TW202304967A - 鳥苷酸環化酶2c結合多肽、鳥苷酸環化酶2c結合抗體、融合蛋白質、嵌合抗原受體、免疫細胞、多核苷酸、用於偵測鳥苷酸環化酶2c的組成物、用於診斷癌症的組成物以及醫藥組成物 - Google Patents
鳥苷酸環化酶2c結合多肽、鳥苷酸環化酶2c結合抗體、融合蛋白質、嵌合抗原受體、免疫細胞、多核苷酸、用於偵測鳥苷酸環化酶2c的組成物、用於診斷癌症的組成物以及醫藥組成物 Download PDFInfo
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Abstract
本發明是關於一種鳥苷酸環化酶2C結合多肽以及其應用,且具體而言,是關於鳥苷酸環化酶2C結合多肽、包括其的融合蛋白質或嵌合抗原受體、表現嵌合抗原受體的免疫細胞以及其癌症治療及/或診斷的應用。
Description
[相關申請案的交叉引用]
本申請案主張基於2021年4月7日申請的韓國專利申請案第10-2021-0045510號的優先權,且在對應韓國專利申請案的文件中所揭露的所有內容作為本說明書中的一部分併入。
本申請案是關於一種GUCY2C結合多肽以及其應用,且具體而言,是關於GUCY2C結合多肽、包括其的融合蛋白質、表現嵌合抗原受體的免疫細胞以及其癌症治療及/或診斷的應用。
鳥苷酸環化酶2C(GUCY2C(Guanylate cyclase 2C;GUCY2C);鳥苷酸環化酶C(guanylyl cyclase C);GC-C或GCC)為作用於腸液、電解質穩態以及維持細胞增殖的跨膜細胞表面受體及類似者。在正常成年哺乳動物中,GUCY2C表現於覆蓋小腸、大腸以及直腸的內壁的黏膜細胞中。此等細胞經歷增殖、遷移、分化以及凋亡的週期,且增殖與凋亡之間的不平衡可誘發胃腸道中的腫瘤形成。
[技術難題]
因此,在本說明書中,提供一種新穎GUCY2C結合多肽、包括其的融合蛋白質以及其癌症治療及/或診斷的應用。
一個實施例提供一種結合於GUCY2C的GUCY2C結合多肽。
GUCY2C結合多肽可包括
重鏈可變區,包括用選自由SEQ ID NO:38至44組成的族群的胺基酸序列表示的重鏈CDR1(下文中為CDR-H1)、用選自由SEQ ID NO:45至53組成的族群的胺基酸序列表示的CDR-H2以及用選自由SEQ ID NO:54至65組成的族群的胺基酸序列表示的CDR-H3;
輕鏈可變區,包括用選自由SEQ ID NO:66至78組成的族群的胺基酸序列表示的輕鏈CDR1(下文中為CDR-L1)、用選自由SEQ ID NO:79至88組成的族群的胺基酸序列表示的CDR-L2以及用選自由SEQ ID NO:89至106組成的族群的胺基酸序列表示的CDR-L3;
或其組合。
在一個實施例中,GUCY2C結合多肽可為包括重鏈可變區及輕鏈可變區的單鏈可變片段(single chain variable fragment;scFv),無論次序如何。scFv可在自N端至C端的方向上按重鏈可變區及輕鏈可變區的次序或輕鏈可變區及重鏈可變區的次序包括重鏈可變區及輕鏈可變區,且舉例而言,其可在自N端至C端的方向上按重鏈可變區及輕鏈可變區的次序包括重鏈可變區及輕鏈可變區。接著,重鏈可變區及輕鏈可變區可經由肽連接子連接或在無連接子的情況下直接連接。在一個特定實施例中,多肽可為用選自由SEQ ID NO:1至18組成的族群的胺基酸序列表示的scFv。
另一實施例提供一種特異性結合於GUCY2C的抗體或其抗原結合片段,其包括重鏈可變區及輕鏈可變區。
另一實施例提供一種融合蛋白質,其包括GUCY2C結合多肽及免疫球蛋白的Fc域。
另一實施例提供一種共軛物,其包括GUCY2C結合多肽、抗體或其抗原結合片段或融合蛋白質,以及藥物。藥物可為選自抗癌劑、造影劑以及類似者的一或多種類別。
另一實施例提供一種嵌合抗原受體,其包括GUCY2C結合多肽。嵌合抗原受體可對GUCY2C具有特異性。
另一實施例提供一種免疫細胞,其包括嵌合抗原受體。免疫細胞可為在細胞表面上表現嵌合抗原受體的免疫細胞。免疫細胞可為GUCY2C特異性免疫細胞。
另一實施例提供一種多核苷酸,其編碼GUCY2C結合多肽、特異性結合於GUCY2C的抗體或其抗原結合片段、融合蛋白質或嵌合抗原受體。另一實施例提供包括多核苷酸的重組載體。另一實施例提供包括多核苷酸或重組載體的重組細胞。
另一實施例提供一種用於預防及/或治療癌症的醫藥組成物,其包括選自由以下組成的族群的一或多種類別作為活性成份:GUCY2C結合多肽、特異性結合於GUCY2C的抗體或其抗原結合片段、融合蛋白質、共軛物、嵌合抗原受體、編碼其的多核苷酸、包括多核苷酸的重組載體、包括重組載體的重組細胞以及表現嵌合抗原受體的免疫細胞。
另一實施例提供一種用於預防及/或治療癌症的方法,其包括將醫藥學有效劑量的選自由以下組成的族群的一或多種類別投與至需要預防及/或治療癌症的個體中:GUCY2C結合多肽、特異性結合於GUCY2C的抗體或其抗原結合片段、融合蛋白質、共軛物、嵌合抗原受體、編碼其的多核苷酸、包括多核苷酸的重組載體、包括重組載體的重組細胞以及表現嵌合抗原受體的免疫細胞。
另一實施例提供一種選自由以下組成的族群的一或多種類別的用於預防及/或治療癌症的應用或用於製備用於預防及/或治療癌症的醫藥組成物的應用:GUCY2C結合多肽、特異性結合於GUCY2C的抗體或其抗原結合片段、融合蛋白質、共軛物、嵌合抗原受體、編碼其的多核苷酸、包括多核苷酸的重組載體、包括重組載體的重組細胞以及表現嵌合抗原受體的免疫細胞。
另一實施例提供一種用於診斷癌症的組成物,其包括選自由以下組成的族群的一或多種類別作為活性成份:GUCY2C結合多肽、特異性結合於GUCY2C的抗體或其抗原結合片段、融合蛋白質、共軛物、嵌合抗原受體、編碼其的多核苷酸、包括多核苷酸的重組載體、包括重組載體的重組細胞以及表現嵌合抗原受體的免疫細胞。
另一實施例提供一種用於診斷癌症的方法或用於提供診斷癌症的資訊的方法,其包括將選自由以下組成的族群的一或多種類別接觸至自個體獲得的生物樣品中:GUCY2C結合多肽、特異性結合於GUCY2C的抗體或其抗原結合片段、融合蛋白質、共軛物、嵌合抗原受體、編碼其的多核苷酸、包括多核苷酸的重組載體、包括重組載體的重組細胞以及表現嵌合抗原受體的免疫細胞。個體可為需要診斷癌症的患者,且生物樣品可為選自由細胞、組織、體液以及其培養物組成的族群的一或多種類別。
另一實施例提供一種選自由以下組成的族群的一或多種類別的用於診斷癌症的應用或用於製備用於診斷癌症的組成物的應用:GUCY2C結合多肽、特異性結合於GUCY2C的抗體或其抗原結合片段、融合蛋白質、共軛物、嵌合抗原受體、編碼其的多核苷酸、包括多核苷酸的重組載體、包括重組載體的重組細胞以及表現嵌合抗原受體的免疫細胞。
另一實施例提供一種用於偵測GUCY2C的組成物,其包括選自由以下組成的族群的一或多種類別作為活性成份:GUCY2C結合多肽、特異性結合於GUCY2C的抗體或其抗原結合片段、融合蛋白質、共軛物、嵌合抗原受體、編碼其的多核苷酸、包括多核苷酸的重組載體、包括重組載體的重組細胞以及表現嵌合抗原受體的免疫細胞。
另一實施例提供一種用於偵測GUCY2C的方法,其包括將選自由以下組成的族群的一或多種類別接觸至生物樣品:GUCY2C結合多肽、特異性結合於GUCY2C的抗體或其抗原結合片段、融合蛋白質、共軛物、嵌合抗原受體、編碼其的多核苷酸、包括多核苷酸的重組載體、包括重組載體的重組細胞以及表現嵌合抗原受體的免疫細胞。生物樣品可為選自由分離細胞、組織、體液以及其培養物組成的族群的一或多種類別。
另一實施例提供一種選自由以下組成的族群的一或多種類別的用於偵測GUCY2C的應用:GUCY2C結合多肽、特異性結合於GUCY2C的抗體或其抗原結合片段、融合蛋白質、共軛物、嵌合抗原受體、編碼其的多核苷酸、包括多核苷酸的重組載體、包括重組載體的重組細胞以及表現嵌合抗原受體的免疫細胞。
[技術解決方案]
術語的定義
在本說明書中,GUCY2C(鳥苷酸環化酶2C;鳥苷酸環化酶C;GC-C或GCC)腸鳥苷酸環化酶、鳥苷酸環化酶-C受體或熱穩定性腸毒素受體(heat-stable enterotoxin receptor;hSTAR)為作用於腸液、電解質穩態、維持細胞增殖的跨膜細胞表面受體及類似者。在一個實施例中,GUCY2C可為衍生自哺乳動物的GUCY2C,且舉例而言,其可為人類GUCY2C(蛋白質:GenBank寄存編號NP_004954.2等;基因:GenBank寄存編號NM_004963.4等)、小鼠GUCY2C(蛋白質:GenBank寄存編號NP_001120790.1、NP_659504.2等;基因:GenBank寄存編號NM_001127318.1、NM_145067.3等),但不限於此。在一個實施例中,GUCY2C可特異性表現於哺乳動物(例如,靈長類動物,諸如人類、猴以及類似者;嚙齒動物,諸如小鼠、大鼠以及類似者等)的大腸直腸癌中,但其可甚至表現於腸系膜及類似者中,諸如大腸及食道、胃、胰臟以及類似者,但不應用特定限制。
在本說明書中,多核苷酸(可與「基因」互換使用)或多肽(可與「蛋白質」互換使用)「包括特定核酸序列或胺基酸序列」或「由特定核酸序列或胺基酸序列組成或由特定核酸序列或胺基酸序列表示」可意謂多核苷酸或多肽基本上包括特定核酸序列或胺基酸序列,且其可解釋為包含「實質上等效的序列」,其中在維持多核苷酸或多肽的原始功能及/或所要功能的範圍內(或不排除突變)將突變(缺失、替換、修飾及/或添加)添加至特定核酸序列或胺基酸序列。
在一個實施例中,多核苷酸或多肽「包括特定核酸序列或胺基酸序列」或「由特定核酸序列或胺基酸序列組成或由特定核酸序列或胺基酸序列表示」可意謂多核苷酸或多肽(i)可基本上包括特定核酸序列或胺基酸序列,或(ii)可由與特定核酸序列或胺基酸序列具有70%或更大、75%或更大、80%或更大、85%或更大、90%或更大、91%或更大、92%或更大、93%或更大、94%或更大、95%或更大、96%或更大、97%或更大、98%或更大、99%或更大、99.5 %或更大或99.9%或更大的同一性的核酸序列或胺基酸序列組成,或基本上包括此且維持原始功能及/或所要功能。在本說明書中,多肽、抗體或其抗原結合片段(例如,CDR、可變區或重鏈/輕鏈)、融合蛋白質以及嵌合抗原受體「包括特定胺基酸序列或由特定胺基酸序列表示或由特定胺基酸序列組成」可意謂基本上包括胺基酸序列的情況及將並不影響原始活性及/或所要活性(例如,GUCY2C結合活性等)的不顯著突變引入至胺基酸序列(例如,替換、缺失及/或添加胺基酸殘基)中的情況中的全部。
在本說明書中,術語「同一性」意謂與既定核酸序列或胺基酸序列的對應程度且可由百分比(%)表示。與核酸序列的一致性可藉由使用文獻的算法BLAST(參見:卡林(Karlin)及阿爾丘爾(Altschul),Pro. Natl. Acad. Sci. USA, 90, 5873, 1993)或皮爾森(Pearson)的FAST(參見:酶學方法(Methods Enzymol),183, 63, 1990)來判定。基於此算法BLAST,已開發稱為BLASTN或BLASTX的程式(參見:http://www.ncbi.nlm.nih.gov)。
