JP6825065B2 - 分泌物の多細胞アッセイにおけるマイクロ流体デバイスおよびその使用方法 - Google Patents
分泌物の多細胞アッセイにおけるマイクロ流体デバイスおよびその使用方法 Download PDFInfo
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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Description
U = Vparticle * (ρparticle - ρliquid) * g * γ-1
ここで、Vparticleは粒子の体積であり、Gは重力加速度であり、γは粒子の抗力係数である。球状粒子の場合、γはストークス抵抗式のように近似される。
γsphere = 6πηr
P(マイクロウェル内の1または複数) = λke-λ/k!
ここで、λはマイクロ流体チャンバのマイクロウェル当たりの粒子の平均数である。この例においては、(3+3)/45=0.133である。このように、本実施形態では、マイクロウェルにおける0または1の粒子を有する確率は、以下のようである。
P(k=0) = e-0.133 = 87.5%, および P(k=1) = 11.7%
P(複数の粒子を有するウェルがない) = (1-0.0083)45= 69%
実施例1 - マイクロ流体デバイスの作製
実施例2 - 選択と再注入による細胞の濃縮のためのマイクロ流体デバイス
実施例3 - エフェクターと読み出し細胞の分離用のマイクロ流体デバイス
実施例4 - 細胞フェンスチャンバの統合
実施例5 - 抗体分泌エフェクター細胞の堅牢なマイクロ流体成長
実施例6 - ASCの不均一な集団の存在下で単一のASCの検出感度
実施例7 - ビーズ系結合アッセイおよび細胞系結合アッセイを使用する単一細胞からモノクローナル抗体の選択
実施例8 - 細胞系免疫化および細胞結合アッセイ
実施例9 - 細胞生存率および分泌のメンテナンス
実施例10 - 形質細胞を濃縮する方法
実施例11 - インフルエンザヒトシステムを用いる濃縮
実施例12 - 抗体分泌の指標としてのビーズ凝集
実施例13 - HEL特異的ハイブリドーマ用の親和性測定
実施例14 - チャンバ分離のあるまたはチャンバ分離のない抗原特異的細胞の同定
実施例15 - 親和性測定に基づく新規なマウス抗体分泌細胞の選択
Mm20 (IGHV1-9*01) IGHD2-4*01, IGHD2-4*01, IGHD2-9*02 IGHJ2*01 重鎖核酸配列 (SEQ ID NO: 1):
ATGGAATGGACCTGGGTCTTTCTCTTCCTCCTGTCAGTAACTGCAGGTGTCCACTCCCAGGTTCAGCTGCAGCAGTCTGGACCTGAGCTGATGAAGCCTGGGGCCTCAGTGAAGATATCCTGCAAGGCAACTGGCTACACATTCAGAAACTACTGGATAGAGTGGATAAAGCAGAGGCCTGGACATGGCCTTGAGTGGATTGGAGAGATTTTACCTGAAAGTGGTAGTATTAATTACAATGAGAAATTCAAGGGCAAGGCCACATTCACTGCAGATACATCCTCCAACACAGCCTACTTGCAACTCCGCAGCCTGACATCTGAGGACTCTGCCGTCTATTATTGTTTTTATGATAATTACGTTTTTGACTACTGGGGCCAaggcacCACTctcAC
Mm20 軽鎖アミノ酸配列 (SEQ ID NO: 2):
M E W T W V F L F L L S V T A G V H S Q V Q L Q Q S G P E L M K P G A S V K I S C K A T G Y T F R N Y W I E W I K Q R P G H G L E W I G E I L P E S G S I N Y N E K F K G K A T F T A D T S S N T A Y L Q L R S L T S E D S A V Y Y C F Y D N Y V F D Y W G Q G T T L
Mm20 (IGKV4-59*01) IGKJ5*01軽鎖核酸配列(SEQ ID NO: 3):
