggagtacaa ctacaacagc 1920 cacaacgtct atatcatggc cgacaagcag aagaacggca tcaaggtgaa cttcaagatc 1980 cgccacaaca tcgaggacgg cagcgtgcag ctcgccgacc actaccagca gaacaccccc 2040 atcggcgacg gccccgtgct gctgcccgac aaccactacc tgagcaccca gtccgccctg 2100 agcaaagacc ccaacgagaa gcgcgatcac atggtcctgc tggagttcgt gaccgccgcc 2160 gggatcactc tcggcatgga cgagctgtac aagtaa 2196 <210> 73 <211> 2181 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 73 gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60 tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120 ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180 gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240 ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300 gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360 tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420 tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480 gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540 ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600 gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660 tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720 ataaaaacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 780 cccctgtccc tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg 840 gggctggact tcgcctgtga tatctacatc tgggcgccct tggccgggac ttgtggggtc 900 cttctcctgt cactggttat caccctttac tgcaaacggg gcagaaagaa actcctgtat 960 atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1020 tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1080 gcagacgccc ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga 1140 cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 1200 aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 1260 gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1320 ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1380 gccctgcccc ctcgcggatc tggcgccacc aacttctctc tgctgaagca ggccggcgac 1440 gtggaggaga acccaggccc aatggtgagc aagggcgagg agctgttcac cggggtggtg 1500 cccatcctgg tcgagctgga cggcgacgta aacggccaca agttcagcgt gtccggcgag 1560 ggcgagggcg atgccaccta cggcaagctg accctgaagt tcatctgcac caccggcaag 1620 ctgcccgtgc cctggcccac cctcgtgacc accctgacct acggcgtgca gtgcttcagc 1680 cgctaccccg accacatgaa gcagcacgac ttcttcaagt ccgccatgcc cgaaggctac 1740 gtccaggagc gcaccatctt cttcaaggac gacggcaact acaagacccg cgccgaggtg 1800 aagttcgagg gcgacaccct ggtgaaccgc atcgagctga agggcatcga cttcaaggag 1860 gacggcaaca tcctggggca caagctggag tacaactaca acagccacaa cgtctatatc 1920 atggccgaca agcagaagaa cggcatcaag gtgaacttca agatccgcca caacatcgag 1980 gacggcagcg tgcagctcgc cgaccactac cagcagaaca cccccatcgg cgacggcccc 2040 gtgctgctgc ccgacaacca ctacctgagc acccagtccg ccctgagcaa agaccccaac 2100 gagaagcgcg atcacatggt cctgctggag ttcgtgaccg ccgccgggat cactctcggc 2160 atggacgagc tgtacaagta a 2181 <210> 74 <211> 2181 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 74 caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60 atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120 tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180 ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240 gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300 accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420 ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480 tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540 acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600 atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660 agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720 tcctcaacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 780 cccctgtccc tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg 840 gggctggact tcgcctgtga tatctacatc tgggcgccct tggccgggac ttgtggggtc 900 cttctcctgt cactggttat caccctttac tgcaaacggg gcagaaagaa actcctgtat 960 atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1020 tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1080 gcagacgccc ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga 1140 cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 1200 aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 1260 gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1320 ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1380 gccctgcccc ctcgcggatc tggcgccacc aacttctctc tgctgaagca ggccggcgac 1440 gtggaggaga acccaggccc aatggtgagc aagggcgagg agctgttcac cggggtggtg 1500 cccatcctgg tcgagctgga cggcgacgta aacggccaca agttcagcgt gtccggcgag 1560 ggcgagggcg atgccaccta cggcaagctg accctgaagt tcatctgcac caccggcaag 1620 ctgcccgtgc cctggcccac cctcgtgacc accctgacct acggcgtgca gtgcttcagc 1680 cgctaccccg accacatgaa gcagcacgac ttcttcaagt ccgccatgcc cgaaggctac 1740 gtccaggagc gcaccatctt cttcaaggac gacggcaact acaagacccg cgccgaggtg 1800 aagttcgagg gcgacaccct ggtgaaccgc atcgagctga agggcatcga cttcaaggag 1860 gacggcaaca tcctggggca caagctggag tacaactaca acagccacaa cgtctatatc 1920 atggccgaca agcagaagaa cggcatcaag gtgaacttca agatccgcca caacatcgag 1980 gacggcagcg tgcagctcgc cgaccactac cagcagaaca cccccatcgg cgacggcccc 2040 gtgctgctgc ccgacaacca ctacctgagc acccagtccg ccctgagcaa agaccccaac 2100 gagaagcgcg atcacatggt cctgctggag ttcgtgaccg ccgccgggat cactctcggc 2160 atggacgagc tgtacaagta a 2181 <210> 75 <211> 2166 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 75 caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60 acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120 ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180 tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240 aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300 tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360 ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420 atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480 actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540 gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600 tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660 tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa aaccacgacg 720 ccagcgccgc gaccaccaac accggcgccc accatcgcgt cgcagcccct gtccctgcgc 780 ccagaggcgt gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 840 tgtgatatct acatctgggc gcccttggcc gggacttgtg gggtccttct cctgtcactg 900 gttatcaccc tttactgcaa acggggcaga aagaaactcc tgtatatatt caaacaacca 960 tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1020 gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 1080 taccagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 1140 gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 1200 aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 1260 gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1320 ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1380 ggatctggcg ccaccaactt ctctctgctg aagcaggccg gcgacgtgga ggagaaccca 1440 ggcccaatgg tgagcaaggg cgaggagctg ttcaccgggg tggtgcccat cctggtcgag 1500 ctggacggcg acgtaaacgg ccacaagttc agcgtgtccg gcgagggcga gggcgatgcc 1560 acctacggca agctgaccct gaagttcatc tgcaccaccg gcaagctgcc cgtgccctgg 1620 cccaccctcg tgaccaccct gacctacggc gtgcagtgct tcagccgcta ccccgaccac 1680 atgaagcagc acgacttctt caagtccgcc atgcccgaag gctacgtcca ggagcgcacc 1740 atcttcttca aggacgacgg caactacaag acccgcgccg aggtgaagtt cgagggcgac 1800 accctggtga accgcatcga gctgaagggc atcgacttca aggaggacgg caacatcctg 1860 gggcacaagc tggagtacaa ctacaacagc cacaacgtct atatcatggc cgacaagcag 1920 aagaacggca tcaaggtgaa cttcaagatc cgccacaaca tcgaggacgg cagcgtgcag 1980 ctcgccgacc actaccagca gaacaccccc atcggcgacg gccccgtgct gctgcccgac 2040 aaccactacc tgagcaccca gtccgccctg agcaaagacc ccaacgagaa gcgcgatcac 2100 atggtcctgc tggagttcgt gaccgccgcc gggatcactc tcggcatgga cgagctgtac 2160 aagtaa 2166 <210> 76 <211> 2166 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 76 gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60 atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120 gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180 cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240 gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300 ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420 tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480 cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540 tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600 ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660 gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc aaccacgacg 720 ccagcgccgc gaccaccaac accggcgccc accatcgcgt cgcagcccct gtccctgcgc 780 ccagaggcgt gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 840 tgtgatatct acatctgggc gcccttggcc gggacttgtg gggtccttct cctgtcactg 900 gttatcaccc tttactgcaa acggggcaga aagaaactcc tgtatatatt caaacaacca 960 tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1020 gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 1080 taccagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 1140 gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 1200 aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 1260 gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1320 ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1380 ggatctggcg ccaccaactt ctctctgctg aagcaggccg gcgacgtgga ggagaaccca 1440 ggcccaatgg tgagcaaggg cgaggagctg ttcaccgggg tggtgcccat cctggtcgag 1500 ctggacggcg acgtaaacgg ccacaagttc agcgtgtccg gcgagggcga gggcgatgcc 1560 acctacggca agctgaccct gaagttcatc tgcaccaccg gcaagctgcc cgtgccctgg 1620 cccaccctcg tgaccaccct gacctacggc gtgcagtgct tcagccgcta ccccgaccac 1680 atgaagcagc acgacttctt caagtccgcc atgcccgaag gctacgtcca ggagcgcacc 1740 atcttcttca aggacgacgg caactacaag acccgcgccg aggtgaagtt cgagggcgac 1800 accctggtga accgcatcga gctgaagggc atcgacttca aggaggacgg caacatcctg 1860 gggcacaagc tggagtacaa ctacaacagc cacaacgtct atatcatggc cgacaagcag 1920 aagaacggca tcaaggtgaa cttcaagatc cgccacaaca tcgaggacgg cagcgtgcag 1980 ctcgccgacc actaccagca gaacaccccc atcggcgacg gccccgtgct gctgcccgac 2040 aaccactacc tgagcaccca gtccgccctg agcaaagacc ccaacgagaa gcgcgatcac 2100 atggtcctgc tggagttcgt gaccgccgcc gggatcactc tcggcatgga cgagctgtac 2160 aagtaa 2166 <210> 77 <211> 2184 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 77 gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60 tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120 catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180 aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240 atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300 tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360 tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420 ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480 actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540 aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600 agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660 acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720 gagctgaaaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 780 cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 840 agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 900 gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 960 tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1020 agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1080 agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 1140 ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1200 ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1260 atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1320 gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1380 caggccctgc cccctcgcgg atctggcgcc accaacttct ctctgctgaa gcaggccggc 1440 gacgtggagg agaacccagg cccaatggtg agcaagggcg aggagctgtt caccggggtg 1500 gtgcccatcc tggtcgagct ggacggcgac gtaaacggcc acaagttcag cgtgtccggc 1560 gagggcgagg gcgatgccac ctacggcaag ctgaccctga agttcatctg caccaccggc 1620 aagctgcccg tgccctggcc caccctcgtg accaccctga cctacggcgt gcagtgcttc 1680 agccgctacc ccgaccacat gaagcagcac gacttcttca agtccgccat gcccgaaggc 1740 tacgtccagg agcgcaccat cttcttcaag gacgacggca actacaagac ccgcgccgag 1800 gtgaagttcg agggcgacac cctggtgaac cgcatcgagc tgaagggcat cgacttcaag 1860 gaggacggca acatcctggg gcacaagctg gagtacaact acaacagcca caacgtctat 1920 atcatggccg acaagcagaa gaacggcatc aaggtgaact tcaagatccg ccacaacatc 1980 gaggacggca gcgtgcagct cgccgaccac taccagcaga acacccccat cggcgacggc 2040 cccgtgctgc tgcccgacaa ccactacctg agcacccagt ccgccctgag caaagacccc 2100 aacgagaagc gcgatcacat ggtcctgctg gagttcgtga ccgccgccgg gatcactctc 2160 ggcatggacg agctgtacaa gtaa 2184 <210> 78 <211> 2184 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 78 caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60 gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120 tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180 ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240 gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300 accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420 atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480 agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540 tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600 tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660 gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720 gtctctgcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 780 cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 840 agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 900 gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 960 tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1020 agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1080 agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 1140 ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1200 ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1260 atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1320 gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1380 caggccctgc cccctcgcgg atctggcgcc accaacttct ctctgctgaa gcaggccggc 1440 gacgtggagg agaacccagg cccaatggtg agcaagggcg aggagctgtt caccggggtg 1500 gtgcccatcc tggtcgagct ggacggcgac gtaaacggcc acaagttcag cgtgtccggc 1560 gagggcgagg gcgatgccac ctacggcaag ctgaccctga agttcatctg caccaccggc 1620 aagctgcccg tgccctggcc caccctcgtg accaccctga cctacggcgt gcagtgcttc 1680 agccgctacc ccgaccacat gaagcagcac gacttcttca agtccgccat gcccgaaggc 1740 tacgtccagg agcgcaccat cttcttcaag gacgacggca actacaagac ccgcgccgag 1800 gtgaagttcg agggcgacac cctggtgaac cgcatcgagc tgaagggcat cgacttcaag 1860 gaggacggca acatcctggg gcacaagctg gagtacaact acaacagcca caacgtctat 1920 atcatggccg acaagcagaa gaacggcatc aaggtgaact tcaagatccg ccacaacatc 1980 gaggacggca gcgtgcagct cgccgaccac taccagcaga acacccccat cggcgacggc 2040 cccgtgctgc tgcccgacaa ccactacctg agcacccagt ccgccctgag caaagacccc 2100 aacgagaagc gcgatcacat ggtcctgctg gagttcgtga ccgccgccgg gatcactctc 2160 ggcatggacg agctgtacaa gtaa 2184 <210> 79 <211> 1386 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 79 ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60 tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120 gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180 tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240 aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300 acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360 tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420 tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480 tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540 ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600 cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660 aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaaaccacg 720 acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 780 cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 840 gcctgtgata tctacatctg ggcgcccttg gccgggactt gtggggtcct tctcctgtca 900 ctggttatca ccctttactg caaacggggc agaaagaaac tcctgtatat attcaaacaa 960 ccatttatga gaccagtaca aactactcaa gaggaagatg gctgtagctg ccgatttcca 1020 gaagaagaag aaggaggatg tgaactgaga gtgaagttca gcaggagcgc agacgccccc 1080 gcgtaccagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1140 tacgatgttt tggacaagag acgtggccgg gaccctgaga tggggggaaa gccgagaagg 1200 aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1260 agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1320 ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1380 cgctaa 1386 <210> 80 <211> 1386 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 80 gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60 atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120 ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180 aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240 gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300 gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420 ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480 tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540 ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600 gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660 tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgcaaccacg 720 acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 780 cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 840 gcctgtgata tctacatctg ggcgcccttg gccgggactt gtggggtcct tctcctgtca 900 ctggttatca ccctttactg caaacggggc agaaagaaac tcctgtatat attcaaacaa 960 ccatttatga gaccagtaca aactactcaa gaggaagatg gctgtagctg ccgatttcca 1020 gaagaagaag aaggaggatg tgaactgaga gtgaagttca gcaggagcgc agacgccccc 1080 gcgtaccagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1140 tacgatgttt tggacaagag acgtggccgg gaccctgaga tggggggaaa gccgagaagg 1200 aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1260 agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1320 ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1380 cgctaa 1386 <210> 81 <211> 1413 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 81 gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120 cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180 actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240 atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300 ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360 ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420 caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480 agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540 ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600 aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660 gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720 gggacaaagt tggaaataaa aaccacgacg ccagcgccgc gaccaccaac accggcgccc 780 accatcgcgt cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcggggggc 840 gcagtgcaca cgagggggct ggacttcgcc tgtgatatct acatctgggc gcccttggcc 900 gggacttgtg gggtccttct cctgtcactg gttatcaccc tttactgcaa acggggcaga 960 aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 1020 gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 1080 aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 1140 gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 1200 cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 1260 cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1320 ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1380 gcccttcaca tgcaggccct gccccctcgc taa 1413 <210> 82 <211> 1413 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 82 gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60 atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120 tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240 agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300 ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360 gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420 cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480 atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540 ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600 aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660 tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720 actctggtca ctgtctctgc aaccacgacg ccagcgccgc gaccaccaac accggcgccc 780 accatcgcgt cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcggggggc 840 gcagtgcaca cgagggggct