本文中,術語「抗體」以最廣泛意義用作特異性結合於特定抗原的蛋白質的通用術語,且可為藉由刺激免疫系統中的抗原製成的蛋白質或藉由化學合成或以重組方式產生的蛋白質,且其類型不受特別限制。具體而言,涵蓋單株抗體(包含全長單株抗體)、多株抗體、多特異性抗體(例如雙特異性抗體)、合成抗體(或亦稱為抗體模擬物)、嵌合抗體、人類化抗體、人類抗體或抗體融合蛋白質(或亦稱為抗體共軛物),只要展現所要生物活性即可。
完整抗體(例如IgG型)具有含有兩個全長輕鏈及2個全長重鏈的結構,且每一輕鏈藉由二硫鍵連接至重鏈。抗體的恆定區劃分成重鏈恆定區及輕鏈不變區,且重鏈恆定區具有伽馬(γ)、米歐(μ)、阿爾法(α)、德耳塔(δ)或艾普西隆(ε)類型,且具有伽馬1(γ1)、伽馬2(γ2)、伽馬3(γ3)、伽馬4(γ4)、阿爾法1(α1)或阿爾法2(α2)作為子類。輕鏈的恆定區具有卡帕(κ)及拉姆達(λ)類型。
術語「抗原結合片段」是指抗體的一部分,其缺乏其全長鏈中存在的胺基酸中的至少一些但仍能夠特異性結合於抗原。此類片段的生物學活性在於其結合於標靶抗原且能夠與其他抗原結合分子(包含完整抗體)競爭以結合於既定抗原決定基。抗原結合片段可不包括完整抗體的Fc區的恆定重鏈域(亦即,取決於抗體同型,亦即CH2、CH3以及CH4)。抗原結合片段的實例包含scFv(單鏈可變片段)(例如,scFv、 (scFv)
2等)、片段抗原結合(fragment antigen binding;Fab)(例如,Fab、Fab'、F(ab')
2等)、域抗體、肽體、微型抗體、胞內抗體、雙功能抗體、三功能抗體或單鏈抗體以及類似者,但不限於此。另外,抗原結合片段可為scFv、scFv與免疫球蛋白(例如IgA、IgD、IgE、IgG(IgG1、IgG2、IgG3、IgG4)、IgM等)的Fc區融合的融合多肽(scFv-Fc),或scFv與輕鏈的恆定區(例如κ或λ)融合的融合多肽(scFv-Cκ(κ恆定區)或scFv-Cλ(λ恆定區)),但不限於此。
術語「重鏈」解釋為包含包括可變域V
H的所有全長重鏈,所述可變域V
H包括具有足以對抗原具有特異性的可變區的胺基酸序列,及3個恆定區域C
H1、恆定區域C
H2以及恆定區域C
H3,以及鉸鏈及其片段。另外,術語「輕鏈」解釋為包含包括可變區域V
L的所有全長輕鏈的含義,所述可變區域V
L包括具有足以對抗原具有特異性的可變區序列的胺基酸序列,及恆定區域C
L及其片段。
術語「互補決定區(complementarity-determining region;CDR)」是指在抗體的可變區中對抗原具有結合特異性或結合親和力的區。一般而言,重鏈可變區中存在3個CDR(CDR-H1、CDR-H2、CDR-H3),且輕鏈可變區中存在3個CDR(CDR-L1、CDR-L2、CDR-L3)。CDR可提供用於將抗體或其片段結合於抗原或抗原決定基的關鍵接觸殘基。「構架區(Framework region;FR)」是指重鏈及輕鏈的可變區的非CDR部分,且一般而言,重鏈可變區中存在4個FR(FR-H1、FR-H2、FR-H3以及FR-H4),且輕鏈可變區中存在4個FR(FR-L1、FR-L2、FR-L3以及FR-L4)。既定CDR或FR的確切胺基酸序列邊界可容易地藉由使用數個熟知系統,諸如Kabat編號系統、Chothia編號系統、Contact編號系統、IMGT編號系統、Abo編號系統、AbM編號系統以及類似者中的任一者來判定。
術語「可變區」是指抗體的重鏈或輕鏈的域,其涉及將抗體與抗原結合。重鏈可變(VH)區及輕鏈可變(VL)區通常具有類似結構,且每一域包含4個保守構架區(FR)及3個CDR。
GUCY2C結合多肽、抗體或其抗原結合片段、融合蛋白質
本說明書中提供的GUCY2C結合多肽、抗體或其抗原結合片段可包括以下:
重鏈可變區,包括用選自由SEQ ID NO:38至44組成的族群的胺基酸序列表示的重鏈CDR1(或更小,CDR-H1)、用選自由SEQ ID NO:45至53組成的族群的胺基酸序列表示的CDR-H2以及用選自由SEQ ID NO:54至65組成的族群的胺基酸序列表示的CDR-H3;
輕鏈可變區,包括用選自由SEQ ID NO:66至78組成的族群的胺基酸序列表示的輕鏈CDR1(或更小,CDR-L1)、用選自由SEQ ID NO:79至88組成的族群的胺基酸序列表示的CDR-L2以及用選自由SEQ ID NO:89至106組成的族群的胺基酸序列表示的CDR-L3;
或重鏈可變區及輕鏈可變區的組合。
本說明書中提供的GUCY2C結合多肽、抗體或其抗原結合片段中包括的每一CDR的胺基酸序列及組合例示於以下表1及表2中:表1展示重鏈可變區的每一CDR的胺基酸序列,且表2展示輕鏈可變區的胺基酸序列。
[表1]
[表2]
純系 ID | CDR-H1 | SEQ ID NO | CDR-H2 | SEQ ID NO | CDR-H3 | SEQ ID NO |
A01 | GYTFTSYY | 38 | INPSGGST | 46 | DGQWLQFDY | 54 |
A02 | GGTLSSYA | 39 | IIPILGIT | 47 | DQRPASMDV | 55 |
A03 | GGTFSSYT | 40 | IIPILGIA | 48 | DYSSSWNSMDV | 56 |
A04 | GGTLSSYA | 39 | IIPILGIT | 47 | DQRPASMDV | 55 |
A05 | GGTFSSYT | 40 | IIPVLGIA | 49 | DYSSSWNSMDV | 56 |
A06 | GGTFGSYT | 41 | IIPILGIA | 48 | DYSSSWNSMDV | 56 |
A07 | GGSISSYY | 42 | IYYSGST | 50 | DVWGSGQSFDS | 57 |
A08 | GFTFSSYW | 43 | IKQDGSEK | 51 | APWYSSSPTPYGMDV | 58 |
A10 | GGTFSSYA | 44 | IIPIFGTA | 52 | TRYIWGSYRAYGMDV | 59 |
A12 | GGTLSSYA | 39 | IIPILGIT | 47 | DQRPASMDV | 55 |
B01 | GGTLSSYA | 39 | IIPILGIT | 47 | DQRPASMDV | 55 |
B07 | GYTFTSYY | 38 | INPSGGST | 46 | GTYSSGWTIDY | 60 |
B08 | GGTFSSYA | 44 | IIPIFGTA | 52 | GHYYYMDV | 61 |
B10 | GGTFSSYA | 44 | IIPIFGTA | 52 | GHYYYMDV | 61 |
B11 | GGTFSSYA | 44 | IIPIFGTA | 52 | GIQPLRYYGMDV | 62 |
B12 | GFTFSSYS | 45 | IYSGGST | 53 | GAGTLNAFDI | 63 |
C01 | GGTFSSYA | 44 | IIPIFGTA | 52 | GYSSIYYYYGMDV | 64 |
C02 | GGTFSSYT | 40 | IIPILGIA | 48 | DRSYNWLDP | 65 |
C07 | GGSFSGYY | 107 | INHRGNT | 108 | ERGYTYGNFDH | 109 |
純系 ID | CDR-L1 | SEQ ID NO | CDR-L2 | SEQ ID NO | CDR-L3 | SEQ ID NO |
A01 | QSLLKKSDGNTY | 66 | KVS | 79 | MQGSHWPPT | 89 |
A02 | SSDVGGYIY | 67 | DVS | 80 | SSYAGSNNYV | 90 |
A03 | SSDIGYYHY | 68 | EDS | 81 | SSFTSRSTWV | 91 |
A04 | SSDVGGYIY | 67 | DVS | 80 | SSYTSSNNYY | 92 |
A05 | SSDVGGYNY | 69 | DVS | 80 | SSYAGSNNFV | 93 |
A06 | SSDVGAYNY | 70 | EVS | 82 | SSYAGSNNWV | 94 |
A07 | SGSIASNY | 71 | EHS | 83 | QSYDVSNRV | 95 |
A08 | QDISNY | 72 | GAS | 84 | QQSYSTPLT | 96 |
A10 | QSISSH | 73 | YAS | 85 | QQSISLPYT | 97 |
A12 | SSDVGGYIY | 67 | DVS | 80 | SSYTSSNNYV | 98 |
B01 | SSDVGGYNY | 69 | EVS | 82 | STVTSLSTYV | 99 |
B07 | QSLVYTDGNTY | 74 | KVS | 79 | MHSKQWPPT | 100 |
B08 | QSVSSN | 75 | GAS | 84 | QQYNNWPS | 101 |
B10 | QSVSSN | 75 | GAS | 84 | QQYNNWPT | 102 |
B11 | SSNIGSNY | 76 | RNN | 86 | AAWDDSLSGRGV | 103 |
B12 | SSDVGAYSY | 77 | AVT | 87 | SSFAGGSTLV | 104 |
C01 | SSDVGGYNY | 69 | DVS | 80 | GSYTSDGTLV | 105 |
C02 | ISDVGDYNY | 78 | DVN | 88 | SSYTSSSTLV | 106 |
C07 | QSVSRN | 110 | GAS | 84 | QQYKTWPRT | 111 |
在一個實施例中,GUCY2C結合多肽可包括包括前述重鏈CDR的重鏈可變區及包括輕鏈CDR的輕鏈可變區。重鏈可變區可包括上文所描述的重鏈CDR及免疫球蛋白(例如,IgA、IgD、IgE、IgG(IgG1、IgG2、IgG3、IgG4)、IgM等)的構架(例如,FR1-(CDR-H1)-FR2-(CDR-H2)-FR3-(CDR-H3)-FR4的結構)。輕鏈可變區可包括上文所描述的輕鏈CDR λ或κ亞型的構架(例如,FR1-(CDR-L1)-FR2-(CDR-L2)-FR3-(CDR-L3)-FR4的結構)。
在一個特定實施例中,GUCY2C結合多肽可為單鏈可變片段(scFv),其為前述重鏈可變區及輕鏈可變區經由或不經由肽連接子連接的單鏈多肽。