ATGGATTCTCAAGTGCAGATTTTCAGCTTCCTGCTAATCAGTGCCTCGGTCATACTATCCAGTGGACAAATTGTTCTCATCCAGTCTCCAACAATCATGTCTGCATCTCCAGGGGAGAAGGTCACCATGACCTGCAGTGCCAACTCAAGTTTCAGTTACATGCACTGGTACCAGCAGAAGTCAGGCACCTCCCCCAAAAGATGGATTTATGACACATCCAAACTGGCTTCTGGAGTCCCTGCTCGCTTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCACAATTAGCAGCATGGAGGCTGAAGATGCTGCCACTTATTACTGTCAGCAGTGGAGTAGAAACCCCACGTTCGGTGCtggacCaAGCtGa
Mm20 軽鎖アミノ酸配列 (SEQ ID NO: 4):
M D S Q V Q I F S F L L I S A S V I L S S G Q I V L I Q S P T I M S A S P G E K V T M T C S A N S S F S Y M H W Y Q Q K S G T S P K R W I Y D T S K L A S G V P A R F S G S G S G T S Y S L T I S S M E A E D A A T Y Y C Q Q W S R N P T F G A G T K L
>Mm25 (IGHV2-9-1*01) IGHD2-3*01 IGHJ3*01重鎖核酸配列 (SEQ ID NO: 5):
ATGCAAGCAGTGGTATCAACGCAGAGTACGGGGAAGGAGTCAGGACCTGGCTTGGTGGCGCCCTCACAGAGCATGTCCATCATGTGCACTGTCTCTGGGTTTTCATTAAGCAACTATGGTGTACACTGGGTTCGCCAGCCTCCAGGAAAGGGTCTGGAGTGGCTGGGAGTAATTTGGGCTGGTGGAAACACAAATTATAATTCGGCTCTCATGTCCAGACTGAGCATCAGCAAAGACAAGTCCAAGAGTCAAGTTTTCTTAAAAATGAACCGTCTGGAAACTGATGACACAGCCATGTACTATCTGTGCCAGTGTAGGATGGTTACCCCTTGCTTACTGGGCCAAGG
Mm25 重鎖アミノ酸配列(SEQ ID NO: 6):
M Q A V V S T Q S T G K E S G P G L V A P S Q S M S I M C T V S G F S L S N Y G V H W V R Q P P G K G L E W L G V I W A G G N T N Y N S A L M S R L S I S K D K S K S Q V F L K M N R L E T D D T A M Y Y L C Q C R M V T P C L L G Q
>Mm25 (IGKV6-17*01) IGKJ4*01 軽鎖核酸配列 (SEQ ID NO: 7):
ATGGAGTCACAGATTCAGGTCTTTGTATTCGTGTTTCTCTGGTTGTCTGGTGTTGACGGAGACATTGTGATGACCCAGTCTCACAAATTCATGTCCACATCAGTAGGAGACAGGGTCAGCATCACCTGCAAGGCCAGTCAGGATGTGAGTATTTCTGTAGCCTGGTATCAACAGAAACCAGGACAATCTCCTAAACTACTGATTTACTCGGCATCCTACCGGTACACTGGAGTCCCTGATCGCTTCACTGGCAGTGGATCTGGGACGGATTTCACTTTCACCATCCGCAGTGTGCAGGCTGAAGACCTGGCAGTTTATTACTGTCAGCAACATTATAGTACTCCttTCACGTCGGCTcggGaCAAagTG
Mm25軽鎖アミノ酸配列 (SEQ ID NO: 8):
M E S Q I Q V F V F V F L W L S G V D G D I V M T Q S H K F M S T S V G D R V S I T C K A S Q D V S I S V A W Y Q Q K P G Q S P K L L I Y S A S Y R Y T G V P D R F T G S G S G T D F T F T I R S V Q A E D L A V Y Y C Q Q H Y S T P F T S A R D K V
実施例16 - HyHEL5ハイブリドーマ細胞のためのK off 値
実施例17 - ヒト抗特異的抗原における希少循環抗体-分泌細胞の検出
実施例18 - 細胞外および細胞内の生体分子の同時分析
実施例19 -ヒト細胞からの抗体スクリーニングおよびシーケンスの回収
Hs7 (IGHV4-39*01) IGHD3-3*02 IGHJ3*02 重鎖核酸配列 (SEQ ID NO: 9):