ggacttcgcc tgtgatatct acatctgggc gcccttggcc 900 gggacttgtg gggtccttct cctgtcactg gttatcaccc tttactgcaa acggggcaga 960 aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 1020 gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 1080 aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 1140 gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 1200 cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 1260 cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1320 ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1380 gcccttcaca tgcaggccct gccccctcgc taa 1413 <210> 83 <211> 1398 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 83 gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60 tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120 ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180 gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240 ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300 gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360 tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420 tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480 gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540 ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600 gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660 tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720 ataaaaacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 780 cccctgtccc tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg 840 gggctggact tcgcctgtga tatctacatc tgggcgccct tggccgggac ttgtggggtc 900 cttctcctgt cactggttat caccctttac tgcaaacggg gcagaaagaa actcctgtat 960 atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1020 tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1080 gcagacgccc ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga 1140 cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 1200 aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 1260 gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1320 ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1380 gccctgcccc ctcgctaa 1398 <210> 84 <211> 1398 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 84 caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60 atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120 tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180 ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240 gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300 accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420 ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480 tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540 acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600 atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660 agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720 tcctcaacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 780 cccctgtccc tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg 840 gggctggact tcgcctgtga tatctacatc tgggcgccct tggccgggac ttgtggggtc 900 cttctcctgt cactggttat caccctttac tgcaaacggg gcagaaagaa actcctgtat 960 atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1020 tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1080 gcagacgccc ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga 1140 cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 1200 aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 1260 gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1320 ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1380 gccctgcccc ctcgctaa 1398 <210> 85 <211> 1383 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 85 caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60 acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120 ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180 tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240 aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300 tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360 ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420 atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480 actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540 gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600 tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660 tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa aaccacgacg 720 ccagcgccgc gaccaccaac accggcgccc accatcgcgt cgcagcccct gtccctgcgc 780 ccagaggcgt gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 840 tgtgatatct acatctgggc gcccttggcc gggacttgtg gggtccttct cctgtcactg 900 gttatcaccc tttactgcaa acggggcaga aagaaactcc tgtatatatt caaacaacca 960 tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1020 gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 1080 taccagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 1140 gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 1200 aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 1260 gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1320 ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1380 taa 1383 <210> 86 <211> 1383 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 86 gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60 atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120 gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180 cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240 gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300 ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420 tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480 cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540 tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600 ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660 gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc aaccacgacg 720 ccagcgccgc gaccaccaac accggcgccc accatcgcgt cgcagcccct gtccctgcgc 780 ccagaggcgt gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 840 tgtgatatct acatctgggc gcccttggcc gggacttgtg gggtccttct cctgtcactg 900 gttatcaccc tttactgcaa acggggcaga aagaaactcc tgtatatatt caaacaacca 960 tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1020 gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 1080 taccagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 1140 gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 1200 aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 1260 gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1320 ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1380 taa 1383 <210> 87 <211> 1401 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 87 gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60 tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120 catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180 aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240 atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300 tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360 tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420 ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480 actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540 aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600 agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660 acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720 gagctgaaaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 780 cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 840 agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 900 gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 960 tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1020 agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1080 agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 1140 ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1200 ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1260 atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1320 gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1380 caggccctgc cccctcgcta a 1401 <210> 88 <211> 1401 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 88 caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60 gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120 tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180 ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240 gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300 accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420 atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480 agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540 tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600 tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660 gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720 gtctctgcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 780 cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 840 agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 900 gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 960 tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1020 agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1080 agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 1140 ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1200 ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1260 atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1320 gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1380 caggccctgc cccctcgcta a 1401 <210> 89 <211> 2160 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 89 ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60 tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120 gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180 tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240 aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300 acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360 tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420 tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480 tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540 ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600 cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660 aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaaattgaa 720 gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780 aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840 ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900 attttctggg tgaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 960 agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1020 gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080 cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140 ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200 caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260 gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320 acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgcggatct 1380 ggcgccacca acttctctct gctgaagcag gccggcgacg tggaggagaa cccaggccca 1440 atggtgagca agggcgagga gctgttcacc ggggtggtgc ccatcctggt cgagctggac 1500 ggcgacgtaa acggccacaa gttcagcgtg tccggcgagg gcgagggcga tgccacctac 1560 ggcaagctga ccctgaagtt catctgcacc accggcaagc tgcccgtgcc ctggcccacc 1620 ctcgtgacca ccctgaccta cggcgtgcag tgcttcagcc gctaccccga ccacatgaag 1680 cagcacgact tcttcaagtc cgccatgccc gaaggctacg tccaggagcg caccatcttc 1740 ttcaaggacg acggcaacta caagacccgc gccgaggtga agttcgaggg cgacaccctg 1800 gtgaaccgca tcgagctgaa gggcatcgac ttcaaggagg acggcaacat cctggggcac 1860 aagctggagt acaactacaa cagccacaac gtctatatca tggccgacaa gcagaagaac 1920 ggcatcaagg tgaacttcaa gatccgccac aacatcgagg acggcagcgt gcagctcgcc 1980 gaccactacc agcagaacac ccccatcggc gacggccccg tgctgctgcc cgacaaccac 2040 tacctgagca cccagtccgc cctgagcaaa gaccccaacg agaagcgcga tcacatggtc 2100 ctgctggagt tcgtgaccgc cgccgggatc actctcggca tggacgagct gtacaagtaa 2160 <210> 90 <211> 2160 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 90 gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60 atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120 ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180 aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240 gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300 gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420 ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480 tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540 ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600 gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660 tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgcaattgaa 720 gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780 aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840 ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900 attttctggg tgaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 960 agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1020 gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080 cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140 ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200 caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260 gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320 acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgcggatct 1380 ggcgccacca acttctctct gctgaagcag gccggcgacg tggaggagaa cccaggccca 1440 atggtgagca agggcgagga gctgttcacc ggggtggtgc ccatcctggt cgagctggac 1500 ggcgacgtaa acggccacaa gttcagcgtg tccggcgagg gcgagggcga tgccacctac 1560 ggcaagctga ccctgaagtt catctgcacc accggcaagc tgcccgtgcc ctggcccacc 1620 ctcgtgacca ccctgaccta cggcgtgcag tgcttcagcc gctaccccga ccacatgaag 1680 cagcacgact tcttcaagtc cgccatgccc gaaggctacg tccaggagcg caccatcttc 1740 ttcaaggacg acggcaacta caagacccgc gccgaggtga agttcgaggg cgacaccctg 1800 gtgaaccgca tcgagctgaa gggcatcgac ttcaaggagg acggcaacat cctggggcac 1860 aagctggagt acaactacaa cagccacaac gtctatatca tggccgacaa gcagaagaac 1920 ggcatcaagg tgaacttcaa gatccgccac aacatcgagg acggcagcgt gcagctcgcc 1980 gaccactacc agcagaacac ccccatcggc gacggccccg tgctgctgcc cgacaaccac 2040 tacctgagca cccagtccgc cctgagcaaa gaccccaacg agaagcgcga tcacatggtc 2100 ctgctggagt tcgtgaccgc cgccgggatc actctcggca tggacgagct gtacaagtaa 2160 <210> 91 <211> 2187 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 91 gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120 cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180 actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240 atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300 ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360 ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420 caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480 agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540 ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600 aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660 gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720 gggacaaagt tggaaataaa aattgaagtt atgtatcctc ctccttacct agacaatgag 780 aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840 cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900 agcttgctag taacagtggc ctttattatt ttctgggtga aacggggcag aaagaaactc 960 ctgtatatat tcaaacaacc atttatgaga ccagtacaaa ctactcaaga ggaagatggc 1020 tgtagctgcc gatttccaga agaagaagaa ggaggatgtg aactgagagt gaagttcagc 1080 aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140 ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200 gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260 aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320 cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380 atgcaggccc tgccccctcg cggatctggc gccaccaact tctctctgct gaagcaggcc 1440 ggcgacgtgg aggagaaccc aggcccaatg gtgagcaagg gcgaggagct gttcaccggg 1500 gtggtgccca tcctggtcga gctggacggc gacgtaaacg gccacaagtt cagcgtgtcc 1560 ggcgagggcg agggcgatgc cacctacggc aagctgaccc tgaagttcat ctgcaccacc 1620 ggcaagctgc ccgtgccctg gcccaccctc gtgaccaccc tgacctacgg cgtgcagtgc 1680 ttcagccgct accccgacca catgaagcag cacgacttct tcaagtccgc catgcccgaa 1740 ggctacgtcc aggagcgcac catcttcttc aaggacgacg gcaactacaa gacccgcgcc 1800 gaggtgaagt tcgagggcga caccctggtg aaccgcatcg agctgaaggg catcgacttc 1860 aaggaggacg gcaacatcct ggggcacaag ctggagtaca actacaacag ccacaacgtc 1920 tatatcatgg ccgacaagca gaagaacggc atcaaggtga acttcaagat ccgccacaac 1980 atcgaggacg gcagcgtgca gctcgccgac cactaccagc agaacacccc catcggcgac 2040 ggccccgtgc tgctgcccga caaccactac ctgagcaccc agtccgccct gagcaaagac 2100 cccaacgaga agcgcgatca catggtcctg ctggagttcg tgaccgccgc cgggatcact 2160 ctcggcatgg acgagctgta caagtaa 2187 <210> 92 <211> 2187 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 92 gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60 atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120 tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240 agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300 ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360 gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420 cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480 atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540 ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600 aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660 tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720 actctggtca ctgtctctgc aattgaagtt atgtatcctc ctccttacct agacaatgag 780 aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840 cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900 agcttgctag taacagtggc ctttattatt ttctgggtga aacggggcag aaagaaactc 960 ctgtatatat tcaaacaacc atttatgaga ccagtacaaa ctactcaaga ggaagatggc 1020 tgtagctgcc gatttccaga agaagaagaa ggaggatgtg aactgagagt gaagttcagc 1080 aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140 ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200 gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260 aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320 cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380 atgcaggccc tgccccctcg cggatctggc gccaccaact tctctctgct gaagcaggcc 1440 ggcgacgtgg aggagaaccc aggcccaatg gtgagcaagg gcgaggagct gttcaccggg 1500 gtggtgccca tcctggtcga gctggacggc gacgtaaacg gccacaagtt cagcgtgtcc 1560 ggcgagggcg agggcgatgc cacctacggc aagctgaccc tgaagttcat ctgcaccacc 1620 ggcaagctgc ccgtgccctg gcccaccctc gtgaccaccc tgacctacgg cgtgcagtgc 1680 ttcagccgct accccgacca catgaagcag cacgacttct tcaagtccgc catgcccgaa 1740 ggctacgtcc aggagcgcac catcttcttc aaggacgacg gcaactacaa gacccgcgcc 1800 gaggtgaagt tcgagggcga caccctggtg aaccgcatcg agctgaaggg catcgacttc 1860 aaggaggacg gcaacatcct ggggcacaag ctggagtaca actacaacag ccacaacgtc 1920 tatatcatgg ccgacaagca gaagaacggc atcaaggtga acttcaagat ccgccacaac 1980 atcgaggacg gcagcgtgca gctcgccgac cactaccagc agaacacccc catcggcgac 2040 ggccccgtgc tgctgcccga caaccactac ctgagcaccc agtccgccct gagcaaagac 2100 cccaacgaga agcgcgatca catggtcctg ctggagttcg tgaccgccgc cgggatcact 2160 ctcggcatgg acgagctgta caagtaa 2187 <210> 93 <211> 2172 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 93 gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60 tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120 ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180 gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240 ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300 gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360 tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420 tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480 gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540 ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600 gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660 tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720 ataaaaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780 attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840 cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900 gtggccttta ttattttctg ggtgaaacgg ggcagaaaga aactcctgta tatattcaaa 960 caaccattta tgagaccagt acaaactact caagaggaag atggctgtag ctgccgattt 1020 ccagaagaag aagaaggagg atgtgaactg agagtgaagt tcagcaggag cgcagacgcc 1080 cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140 gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200 aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260 tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320 cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380 cctcgcggat ctggcgccac caacttctct ctgctgaagc aggccggcga cgtggaggag 1440 aacccaggcc caatggtgag caagggcgag gagctgttca ccggggtggt gcccatcctg 1500 gtcgagctgg acggcgacgt aaacggccac aagttcagcg tgtccggcga gggcgagggc 1560 gatgccacct acggcaagct gaccctgaag ttcatctgca ccaccggcaa gctgcccgtg 1620 ccctggccca ccctcgtgac caccctgacc tacggcgtgc agtgcttcag ccgctacccc 1680 gaccacatga agcagcacga cttcttcaag tccgccatgc ccgaaggcta cgtccaggag 1740 cgcaccatct tcttcaagga cgacggcaac tacaagaccc gcgccgaggt gaagttcgag 1800 ggcgacaccc tggtgaaccg catcgagctg aagggcatcg acttcaagga ggacggcaac 1860 atcctggggc acaagctgga gtacaactac aacagccaca acgtctatat catggccgac 1920 aagcagaaga acggcatcaa ggtgaacttc aagatccgcc acaacatcga ggacggcagc 1980 gtgcagctcg ccgaccacta ccagcagaac acccccatcg gcgacggccc cgtgctgctg 2040 cccgacaacc actacctgag cacccagtcc gccctgagca aagaccccaa cgagaagcgc 2100 gatcacatgg tcctgctgga gttcgtgacc gccgccggga tcactctcgg catggacgag 2160 ctgtacaagt aa 2172 <210> 94 <211> 2172 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 94 caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60 atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120 tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180 ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240 gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300 accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420 ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480 tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540 acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600 atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660 agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720 tcctcaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780 attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840 cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900 gtggccttta ttattttctg ggtgaaacgg ggcagaaaga aactcctgta tatattcaaa 960 caaccattta tgagaccagt acaaactact caagaggaag atggctgtag ctgccgattt 1020 ccagaagaag aagaaggagg atgtgaactg agagtgaagt tcagcaggag cgcagacgcc 1080 cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140 gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200 aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260 tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320 cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380 cctcgcggat ctggcgccac caacttctct ctgctgaagc aggccggcga cgtggaggag 1440 aacccaggcc caatggtgag caagggcgag gagctgttca ccggggtggt gcccatcctg 1500 gtcgagctgg acggcgacgt aaacggccac aagttcagcg tgtccggcga gggcgagggc 1560 gatgccacct acggcaagct gaccctgaag ttcatctgca ccaccggcaa gctgcccgtg 1620 ccctggccca ccctcgtgac caccctgacc tacggcgtgc agtgcttcag ccgctacccc 1680 gaccacatga agcagcacga cttcttcaag tccgccatgc ccgaaggcta cgtccaggag 1740 cgcaccatct tcttcaagga cgacggcaac tacaagaccc gcgccgaggt gaagttcgag 1800 ggcgacaccc tggtgaaccg catcgagctg aagggcatcg acttcaagga ggacggcaac 1860 atcctggggc acaagctgga gtacaactac aacagccaca acgtctatat catggccgac 1920 aagcagaaga acggcatcaa ggtgaacttc aagatccgcc acaacatcga ggacggcagc 1980 gtgcagctcg ccgaccacta ccagcagaac acccccatcg gcgacggccc cgtgctgctg 2040 cccgacaacc actacctgag cacccagtcc gccctgagca aagaccccaa cgagaagcgc 2100 gatcacatgg tcctgctgga gttcgtgacc gccgccggga tcactctcgg catggacgag 2160 ctgtacaagt aa 2172 <210> 95 <211> 2157 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 95 caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60 acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120 ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180 tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240 aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300 tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360 ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420 atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480 actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540 gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600 tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660 tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa aattgaagtt 720 atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780 gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840 gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900 ttctgggtga aacggggcag aaagaaactc ctgtatatat tcaaacaacc atttatgaga 960 ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga agaagaagaa 1020 ggaggatgtg aactgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080 ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140 gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200 gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260 atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320 gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg cggatctggc 1380 gccaccaact tctctctgct gaagcaggcc ggcgacgtgg aggagaaccc aggcccaatg 1440 gtgagcaagg gcgaggagct gttcaccggg gtggtgccca tcctggtcga gctggacggc 1500 gacgtaaacg gccacaagtt cagcgtgtcc ggcgagggcg agggcgatgc cacctacggc 1560 aagctgaccc tgaagttcat ctgcaccacc ggcaagctgc ccgtgccctg gcccaccctc 1620 gtgaccaccc tgacctacgg cgtgcagtgc ttcagccgct accccgacca catgaagcag 1680 cacgacttct tcaagtccgc catgcccgaa ggctacgtcc aggagcgcac catcttcttc 1740 aaggacgacg gcaactacaa gacccgcgcc gaggtgaagt tcgagggcga caccctggtg 1800 aaccgcatcg agctgaaggg catcgacttc aaggaggacg gcaacatcct ggggcacaag 1860 ctggagtaca actacaacag ccacaacgtc tatatcatgg ccgacaagca gaagaacggc 1920 atcaaggtga acttcaagat ccgccacaac atcgaggacg gcagcgtgca gctcgccgac 1980 cactaccagc agaacacccc catcggcgac ggccccgtgc tgctgcccga caaccactac 2040 ctgagcaccc agtccgccct gagcaaagac cccaacgaga agcgcgatca catggtcctg 2100 ctggagttcg tgaccgccgc cgggatcact ctcggcatgg acgagctgta caagtaa 2157 <210> 96 <211> 2157 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 96 gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60 atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120 gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180 cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240 gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300 ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420 tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480 cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540 tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600 ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660 gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc aattgaagtt 720 atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780 gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840 gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900 ttctgggtga aacggggcag aaagaaactc ctgtatatat tcaaacaacc atttatgaga 960 ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga agaagaagaa 1020 ggaggatgtg aactgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080 ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140 gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200 gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260 atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320 gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg cggatctggc 1380 gccaccaact tctctctgct gaagcaggcc ggcgacgtgg aggagaaccc aggcccaatg 1440 gtgagcaagg gcgaggagct gttcaccggg gtggtgccca tcctggtcga gctggacggc 1500 gacgtaaacg gccacaagtt cagcgtgtcc ggcgagggcg agggcgatgc cacctacggc 1560 aagctgaccc tgaagttcat ctgcaccacc ggcaagctgc ccgtgccctg gcccaccctc 1620 gtgaccaccc tgacctacgg cgtgcagtgc ttcagccgct accccgacca catgaagcag 1680 cacgacttct tcaagtccgc catgcccgaa ggctacgtcc aggagcgcac catcttcttc 1740 aaggacgacg gcaactacaa gacccgcgcc gaggtgaagt tcgagggcga caccctggtg 1800 aaccgcatcg agctgaaggg catcgacttc aaggaggacg gcaacatcct ggggcacaag 1860 ctggagtaca actacaacag ccacaacgtc tatatcatgg ccgacaagca gaagaacggc 1920 atcaaggtga acttcaagat ccgccacaac atcgaggacg gcagcgtgca gctcgccgac 1980 cactaccagc agaacacccc catcggcgac ggccccgtgc tgctgcccga caaccactac 2040 ctgagcaccc agtccgccct gagcaaagac cccaacgaga agcgcgatca catggtcctg 2100 ctggagttcg tgaccgccgc cgggatcact ctcggcatgg acgagctgta caagtaa 2157 <210> 97 <211> 2175 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 97 gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60 tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120 catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180 aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240 atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300 tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360 tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420 ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480 actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540 aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600 agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660 acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720 gagctgaaaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780 accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840 aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900 acagtggcct ttattatttt ctgggtgaaa cggggcagaa agaaactcct gtatatattc 960 aaacaaccat ttatgagacc agtacaaact actcaagagg aagatggctg tagctgccga 1020 tttccagaag aagaagaagg aggatgtgaa ctgagagtga agttcagcag gagcgcagac 1080 gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140 gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200 agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260 gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320 taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380 ccccctcgcg gatctggcgc caccaacttc tctctgctga agcaggccgg cgacgtggag 1440 gagaacccag gcccaatggt gagcaagggc gaggagctgt tcaccggggt ggtgcccatc 1500 ctggtcgagc tggacggcga cgtaaacggc cacaagttca gcgtgtccgg cgagggcgag 1560 ggcgatgcca cctacggcaa gctgaccctg aagttcatct gcaccaccgg caagctgccc 1620 gtgccctggc ccaccctcgt gaccaccctg acctacggcg tgcagtgctt cagccgctac 1680 cccgaccaca tgaagcagca cgacttcttc aagtccgcca tgcccgaagg ctacgtccag 1740 gagcgcacca tcttcttcaa ggacgacggc aactacaaga cccgcgccga ggtgaagttc 1800 gagggcgaca ccctggtgaa ccgcatcgag ctgaagggca tcgacttcaa ggaggacggc 1860 aacatcctgg ggcacaagct ggagtacaac tacaacagcc acaacgtcta tatcatggcc 1920 gacaagcaga agaacggcat caaggtgaac ttcaagatcc gccacaacat cgaggacggc 1980 agcgtgcagc tcgccgacca ctaccagcag aacaccccca tcggcgacgg ccccgtgctg 2040 ctgcccgaca accactacct gagcacccag tccgccctga gcaaagaccc caacgagaag 2100 cgcgatcaca tggtcctgct ggagttcgtg accgccgccg ggatcactct cggcatggac 2160 gagctgtaca agtaa 2175 <210> 98 <211> 2175 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 98 caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60 gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120 tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180 ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240 gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300 accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420 atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480 agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540 tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600 tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660 gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720 gtctctgcaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780 accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840 aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900 acagtggcct ttattatttt ctgggtgaaa cggggcagaa agaaactcct gtatatattc 960 aaacaaccat ttatgagacc agtacaaact actcaagagg aagatggctg tagctgccga 1020 tttccagaag aagaagaagg aggatgtgaa ctgagagtga agttcagcag gagcgcagac 1080 gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140 gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200 agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260 gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320 taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380 ccccctcgcg gatctggcgc caccaacttc tctctgctga agcaggccgg cgacgtggag 1440 gagaacccag gcccaatggt gagcaagggc gaggagctgt tcaccggggt ggtgcccatc 1500 ctggtcgagc tggacggcga cgtaaacggc cacaagttca gcgtgtccgg cgagggcgag 1560 ggcgatgcca cctacggcaa gctgaccctg aagttcatct gcaccaccgg caagctgccc 1620 gtgccctggc ccaccctcgt gaccaccctg acctacggcg tgcagtgctt cagccgctac 1680 cccgaccaca tgaagcagca cgacttcttc aagtccgcca tgcccgaagg ctacgtccag 1740 gagcgcacca tcttcttcaa ggacgacggc aactacaaga cccgcgccga ggtgaagttc 1800 gagggcgaca ccctggtgaa ccgcatcgag ctgaagggca tcgacttcaa ggaggacggc 1860 aacatcctgg ggcacaagct ggagtacaac tacaacagcc acaacgtcta tatcatggcc 1920 gacaagcaga agaacggcat caaggtgaac ttcaagatcc gccacaacat cgaggacggc 1980 agcgtgcagc tcgccgacca ctaccagcag aacaccccca tcggcgacgg ccccgtgctg 2040 ctgcccgaca accactacct gagcacccag tccgccctga gcaaagaccc caacgagaag 2100 cgcgatcaca tggtcctgct ggagttcgtg accgccgccg ggatcactct cggcatggac 2160 gagctgtaca agtaa 2175 <210> 99 <211> 1377 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 99 ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60 tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120 gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180 tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240 aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300 acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360 tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420 tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480 tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540 ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600 cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660 aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaaattgaa 720 gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780 aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840 ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900 attttctggg tgaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 960 agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1020 gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080 cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140 ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200 caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260 gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320 acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1377 <210> 100 <211> 1377 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 100 gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60 atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120 ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180 aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240 gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300 gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420 ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480 tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540 ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600 gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660 tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgcaattgaa 720 gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780 aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840 ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900 attttctggg tgaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 960 agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1020 gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080 cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140 ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200 caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260 gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320 acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1377 <210> 101 <211> 1404 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 101 gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120 cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180 actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240 atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300 ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360 ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420 caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480 agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540 ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600 aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660 gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720 gggacaaagt tggaaataaa aattgaagtt atgtatcctc ctccttacct agacaatgag 780 aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840 cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900 agcttgctag taacagtggc ctttattatt ttctgggtga aacggggcag aaagaaactc 960 ctgtatatat tcaaacaacc atttatgaga ccagtacaaa ctactcaaga ggaagatggc 1020 tgtagctgcc gatttccaga agaagaagaa ggaggatgtg aactgagagt gaagttcagc 1080 aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140 ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200 gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260 aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320 cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380 atgcaggccc tgccccctcg ctaa 1404 <210> 102 <211> 1404 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 102 gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60 atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120 tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240 agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300 ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360 gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420 cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480 atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540 ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600 aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660 tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720 actctggtca ctgtctctgc aattgaagtt atgtatcctc ctccttacct agacaatgag 780 aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840 cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900 agcttgctag taacagtggc ctttattatt ttctgggtga aacggggcag aaagaaactc 960 ctgtatatat tcaaacaacc atttatgaga ccagtacaaa ctactcaaga ggaagatggc 1020 tgtagctgcc gatttccaga agaagaagaa ggaggatgtg aactgagagt gaagttcagc 1080 aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140 ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200 gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260 aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320 cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380 atgcaggccc tgccccctcg ctaa 1404 <210> 103 <211> 1389 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 103 gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60 tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120 ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180 gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240 ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300 gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360 tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420 tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480 gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540 ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600 gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660 tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720 ataaaaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780 attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840 cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900 gtggccttta ttattttctg ggtgaaacgg ggcagaaaga aactcctgta tatattcaaa 960 caaccattta tgagaccagt acaaactact caagaggaag atggctgtag ctgccgattt 1020 ccagaagaag aagaaggagg atgtgaactg agagtgaagt tcagcaggag cgcagacgcc 1080 cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140 gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200 aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260 tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320 cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380 cctcgctaa 1389 <210> 104 <211> 1389 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 104 caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60 atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120 tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180 ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240 gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300 accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420 ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480 tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540 acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600 atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660 agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720 tcctcaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780 attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840 cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900 gtggccttta ttattttctg ggtgaaacgg ggcagaaaga aactcctgta tatattcaaa 960 caaccattta tgagaccagt acaaactact caagaggaag atggctgtag ctgccgattt 1020 ccagaagaag aagaaggagg atgtgaactg agagtgaagt tcagcaggag cgcagacgcc 1080 cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140 gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200 aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260 tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320 cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380 cctcgctaa 1389 <210> 105 <211> 1374 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 105 caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60 acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120 ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180 tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240 aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300 tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360 ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420 atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480 actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540 gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600 tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660 tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa aattgaagtt 720 atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780 gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840 gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900 ttctgggtga aacggggcag aaagaaactc ctgtatatat tcaaacaacc atttatgaga 960 ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga agaagaagaa 1020 ggaggatgtg aactgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080 ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140 gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200 gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260 atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320 gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg ctaa 1374 <210> 106 <211> 1374 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 106 gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60 atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120 gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180 cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240 gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300 ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420 tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480 cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540 tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600 ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660 gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc aattgaagtt 720 atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780 gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840 gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900 ttctgggtga aacggggcag aaagaaactc ctgtatatat tcaaacaacc atttatgaga 960 ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga agaagaagaa 1020 ggaggatgtg aactgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080 ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140 gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200 gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260 atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320 gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg ctaa 1374 <210> 107 <211> 1392 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 107 gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60 tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120 catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180 aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240 atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300 tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360 tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420 ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480 actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540 aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600 agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660 acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720 gagctgaaaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780 accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840 aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900 acagtggcct ttattatttt ctgggtgaaa cggggcagaa agaaactcct gtatatattc 960 aaacaaccat ttatgagacc agtacaaact actcaagagg aagatggctg tagctgccga 1020 tttccagaag aagaagaagg aggatgtgaa ctgagagtga agttcagcag gagcgcagac 1080 gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140 gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200 agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260 gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320 taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380 ccccctcgct aa 1392 <210> 108 <211> 1392 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 108 caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60 gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120 tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180 ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240 gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300 accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420 atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480 agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540 tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600 tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660 gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720 gtctctgcaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780 accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840 aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900 acagtggcct ttattatttt ctgggtgaaa cggggcagaa agaaactcct gtatatattc 960 aaacaaccat ttatgagacc agtacaaact actcaagagg aagatggctg tagctgccga 1020 tttccagaag aagaagaagg aggatgtgaa ctgagagtga agttcagcag gagcgcagac 1080 gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140 gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200 agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260 gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320 taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380 ccccctcgct aa 1392 <210> 109 <211> 2160 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 109 ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60 tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120 gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180 tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240 aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300 acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360 tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420 tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480 tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540 ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600 cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660 aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaaattgaa 720 gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780 aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840 ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900 attttctggg tgaggagtaa gaggagcagg ctcctgcaca gtgactacat gaacatgact 960 ccccgccgcc ccgggcccac ccgcaagcat taccagccct atgccccacc acgcgacttc 1020 gcagcctatc gctccctgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080 cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140 ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200 caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260 gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320 acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgcggatct 1380 ggcgccacca acttctctct gctgaagcag gccggcgacg tggaggagaa cccaggccca 1440 atggtgagca agggcgagga gctgttcacc ggggtggtgc ccatcctggt cgagctggac 1500 ggcgacgtaa acggccacaa gttcagcgtg tccggcgagg gcgagggcga tgccacctac 1560 ggcaagctga ccctgaagtt catctgcacc accggcaagc tgcccgtgcc ctggcccacc 1620 ctcgtgacca ccctgaccta cggcgtgcag tgcttcagcc gctaccccga ccacatgaag 1680 cagcacgact tcttcaagtc cgccatgccc gaaggctacg tccaggagcg caccatcttc 1740 ttcaaggacg acggcaacta caagacccgc gccgaggtga agttcgaggg cgacaccctg 1800 gtgaaccgca tcgagctgaa gggcatcgac ttcaaggagg acggcaacat cctggggcac 1860 aagctggagt acaactacaa cagccacaac gtctatatca tggccgacaa gcagaagaac 1920 ggcatcaagg tgaacttcaa gatccgccac aacatcgagg acggcagcgt gcagctcgcc 1980 gaccactacc agcagaacac ccccatcggc gacggccccg tgctgctgcc cgacaaccac 2040 tacctgagca cccagtccgc cctgagcaaa gaccccaacg agaagcgcga tcacatggtc 2100 ctgctggagt tcgtgaccgc cgccgggatc actctcggca tggacgagct gtacaagtaa 2160 <210> 110 <211> 2169 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 110 gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60 atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120 ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180 aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240 gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300 gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420 ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480 tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540 ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600 gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660 tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgcaaccacg 720 acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 780 cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 840 gcctgtgata tctacatctg ggcgcccttg gccgggactt gtggggtcct tctcctgtca 900 ctggttatca ccctttactg caaacggggc agaaagaaac tcctgtatat attcaaacaa 960 ccatttatga gaccagtaca aactactcaa gaggaagatg gctgtagctg ccgatttcca 1020 gaagaagaag aaggaggatg tgaactgaga gtgaagttca gcaggagcgc agacgccccc 1080 gcgtaccagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1140 tacgatgttt tggacaagag acgtggccgg gaccctgaga tggggggaaa gccgagaagg 1200 aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1260 agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1320 ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1380 cgcggatctg gcgccaccaa cttctctctg ctgaagcagg ccggcgacgt ggaggagaac 1440 ccaggcccaa tggtgagcaa gggcgaggag ctgttcaccg gggtggtgcc catcctggtc 1500 gagctggacg gcgacgtaaa cggccacaag ttcagcgtgt ccggcgaggg cgagggcgat 1560 gccacctacg gcaagctgac cctgaagttc atctgcacca ccggcaagct gcccgtgccc 1620 tggcccaccc tcgtgaccac cctgacctac ggcgtgcagt gcttcagccg ctaccccgac 1680 cacatgaagc agcacgactt cttcaagtcc gccatgcccg aaggctacgt ccaggagcgc 1740 accatcttct tcaaggacga cggcaactac aagacccgcg ccgaggtgaa gttcgagggc 1800 gacaccctgg tgaaccgcat cgagctgaag ggcatcgact tcaaggagga cggcaacatc 1860 ctggggcaca agctggagta caactacaac agccacaacg tctatatcat ggccgacaag 1920 cagaagaacg gcatcaaggt gaacttcaag atccgccaca acatcgagga cggcagcgtg 1980 cagctcgccg accactacca gcagaacacc cccatcggcg acggccccgt gctgctgccc 2040 gacaaccact acctgagcac ccagtccgcc ctgagcaaag accccaacga gaagcgcgat 2100 cacatggtcc tgctggagtt cgtgaccgcc gccgggatca ctctcggcat ggacgagctg 2160 tacaagtaa 2169 <210> 111 <211> 2187 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 111 gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120 cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180 actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240 atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300 ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360 ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420 caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480 agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540 ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600 aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660 gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720 gggacaaagt tggaaataaa aattgaagtt atgtatcctc ctccttacct agacaatgag 780 aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840 cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900 agcttgctag taacagtggc ctttattatt ttctgggtga ggagtaagag gagcaggctc 960 ctgcacagtg actacatgaa catgactccc cgccgccccg ggcccacccg caagcattac 1020 cagccctatg ccccaccacg cgacttcgca gcctatcgct ccctgagagt gaagttcagc 1080 aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140 ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200 gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260 aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320 cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380 atgcaggccc tgccccctcg cggatctggc gccaccaact tctctctgct gaagcaggcc 1440 ggcgacgtgg aggagaaccc aggcccaatg gtgagcaagg gcgaggagct gttcaccggg 1500 gtggtgccca tcctggtcga gctggacggc gacgtaaacg gccacaagtt cagcgtgtcc 1560 ggcgagggcg agggcgatgc cacctacggc aagctgaccc tgaagttcat ctgcaccacc 1620 ggcaagctgc ccgtgccctg gcccaccctc gtgaccaccc tgacctacgg cgtgcagtgc 1680 ttcagccgct accccgacca catgaagcag cacgacttct tcaagtccgc catgcccgaa 1740 ggctacgtcc aggagcgcac catcttcttc aaggacgacg gcaactacaa gacccgcgcc 1800 gaggtgaagt tcgagggcga caccctggtg aaccgcatcg agctgaaggg catcgacttc 1860 aaggaggacg gcaacatcct ggggcacaag ctggagtaca actacaacag ccacaacgtc 1920 tatatcatgg ccgacaagca gaagaacggc atcaaggtga acttcaagat ccgccacaac 1980 atcgaggacg gcagcgtgca gctcgccgac cactaccagc agaacacccc catcggcgac 2040 ggccccgtgc tgctgcccga caaccactac ctgagcaccc agtccgccct gagcaaagac 2100 cccaacgaga agcgcgatca catggtcctg ctggagttcg tgaccgccgc cgggatcact 2160 ctcggcatgg acgagctgta caagtaa 2187 <210> 112 <211> 2187 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 112 gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60 atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120 tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240 agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300 ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360 gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420 cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480 atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540 ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600 aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660 tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720 actctggtca ctgtctctgc aattgaagtt atgtatcctc ctccttacct agacaatgag 780 aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840 cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900 agcttgctag taacagtggc ctttattatt ttctgggtga ggagtaagag gagcaggctc 960 ctgcacagtg actacatgaa catgactccc cgccgccccg ggcccacccg caagcattac 1020 cagccctatg ccccaccacg cgacttcgca gcctatcgct ccctgagagt gaagttcagc 1080 aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140 ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200 gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260 aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320 cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380 atgcaggccc tgccccctcg cggatctggc gccaccaact tctctctgct gaagcaggcc 1440 ggcgacgtgg aggagaaccc aggcccaatg gtgagcaagg gcgaggagct gttcaccggg 1500 gtggtgccca tcctggtcga gctggacggc gacgtaaacg gccacaagtt cagcgtgtcc 1560 ggcgagggcg agggcgatgc cacctacggc aagctgaccc tgaagttcat ctgcaccacc 1620 ggcaagctgc ccgtgccctg gcccaccctc gtgaccaccc tgacctacgg cgtgcagtgc 1680 ttcagccgct accccgacca catgaagcag cacgacttct tcaagtccgc catgcccgaa 1740 ggctacgtcc aggagcgcac catcttcttc aaggacgacg gcaactacaa gacccgcgcc 1800 gaggtgaagt tcgagggcga caccctggtg aaccgcatcg agctgaaggg catcgacttc 1860 aaggaggacg gcaacatcct ggggcacaag ctggagtaca actacaacag ccacaacgtc 1920 tatatcatgg ccgacaagca gaagaacggc atcaaggtga acttcaagat ccgccacaac 1980 atcgaggacg gcagcgtgca gctcgccgac cactaccagc agaacacccc catcggcgac 2040 ggccccgtgc tgctgcccga caaccactac ctgagcaccc agtccgccct gagcaaagac 2100 cccaacgaga agcgcgatca catggtcctg ctggagttcg tgaccgccgc cgggatcact 2160 ctcggcatgg acgagctgta caagtaa 2187 <210> 113 <211> 2172 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 113 gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60 tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120 ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180 gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240 ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300 gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360 tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420 tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480 gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540 ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600 gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660 tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720 ataaaaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780 attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840 cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900 gtggccttta ttattttctg ggtgaggagt aagaggagca ggctcctgca cagtgactac 960 atgaacatga ctccccgccg ccccgggccc acccgcaagc attaccagcc ctatgcccca 1020 ccacgcgact tcgcagccta tcgctccctg agagtgaagt tcagcaggag cgcagacgcc 1080 cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140 gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200 aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260 tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320 cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380 cctcgcggat ctggcgccac caacttctct ctgctgaagc aggccggcga cgtggaggag 1440 aacccaggcc caatggtgag caagggcgag gagctgttca ccggggtggt gcccatcctg 1500 gtcgagctgg acggcgacgt aaacggccac aagttcagcg tgtccggcga gggcgagggc 1560 gatgccacct acggcaagct gaccctgaag ttcatctgca ccaccggcaa gctgcccgtg 1620 ccctggccca ccctcgtgac caccctgacc tacggcgtgc agtgcttcag ccgctacccc 1680 gaccacatga agcagcacga cttcttcaag tccgccatgc ccgaaggcta cgtccaggag 1740 cgcaccatct tcttcaagga cgacggcaac tacaagaccc gcgccgaggt gaagttcgag 1800 ggcgacaccc tggtgaaccg catcgagctg aagggcatcg acttcaagga ggacggcaac 1860 atcctggggc acaagctgga gtacaactac aacagccaca acgtctatat catggccgac 1920 aagcagaaga acggcatcaa ggtgaacttc aagatccgcc acaacatcga ggacggcagc 1980 gtgcagctcg ccgaccacta ccagcagaac acccccatcg gcgacggccc cgtgctgctg 2040 cccgacaacc actacctgag cacccagtcc gccctgagca aagaccccaa cgagaagcgc 2100 gatcacatgg tcctgctgga gttcgtgacc gccgccggga tcactctcgg catggacgag 2160 ctgtacaagt aa 2172 <210> 114 <211> 2181 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 114 caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60 atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120 tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180 ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240 gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300 accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420 ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480 tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540 acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600 atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660 agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720 tcctcaacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 780 cccctgtccc tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg 840 gggctggact tcgcctgtga tatctacatc tgggcgccct tggccgggac ttgtggggtc 900 cttctcctgt cactggttat caccctttac tgcaaacggg gcagaaagaa actcctgtat 960 atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1020 tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1080 gcagacgccc ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga 1140 cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 1200 aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 1260 gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1320 ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1380 gccctgcccc ctcgcggatc tggcgccacc aacttctctc tgctgaagca ggccggcgac 1440 gtggaggaga acccaggccc aatggtgagc aagggcgagg agctgttcac cggggtggtg 1500 cccatcctgg tcgagctgga cggcgacgta aacggccaca agttcagcgt gtccggcgag 1560 ggcgagggcg atgccaccta cggcaagctg accctgaagt tcatctgcac caccggcaag 1620 ctgcccgtgc cctggcccac cctcgtgacc accctgacct acggcgtgca gtgcttcagc 1680 cgctaccccg accacatgaa gcagcacgac ttcttcaagt ccgccatgcc cgaaggctac 1740 gtccaggagc gcaccatctt cttcaaggac gacggcaact acaagacccg cgccgaggtg 1800 aagttcgagg gcgacaccct ggtgaaccgc atcgagctga agggcatcga cttcaaggag 1860 gacggcaaca tcctggggca caagctggag tacaactaca acagccacaa cgtctatatc 1920 atggccgaca agcagaagaa cggcatcaag gtgaacttca agatccgcca caacatcgag 1980 gacggcagcg tgcagctcgc cgaccactac cagcagaaca cccccatcgg cgacggcccc 2040 gtgctgctgc ccgacaacca ctacctgagc acccagtccg ccctgagcaa agaccccaac 2100 gagaagcgcg atcacatggt cctgctggag ttcgtgaccg ccgccgggat cactctcggc 2160 atggacgagc tgtacaagta a 2181 <210> 115 <211> 2157 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 115 caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60 acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120 ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180 tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240 aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300 tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360 ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420 atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480 actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540 gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600 tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660 tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa aattgaagtt 720 atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780 gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840 gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900 ttctgggtga ggagtaagag gagcaggctc ctgcacagtg actacatgaa catgactccc 960 cgccgccccg ggcccacccg caagcattac cagccctatg ccccaccacg cgacttcgca 1020 gcctatcgct ccctgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080 ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140 gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200 gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260 atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320 gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg cggatctggc 1380 gccaccaact tctctctgct gaagcaggcc ggcgacgtgg aggagaaccc aggcccaatg 1440 gtgagcaagg gcgaggagct gttcaccggg gtggtgccca tcctggtcga gctggacggc 1500 gacgtaaacg gccacaagtt cagcgtgtcc ggcgagggcg agggcgatgc cacctacggc 1560 aagctgaccc tgaagttcat ctgcaccacc ggcaagctgc ccgtgccctg gcccaccctc 1620 gtgaccaccc tgacctacgg cgtgcagtgc ttcagccgct accccgacca catgaagcag 1680 cacgacttct tcaagtccgc catgcccgaa ggctacgtcc aggagcgcac catcttcttc 1740 aaggacgacg gcaactacaa gacccgcgcc gaggtgaagt tcgagggcga caccctggtg 1800 aaccgcatcg agctgaaggg catcgacttc aaggaggacg gcaacatcct ggggcacaag 1860 ctggagtaca actacaacag ccacaacgtc tatatcatgg ccgacaagca gaagaacggc 1920 atcaaggtga acttcaagat ccgccacaac atcgaggacg gcagcgtgca gctcgccgac 1980 cactaccagc agaacacccc catcggcgac ggccccgtgc tgctgcccga caaccactac 2040 ctgagcaccc agtccgccct gagcaaagac cccaacgaga agcgcgatca catggtcctg 2100 ctggagttcg tgaccgccgc cgggatcact ctcggcatgg acgagctgta caagtaa 2157 <210> 116 <211> 2166 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 116 gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60 atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120 gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180 cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240 gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300 ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420 tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480 cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540 tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600 ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660 gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc aaccacgacg 720 ccagcgccgc gaccaccaac accggcgccc accatcgcgt cgcagcccct gtccctgcgc 780 ccagaggcgt gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 840 tgtgatatct acatctgggc gcccttggcc gggacttgtg gggtccttct cctgtcactg 900 gttatcaccc tttactgcaa acggggcaga aagaaactcc tgtatatatt caaacaacca 960 tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1020 gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 1080 taccagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 1140 gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 1200 aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 1260 gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1320 ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1380 ggatctggcg ccaccaactt ctctctgctg aagcaggccg gcgacgtgga ggagaaccca 1440 ggcccaatgg tgagcaaggg cgaggagctg ttcaccgggg tggtgcccat cctggtcgag 1500 ctggacggcg acgtaaacgg ccacaagttc agcgtgtccg gcgagggcga gggcgatgcc 1560 acctacggca agctgaccct gaagttcatc tgcaccaccg gcaagctgcc cgtgccctgg 1620 cccaccctcg tgaccaccct gacctacggc gtgcagtgct tcagccgcta ccccgaccac 1680 atgaagcagc acgacttctt caagtccgcc atgcccgaag gctacgtcca ggagcgcacc 1740 atcttcttca aggacgacgg caactacaag acccgcgccg aggtgaagtt cgagggcgac 1800 accctggtga accgcatcga gctgaagggc atcgacttca aggaggacgg caacatcctg 1860 gggcacaagc tggagtacaa ctacaacagc cacaacgtct atatcatggc cgacaagcag 1920 aagaacggca tcaaggtgaa cttcaagatc cgccacaaca tcgaggacgg cagcgtgcag 1980 ctcgccgacc actaccagca gaacaccccc atcggcgacg gccccgtgct gctgcccgac 2040 aaccactacc tgagcaccca gtccgccctg agcaaagacc ccaacgagaa gcgcgatcac 2100 atggtcctgc tggagttcgt gaccgccgcc gggatcactc tcggcatgga cgagctgtac 2160 aagtaa 2166 <210> 117 <211> 2175 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 117 gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60 tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120 catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180 aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240 atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300 tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360 tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420 ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480 actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540 aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600 agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660 acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720 gagctgaaaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780 accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840 aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900 acagtggcct ttattatttt ctgggtgagg agtaagagga gcaggctcct gcacagtgac 960 tacatgaaca tgactccccg ccgccccggg cccacccgca agcattacca gccctatgcc 1020 ccaccacgcg acttcgcagc ctatcgctcc ctgagagtga agttcagcag gagcgcagac 1080 gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140 gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200 agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260 gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320 taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380 ccccctcgcg gatctggcgc caccaacttc tctctgctga agcaggccgg cgacgtggag 1440 gagaacccag gcccaatggt gagcaagggc gaggagctgt tcaccggggt ggtgcccatc 1500 ctggtcgagc tggacggcga cgtaaacggc cacaagttca gcgtgtccgg cgagggcgag 1560 ggcgatgcca cctacggcaa gctgaccctg aagttcatct gcaccaccgg caagctgccc 1620 gtgccctggc ccaccctcgt gaccaccctg acctacggcg tgcagtgctt cagccgctac 1680 cccgaccaca tgaagcagca cgacttcttc aagtccgcca tgcccgaagg ctacgtccag 1740 gagcgcacca tcttcttcaa ggacgacggc aactacaaga cccgcgccga ggtgaagttc 1800 gagggcgaca ccctggtgaa ccgcatcgag ctgaagggca tcgacttcaa ggaggacggc 1860 aacatcctgg ggcacaagct ggagtacaac tacaacagcc acaacgtcta tatcatggcc 1920 gacaagcaga agaacggcat caaggtgaac ttcaagatcc gccacaacat cgaggacggc 1980 agcgtgcagc tcgccgacca ctaccagcag aacaccccca tcggcgacgg ccccgtgctg 2040 ctgcccgaca accactacct gagcacccag tccgccctga gcaaagaccc caacgagaag 2100 cgcgatcaca tggtcctgct ggagttcgtg accgccgccg ggatcactct cggcatggac 2160 gagctgtaca agtaa 2175 <210> 118 <211> 2184 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 118 caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60 gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120 tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180 ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240 gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300 accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420 atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480 agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540 tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600 tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660 gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720 gtctctgcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 780 cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 840 agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 900 gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 960 tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1020 agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1080 agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 1140 ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1200 ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1260 atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1320 gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1380 caggccctgc cccctcgcgg atctggcgcc accaacttct ctctgctgaa gcaggccggc 1440 gacgtggagg agaacccagg cccaatggtg agcaagggcg aggagctgtt caccggggtg 1500 gtgcccatcc tggtcgagct ggacggcgac gtaaacggcc acaagttcag cgtgtccggc 1560 gagggcgagg gcgatgccac ctacggcaag ctgaccctga agttcatctg caccaccggc 1620 aagctgcccg tgccctggcc caccctcgtg accaccctga cctacggcgt gcagtgcttc 1680 agccgctacc ccgaccacat gaagcagcac gacttcttca agtccgccat gcccgaaggc 1740 tacgtccagg agcgcaccat cttcttcaag gacgacggca actacaagac ccgcgccgag 1800 gtgaagttcg agggcgacac cctggtgaac cgcatcgagc tgaagggcat cgacttcaag 1860 gaggacggca acatcctggg gcacaagctg gagtacaact acaacagcca caacgtctat 1920 atcatggccg acaagcagaa gaacggcatc aaggtgaact tcaagatccg ccacaacatc 1980 gaggacggca gcgtgcagct cgccgaccac taccagcaga acacccccat cggcgacggc 2040 cccgtgctgc tgcccgacaa ccactacctg agcacccagt ccgccctgag caaagacccc 2100 aacgagaagc gcgatcacat ggtcctgctg gagttcgtga ccgccgccgg gatcactctc 2160 ggcatggacg agctgtacaa gtaa 2184 <210> 119 <211> 1377 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 119 ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60 tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120 gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180 tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240 aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300 acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360 tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420 tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480 tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540 ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600 cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660 aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaaattgaa 720 gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780 aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840 ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900 attttctggg tgaggagtaa gaggagcagg ctcctgcaca gtgactacat gaacatgact 960 ccccgccgcc ccgggcccac ccgcaagcat taccagccct atgccccacc acgcgacttc 1020 gcagcctatc gctccctgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080 cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140 ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200 caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260 gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320 acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1377 <210> 120 <211> 1377 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 120 gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60 atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120 ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180 aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240 gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300 gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420 ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480 tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540 ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600 gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660 tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgcaattgaa 720 gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780 aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840 ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900 attttctggg tgaggagtaa gaggagcagg ctcctgcaca gtgactacat gaacatgact 960 ccccgccgcc ccgggcccac ccgcaagcat taccagccct atgccccacc acgcgacttc 1020 gcagcctatc gctccctgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080 cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140 ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200 caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260 gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320 acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1377 <210> 121 <211> 1404 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 121 gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60 tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120 cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180 actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240 atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300 ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360 ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420 caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480 agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540 ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600 aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660 gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720 gggacaaagt tggaaataaa aattgaagtt atgtatcctc ctccttacct agacaatgag 780 aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840 cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900 agcttgctag taacagtggc ctttattatt ttctgggtga ggagtaagag gagcaggctc 960 ctgcacagtg actacatgaa catgactccc cgccgccccg ggcccacccg caagcattac 1020 cagccctatg ccccaccacg cgacttcgca gcctatcgct ccctgagagt gaagttcagc 1080 aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140 ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200 gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260 aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320 cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380 atgcaggccc tgccccctcg ctaa 1404 <210> 122 <211> 1404 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 122 gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60 atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120 tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240 agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300 ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360 gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420 cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480 atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540 ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600 aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660 tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720 actctggtca ctgtctctgc aattgaagtt atgtatcctc ctccttacct agacaatgag 780 aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840 cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900 agcttgctag taacagtggc ctttattatt ttctgggtga ggagtaagag gagcaggctc 960 ctgcacagtg actacatgaa catgactccc cgccgccccg ggcccacccg caagcattac 1020 cagccctatg ccccaccacg cgacttcgca gcctatcgct ccctgagagt gaagttcagc 1080 aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140 ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200 gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260 aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320 cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380 atgcaggccc tgccccctcg ctaa 1404 <210> 123 <211> 1389 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 123 gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60 tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120 ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180 gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240 ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300 gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360 tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420 tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480 gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540 ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600 gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660 tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720 ataaaaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780 attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840 cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900 gtggccttta ttattttctg ggtgaggagt aagaggagca ggctcctgca cagtgactac 960 atgaacatga ctccccgccg ccccgggccc acccgcaagc attaccagcc ctatgcccca 1020 ccacgcgact tcgcagccta tcgctccctg agagtgaagt tcagcaggag cgcagacgcc 1080 cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140 gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200 aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260 tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320 cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380 cctcgctaa 1389 <210> 124 <211> 1389 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 124 caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60 atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120 tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180 ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240 gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300 accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420 ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480 tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540 acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600 atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660 agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720 tcctcaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780 attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840 cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900 gtggccttta ttattttctg ggtgaggagt aagaggagca ggctcctgca cagtgactac 960 atgaacatga ctccccgccg ccccgggccc acccgcaagc attaccagcc ctatgcccca 1020 ccacgcgact tcgcagccta tcgctccctg agagtgaagt tcagcaggag cgcagacgcc 1080 cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140 gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200 aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260 tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320 cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380 cctcgctaa 1389 <210> 125 <211> 1374 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 125 caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60 acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120 ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180 tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240 aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300 tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360 ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420 atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480 actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540 gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600 tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660 tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa aattgaagtt 720 atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780 gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840 gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900 ttctgggtga ggagtaagag gagcaggctc ctgcacagtg actacatgaa catgactccc 960 cgccgccccg ggcccacccg caagcattac cagccctatg ccccaccacg cgacttcgca 1020 gcctatcgct ccctgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080 ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140 gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200 gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260 atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320 gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg ctaa 1374 <210> 126 <211> 1374 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 126 gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60 atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120 gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180 cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240 gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300 ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360 ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420 tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480 cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540 tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600 ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660 gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc aattgaagtt 720 atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780 gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840 gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900 ttctgggtga ggagtaagag gagcaggctc ctgcacagtg actacatgaa catgactccc 960 cgccgccccg ggcccacccg caagcattac cagccctatg ccccaccacg cgacttcgca 1020 gcctatcgct ccctgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080 ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140 gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200 gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260 atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320 gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg ctaa 1374 <210> 127 <211> 1392 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 127 gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60 tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120 catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180 aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240 atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300 tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360 tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420 ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480 actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540 aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600 agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660 acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720 gagctgaaaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780 accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840 aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900 acagtggcct ttattatttt ctgggtgagg agtaagagga gcaggctcct gcacagtgac 960 tacatgaaca tgactccccg ccgccccggg cccacccgca agcattacca gccctatgcc 1020 ccaccacgcg acttcgcagc ctatcgctcc ctgagagtga agttcagcag gagcgcagac 1080 gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140 gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200 agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260 gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320 taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380 ccccctcgct aa 1392 <210> 128 <211> 1392 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 128 caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60 gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120 tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180 ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240 gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300 accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360 tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420 atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480 agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540 tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600 tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660 gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720 gtctctgcaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780 accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840 aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900 acagtggcct ttattatttt ctgggtgagg agtaagagga gcaggctcct gcacagtgac 960 tacatgaaca tgactccccg ccgccccggg cccacccgca agcattacca gccctatgcc 1020 ccaccacgcg acttcgcagc ctatcgctcc ctgagagtga agttcagcag gagcgcagac 1080 gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140 gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200 agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260 gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320 taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380 ccccctcgct aa 1392 <210> 129 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 129 ggattcactt tcagtagata c 21 <210> 130 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 130 agtaatagtg gtagttat 18 <210> 131 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 131 gggtcgccc 9 <210> 132 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 132 ggagcaagtg agaacattta cggtgcttta aat 33 <210> 133 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 133 ggtgcaacca agttggcaga t 21 <210> 134 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 134 caaaatgtgt taagtaagcc gtacgcg 27 <210> 135 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 135 ggctatacct ttagtaccta c 21 <210> 136 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 136 tatcctggag atggtgat 18 <210> 137 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 137 gggggactct attatggtta cgacattgct tac 33 <210> 138 <211> 48 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 138 agatctagtc agagcattgt acatagtaat ggaaacacct atttagaa 48 <210> 139 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 139 aaagtctcca accgattttc t 21 <210> 140 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 140 tttcaaggtt cacatgttcc attcacg 27 <210> 141 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 141 ggattcacct tcactgatta c 21 <210> 142 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 142 agaaacaaag ttaatggtga caca 24 <210> 143 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 143 gataagggaa tagcgtacta ctttgactat 30 <210> 144 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 144 agggccagct caagtgtaag ttacattcac 30 <210> 145 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 145 ggcacatcca acctggcttc t 21 <210> 146 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 146 cagcagtgga gtagtaattt atccacg 27 <210> 147 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 147 gggttctcat taaccagcta t 21 <210> 148 <211> 15 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 148 tggactggtg gaggc 15 <210> 149 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 149 ggggtgtact actttgacta c 21 <210> 150 <211> 33 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 150 aaggccagtc aggatgtgac tactgctgta gcc 33 <210> 151 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 151 tgggcatcca cccggcacac t 21 <210> 152 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 152 cagcaatatt atagaactcc tcggacg 27 <210> 153 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 153 ggctacacat tcaatgacta c 21 <210> 154 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 154 aatcctaact atgatagc 18 <210> 155 <211> 39 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 155 cgagactacg atggtaggag gggggcctgg ttttcttac 39 <210> 156 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 156 actgccagct caagtgtaag ttacatgtac 30 <210> 157 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 157 ctcacatcca acctggcttc t 21 <210> 158 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 158 cagcagtggg atagtaaccc gctcacg 27 <210> 159 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 159 gcggatccgg tgtccagtgt gacgtgaag 29 <210> 160 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 160 gcggatccga catccagatg actcagtc 28 <210> 161 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 161 gcggatccga ggtgaagctg cagcaatc 28 <210> 162 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 162 gcggatccga tattttgatg acccaaac 28 <210> 163 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 163 gcggatccga ggtgaagctg gtggagtctg 30 <210> 164 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 164 gcggatccca aattgttctc tcccagtc 28 <210> 165 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 165 gcggatccca ggtgcagctg aaggagtcag 30 <210> 166 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 166 gcggatccca aattgttctc tcccagtc 28 <210> 167 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 167 gcggatccga ggtgaagctg caggaatctg 30 <210> 168 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 168 gcggatccca aattgttctc acccagtc 28 <210> 169 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 169 gcgaattctt acttgtacag ctcgtccat 29 <210> 170 <211> 29 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 170 gcgaattctt agcgaggggg cagggcctg 29 <210> 171 <211> 238 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 171 Gly Val Gln Cys Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val 1 5 10 15 Lys Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr 20 25 30 Phe Ser Arg Tyr Thr Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg 35 40 45 Leu Glu Trp Val Ala Thr Ile Ser Asn Ser Gly Ser Tyr Thr Tyr Tyr 50 55 60 Arg Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys 65 70 75 80 Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala 85 90 95 Met Tyr Tyr Cys Thr Arg Gly Ser Pro Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ser Ala 130 135 140 Ser Val Gly Glu Thr Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile 145 150 155 160 Tyr Gly Ala Leu Asn Trp Tyr Gln Arg Lys Gln Gly Lys Ser Pro Gln 165 170 175 Leu Leu Ile Tyr Gly Ala Thr Lys Leu Ala Asp Gly Met Ser Ser Arg 180 185 190 Phe Ser Gly Ser Gly Ser Asn Arg Gln Tyr Ser Leu Lys Ile Ser Ser 195 200 205 Leu His Pro Asp Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser 210 215 220 Lys Pro Tyr Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 225 230 235 <210> 172 <211> 247 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 172 Glu Val Lys Leu Gln Gln Ser Gly Ala Asp Leu Ala Thr Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Thr Tyr 20 25 30 Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Thr Ile Tyr Pro Gly Asp Gly Asp Thr Arg Tyr Thr Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala His 65 70 75 80 Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Leu Tyr Tyr Gly Tyr Asp Ile Ala Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Asp Ile Leu Met Thr Gln Thr Pro Leu 130 135 140 Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser 145 150 155 160 Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr 165 170 175 Leu Gln Lys Pro Gly Gln Ser Pro Lys Pro Leu Ile Lys Lys Val Ser 180 185 190 Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Glu Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly 210 215 220 Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Phe Thr Phe Gly Ser 225 230 235 240 Gly Thr Lys Leu Glu Ile Lys 245 <210> 173 <211> 242 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 173 Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ile Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Asn Trp Val Arg Gln Ser Pro Gly Lys Ala Leu Glu Trp Leu 35 40 45 Gly Phe Ile Arg Asn Lys Val Asn Gly Asp Thr Thr Glu Tyr Ser Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ser Gln Ser Ile 65 70 75 80 Leu Tyr Leu Gln Met Asn Thr Leu Arg Thr Glu Asp Ser Ala Thr Tyr 85 90 95 Tyr Cys Ala Arg Asp Lys Gly Ile Ala Tyr Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Ser Gln Ser Pro 130 135 140 Ala Ile Leu Phe Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg 145 150 155 160 Ala Ser Ser Ser Val Ser Tyr Ile His Trp Tyr Gln Gln Lys Pro Gly 165 170 175 Ser Ser Pro Lys Pro Trp Ile His Gly Thr Ser Asn Leu Ala Ser Gly 180 185 190 Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu 195 200 205 Thr Ile Ser Arg Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln 210 215 220 Gln Trp Ser Ser Asn Leu Ser Thr Phe Gly Gly Gly Thr Lys Leu Glu 225 230 235 240 Ile Lys <210> 174 <211> 237 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 174 Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Asn Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr 20 25 30 Ala Ile Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Ile Ile Trp Thr Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Lys 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Arg Tyr Tyr Cys Ala 85 90 95 Ser Gly Val Tyr Tyr Phe Asp Tyr Trp Gly Leu Gly Thr Thr Leu Thr 100 105 110 Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser 130 135 140 Val Gly Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Thr 145 150 155 160 Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Val 165 170 175 Leu Ile Phe Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe 180 185 190 Thr Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val 195 200 205 Gln Ala Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln Tyr Tyr Arg Thr 210 215 220 Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 225 230 235 <210> 175 <211> 243 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 175 Glu Val Lys Leu Gln Glu Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Asn Asp Tyr 20 25 30 Asn Met Asp Tyr Leu Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asp Ile Asn Pro Asn Tyr Asp Ser Thr Ile Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Asp Tyr Asp Gly Arg Arg Gly Ala Trp Phe Ser Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser 130 135 140 Pro Ala Leu Met Ser Ala Ser Pro Gly Glu Lys Val Thr Val Thr Cys 145 150 155 160 Thr Ala Ser Ser Ser Val Ser Tyr Met Tyr Trp Tyr Gln Gln Lys Pro 165 170 175 Arg Ser Ser Pro Lys Pro Trp Ile Tyr Leu Thr Ser Asn Leu Ala Ser 180 185 190 Gly Val Pro Thr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser 195 200 205 Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Trp Asp Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu 225 230 235 240 Glu Leu Lys <210> 176 <211> 238 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 176 Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Ala 20 25 30 Leu Asn Trp Tyr Gln Arg Lys Gln Gly Lys Ser Pro Gln Leu Leu Ile 35 40 45 Tyr Gly Ala Thr Lys Leu Ala Asp Gly Met Ser Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Asn Arg Gln Tyr Ser Leu Lys Ile Ser Ser Leu His Pro 65 70 75 80 Asp Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Lys Pro Tyr 85 90 95 Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Val Gln Cys Asp Val 115 120 125 Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu 130 135 140 Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr Thr Met 145 150 155 160 Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val Ala Thr 165 170 175 Ile Ser Asn Ser Gly Ser Tyr Thr Tyr Tyr Arg Asp Ser Val Lys Gly 180 185 190 Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln 195 200 205 Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys Thr Arg 210 215 220 Gly Ser Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 225 230 235 <210> 177 <211> 247 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 177 Asp Ile Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Pro Leu Ile Lys Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 115 120 125 Val Lys Leu Gln Gln Ser Gly Ala Asp Leu Ala Thr Pro Gly Ala Ser 130 135 140 Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Thr Tyr Trp 145 150 155 160 Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly 165 170 175 Thr Ile Tyr Pro Gly Asp Gly Asp Thr Arg Tyr Thr Gln Lys Phe Lys 180 185 190 Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala His Met 195 200 205 Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala 210 215 220 Arg Gly Gly Leu Tyr Tyr Gly Tyr Asp Ile Ala Tyr Trp Gly Gln Gly 225 230 235 240 Thr Leu Val Thr Val Ser Ala 245 <210> 178 <211> 242 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 178 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Phe Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile His 35 40 45 Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Leu Ser Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly 100 105 110 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Val Glu Ser 115 120 125 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ser 130 135 140 Ile Ser Gly Phe Thr Phe Thr Asp Tyr Tyr Met Asn Trp Val Arg Gln 145 150 155 160 Ser Pro Gly Lys Ala Leu Glu Trp Leu Gly Phe Ile Arg Asn Lys Val 165 170 175 Asn Gly Asp Thr Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr 180 185 190 Ile Ser Arg Asp Ile Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn Thr 195 200 205 Leu Arg Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Ala Arg Asp Lys Gly 210 215 220 Ile Ala Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val 225 230 235 240 Ser Ser <210> 179 <211> 237 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 179 Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Thr Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Val Leu Ile 35 40 45 Phe Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln Tyr Tyr Arg Thr Pro Arg 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Lys Glu 115 120 125 Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Asn Leu Ser Ile Thr Cys 130 135 140 Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr Ala Ile Asn Trp Val Arg 145 150 155 160 Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu Gly Ile Ile Trp Thr Gly 165 170 175 Gly Gly Thr Asn Tyr Asn Ser Ala Leu Lys Ser Arg Leu Ser Ile Ser 180 185 190 Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln 195 200 205 Thr Asp Asp Thr Ala Arg Tyr Tyr Cys Ala Ser Gly Val Tyr Tyr Phe 210 215 220 Asp Tyr Trp Gly Leu Gly Thr Thr Leu Thr Val Ser Ser 225 230 235 <210> 180 <211> 243 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 180 Gln Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Val Thr Cys Thr Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Tyr Trp Tyr Gln Gln Lys Pro Arg Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Thr Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Asp Ser Asn Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly 100 105 110 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu Ser 115 120 125 Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys 130 135 140 Ala Ser Gly Tyr Thr Phe Asn Asp Tyr Asn Met Asp Tyr Leu Lys Gln 145 150 155 160 Ser His Gly Lys Ser Leu Glu Trp Ile Gly Asp Ile Asn Pro Asn Tyr 165 170 175 Asp Ser Thr Ile Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr 180 185 190 Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr 195 200 205 Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Arg Asp Tyr Asp Gly 210 215 220 Arg Arg Gly Ala Trp Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr 225 230 235 240 Val Ser Ala