肽連接子可為由1至100或2至50的任何胺基酸組成的多肽,且所包括的胺基酸之的類型不受限制。舉例而言,肽連接子可包括Gly、Asn及/或Ser殘基,且可包括中性胺基酸,諸如Thr及/或Ala。適用於肽連接子的胺基酸序列為所屬領域中已知的。另一方面,對於連接子,其長度可在不影響scFv的GUCY2C結合功能的限制內不同地判定。舉例而言,肽連接子可由包括選自由Gly、Asn、Ser、Thr以及Ala組成的族群的一或多種類別中的總計1至200、2至50或5至25構成。在一個實施例中,肽連接子為(G4S)n(n為(G4S)的重複數目),且可由1至10的整數表示,例如2至5的整數。
在一個特定實施例中,呈scFv形式的GUCY2C結合多肽可用選自SEQ ID NO:1至18的胺基酸序列表示,且此等胺基酸序列在以下表3中示出:
[表3]
(在表3中,粗體且加下劃線區按次序表示CDR-H1、CDR-H2以及CDR-H3、CDR-L1、CDR-L2以及CDR-L3)
scFv ID | scFV 區(蛋白質;N→C ) | SEQ ID NO |
A01 | QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSYY MHWVRQAPGQGLEWMGI INPSGGST SYAQEFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR DGQWLQFDY WGQGTLVTVSSGGGGSGGGGSGGGASDIVMTQSPLSLPVTLGQPASISCRSS QSLLKKSDGNTY LSWYHQRPGQSPRRLIY KVS NRDSGVPDRFSGSGSDTDFTLKISRVETEDVGIYYC MQGSHWPPT FGQGTKVEIK | 1 |
A02 | EVQLVQPGAEVKKPGSSVKVSCKAS GGTLSSYA ISWVRQAPGQGLEWMGR IIPILGIT NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYFCAR DQRPASMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSELTQPASVSGSPGQSITISCTGT SSDVGGYIY VSWYQQHPGKVPKLMIH DVS HRPSGVSNRFSGSRSGNTASLTISGLQAEDEADYFC SSYAGSNNYV FGTGTKVTVL | 2 |
A03 | QVQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYT ISWVRQAPGQELEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR DYSSSWNSMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSGLTQPPSASGSPGQSVTISCTGT SSDIGYYHY VSWYQQHPGKAPKLMIY EDS KRPSGISNRFSGSKSGTTASLTVSGLQAEDEAHYYC SSFTSRSTWV FGGGTQLTVL | 3 |
A04 | EVQLVQPGAEVKKPGSSVKVSCKAS GGTLSSYA ISWVRQAPGQGLEWMGR IIPILGIT NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYFCAR DQRPASMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSELTQPASVSGSPGQSITISCTGT SSDVGGYIY VSWYQQHPGKVPKLMIH DVS HRPSGVSNRFSGSRSGNTASLTISGLQAEDEADYFC SSYTSSNNYY FGTGTKVTVL | 4 |
A05 | QVQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYT ITWVRQAPGQGLEWMGR IIPVLGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR DYSSSWNSMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSGLTQPRSVSGSPGQSVTISCTGT SSDVGGYNY VSWYQQHPGKAPKLMIY DVS KRPSGVPDRFSGSKSGNTASLTVSGLHAEDEADYYC SSYAGSNNFV FGTGTKVTVL | 5 |
A06 | QVQLVQSGAEVKKPGSSVKVSCKAS GGTFGSYT ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR DYSSSWNSMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSGLTQPRSVSGSPGQSVTISCTGT SSDVGAYNY VSWYQQHPGKAPKLMIY EVS KRPSGVPDRFSASKSGNTASLTVSGLQAEDEADYYC SSYAGSNNWV FGGGTKLTVL | 6 |
A07 | QVQLQESGPGLVKPSETLSLTCTVS GGSISSYY WSWIRQPPGKGLEWIGS IYYSGST NYNPSLKSRVTISRDKSKNQLFLKLNSMTAADTAVYYCAR DVWGSGQSFDS WGQGTLVTVSSGGGGSGGGGSGGGASNFMLTQPHSVSESPGKTVTISCTRS SGSIASNY VQWYQQRLGSSPTTVIY EHS RRPSGVPDRFSASIDSSSNSASLTISGLKTEDEADYYC QSYDVSNRV FGGGTKLTVL | 7 |
A08 | EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYW MSWVRQAPGKGLEWVAN IKQDGSEK YYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAK APWYSSSPTPYGMDV WGQGTLVTVSSGGGGSGGGGSGGGASDIQMTQSPSSLSASVGDRVTITCQAS QDISNY LNWYQQKPGKAPRRLIY GAS TLMSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPLT FGGGTKVEIK | 8 |
A10 | EVQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGG IIPIFGTA NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAR TRYIWGSYRAYGMDV WGQGTMVTVSSGGGGSGGGGSGGGASDIQMTQSPSSMSASVGDRVTITCRAS QSISSH LNWYQQLPGNAPTLLIY YAS NLQSGVPSRFSGSGSGTDFTLTISSLQPDDFATYYC QQSISLPYT FGQGTKVEIK | 9 |
A12 | EVQLVQPGAEVKKPGSSVKVSCKAS GGTLSSYA ISWVRQAPGQGLEWMGR IIPILGIT NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYFCAR DQRPASMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSELTQPASVSGSPGQSITISCTGT SSDVGGYIY VSWYQQHPGKVPKLMIH DVS HRPSGVSNRFSGSRSGNTASLTISGLQAEDEADYFC SSYTSSNNYV FGTGTKVTVL | 10 |
B01 | EVQLVQPGAEVKKPGSSVKVSCKAS GGTLSSYA ISWVRQAPGQGLEWMGR IIPILGIT NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYFCAR DQRPASMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSGLTQPASVSGSPGQSITISCTGT SSDVGGYNY VSWYQQHPGKAPKLMIY EVS NRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYC STVTSLSTYV FGTGTKLTVL | 11 |
B07 | EVQLVQSGAEVKRPGSSVKVSCKAS GYTFTSYY MHWVRQAPGQGLEWMGI INPSGGST SYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAA GTYSSGWTIDY WGQGTTVTVSSGGGGSGGGGSGGGASDIVMTQSPLSLPVTLGQPASISCRSS QSLVYTDGNTY LNWFQQRPGQSPRRLIY KVS NRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGIYYC MHSKQWPPT FGGGTKVEIK | 12 |
B08 | EVQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGG IIPIFGTA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR GHYYYMDV WGQGTTVTVSSGGGGSGGGGSGGGASDIVMTQSPATLSVSPGEGATLSCRAS QSVSSN LAWYQQKPGRAPRLLIY GAS TRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYC QQYNNWPS FGGGTKLEIK | 13 |
B10 | EVQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGG IIPIFGTA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR GHYYYMDV WGQGTTVTVSSGGGGSGGGGSGGGASDIVMTQSPATLSVSPGEGATLSCRAS QSVSSN LAWYQQKPGRAPRLLIY GAS TRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYC QQYNNWPT FGGGTKLEIK | 14 |