ATGAAGCACCTGTGGTTCTTCCTCCTGCTGGTGGCGGCTCCCAGATGGGTCCTGTCTCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGTCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGACTCCATCACCAGCAGTACTTACGACTGGGGCTGGATCCGTCAGCCCCCCGGGAAGGGCCTGGAGTGGATTGGCAATGTCTATTATAGAGGGAGCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTAGACAGGTCCAGGACCCAGATCTCCCTGAGGCTGAGCTCTGTGACCGCCGCTGACACGGCTCTGTATTTCTGTGCGAGACACCCGAAACGTCTAACGGTTTTTGAAGTGGTCAACGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTTTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCTGCTGACGAGGCACTGAGGACTG
Hs7 重鎖アミノ酸配列 (SEQ ID NO: 10):
M K H L W F F L L L V A A P R W V L S Q V Q L Q E S G P G L V K S S E T L S L T C T V S G D S I T S S T Y D W G W I R Q P P G K G L E W I G N V Y Y R G S T Y Y N P S L K S R V T I S V D R S R T Q I S L R L S S V T A A D T A L Y F C A R H P K R L T V F E V V N A F D I W G Q G Q T M V T V F S A S T K G P S V F P L A P S S K S T S G G T A
Hs7 (IGLV2-14*01) IGLJ3*02 軽鎖核酸配列 (SEQ ID NO: 11):
ATGGCCTGGGCTCTGCTACTCCTCACCCTCCTCACTCAGGGCACAGGGTCCTGGGCCCAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGCATCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAATCAGCAGTGACATTGGTGGTTATAGCTCTGTCTCCTGGTACCAAGCGCACCCAGGCAAAGCCCCCAAACTCATGATCTATGATGTCAATAATCGGCCCTCAGGCATTTCTAATCGCTTCTCTGGTTCCAAGTCTGGCAACACGGCCTCCCTGGCCATCTCTGGGCTCCAGgctgaGGACGAGGCAGATTATTACTGCAGCTTATATACAAGTATCAACGCTTCCATAGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACA
Hs7 軽鎖アミノ酸配列 (SEQ ID NO: 12):
M A W A L L L L T L L T Q G T G S W A Q S A L T Q P A S V S A S P G Q S I T I S C T G I S S D I G G Y S S V S W Y Q A H P G K A P K L M I Y D V N N R P S G I S N R F S G S K S G N T A S L A I S G L Q A E D E A D Y Y C S L Y T S I N A S I V F G G G T K L T V L G Q P K A A P S V T L F P P S S
Hs15 (IGHV4-39*01) IGHD3-3*01 IGHJ3*02 重鎖核酸配列 (SEQ ID NO: 13):