Claims (13)

  1. i) 글리코실화된 CEA를 표적하는 항원-결합 도메인;
    ii) 막 관통 도메인; 및
    iii) 공동자극 도메인(costimulatory domain)을 포함하는 세포 내 신호전달 도메인;을 포함하는 키메라 항원 수용체 (chimeric antigen receptor, CAR)로서,
    상기 글리코실화된 CEA를 표적하는 항원-결합 도메인은 중쇄 가변영역 및 경쇄 가변영역을 포함하되, 상기 중쇄 가변영역은 SEQ ID NO: 13에 제시된 CDR-H1, SEQ ID NO: 14에 제시된 CDR-H2, 및 SEQ ID NO: 15에 제시된 CDR-H3을 포함하고, 상기 경쇄 가변영역은 SEQ ID NO: 16에 제시된 CDR-L1, SEQ ID NO: 17에 제시된 CDR-L2, 및 SEQ ID NO: 18에 제시된 CDR-L3을 포함하는 것을 특징으로 하는, 키메라 항원 수용체.
  2. 제1항에 있어서,
    상기 중쇄 가변영역은 SEQ ID NO: 35에 제시된 폴리펩티드 단편을 포함하고, 상기 경쇄 가변영역은 SEQ ID NO: 36에 제시된 폴리펩티드 단편을 포함하는 것인, 키메라 항원 수용체.
  3. 제1항에 있어서,
    상기 항원-결합 도메인은 인간 글리코실화된 CEA(human glycosylated CEA)를 특이적으로 인식하는 단일쇄 항체(single-chain antibody)이고, 상기 단일쇄 항체의 아미노산 서열은 SEQ ID NO: 173 또는 SEQ ID NO: 178인 것인, 키메라 항원 수용체.
  4. 제1항에 있어서,
    상기 키메라 항원 수용체는 힌지 영역을 더 포함하고, 상기 막 관통 도메인은 CD8α 및/또는 CD28을 포함하며, 상기 세포 내 신호전달 도메인은 CD28, CD137, 및 CD3제타 중 하나 이상을 포함하는 것인, 키메라 항원 수용체.
  5. 제4항에 있어서,
    상기 힌지 영역은 SEQ ID NO: 52 또는 SEQ ID NO:53에 제시된 서열에 의해 암호화되고, 막 관통 영역은 SEQ ID NO:54 또는 SEQ ID NO: 55에 제시된 서열에 의해 암호화되며, 상기 세포 내 신호전달 도메인은 SEQ ID NO:56 또는 SEQ ID NO:57 또는 SEQ ID NO:58에 제시된 서열에 의해 암호화되는 것인, 키메라 항원 수용체.
  6. 제1항 내지 제5항 중 어느 한 항에 기재된 키메라 항원 수용체를 암호화하는, 핵산 분자.
  7. 제1항 내지 제5항 중 어느 한 항에 기재된 키메라 항원 수용체를 발현하는 세포로서, 상기 세포는 T 세포, NK 세포 및 B 세포로 이루어진 군으로부터 선택되는 것인, 키메라 항원 수용체를 발현하는 세포.
  8. 인간 글리코실화된 CEA에 특이적으로 결합하는 단일쇄 항체로서, 상기 단일쇄 항체는 중쇄 가변영역 및 경쇄 가변영역을 포함하되,
    상기 중쇄 가변영역은 SEQ ID NO: 13에 제시된 CDR-H1, SEQ ID NO: 14에 제시된 CDR-H2, 및 SEQ ID NO: 15에 제시된 CDR-H3을 포함하고, 상기 경쇄 가변영역은 SEQ ID NO: 16에 제시된 CDR-L1, SEQ ID NO: 17에 제시된 CDR-L2, 및 SEQ ID NO: 18에 제시된 CDR-L3을 포함하는 것을 특징으로 하는, 단일쇄 항체.
  9. 제8항에 있어서,
    상기 중쇄 가변영역은 SEQ ID NO: 35에 제시된 폴리펩티드 단편을 포함하고, 상기 경쇄 가변영역은 SEQ ID NO: 36에 제시된 폴리펩티드 단편을 포함하는 것인, 단일쇄 항체.
  10. 제8항 또는 제9항에 있어서,
    상기 단일쇄 항체의 아미노산 서열은 SEQ ID NO:173 또는 SEQ ID NO:178인 것인, 단일쇄 항체.
  11. 제1항 내지 제5항 중 어느 한 항에 기재된 키메라 항원 수용체를 포함하는 종양 치료용 약제학적 조성물로서, 상기 종양은 위암(gastric cancer), 대장암(colorectal cancer), 및 식도암(esophageal cancer)으로 이루어진 군으로부터 선택되는 소화관 종양(digestive tract tumor)인 것인, 약제학적 조성물.
  12. 제7항에 기재된 세포를 포함하는 종양 치료용 약제학적 조성물로서, 상기 종양은 위암, 대장암, 및 식도암으로 이루어진 군으로부터 선택되는 소화관 종양인 것인, 약제학적 조성물.
  13. 제8항 또는 제9항에 기재된 단일쇄 항체를 포함하는 종양 치료용 약제학적 조성물로서, 상기 종양은 위암, 대장암, 및 식도암으로 이루어진 군으로부터 선택되는 소화관 종양인 것인, 약제학적 조성물.
KR1020197006047A 2016-07-29 2017-07-27 고도로 글리코실화된 cea인 mg7에 특이적으로 결합하는 단일쇄 항체 및 검출 및 치료에서 이의 용도 KR102460843B1 (ko)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN201610614701.3 2016-07-29
CN201610614701.3A CN107663240B (zh) 2016-07-29 2016-07-29 高度糖基化cea特异性结合的单链抗体及其在检测和治疗上的应用
PCT/CN2017/094755 WO2018019275A1 (zh) 2016-07-29 2017-07-27 Mg7，高度糖基化cea特异性结合的单链抗体及其在检测和治疗上的应用