B11 | QVQLVESGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGG IIPIFGTA NYAQKFQGRVTITADESTSTAYMELSGLRSEDTAVYYCAR GIQPLRYYGMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSALTQPPSASGTPGQRVTISCSGS SSNIGSNY VYWYQQLPGTAPKLLIY RNN QRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYC AAWDDSLSGRGV FGGGTQLTVL | 15 |
B12 | QVQLVESGGGLVKPGGSLRLSCAAS GFTFSSYS MNWVRQAPGKGLEWVSV IYSGGST HYADSVKGRFTISRHNSKNTLYLQMNSLRAEDTAVYYCAR GAGTLNAFDI WGQGTTVTVSSGGGGSGGGGSGGGASQSGLTQPPSTSGSPGQSVTISCTGT SSDVGAYSY VSWYQQHPGKAPKLLIY AVT KRPSGVPDRFSGSKSGNTASLTVSGLQDEDEADYYC SSFAGGSTLV FGGGTKLTVL | 16 |
C01 | QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGG IIPIFGTA NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCVR GYSSIYYYYGMDV WGQGTMVTVSSGGGGSGGGGSGGGASQSGLTQPRSVSGSPGQSVTISCTGT SSDVGGYNY VSWYQQHPGKAPKLMIY DVS KRPSGVSDRFSGSKSGNTASLTISGLQAEDEADYYC GSYTSDGTLV FGGGTKLTVL | 17 |
C02 | QVQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYT ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR DRSYNWLDP WGRGTLVTVSSGGGGSGGGGSGGGASQSALTQPVSVSGSPGQSITISCTGT ISDVGDYNY VSWYQQHPGKAPKLMIY DVN NRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYC SSYTSSSTLV FGGGTKLTVL | 18 |
在另一特定實施例中,抗體或其抗原結合片段可包括前述6個CDR,且基於免疫球蛋白(例如,IgA、IgD、IgE、IgG(IgG1、IgG2、IgG3、IgG4)、IgM等)及λ或κ類型。抗體可為單株抗體,且可為動物(例如,小鼠、兔等)衍生抗體、嵌合抗體、人類化抗體或人類抗體。
另一實施例提供一種融合蛋白質,其包括GUCY2C結合多肽及免疫球蛋白的Fc域。
GUCY2C結合多肽如上文所描述。免疫球蛋白的Fc域可為哺乳動物(例如,靈長類動物,諸如人類、猴;嚙齒動物,諸如小鼠、大鼠以及類似者)的免疫球蛋白(例如,IgA、IgD、IgE、IgG(IgG1、IgG2、IgG3、IgG4)、IgM等)的Fc域。Fc域可包括或不包括鉸鏈區,且可包括CH2、CH3或其兩者。在本說明書中提供的融合蛋白質中,GUCY2C結合多肽及免疫球蛋白的Fc域可不考慮次序進行連接,且舉例而言,GUCY2C結合多肽可連接至免疫球蛋白的Fc域的C端或N端,或GUCY2C結合多肽中的兩者或更多者可連接至免疫球蛋白的Fc域的C端或N端中的一或多者。GUCY2C結合多肽及免疫球蛋白的Fc域多肽可經由連接子連接,或在無連接子的情況下直接連接。
例如基於藉由表面電漿子共振(surface plasmon resonance;SPR)量測的情況,本說明書中提供的GUCY2C結合多肽、抗GUCY2C抗體或其抗原結合片段對GUCY2C(例如人類GUCY2C)的結合親和力(K
D)可為10毫莫耳/升或更小、5毫莫耳/升或更小、1毫莫耳/升或更小、0.5毫莫耳/升或更小、0.2毫莫耳/升或更小或0.15毫莫耳/升或更小,且舉例而言,其可為0.001奈莫耳/升至10毫莫耳/升、0.005奈莫耳/升至10毫莫耳/升、0.01奈莫耳/升至10毫莫耳/升、0.05奈莫耳/升至10毫莫耳/升、0.1奈莫耳/升至10毫莫耳/升、0.5奈莫耳/升至10毫莫耳/升、1奈莫耳/升至10毫莫耳/升、0.001奈莫耳/升至5毫莫耳/升、0.005奈莫耳/升至5毫莫耳/升、0.01奈莫耳/升至5毫莫耳/升、0.05奈莫耳/升至5毫莫耳/升、0.1奈莫耳/升至5毫莫耳/升、0.5奈莫耳/升至5毫莫耳/升、1奈莫耳/升至5毫莫耳/升、0.001奈莫耳/升至1毫莫耳/升、0.005奈莫耳/升至1毫莫耳/升、0.01奈莫耳/升至1毫莫耳/升、0.05奈莫耳/升至1毫莫耳/升、0.1奈莫耳/升至1毫莫耳/升、0.5奈莫耳/升至1毫莫耳/升、1奈莫耳/升至1毫莫耳/升、0.001奈莫耳/升至0.5毫莫耳/升、0.005奈莫耳/升至0.5毫莫耳/升、0.01奈莫耳/升至0.5毫莫耳/升、0.05奈莫耳/升至0.5毫莫耳/升、0.1奈莫耳/升至0.5毫莫耳/升、0.5奈莫耳/升至0.5毫莫耳/升、1奈莫耳/升至0.5毫莫耳/升、0.001奈莫耳/升至0.2毫莫耳/升、0.005奈莫耳/升至0.2毫莫耳/升、0.01奈莫耳/升至0.2毫莫耳/升、0.05奈莫耳/升至0.2毫莫耳/升、0.1奈莫耳/升至0.2毫莫耳/升、0.5奈莫耳/升至0.2毫莫耳/升、1奈莫耳/升至0.2毫莫耳/升、0.001奈莫耳/升至0.15毫莫耳/升、0.005奈莫耳/升至0.15毫莫耳/升、0.01奈莫耳/升至0.15毫莫耳/升、0.05奈莫耳/升至0.15毫莫耳/升、0.1奈莫耳/升至0.15毫莫耳/升、0.5奈莫耳/升至0.15毫莫耳/升或1奈莫耳/升至0.15毫莫耳/升。
另一實施例提供一種共軛物,其中有前述抗體或其抗原結合片段或融合蛋白質,以及藥物。藥物可為選自由抗癌劑、恆定介質以及類似者組成的族群的一或多種類別。
抗癌劑可為選自以下的一或多種類別:美登素(maytansine)、奧瑞他汀類藥物(auristatin-based drug)、卡奇黴素類藥物(calicheamicin-based drug)、吡咯并苯并二氮雜類藥物(pyrrolobenzodiazepine-based drug)、倍癌黴素(duocarmycin)、多西他賽(Docetaxel)、多柔比星(Doxorubicin)、卡鉑(Carboplatin)(鉑爾定(paraplatin))、順鉑(順鉑)、環磷醯胺(Cyclophosphamide)、異環磷醯胺(Ifosfamide)、寧得朗(Nidran)、氮芥(Nitrogen mustard)、氮芥HCL(Mechlorethamine HCL)、博萊黴素(Bleomycin)、絲裂黴素C(Mitomycin C)、阿糖胞苷(Cytarabine)、氟脲嘧啶(Flurouracil)、吉西他濱(Gemcitabine)、三甲曲沙(Trimetrexate)、甲胺喋呤(Methotrexate)、依託泊苷(Etoposide)、長春鹼(Vinblastine)、長春瑞濱(vinorelbine)、力比泰(Alimta)、六甲蜜胺(Altretamine)、丙卡巴肼(Procarbazine)、紫杉醇(Paclitaxel)(紫杉醇(Taxol))、泰素帝(Taxotere)、拓樸替康(Topotecan)、伊立替康(Irinotecan)以及類似者,但不限於此。恆定介質可為選自諸如氧化鐵、釓、放射性同位素(例如,碘、金、鉈、鈀、銫、釔、鎵、銅、鏑、銣、釕、鐳、氟、鉍等)以及類似者的磁共振成像(magnetic resonance imaging;MRI)恆定介質及正電子發射斷層攝影術(Positron Emission Tomography;PET)恆定介質以及類似者的一或多種類別,但不限於此。
嵌合抗原受體(CAR)、表現嵌合抗原受體的細胞
另一實施例提供一種嵌合抗原受體(chimeric antigen receptor;CAR),其包括GUCY2C結合多肽。GUCY2C結合多肽可適用於嵌合抗原受體,因為其可操作以表現為具有其他CAR組分的單鏈的一部分。嵌合抗原受體可為GUCY2C特異性的。
嵌合抗原受體可通常包括:細胞外域(胞外域),包括GUCY2C結合多肽;跨膜域;以及細胞內傳訊域(或T細胞活化域;胞內域)。另外,細胞外域可在多肽與跨膜域之間更包括間隔子區(或鉸鏈區)。此外,嵌合抗原受體可更包括一或多個共刺激域,且較佳地,共刺激域可定位於跨膜域與細胞內傳訊域之間。
因此,作為一個較佳實施例,嵌合抗原受體可包括:細胞外域,包括GUCY2C結合多肽;跨膜域;一或多個共刺激域;以及細胞內傳訊域。每一域可為異質的。換言之,其可由衍生自不同蛋白質鏈的序列構成。每一域可藉由短寡肽或多肽連接子連接,例如長度為2至10個胺基酸的連接子。另外,嵌合抗原受體可由連接每一域的一個多肽鏈組成。
細胞外域包括前述GUCY2C結合多肽,且此識別表現於癌細胞表面上的GUCY2C。
細胞外域可更包括間隔子區(或鉸鏈區)。間隔子區可定位於GUCY2C結合多肽與跨膜域之間。間隔子區允許GUCY2C結合多肽更靈活地識別標靶抗原,其與表現嵌合抗原受體的免疫細胞(下文中稱為『CAR表現的免疫細胞』;例如,包含CAR-NK、CAR-T細胞等)的細胞膜間隔一定距離。間隔子區可通常為多肽,且其可具有10或更大的胺基酸長度,例如10至300的胺基酸長度、10至250的胺基酸長度、10至200的胺基酸長度、10至150的胺基酸長度、10至100的胺基酸長度、10至50的胺基酸長度,但不限於此。
可示出CD8α或CD28的鉸鏈區或免疫球蛋白(IgG)的恆定區或類似者作為間隔子區,且藉此可引入突變以便移除脫靶效應。舉例而言,免疫球蛋白恆定區可單獨衍生自IgG鉸鏈,或CH2及/或CH3域的全部或一部分,且例如其可為Fc區。IgG(IgG1、IgG2、IgG3、IGG4等)可為IgG2或IgG4。在一些實施例中,間隔子可為含有鉸鏈以及CH2及CH3序列中的一或多者的嵌合多肽,其衍生自IgG2、IgG4及/或IgG2及IgG4。