ATGAAGCACCTGTGGTTCTTCCTTCTGCTGGTGGCGGCTCCCAGATGGGTCCTGTCCCAGCTGCAACTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGACTCCATCAGCAGTAGTACTTACTACTGGGGCTGGATCCGCCAGCCCCCAGGAAAGGGGCTGGAGTGGATTGCCTTTATCTTTTATAGCGGGAGCACCTTCTACAACCCGTCCCTCAAGAGTCGAGTCACCGTCTCCGTAGACAGGTCCACGAACCAGTTCTCCCTGAGGCTGAAGTCTGTGACCGCCGCAGACACGTCCAGATATTACTGTGCGAGACACCCAAAACGTATCTCGATTTTTGAAGTGGTCAACGCTTTTGATATCtGGGGCCAGGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCTGCTGACGAGGCACTGAGGACTG
Hs15 重鎖アミノ酸配列 (SEQ ID NO: 14):
M K H L W F F L L L V A A P R W V L S Q L Q L Q E S G P G L V K P S E T L S L T C T V S G D S I S S S T Y Y W G W I R Q P P G K G L E W I A F I F Y S G S T F Y N P S L K S R V T V S V D R S T N Q F S L R L K S V T A A D T S R Y Y C A R H P K R I S I F E V V N A F D I W G Q G T M V T V S S A S T K G P S V F P L A P S S K S T S G G T A
>Hs15 (IGLV2-14*01) IGLJ2*01 IGLJ3*01軽鎖核酸配列 (SEQ ID NO: 15):
ATGGCCTGGACTCTGCTATTCCTCACCCTCCTCACTCAGGGCACAGGGTCCTGGGCCCAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCACCTGCACTGGAATCAGCAGTGACGTTGGTGCTTATAATTCTGTCTCCTGGTACCAGCAGTACCCAGGCAAATCCCCCAAGCTCATGATTTATGATGTCAGTAATCGGTCCTCAGGGGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGACAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTTCTTATTTCTGCAGCTTATATAGAAGCAGCACCACTTCCGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTACGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACA
Hs15 軽鎖核酸配列 (SEQ ID NO: 16):
M A W T L L F L T L L T Q G T G S W A Q S A L T Q P A S V S G S P G Q S I T I T C T G I S S D V G A Y N S V S W Y Q Q Y P G K S P K L M I Y D V S N R S S G V S N R F S G S K S D N T A S L T I S G L Q A E D E A S Y F C S L Y R S S T T S V V F G G G T K L T V L R Q P K A A P S V T L F P P S S
実施例20 - ウサギの不均一な細胞集団からの抗体スクリーニングおよびシーケンス回収
重 1 (SEQ ID NO: 17):
GCTAGCCACCATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCATAGTCTCTGGAATCGACCTCAGTAGCTATGCAATGGGCTGGGTCCGCCAGGCTCCAGGAAAGGGGCTGGAATACATCGGAATCATTAGTAGCAGTGGTATCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGACTCTGACAATCACCGATCTGCAACCTTCAGACACGGGCACCTATTTCTGTGCCAGAGGGTCTCGTTATAGTGCTTTTGGTGCTTTTGATACCTGGGGCCCAGGCACCCTGGTCACCGTCTCCTCAGCAAGCTTNAN
重3 (SEQ ID NO: 18):
TTTGGCTAGCCACCATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAGTAGCTATGCAATGGGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAGTCATTAATAATAATGGTGACACATACTACGCGAGCTGGCCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGATCGTGGTAATAGTTATTACTTTGGATTGGACTACTTTAACTTGTGGGGCCCAGGCACCCTGGTCACCGTCTCCTCAGCAAGCTTTATAN
軽 1 (SEQ ID NO: 19):
CTCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTTCGAATTGACCCAGACTCCATCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGTATTAATAGTTGGTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCATCCAATCTGGCATCTGGGGTCCCATCGCGGTTCAGAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGNCGATGCTGCCACTTACTACTGTCAAAGCNATTATGCTACTAGTAGTGTTGATTATNATGCTTTCGGCGGAAGGACCGAGGTGGTGGTCAANACTGCGGCNGTANTANTNNN
軽 3 (SEQ ID NO: 20):
TGCAGCTAGCCACCATGGACACGAGGGCCCCCATCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGGTGTGCCCTTGTGATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTGATAGTTGGTTATCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAGGCTCCTGATCTATTATGCATCCAATCTGGCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAATACACTCTCACCATCAGCGGCGTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAGAGGGTTATAGTAGTGGTAATGTTGATAATGTTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAACTGCGNCCGCTATAN
実施例21 -ヒト配列からの抗体の発現と検証
aMCP1-重 (SEQ ID NO: 21):
GAATTCCATGCAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCCGGCAGCAGCGTGAAGGTGTCCTGCAAGGCCAGCGGCCTGACCATCAGCGACACCTACATGCACTGGGTGCGCCAGGCTCCAGGCCAGGGACTGGAATGGATGGGCAGAATCGACCCCGCCAACGGCAACACCAAGTTCGACCCCAAGTTCCAGGGCAGAGTGACCATCACCGCCGACACCAGCACCTCCACCGCCTACATGGAACTGAGCAGCCTGCGGAGCGAGGACACCGCCGTGTACTATTGTGCCAGAGGCGTGTTCGGCTTCTTCGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCATCTGCTAGC
aMCP1-軽 (SEQ ID NO: 22):
ACCGGTGCCACCATGTACCGGATGCAGCTGCTGAGCTGTATCGCCCTGTCTCTGGCCCTCGTGACGAATTCAGCCATGGACATCCAGATGACCCAGAGCCCCAGCAGCCTGTCTGCCAGCGTGGGCGACAGAGTGACCATCACATGCAAGGCCACCGAGGACATCTACAACCGGCTGGCCTGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATTAGCGGAGCCACCAGCCTGGAAACCGGCGTGCCAAGCAGATTTTCCGGCAGCGGCTCCGGCAAGGACTACACCCTGACCATCAGCTCCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCAGCAGTTTTGGAGCGCCCCCTACACCTTTGGCGGAGGCACCAAGGTGGAAATCAAGCGTACG