Publications (2)

Publication Number Publication Date
KR20190034626A KR20190034626A (ko) 2019-04-02
KR102460843B1 true KR102460843B1 (ko) 2022-10-31

Family

ID=61017506

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020197006047A KR102460843B1 (ko) 2016-07-29 2017-07-27 고도로 글리코실화된 cea인 mg7에 특이적으로 결합하는 단일쇄 항체 및 검출 및 치료에서 이의 용도

Country Status (7)

Country Link
US (1) US11266688B2 (ko)
EP (1) EP3492497B1 (ko)
JP (1) JP7195253B2 (ko)
KR (1) KR102460843B1 (ko)
CN (2) CN107663240B (ko)
AU (1) AU2017303944C1 (ko)
WO (1) WO2018019275A1 (ko)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3687546A4 (en) 2017-09-26 2022-01-26 The Trustees Of The University Of Pennsylvania COMPOSITIONS AND METHODS FOR TREATING HEART DISEASE WITH REDIRECTED T-LYMPHOCYTE IMMUNOTHERAPIES
CN109517798B (zh) * 2018-11-28 2022-05-10 北京康爱瑞浩生物科技股份有限公司 一种嵌合cea抗原受体的nk细胞及其制备方法与应用
US20210087295A1 (en) * 2019-09-23 2021-03-25 The Trustees Of The University Of Pennsylvania Disrupting tumor tissues by targeting fibroblast activation protein (fap)
KR20220066090A (ko) * 2019-09-23 2022-05-23 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 마우스 및 인간 섬유아세포 활성화 단백질(fap)과 교차 반응하는 개과 섬유아세포 활성화 단백질에 대한 모노클로날 항체
KR20230048150A (ko) * 2020-08-21 2023-04-10 상하이 젠베이스 바이오테크놀로지 씨오., 엘티디. 글리코실화된 ceacam5에 특이적으로 결합하는 항체
TWI804099B (zh) * 2021-12-10 2023-06-01 大陸商上海吉倍生物技術有限公司 特異性結合糖基化ｃｅａｃａｍ５的抗體及其製備方法
CN118005795A (zh) * 2024-04-09 2024-05-10 天津旷博同生生物技术有限公司 一种抗人cd64抗体及应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007146172A2 (en) * 2006-06-07 2007-12-21 Bioalliance C.V. Antibodies recognizing a carbohydrate containing epitope on cd-43 and cea expressed on cancer cells and methods using same

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5872215A (en) * 1991-12-02 1999-02-16 Medical Research Council Specific binding members, materials and methods
EP2224006A1 (en) * 1991-12-02 2010-09-01 MedImmune Limited Production of anti-self antibodies from antibody segment repertoires and displayed on phage
CU23228A1 (en) * 2002-04-29 2007-09-26 Ct Ingenieria Genetica Biotech FRAGMENTS OF SPECIFIC ANTIBODIES FOR THE HUMAN CARCINOEMBRIONARY ANTIGEN (CEA) SEQUENCES OF ITS VARIABLE REGIONS AND VECTORS FOR THE MICROBIAL EXPRESSION OF THE SAME
CA2501757C (en) 2002-10-08 2012-04-24 Immunomedics, Inc. Combination therapy with class iii anti-cea monoclonal antibodies and therapeutic agents
EP2527370A1 (en) 2005-12-21 2012-11-28 Amgen Research (Munich) GmbH Compounds having resistance to soluble CEA
CA2633756C (en) * 2005-12-21 2015-11-24 Micromet Ag Pharmaceutical antibody compositions with resistance to soluble cea
WO2009129538A2 (en) * 2008-04-18 2009-10-22 Xencor, Inc. Human equivalent monoclonal antibodies engineered from nonhuman variable regions
WO2011023787A1 (en) 2009-08-31 2011-03-03 Roche Glycart Ag Affinity-matured humanized anti cea monoclonal antibodies
WO2011163401A2 (en) 2010-06-22 2011-12-29 Neogenix Oncology, Inc. Colon and pancreas cancer specific antigens and antibodies
CN104371019B (zh) * 2013-08-13 2019-09-10 鸿运华宁（杭州）生物医药有限公司 一种能与glp-1r特异性结合的抗体及其与glp-1的融合蛋白质
EP3126385B1 (en) 2014-03-31 2019-09-18 Board Of Regents, The University Of Texas System Humanized pertussis antibodies and uses thereof
CA2945388A1 (en) * 2014-04-23 2015-10-29 Board Of Regents, The University Of Texas System Chimeric antigen receptors (car) for use in therapy and methods for making the same
CN104628859A (zh) 2015-01-26 2015-05-20 佳德资本投资管理（Bvi）有限公司 抗人癌胚抗原抗体及其编码基因和应用
CN104829733B (zh) 2015-05-25 2018-06-05 广州百暨基因科技有限公司 抗原结合单元稳定的嵌合抗原受体及制备方法与应用
CN104910279B (zh) 2015-06-05 2019-02-22 重庆精准生物技术有限公司 靶向癌胚抗原的嵌合抗原受体、慢病毒表达载体及其制备方法和应用
CN105331585A (zh) * 2015-11-13 2016-02-17 科济生物医药（上海）有限公司 携带pd-l1阻断剂的嵌合抗原受体修饰的免疫效应细胞
CN105330750B (zh) 2015-11-20 2019-02-01 上海细胞治疗研究院 一种快速中止car-t细胞杀伤作用的分子刹车及其用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007146172A2 (en) * 2006-06-07 2007-12-21 Bioalliance C.V. Antibodies recognizing a carbohydrate containing epitope on cd-43 and cea expressed on cancer cells and methods using same
JP2009539380A (ja) 2006-06-07 2009-11-19 バイオアライアンス セー．フェー． 癌細胞で発現するｃｄ−４３およびｃｅａの炭水化物含有エピトープを認識する抗体およびそれを使用する方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Dotti G. et al, Immunological Reviews 257:pp.107~126 (2014.)*

Also Published As

Publication number Publication date
CN107663240B (zh) 2021-01-12
JP7195253B2 (ja) 2022-12-23
AU2017303944C1 (en) 2022-09-08
AU2017303944B2 (en) 2022-03-31
EP3492497B1 (en) 2023-09-06
EP3492497A4 (en) 2020-06-17
US11266688B2 (en) 2022-03-08
CN110072892A (zh) 2019-07-30
US20190167721A1 (en) 2019-06-06
JP2019526275A (ja) 2019-09-19
CN110072892B (zh) 2023-08-29
EP3492497A1 (en) 2019-06-05
KR20190034626A (ko) 2019-04-02
CN107663240A (zh) 2018-02-06
WO2018019275A1 (zh) 2018-02-01
AU2017303944A1 (en) 2019-02-21

Similar Documents

Publication Publication Date Title
KR102460843B1 (ko) 고도로 글리코실화된 cea인 mg7에 특이적으로 결합하는 단일쇄 항체 및 검출 및 치료에서 이의 용도
RU2744245C2 (ru) Антитело против глипикана-3 и его применение
CN110662771B (zh) 一种结合bcma的嵌合抗原受体(car)及其应用
KR101837053B1 (ko) 종간 특이적 ＰＳＣＡｘＣＤ３, ＣＤ19ｘＣＤ3, ｃ-ＭＥＴｘＣＤ3, 엔도시알린ｘＣＤ3, ＥｐＣＡＭｘＣＤ3, ＩＧＦ-1ＲｘＣＤ3 또는 ＦＡＰαｘＣＤ3 이중특이적 단일쇄 항체
KR102099073B1 (ko) 항 ｓｅｚ6 항체들 및 사용 방법
CN116082518A (zh) 一种结合bcma的嵌合抗原受体（car）及其应用
CN112638947B (zh) 用于治疗实体瘤的嵌合抗原受体细胞
CA3032581A1 (en) Treatment of cancer using a chimeric antigen receptor in combination with an inhibitor of a pro-m2 macrophage molecule
AU2017250304A1 (en) Compositions and methods for selective protein expression
JP2018523686A (ja) Ｂ７‐ｈ３及びｃｄ３に結合できる二重特異性１価ダイアボディ並びにその使用
CN114585645A (zh) 对杂合性丧失作出响应的细胞表面受体
KR20220018081A (ko) Ｃｄ20 결합 분자 및 그의 용도
KR102520550B1 (ko) Cd19 및 cd20을 표적화하는 조합된 키메라 항원 수용체 및 그의 적용
CN111247168A (zh) 靶向多种抗原的复合嵌合抗原受体(cCAR)及其组成和使用方法
KR20220016083A (ko) 키메라 수용체 및 이의 사용 방법
JP2018528786A (ja) 腫瘍特異的抗ｅｇｆｒ抗体およびその使用
CN112390892B (zh) 一种嵌合抗原受体以及表达该嵌抗原受体的免疫效应细胞
CN114008079A (zh) 抗adam12抗体和嵌合抗原受体以及包含其的组合物和方法
CN113164538A (zh) 修饰的溶瘤病毒、其组合物和用途
WO2015172341A1 (zh) 针对磷脂酰肌醇蛋白多糖-3和t细胞抗原的双特异性抗体
CN112661857B (zh) 一种嵌合抗原受体及其用途
CN111971303B (zh) 抗cd27抗体及其用途
CN116390941A (zh) 多特异性嵌合抗原受体及其用途
CN115667500A (zh) Gpc3 car-t细胞组合物及其制备和使用方法

Legal Events

Date Code Title Description
A201 Request for examination
E902 Notification of reason for refusal
E701 Decision to grant or registration of patent right
GRNT Written decision to grant