跨膜域起連接細胞膜域與細胞膜內的傳訊域的作用,且可衍生自天然或合成的來源。當來源為天然的時,域可為任何膜結合或膜穿越蛋白質。舉例而言,跨膜域可為T細胞受體的α鏈、β鏈或ζ鏈、CD3ε、CD4、CD5、CD8、CD9、CD16、CD22、CD28、CD33、CD37、CD45、CD64、CD80、CD86、CD134、CD137或CD154的跨膜域,但不限於此。作為一個較佳實施例,跨膜域可為CD28或CD8的跨膜域,但不限於此。當來源為合成的時,合成跨膜域可包括疏水性殘基,諸如白胺酸及纈胺酸,且可在每一末端包括苯丙胺酸、色胺酸及纈胺酸以及類似者,但不限於此。
共刺激域為共刺激信號所傳輸至的位點,且為用於傳輸信號以使得CAR表現的免疫細胞產生免疫反應及自增殖的位點。此可選擇性地引入以改良CAR表現的免疫細胞的增殖、細胞毒性、持續反應、壽命延長。共刺激域可為選自以下的傳訊位點的一或多種類別,例如1種、2種或3種:CD28、OX-40(CD134)、4-1BB(CD137)、CD2、CD7、CD27、CD30、CD40、PD-1、ICOS、LFA-1(CD11a/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT、(TNFSF14)、NKG2C、Igα(CD79a)、DAP-10、Fcγ受體、MHC1類分子、TNF受體蛋白質、免疫球蛋白蛋白質、細胞介素受體、整合素、傳訊淋巴細胞活化分子(signaling lymphocytic activation molecule;SLAM)、活化NK細胞受體、BTLA、toll配體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2Rβ、IL-2Rγ、IL-7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD11a、LFA-1、ITGAM、CD11b、ITGAX、CD11c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRTAM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAMF1(CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp或CD19a,但不限於此。作為較佳實施例,其可為選自CD28、OX-40(CD134)、4-1BB(CD137)、CD27或ICOS的傳訊位點的一或多種類別,例如1種、2種或3種,但不限於此。
細胞內傳訊域為活化免疫細胞對與GUCY2C結合多肽結合的抗原的免疫反應的位點。傳訊域可含有已知為免疫細胞受體(例如,T細胞受體(T cell receptor;TCR)等)的組分的傳訊模體,或基於酪胺酸的活化模體(基於免疫受體酪胺酸的活化模體,ITAM)。作為實施例,傳訊域可為衍生自TCR或CD3ζ、FcRγ、CD3γ、CD3δ以及CD3ε的傳訊域,但不限於此。作為較佳實施例,其可為CD3ζ的傳訊域,但不限於此。當細胞外域的GUCY2C結合多肽位點結合於標靶時,細胞內傳訊域可活化CAR表現的免疫細胞。舉例而言,CAR可刺激免疫細胞(例如,NK細胞、T細胞等)的功能,例如細胞裂解活性或T輔助活性,且誘導細胞介素或其他因子的分泌。
在一些實施例中,CAR可以包括信號序列的形式表現。另外,CAR可利用適用於監測的額外序列表現,例如核糖體跳躍序列,諸如2A肽或截短細胞表面多肽(tHER2或tEGFR或截短PSMA等)。
在嵌合抗原受體中,外部域(抗原結合域及間隔子域)、跨膜域以及內部域(兩者中的任一個輔助刺激因子或至少一或多個輔助刺激因子,及傳訊域)可為在自N端至C端的方向上或在自C端至N端的方向上按次序連接的單股多肽。
另一實施例提供一種免疫細胞,其包括上文所描述的嵌合抗原受體。免疫細胞可為對細胞表面上表現GUCY2C特異性嵌合抗原受體的GUCY2C具有特異性的免疫細胞。在一個實施例中,免疫細胞可為基因工程改造細胞以表現嵌合抗原受體,例如其中引入嵌合抗原受體的編碼多核苷酸或包括所述多核苷酸的重組載體(表現載體)的免疫細胞。
免疫細胞包含T細胞、腫瘤浸潤淋巴細胞(tumor infiltrating lymphocyte;TIL)、自然殺手(natural killer;NK)細胞、TCR(T細胞抗原受體)表現的細胞、樹突狀細胞或NK-T細胞,但不限於此。另外,免疫細胞可衍生自人類誘導性多能幹細胞(induced pluripotent stem cell;iPSC)。免疫細胞可衍生自任何已知來源。舉例而言,免疫細胞可活體外自造血幹細胞群分化或自患者獲得。免疫細胞可自例如周邊血液單核細胞(peripheral blood mononuclear cell;PBMC)、骨髓、淋巴腺組織、臍帶血、胸腺組織、來自感染位點的組織、腹水、肋膜積液、脾臟組織以及腫瘤獲得。另外,免疫細胞可衍生自所屬領域中可用的一或多種類別的免疫細胞株。免疫細胞可為衍生自哺乳動物(例如,靈長類動物,諸如人類、猴;嚙齒動物,諸如小鼠、大鼠以及類似者)的細胞。
免疫細胞可為自體的或同種異體的。自體是指衍生自待治療的患者。同種異體是指衍生自與待治療患者相同物種的另一個體。
此外,免疫細胞可衍生自人類誘導性多能幹細胞(iPSC)。與自體或同種異體免疫細胞相比,衍生自iPSC的免疫細胞的優勢在於,有可能自增殖且易於大量增殖,並且有可能製造適用於所有人的通用細胞治療劑。
免疫細胞可藉由載體使用以下方法傳染或轉導:顯微注射、電穿孔、超聲處理、生物彈道(例如基因槍)、脂質轉染、聚合物轉染、磷酸鈣沈澱、原生質體融合、脂質體介導的轉染、奈米粒子或多聚體或類似者,但不限於此。
在本說明書中,術語「自然殺手細胞」或「NK細胞」為構成先天性免疫系統的主要組分的細胞毒性淋巴細胞,且定義為大顆粒淋巴細胞(large granular lymphocyte;LGL),且由自產生B及T淋巴細胞的常見淋巴祖細胞(common lymphoid progenitor;CLP)分化而來的第三細胞組成。「自然殺手細胞」或「NK細胞」可包括衍生自任何組織來源的無額外修飾的自然殺手細胞,且不僅包括成熟的自然殺手細胞而且包括自然殺手前驅體。自然殺手細胞藉由干擾素或巨噬細胞衍生的細胞介素的反應活化,且自然殺手細胞包括控制細胞的細胞毒活性的兩種類型的表面受體,標記為「活化受體」及「抑制受體」。自然殺手細胞可由造血細胞產生,例如來自任何來源的造血幹細胞或前驅體,例如胎盤組織、胎盤灌注液、臍帶血、胎盤血、周邊血液、脾、肝以及類似者。
術語「受體」是指與特定物質結合以修飾NK細胞的活性的所有分子。特定物質可包含化學組成物、體源性或人工特異性蛋白質、肽、膽固醇以及醣蛋白,且包含其他免疫細胞或NK細胞自身的細胞介素或趨化介素,或標靶細胞或NK細胞自身的特異性受體或膜蛋白。舉例而言,受體不僅包含定位於NK細胞的細胞表面且結合於特定物質以將信號傳輸至細胞中並引起NK細胞活性的情況,而且包含所有受體,其為穿過細胞膜且存在於細胞膜或細胞質的內表面中並可結合於外部特定刺激物質以引起傳訊作用的受體。受體的實例可包含CD16、CD25、CD69、CD117、NKG2D、CD94/NKG2A、2B4(CD244)、DNAM-1(CD226)、CD2、CXCR3、NKp30、NKp44、NKp46以及NKp80,但不限於此。在受體當中,當CD117表現較低且CD94/NKG2D表現較高時,可判定NK細胞展現成熟表型。對於「受體」,亦包含細胞介素相關受體,「細胞介素受體」,且對於細胞介素受體,包含IL-15Ra、IL-18Ra、CD122、PD-1(CD279)以及ICAM-1(CD54),但不限於此。
NK細胞可藉由經由分泌細胞介素,諸如穿孔素(Prf1)、顆粒酶B(GzmB)、干擾素-γ(IFN-γ)、腫瘤壞死因子-α(TNF-α)以及類似者直接介導標靶癌細胞凋亡來殺死癌細胞。因此,藉由證實效應分子的分泌程度,包含凋亡過程中的主要因子、IFN-γ、顆粒酶B以及穿孔素,可證實NK細胞的殺死能力。
多核苷酸、重組載體、重組細胞
在本說明書中,前述GUCY2C結合多肽、特異性結合於GUCY2的抗體或其抗原結合片段、融合蛋白質及嵌合抗原受體以及編碼其的多核苷酸可以重組方式或以合成方式產生。
另一實施例提供一種多核苷酸,其編碼GUCY2C結合多肽、特異性結合於GUCY2C的抗體或其抗原結合片段、融合蛋白質或嵌合抗原受體。在一個特定實施例中,多核苷酸可經密碼子優化以表現於人類中。
在一個實施例中,編碼由SEQ ID NO:1至18的胺基酸序列表示的GUCY2C結合多肽的多核苷酸可由SEQ ID NO:20至37的核酸序列表示。
另一實施例提供一種包括多核苷酸的重組載體。重組載體可為用於在宿主細胞中表現多核苷酸的表現載體。另一實施例提供包括多核苷酸或重組載體的重組細胞。重組細胞可為多核苷酸或重組載體引入至宿主細胞中的細胞。
另一實施例提供一種用於準備GUCY2C結合多肽、特異性結合於GUCY2的抗體或其抗原結合片段、融合蛋白質或嵌合抗原受體的方法,其包括在適當宿主細胞中表現多核苷酸。表現可包括培養包括多核苷酸的重組細胞。
術語「載體」意謂用於在宿主細胞中表現標靶基因(DNA或RNA)的手段。舉例而言,可例示質體載體、黏質體載體以及噬菌體載體、病毒載體以及類似者。在一個特定實施例中,載體可為選自由以下組成的族群的病毒載體:慢病毒載體、腺病毒載體、反轉錄病毒載體、腺相關病毒載體(adeno-associated virus vector;AAV)、鼠白血病病毒載體、SFG載體、桿狀病毒載體、埃-巴二氏病毒載體、乳多泡病毒載體、牛痘病毒載體、單純皰疹病毒載體以及類似者,但不限於此。在一個特定實施例中,重組載體可藉由對所屬領域中常用的質體(例如,pSC101、pGV1106、pACYC177、ColE1、pKT230、pME290、pBR322、pUC8/9、pUC6、pBD9、pHC79、pIJ61、pLAFR1、pHV14、pGEX系列、pET系列以及pUC19等)、噬菌體(例如,λgt4λB、λ-Charon、λΔz1以及M13等)或病毒(例如,SV40等)進行工程改造而產生。
在重組載體中,核酸分子可以操作方式連接至啟動子。術語「以操作方式連接」意謂核苷酸表現調節序列(例如啟動子序列)與其他核苷酸序列之間的功能性結合。調節序列可調節藉由「以操作方式連接」的其他核苷酸序列的轉錄及/或轉譯。
重組載體可通常建構為用於選殖的載體或用於表現的載體。可使用所屬領域中用於在植物、動物或微生物中表現外來蛋白質的常見者作為用於表現的載體。重組載體可藉由所屬領域中已知的各種方法來建構。
重組載體可藉由使用原核細胞或真核細胞作為宿主來建構。舉例而言,當所用載體為表現載體且原核細胞用作宿主時,通常包括能夠進行轉錄的強啟動子(例如,pL
λ啟動子、CMV啟動子、
trp啟動子、
lac啟動子、
tac啟動子、T7啟動子等)、用於起始轉譯的核糖體結合位點以及轉錄/轉譯終止序列。當真核細胞用作宿主時,在載體中所包括的真核細胞中操作的複製起點包含f1複製起點、SV40複製起點、pMB1複製起點、腺複製起點、AAV複製起點以及BBV複製起點以及類似者,但不限於此。另外,可使用衍生自哺乳動物細胞的基因體的啟動子(例如,金屬硫蛋白啟動子)或衍生自哺乳動物病毒的啟動子(例如,腺病毒晚期啟動子、牛痘病毒7.5K啟動子、SV40啟動子、巨細胞病毒啟動子、HSV的