実施例22 - 単一細胞からマウスシーケンス回収に続く検証用抗体のクローニングおよび発現
D1.3-重 (SEQ ID NO: 23):
ATGCAGGTGCAGCTGAAGGAGTCAGGACCTGGCCTGGTGGCGCCCTCACAGAGCCTGTCCATCACATGCACCGTCTCAGGGTTCTCATTAACCGGCTATGGTGTAAACTGGGTTCGCCAGCCTCCAGGAAAGGGTCTGGAGTGGCTGGGAATGATTTGGGGTGATGGAAACACAGACTATAATTCAGCTCTCAAATCCAGACTGAGCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCACACTGATGACACAGCCAGGTACTACTGTGCCAGAGAGAGAGATTATAGGCTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGCTAGC
D1.3-軽 (SEQ ID NO: 24):
ATGGACATCCAGATGACTCAGTCTCCAGCCTCCCTTTCTGCGTCTGTGGGAGAAACTGTCACCATCACATGTCGAGCAAGTGGGAATATTCACAATTATTTAGCATGGTATCAGCAGAAACAGGGAAAATCTCCTCAGCTCCTGGTCTATTATACAACAACCTTAGCAGATGGTGTGCCATCAAGGTTCAGTGGCAGTGGATCAGGAACACAATATTCTCTCAAGATCAACAGCCTGCAGCCTGAAGATTTTGGGAGTTATTACTGTCAACATTTTTGGAGTACTCCTCGGACGTTCGGTGGAGGCACCAAGCTCGAG
HyHEL5-重 (SEQ ID NO: 25):
ATGGAGGTCCAGCTGCAGCAGTCTGGAGCTGAGCTGATGAAGCCAGGGGCCTCAGTGAAGATATCCTGCAAAGCTTCTGGCTACACATTCAGTGACTACTGGATAGAGTGGGTAAAGCAGAGGCCTGGACATGGCCTTGAGTGGATTGGAGAGATTTTACCTGGAAGTGGTAGCACTAATTACCATGAGAGATTCAAGGGCAAGGCCACATTCACTGCAGATACATCCTCCAGCACAGCCTACATGCAACTCAACAGCCTGACATCTGAAGACTCTGGCGTCTATTACTGCCTCCATGGTAACTACGACTTTGACGGCTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGCTAGC
HyHEL5-軽 (SEQ ID NO: 26):
ATGGATATCGTTCTCACACAGTCTCCAGCAATCATGTCTGCATCTCCAGGGGAGAAGGTCACCATGACCTGCAGTGCCAGTTCAAGTGTAAATTACATGTACTGGTACCAGCAGAAGTCAGGCACTTCCCCCAAAAGATGGATTTATGACACATCCAAACTGGCTTCTGGAGTCCCTGTTCGCTTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCACAATCAGCAGCATGGAGACTGAAGATGCTGCCACTTATTACTGCCAACAGTGGGGTCGTAACCCCACGTTCGGAGGGGGGACCAAGCTCGAG
実施例23 - マイクロ流体スクリーニングから得られた新規のマウス抗体配列の検証
R05C14-重可変 (SEQ ID NO: 27):
TGGAAGGTGGTGCACACTGCTGGACAGGGATCCAGAGTTCCAGGTCACTGTCACTGGCTCAGGGAAATAGCCCTTGACCAGGCATCCCAGGGTCACCATGGAGTTAGTTTGGGCAGCAGATCCAGGGGCCAGTGGATAGACAGATGGGGGTGTCGTTTTGGCTGAGGAGACTGTGAGAGTGGTGCCTTGGCCCCAGCAGTCCCCGTCCCAGTTTGCACAGTAATATGTGGCTGTGTCCTCAGGAGTCACAGAAATCAACTGCAGGTAGCACTGGTTCTTGGATGTGTCTCGAGTGATAGAGATTCGACCTTTGAGAGATGGATTGTAGTAAGTGCTACCACTGTAGCTTATGTACCCCATATACTCAAGTTTGTTCCCTGGGAATTTCCGGATCCAGCTCCAGTAATCATTGGTGATGGAGTCGCCAGTGACAGAACAGGTGAGGGACAGAGTCTGAGAAGGTTTCACGAGGCTAGGTCCAGACTCCTGCAGCTGCACCTCGAATTCCCA
R05C14-軽可変 (SEQ ID NO: 28):
TTGGTCCCCCCTCCGAACGTGTACGGCCAGTTGTTACTCTGTTGACAGAAATACATTCCAAAATCTTCAGTCTCCACACTGATGATACTGAGAGTGAAATCCGTCCCTGATCCACTGCCACTGAACCTGGAGGGGATCCCAGAGATGGACTGGGAAGCATACTTGATGAGAAGCCTTGGAGACTCATGTGATTTTTGTTGATACCAGTGTAGGTTGTTGCTAATACTTTGGCTGGCCCTGCAGGAAAGACTGACGCTATCTCCTGGAGTCACAGACAGGGTGTCTGGAGACTGAGTTAGCACAATATCACCTCTGGAGGCTGAAATCCAGAAAAGCAAAAAA
実施例24 -エフェクター細胞抗体の増幅のシーケンス回収
実施例25 - デバイスから回収された単一細胞のNGSシーケンシング
実施例26 - 光学的にコード化されたビーズを使用する多重化ビーズアッセイ
実施例27 - マイクロ流体アポトーシスエフェクターアッセイ
実施例28 - マイクロ流体細胞シグナリングエフェクターアッセイ
実施例29 - マイクロ流体増殖およびオートファジーエフェクター細胞アッセイ
実施例30 - 抗原特異的T細胞の検出および回収
実施例31 - シグナリングのためのBAF3 PDGFRαアッセイ
実施例32 - DiscoveRx細胞を用いるリガンドに対するGPCR応答
Claims (22)
- 標的エピトープに結合する抗体を分泌する抗体分泌細胞(ASC)を含む不均一細胞集団を同定する方法であって、
10〜500の細胞を含む不均一細胞集団をマイクロリアクターに保持する工程であって、前記不均一細胞集団は抗体を分泌するASCを含み、前記マイクロリアクターの中身は、標的エピトープを提示する1または複数の読み出し粒子を含む、読み出し粒子集団をさらに含む、工程と、
前記マイクロリアクター内で、前記不均一細胞集団と、前記読み出し粒子とをインキュベートする工程であって、前記マイクロリアクターはその周囲の環境から実質的に隔離されている、工程と、
前記ASCから分泌された抗体が前記不均一細胞集団中で前記標的エピトープに結合しているかをアッセイする工程と、および
前記アッセイする工程の結果に基づいて、前記不均一細胞集団が前記標的エピトープに結合する抗体を分泌する前記ASCを含むかどうかを決定する工程、を含む方法。 - 前記読み出し粒子集団は、前記標的エピトープで官能化された1または複数の読み出しビーズを含む、読み出しビーズ集団である、請求項1に記載の方法。
- 前記標的エピトープがタンパク質、ペプチド、脂質、膜抽出物又はこれらの組合せである請求項1又は2に記載の方法。
- 前記標的エピトープが抗体エピトープである請求項1又は2に記載の方法。
- 前記結合の相互作用は、抗原−抗体結合特異性、抗原−抗体結合親和性、または抗原−抗体結合動態である請求項4に記載の方法。
- 前記読み出し粒子集団は、1または複数の読み出し細胞を含む読み出し細胞集団である請求項1に記載の方法。
- 前記1または複数の読み出し細胞は膜貫通タンパク質を発現する請求項6に記載の方法。
- 前記標的エピトープが前記膜貫通タンパク質上に在る請求項7に記載の方法。
- 前記膜貫通タンパク質はGタンパク質共役受容体(GPCR)、チロシンキナーゼ受容体(RTK)、イオンチャネル又はATP結合カセット(ABC)トランスポーターである請求項8に記載の方法。
- 前記膜貫通タンパク質はGPCRである請求項8に記載の方法。
- 前記膜貫通タンパク質はRTKである請求項8に記載の方法。
- 前記膜貫通タンパク質はイオンチャネルである請求項8に記載の方法。
- 前記膜貫通タンパク質はABCトランスポーターである請求項8に記載の方法。