tk啟動子等),且作為轉錄終止序列,其通常具有聚腺苷酸化序列。
重組細胞可藉由將重組載體引入至適當宿主細胞而獲得。作為宿主細胞,所屬領域中已知的任何宿主細胞可用作能夠穩定地且連續地選殖或表現重組載體的細胞,且原核細胞包含例如:大腸桿菌,諸如大腸桿菌JM109、大腸桿菌BL21、大腸桿菌RR1、大腸桿菌LE392、大腸桿菌B、大腸桿菌×1776、大腸桿菌W3110以及類似者;芽孢桿菌菌株,諸如枯草芽孢桿菌及蘇雲金桿菌;以及腸內菌科菌株,諸如鼠傷寒沙門氏菌、黏質沙雷菌以及各種假單胞菌屬以及類似者,且當在真核細胞中轉化時,作為宿主細胞,可使用酵母(釀酒酵母)、昆蟲細胞、植物細胞以及動物細胞,例如Sp2/0、CHO(中國倉鼠卵巢)K1、CHO DG44、CHO S、CHO DXB11、CHO GS-KO、PER.C6、W138、BHK、COS-7、293、HepG2、Huh7、3T3、RIN、MDCK細胞株以及類似者,但不限於此。
將核酸分子及包括其的重組載體遞送(引入)至宿主細胞中可使用所屬領域中廣泛已知的遞送方法。遞送方法例如可在宿主細胞為原核細胞時使用CaCl
2方法或電穿孔方法或類似者,且可在宿主細胞為真核細胞時使用顯微注射、磷酸鈣沈澱、電穿孔、脂質體介導的轉染以及基因轟擊以及類似者,但不限於此。
用於選擇經轉化宿主細胞的方法可根據所屬領域中廣泛使用的方法,藉由使用由選擇性標記表現的表型來容易地進行。舉例而言,在選擇性標記為特定抗生素抗性基因時,可藉由在含有抗生素的培養基中培養轉化體來容易地選擇轉化體。
另一實施例提供一種製備抗GUCY2C抗體或其抗原結合片段的方法,其包括在宿主細胞中表現核酸分子或包括其的重組載體。表現可藉由在允許表現核酸分子的條件下培養包括(例如,重組載體中包括的)核酸分子的重組物來進行。製備方法可包括在表現或培養之後自培養基分離及/或純化抗體或抗原結合片段。
醫療應用
另一實施例提供一種用於偵測GUCY2C的組成物,其包括選自由以下組成的族群的一或多種類別作為活性成份:GUCY2C結合多肽、特異性結合於GUCY2C的抗原或其抗原結合片段、融合蛋白質、嵌合抗原受體、編碼其的多核苷酸以及免疫細胞。
另一實施例提供一種用於偵測GUCY2C的方法,其包括將選自由以下組成的族群的一或多種類別接觸至生物樣品:GUCY2C結合多肽、特異性結合於GUCY2C的抗原或其抗原結合片段、融合蛋白質、嵌合抗原受體、編碼其的多核苷酸以及免疫細胞。生物樣品可為選自由分離細胞、組織、體液以及其培養物組成的族群的一或多種類別。在所述方法中,樣品中的GUCY2C偵測可藉由證實GUCY2C結合多肽、特異性結合於GUCY2C的抗原或其抗原結合片段、融合蛋白、嵌合抗原受體、編碼其的多核苷酸以及具有GUCY2C的免疫細胞(例如,證實複合物形成)的反應來進行。
另一實施例提供一種選自由以下組成的族群的一或多種類別的用於偵測GUCY2C的應用:GUCY2C結合多肽、特異性結合於GUCY2C的抗原或其抗原結合片段、融合蛋白質、嵌合抗原受體、編碼其的多核苷酸以及免疫細胞。
另一實施例提供一種用於診斷癌症的組成物,其包括選自由以下組成的族群的一或多種類別作為活性成份:GUCY2C結合多肽、特異性結合於GUCY2C的抗原或其抗原結合片段、融合蛋白質、嵌合抗原受體、編碼其的多核苷酸以及免疫細胞。
另一實施例提供一種用於診斷癌症的方法或用於提供診斷癌症的資訊的方法,其包括將選自由以下組成的族群的一或多種類別接觸至自個體獲得的生物樣品:GUCY2C結合多肽、特異性結合於GUCY2C的抗原或其抗原結合片段、融合蛋白質、嵌合抗原受體、編碼其的多核苷酸以及免疫細胞。個體可為需要診斷癌症的患者,且生物樣品可為選自由細胞、組織、體液以及其培養物組成的族群的一或多種類別。在所述方法中,在偵測GUCY2C時,更具體而言,在偵測GUCY2C結合多肽、特異性結合於GUCY2C的抗原或其抗原結合片段、融合蛋白、嵌合抗原受體、編碼其的多核苷酸以及免疫細胞與GUCY2C的複合物時,可證實(決定、判定)生物樣品包括癌細胞,或自其獲得生物樣品的患者為癌症患者。
另一實施例提供一種選自由以下組成的族群的一或多種類別的用於診斷癌症的應用或用於製備用於診斷癌症的組成物的應用:GUCY2C結合多肽、特異性結合於GUCY2C的抗原或其抗原結合片段、融合蛋白質、嵌合抗原受體、編碼其的多核苷酸以及免疫細胞。
GUCY2C偵測及/或複合物形成證實可藉由證實蛋白質-蛋白質之間的蛋白質-蛋白質相互作用或複合物形成的常見手段來進行,且舉例而言,其可藉由選自由以下組成的族群的方法來量測:免疫層析、免疫組織化學染色、酶聯免疫吸附分析(enzyme linked immunosorbent assay;ELISA)、放射免疫化驗(radioimmunoassay;RIA)、酶免疫分析法(enzyme immunoassay;EIA)、螢光免疫分析(florescence immunoassay;FIA)、發光免疫分析(luminescence immunoassay;LIA)、西方墨點法、微陣列以及類似者,但不限於此。
生物樣品可為個體(例如哺乳動物,包含靈長類動物,諸如人類、猴;嚙齒動物,諸如小鼠、大鼠以及類似者)或與個體分離或人工培養的細胞、組織、體液(例如,血液、血清、尿液、唾液等)或類似者。
另一實施例提供一種用於預防及/或治療癌症的醫藥組成物,其包括選自由以下組成的族群的一或多種類別作為活性成份:GUCY2C結合多肽、特異性結合於GUCY2C的抗原或其抗原結合片段、融合蛋白質、共軛物、嵌合抗原受體、編碼其的多核苷酸、包括多核苷酸的重組載體、包括重組載體的重組細胞以及表現嵌合抗原受體的免疫細胞。
另一實施例提供一種用於預防及/或治療癌症的方法,其包括將醫藥學有效劑量的選自由以下組成的族群的一或多種類別投與至需要預防及/或治療癌症的個體中:GUCY2C結合多肽、特異性結合於GUCY2C的抗原或其抗原結合片段、融合蛋白質、共軛物、嵌合抗原受體、編碼其的多核苷酸、包括多核苷酸的重組載體、包括重組載體的重組細胞以及表現嵌合抗原受體的免疫細胞。
另一實施例提供一種選自由以下組成的族群的一或多種類別的用於預防及/或治療癌症的應用或用於製備用於預防及/或治療癌症的醫藥組成物的應用:GUCY2C結合多肽、特異性結合於GUCY2C的抗原或其抗原結合片段、融合蛋白質、共軛物、嵌合抗原受體、編碼其的多核苷酸、包括多核苷酸的重組載體、包括重組載體的重組細胞以及表現嵌合抗原受體的免疫細胞。
除活性成份(GUCY2C結合多肽、特異性結合於GUCY2C的抗原或其抗原結合片段、融合蛋白質、嵌合抗原受體、編碼其的多核苷酸、包括多核苷酸的重組載體、包括重組載體的重組細胞以及表現嵌合抗原受體的免疫細胞)以外,本說明書中提供的醫藥組成物可更包括醫藥學上可接受的載劑。醫藥學上可接受的載劑可為常用於製備藥物的載劑,且可為選自由以下組成的族群的一或多種類別:乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、澱粉、阿拉伯樹膠、磷酸鈣、海藻酸鹽、明膠、矽酸鈣、微晶纖維素、聚乙烯吡咯啶酮、纖維素、水、糖漿、甲基纖維素、甲基羥基苯甲酸酯、丙基羥基苯甲酸酯、滑石、硬脂酸鎂、礦物油以及類似者,但不限於此。醫藥組成物可更包括選自由以下組成的族群的一或多種類別:稀釋劑、賦形劑、潤滑劑、潤濕劑、甜味劑、調味劑、乳化劑、懸浮劑、防腐劑以及類似者,其常用於製備醫藥組成物。
有效劑量的醫藥組成物或抗體或其抗原結合片段可經口或非經腸投與。在非經腸投與的情況下,其可藉由靜脈內注射、皮下注射、肌肉內注射、腹膜內注射、內皮投與、肺內投與、直腸內投與或病變部位局部投與或類似者來投與。在經口投與的情況下,當蛋白質或肽被消化時,可調配經口組成物以包覆活性藥物或防止其在胃中降解。另外,組成物可藉由活性物質可移動至標靶細胞(例如癌細胞)的任何裝置投與。
抗GUCY2C抗體或其抗原結合片段可包括於醫藥組成物中或以藥學上有效劑量投與患者。在本說明書中,「醫藥學上有效劑量」可意謂能夠展現活性成份(GUCY2C結合多肽、特異性結合於GUCY2C的抗體或其抗原結合片段、融合蛋白質、嵌合抗原受體及/或免疫細胞)的所要作用(例如抗癌作用)的活性成份的量。醫藥學上有效劑量可由諸如以下的因素不同地規定:患者的年齡、體重、性別、病態狀況、食物、排泄速率、反應敏感性、製備方法、投與時間、投與間隔、投與途徑、投與方法以及類似者。舉例而言,活性成份的每日劑量可在以下範圍內:0.005微克/公斤至1000毫克/公斤、0.005微克/公斤至500毫克/公斤、0.005微克/公斤至250毫克/公斤、0.005微克/公斤至100毫克/公斤、0.005微克/公斤至75毫克/公斤、0.005微克/公斤至50毫克/公斤、0.01微克/公斤至1000毫克/公斤、0.01微克/公斤至500毫克/公斤、0.01微克/公斤至250毫克/公斤、0.01微克/公斤至100毫克/公斤、0.01微克/公斤至75毫克/公斤、0.01微克/公斤至50毫克/公斤、0.05微克/公斤至1000毫克/公斤、0.05微克/公斤至500毫克/公斤、0.05微克/公斤至250毫克/公斤、0.05微克/公斤至100毫克/公斤、0.05微克/公斤至75毫克/公斤或0.05微克/公斤至50毫克/公斤,但不限於此。每日劑量可藉由以單一劑量形式調配成一種製劑、藉由恰當分配調配或在多劑量容器中內化來製備。
醫藥組成物可以油或水介質中的溶液、懸浮液、糖漿或乳液的形式調配,或以提取物、粉末、粉末、顆粒劑、錠劑或膠囊或類似者的形式調配,且可另外包括用於調配的分散劑或穩定劑。
本發明的應用個體患者可為哺乳動物,包含靈長類動物,諸如人類、猴,嚙齒動物,諸如小鼠、大鼠以及類似者。
本說明書中提供的組成物及/或方法的用於診斷及/或治療的個體癌症可為實體癌症或血液癌症,且其不限於此,但其可為大腸直腸癌、結腸癌、大腸直腸癌、直腸癌、乳癌、肺癌、前列腺癌、卵巢癌、腦癌、肝癌、宮頸癌、子宮內膜癌、子宮癌、腎癌、腎胚細胞瘤、皮膚癌、口腔鱗狀癌、表皮癌、鼻咽癌、頭頸癌、黏連癌、食道癌、膀胱癌、淋巴癌(例如霍奇金氏淋巴瘤)、胃癌、胰臟癌、睪丸癌、甲狀腺癌、甲狀腺濾泡癌、黑色素瘤、骨髓瘤、多發性骨髓瘤、間皮瘤、骨肉瘤、骨髓增生異常症候群、間葉來源腫瘤、軟組織肉瘤、脂肪肉瘤、胃腸道間質肉瘤、惡性周邊神經鞘膜瘤(malignant peripheral nerve sheath tumor;MPNST)、尤文氏肉瘤、平滑肌肉瘤、間葉軟骨肉瘤、淋巴肉瘤、纖維肉瘤、橫紋肌肉瘤、畸胎癌、神經母細胞瘤、神經管胚細胞瘤、神經膠質瘤、皮膚良性腫瘤或白血病。肺癌可為例如小細胞肺癌(small cell lung carcinoma;SCLC)或非小細胞肺癌(non-small cell lung carcinoma;NSCLC)。白血病可為例如急性骨髓白血病(acute myeloid leukemia;AML)、慢性骨髓白血病(chronic myeloid leukemia;CML)、急性淋巴細胞白血病(acute lymphocytic leukemia;ALL)或慢性淋巴細胞白血病(chronic lymphocytic leukemia;CLL)。癌症可為原發癌或轉移癌。癌症可為表現或過度表現GUCY2C的癌症,例如表現或過度表現GUCY2C的大腸直腸癌,或大腸直腸癌衍生的轉移癌,但不限於此。
本說明書中的癌症治療可意謂預防或緩解或改良癌症症狀的退化,或部分或完全破壞癌症的所有抗癌作用,諸如抑制癌細胞增殖、癌細胞死亡、轉移抑制以及類似者。
在一個特定實施例中,治療個體患者可為接受二級抗過度增殖性療法的患者。舉例而言,二級抗過度增殖性療法可為化學療法、放射療法、免疫療法、光電療法、超低溫療法、毒素療法、激素療法或手術操作。
在一個實施例中,使用包括包括本申請案的GUCY2C結合多肽的嵌合抗原受體的免疫細胞的抗癌治療可藉由以下一系列過程來實現:提取待治療的健康人或患者的血液中的免疫細胞(例如,NK細胞、T細胞等),且接著進行基因工程改造以表現包括本申請案的GUCY2C結合多肽的嵌合抗原受體,且擴增及培養工程改造的免疫細胞,並且將培養的工程改造的免疫細胞投與至患者。
作為較佳實施例,提取待治療的健康人或患者的血液中的免疫細胞例如可藉由通過使用白細胞去除術(或aphresis)分離白細胞且接著濃縮免疫細胞的過程來提取免疫細胞。免疫細胞可藉由在CD4/CD8組態水準下使用特異性抗體珠黏合劑或標記物來分離。替代地,有可能經由自幹細胞分化而穩定地獲得大量免疫細胞。
本申請案中提供的使得所提取免疫細胞表現嵌合抗原受體的基因工程改造例如可藉由使用載體,例如病毒載體(慢病毒載體或反轉錄病毒載體等)而注射經設計以表現嵌合抗原受體(CAR)的核酸分子。CAR可以DNA形式引入,且可在以RNA形式引入之後整合於免疫細胞的基因體中,且接著利用反轉錄酶反轉錄成DNA。
擴增及培養工程改造的免疫細胞可根據所屬領域中已知的培養技術培養、增殖以及擴增(擴充)免疫細胞。接著,需要針對使用病毒的安全性及用於選擇生產良好的CAR表現的免疫細胞的技術。
最後,將工程改造的免疫細胞再次投與至患者例如可藉由輸注來實現。作為一個實施例,在輸注CAR表現的免疫細胞之前,為了降低白細胞計數,患者可接受化學療法以使用環磷醯胺或氟達拉濱或類似物來控制淋巴細胞移除。另外,為了改良CAR表現的免疫細胞的持久性,可一起投與細胞介素,諸如IL-2及類似者。
投與至患者的工程改造的免疫細胞可介導腫瘤細胞的免疫反應。此免疫反應包含免疫細胞的活化、免疫細胞分泌諸如IL-2及IFN-γ的細胞介素、增殖及延伸識別腫瘤抗原的免疫細胞以及免疫細胞介導的標靶陽性細胞的特異性死亡(腫瘤移除)。舉例而言,當CAR特異性結合於CAR表現的免疫細胞中的GUCY2C時,可經由磷酸化CD3ζ的酪胺酸類活化模體(免疫受體酪胺酸類活化模體,ITAM)來活化免疫細胞,且接著可誘導免疫細胞的增殖、細胞毒性及/或細胞介素的分泌。
如上文所描述,使用CAR表現的免疫細胞的抗癌療法從根本上活化患者的免疫系統以展現連續抗癌作用,且因此,其具有無需連續投與且能夠藉由使用患者自身的免疫細胞進行個性化治療的優勢。
本說明書中提供的組成物的投與可抑制或停止或延遲疾病狀況的出現或進展,或引起或誘導或促進保護性免疫反應。
[有利作用]
表現以高親和力結合於本說明書中提供的GUCY2C的結合片段(抗體,scFv)的免疫細胞及在表面上包括所述結合片段的嵌合抗原受體(CAR)可有效地用作抗癌劑,所述抗癌劑對癌症,特別是表現GUCY2C的癌症具有優異的抗癌作用。
在下文中,將藉由實例更詳細地描述本發明,但所述實例僅為說明性的,且並不意欲限制本發明的範疇。所屬技術領域中具有通常知識者顯而易見,下文所描述的實例可在不脫離本發明的基本要旨的情況下在一定範圍內進行修改。
實例 1 :產生結合 GUCY2C 的 scFv
藉由將人類GUCY2C(R&D系統,目錄號2157-GC;SEQ ID NO:112)與CD4(SEQ ID NO:115)共軛來製備重組抗原,且篩選分泌對抗原具有特異性的scFv的純系,以確保特異性結合於GCUCY2C的18個scFv。
如上所獲得的scFv及編碼其的核酸分子分別展示於以下表4及表5中:
[ 表 4]scFv胺基酸序列
(在表4中,粗體且加下劃線區按次序表示CDR-H1、CDR-H2以及CDR-H3、CDR-L1、CDR-L2以及CDR-L3)
[ 表 5]編碼核酸分子的scFv
實例 2 : 所選 scFv 對 GUCY2C 的結合親和力
scFv ID | 純系 ID | 輕鏈亞型 | scFV 區(蛋白質; N→C ) | SEQ ID NO |
A01 | 2426_01_A02 | κ | QVQLVQSGAEVKKPGASVKVSCKAS GYTFTSYY MHWVRQAPGQGLEWMGI INPSGGST SYAQEFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR DGQWLQFDY WGQGTLVTVSSGGGGSGGGGSGGGASDIVMTQSPLSLPVTLGQPASISCRSS QSLLKKSDGNTY LSWYHQRPGQSPRRLIY KVS NRDSGVPDRFSGSGSDTDFTLKISRVETEDVGIYYC MQGSHWPPT FGQGTKVEIK | 1 |
A02 | 2427_01_A08 | λ | EVQLVQPGAEVKKPGSSVKVSCKAS GGTLSSYA ISWVRQAPGQGLEWMGR IIPILGIT NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYFCAR DQRPASMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSELTQPASVSGSPGQSITISCTGT SSDVGGYIY VSWYQQHPGKVPKLMIH DVS HRPSGVSNRFSGSRSGNTASLTISGLQAEDEADYFC SSYAGSNNYV FGTGTKVTVL | 2 |
A03 | 2427_01_A12 | λ | QVQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYT ISWVRQAPGQELEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR DYSSSWNSMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSGLTQPPSASGSPGQSVTISCTGT SSDIGYYHY VSWYQQHPGKAPKLMIY EDS KRPSGISNRFSGSKSGTTASLTVSGLQAEDEAHYYC SSFTSRSTWV FGGGTQLTVL | 3 |
A04 | 2427_01_B02 | λ | EVQLVQPGAEVKKPGSSVKVSCKAS GGTLSSYA ISWVRQAPGQGLEWMGR IIPILGIT NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYFCAR DQRPASMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSELTQPASVSGSPGQSITISCTGT SSDVGGYIY VSWYQQHPGKVPKLMIH DVS HRPSGVSNRFSGSRSGNTASLTISGLQAEDEADYFC SSYTSSNNYY FGTGTKVTVL | 4 |
A05 | 2427_01_B07 | λ | QVQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYT ITWVRQAPGQGLEWMGR IIPVLGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR DYSSSWNSMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSGLTQPRSVSGSPGQSVTISCTGT SSDVGGYNY VSWYQQHPGKAPKLMIY DVS KRPSGVPDRFSGSKSGNTASLTVSGLHAEDEADYYC SSYAGSNNFV FGTGTKVTVL | 5 |
A06 | 2427_01_C01 | λ | QVQLVQSGAEVKKPGSSVKVSCKAS GGTFGSYT ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR DYSSSWNSMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSGLTQPRSVSGSPGQSVTISCTGT SSDVGAYNY VSWYQQHPGKAPKLMIY EVS KRPSGVPDRFSASKSGNTASLTVSGLQAEDEADYYC SSYAGSNNWV FGGGTKLTVL | 6 |
A07 | 2427_01_C02 | λ | QVQLQESGPGLVKPSETLSLTCTVS GGSISSYY WSWIRQPPGKGLEWIGS IYYSGST NYNPSLKSRVTISRDKSKNQLFLKLNSMTAADTAVYYCAR DVWGSGQSFDS WGQGTLVTVSSGGGGSGGGGSGGGASNFMLTQPHSVSESPGKTVTISCTRS SGSIASNY VQWYQQRLGSSPTTVIY EHS RRPSGVPDRFSASIDSSSNSASLTISGLKTEDEADYYC QSYDVSNRV FGGGTKLTVL | 7 |
A08 | 2432_01_D05 | κ | EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYW MSWVRQAPGKGLEWVAN IKQDGSEK YYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAK APWYSSSPTPYGMDV WGQGTLVTVSSGGGGSGGGGSGGGASDIQMTQSPSSLSASVGDRVTITCQAS QDISNY LNWYQQKPGKAPRRLIY GAS TLMSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPLT FGGGTKVEIK | 8 |