- 前記Gタンパク質共役受容体は、ケモカイン受容体、サイトカイン受容体、クラスA GPCR、クラスB GPCR、接着GPCR、フリズルドGPCR、アセチルコリン受容体、メラトニン受容体、メラコルチン受容体、モチリン受容体、リゾリン脂質(LPA)受容体、アデノシン受容体、アドレナリン受容体、アンギオテンシン受容体、ブラジキニン受容体、カルシトニン受容体、カルシウム感知受容体、カンナビノイド受容体、ケモカイン受容体、コレシストキニン受容体、補体成分(C5AR1)受容体、副腎皮質放出因子受容体、ドーパミン受容体、内皮分化遺伝子受容体、エンドセリン受容体、ホルミルペプチド様受容体、ガラニン受容体、ガストリン放出ペプチド受容体、受容体グレリン受容体、胃抑制ポリペプチド受容体、グルカゴン受容体、ゴナドトロピン放出ホルモン受容体、ヒスタミン受容体、キスペプチン(KiSS1)受容体、ロイコトリエン受容体、メラニン凝集ホルモン受容体、メラノコルチン受容体、メラトニン受容体、モチリン受容体、神経ペプチド受容体、ニコチン酸、オピオイド受容体、オレキシン受容体、オーファン受容体、血小板活性化因子受容体、プロキネチシン受容体、プロラクチン放出ペプチド、プロスタノイド受容体、プロテアーゼ活性化受容体、P2Y(プリン)受容体、リラキシン受容体、セクレチン受容体、セロトニン受容体、ソマトスタチン受容体、タキキニン受容体、バソプレッシン受容体、オキシトシン受容体、血管作動性腸管ペプチド(VIP)受容体または下垂体アデニル酸シクラーゼ活性化ポリペプチド(PACAP)受容体、テースト1受容体、メタボトロピックグルタミン酸受容体、カルシウム感知受容体、脳特異的血管新生阻害剤受容体(1、2または3)、カドヘリン受容体またはエストロゲン受容体である請求項10に記載の方法。
- 前記チロシンキナーゼ受容体(RTK)は、ErbB−1、ErbB−2、ErbB−3、ErbB−4、インスリン受容体、血小板由来成長因子α受容体、血小板由来増殖因子β受容体、マスト/ステム細胞成長因子受容体(SCFR)、コロニー刺激因子1受容体、CD135、線維芽細胞増殖因子受容体‐1(CD331)、線維芽細胞成長因子受容体‐2(CD332)、線維芽細胞成長因子受容体‐3(CD333)、線維芽細胞成長因子受容体‐4(CD334)、線維芽細胞増殖因子受容体‐6、血管内皮増殖因子(VEGF)1受容体、VEGF 2受容体、VEGF 3受容体、肝細胞増殖因子受容体、トロポミオシン受容体キナーゼ(Trk)A、Trk B、Trk C、エフリン(EPH)受容体A1、EPH受容体A2、EPH受容体A3、EPH受容体A4、EPH受容体A5、EPH受容体A6、EPH受容体A7、EPH受容体A8、EPH受容体A9、EPH受容体A10、EPH受容体B1、EPH受容体B2、EPH受容体B3、EPH受容体B4、EPH受容体B5、EPH受容体B6、AXL、RTKクラスIX受容体ファミリーのメンバー、未分化リンパ腫キナーゼ/白血球チロシンキナーゼ(ALK/LTK)受容体ファミリーのメンバー、RTKクラスXI受容体ファミリーのメンバー、神経栄養性チロシンキナーゼ、受容体関連1受容体、ジスコイジンドメイン受容体、RTKクラスXIV受容体ファミリーのメンバー、RTKクラスXV受容体ファミリーのメンバー、RTKクラスXVI受容体ファミリーのメンバーまたは筋肉特異的キナーゼ受容体である請求項11に記載の方法。
- 前記イオンチャネルは、GABA A 受容体、グリシン受容体(GlyR)、セロトニン(5‐ヒドロキシトリプトアミン)受容体、ニコチン性アセチルコリン受容体(nAChR)、亜鉛活性化イオンチャネル、イオンチャネル型グルタミン酸受容体、AMPA受容体、カイナイト受容体、NMDA受容体またはATP依存性チャネルである請求項12に記載の方法。
- 前記不均一細胞集団および前記読み出し粒子集団を複数のアクセサリー粒子と共にインキュベートする工程をさらに含む請求項1〜16のいずれか1項に記載の方法。
- 前記複数のアクセサリー粒子は、複数の蛍光標識二次抗体を含む請求項17に記載の方法。
- 前記複数のアクセサリー粒子は、下記を含む請求項17に記載の方法、
a)細胞、ビーズ、タンパク質、ペプチド、成長因子、サイトカイン、神経伝達物質、脂質、リン脂質、アミノ酸、モノアミン、糖タンパク質、炭水化物、ホルモン、ウイルス粒子、抗体、抗体フラグメント、蛍光基質、フルオロフォア、二次抗体、またはそれらの組み合わせ;
b)スフィンゴシン−1−リン酸、リゾホスファチジン酸またはそれらの組合せ;
c)蛍光基質または開裂されたとき蛍光になる非蛍光基質;
d)線維芽細胞、ナチュラルキラー(NK)細胞、キラーT細胞、抗原提示細胞、樹状細胞、組換え細胞またはそれらの組み合わせ;
e)複数のウイルス粒子;又は
f)複数の、補体経路誘導因子。 - 前記アッセイが、蛍光強度のレベルの検出により行われる請求項1〜19のいずれか1項に記載の方法。
- 前記不均一細胞集団は、前記標的エピトープに結合する抗体を分泌するASCを含み、前記方法は、前記不均一細胞集団またはその一部を回収して回収された細胞集団を得る工程をさらに含む、請求項1記載の方法。
- 前記読み出し粒子集団は、蛍光標識された抗原を含む請求項1に記載の方法。
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