A10 | 2432_01_D08 | κ | EVQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGG IIPIFGTA NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAR TRYIWGSYRAYGMDV WGQGTMVTVSSGGGGSGGGGSGGGASDIQMTQSPSSMSASVGDRVTITCRAS QSISSH LNWYQQLPGNAPTLLIY YAS NLQSGVPSRFSGSGSGTDFTLTISSLQPDDFATYYC QQSISLPYT FGQGTKVEIK | 9 |
A12 | 2433_01_G08 | λ | EVQLVQPGAEVKKPGSSVKVSCKAS GGTLSSYA ISWVRQAPGQGLEWMGR IIPILGIT NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYFCAR DQRPASMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSELTQPASVSGSPGQSITISCTGT SSDVGGYIY VSWYQQHPGKVPKLMIH DVS HRPSGVSNRFSGSRSGNTASLTISGLQAEDEADYFC SSYTSSNNYV FGTGTKVTVL | 10 |
B01 | 2433_01_H07 | λ | EVQLVQPGAEVKKPGSSVKVSCKAS GGTLSSYA ISWVRQAPGQGLEWMGR IIPILGIT NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYFCAR DQRPASMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSGLTQPASVSGSPGQSITISCTGT SSDVGGYNY VSWYQQHPGKAPKLMIY EVS NRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYC STVTSLSTYV FGTGTKLTVL | 11 |
B07 | 2436_02_F10 | κ | EVQLVQSGAEVKRPGSSVKVSCKAS GYTFTSYY MHWVRQAPGQGLEWMGI INPSGGST SYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAA GTYSSGWTIDY WGQGTTVTVSSGGGGSGGGGSGGGASDIVMTQSPLSLPVTLGQPASISCRSS QSLVYTDGNTY LNWFQQRPGQSPRRLIY KVS NRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGIYYC MHSKQWPPT FGGGTKVEIK | 12 |
B08 | 2436_02_F11 | κ | EVQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGG IIPIFGTA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR GHYYYMDV WGQGTTVTVSSGGGGSGGGGSGGGASDIVMTQSPATLSVSPGEGATLSCRAS QSVSSN LAWYQQKPGRAPRLLIY GAS TRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYC QQYNNWPS FGGGTKLEIK | 13 |
B10 | 2436_02_G01 | κ | EVQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGG IIPIFGTA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR GHYYYMDV WGQGTTVTVSSGGGGSGGGGSGGGASDIVMTQSPATLSVSPGEGATLSCRAS QSVSSN LAWYQQKPGRAPRLLIY GAS TRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYC QQYNNWPT FGGGTKLEIK | 14 |
B11 | 2437_02_G07 | λ | QVQLVESGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGG IIPIFGTA NYAQKFQGRVTITADESTSTAYMELSGLRSEDTAVYYCAR GIQPLRYYGMDV WGQGTLVTVSSGGGGSGGGGSGGGASQSALTQPPSASGTPGQRVTISCSGS SSNIGSNY VYWYQQLPGTAPKLLIY RNN QRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYC AAWDDSLSGRGV FGGGTQLTVL | 15 |
B12 | 2437_02_G10 | λ | QVQLVESGGGLVKPGGSLRLSCAAS GFTFSSYS MNWVRQAPGKGLEWVSV IYSGGST HYADSVKGRFTISRHNSKNTLYLQMNSLRAEDTAVYYCAR GAGTLNAFDI WGQGTTVTVSSGGGGSGGGGSGGGASQSGLTQPPSTSGSPGQSVTISCTGT SSDVGAYSY VSWYQQHPGKAPKLLIY AVT KRPSGVPDRFSGSKSGNTASLTVSGLQDEDEADYYC SSFAGGSTLV FGGGTKLTVL | 16 |
C01 | 2437_02_H05 | λ | QMQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYA ISWVRQAPGQGLEWMGG IIPIFGTA NYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCVR GYSSIYYYYGMDV WGQGTMVTVSSGGGGSGGGGSGGGASQSGLTQPRSVSGSPGQSVTISCTGT SSDVGGYNY VSWYQQHPGKAPKLMIY DVS KRPSGVSDRFSGSKSGNTASLTISGLQAEDEADYYC GSYTSDGTLV FGGGTKLTVL | 17 |
C02 | 2437_02_H08 | λ | QVQLVQSGAEVKKPGSSVKVSCKAS GGTFSSYT ISWVRQAPGQGLEWMGR IIPILGIA NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR DRSYNWLDP WGRGTLVTVSSGGGGSGGGGSGGGASQSALTQPVSVSGSPGQSITISCTGT ISDVGDYNY VSWYQQHPGKAPKLMIY DVN NRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYC SSYTSSSTLV FGGGTKLTVL | 18 |
C07 (陽性對照組) | 5F9 scFv | κ | EIVMTQSPATLSVSPGERATLSCRASQSVSRNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTIGSLQSEDFAVYYCQQYKTWPRTFGQGTNVEIKASGGGGSGGGGSGGGGSGGGGSELQVQLQQWGAGLLKPSETLSLTCAVFGGSFSGYYWSWIRQPPGKGLEWIGEINHRGNTNDNPSLKSRVTISVDTSKNQFALKLSSVTAADTAVYYCARERGYTYGNFDHWGQGTLVTVSS | 19 |
scFv ID | scFv 區(核苷酸; 5'→3' ) | SEQ ID NO |
A01 | CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGATACACCTTCACCAGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAATAATCAACCCTAGTGGTGGTAGCACAAGCTACGCACAGGAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGATGGGCAGTGGCTTCAATTTGACTACTGGGGCCAAGGAACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCGATATTGTGATGACACAGTCTCCACTCTCCCTGCCCGTCACCCTTGGGCAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCCTAAAAAAGAGTGATGGGAACACCTACTTGAGTTGGTATCACCAGAGGCCAGGCCAATCTCCACGGCGCCTAATTTATAAGGTTTCTAATCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGACACTGATTTCACTCTGAAAATCAGCAGAGTGGAGACTGAGGATGTTGGAATTTATTACTGCATGCAAGGTTCACACTGGCCTCCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA | 20 |
A02 | GAGGTGCAGCTGGTGCAGCCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCCTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAAGGATCATCCCTATCCTTGGTATAACAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTTCTGTGCGAGAGATCAGCGGCCGGCGAGCATGGACGTCTGGGGCCAGGGCACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCCAGTCTGAGCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATATCTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGTCCCCAAACTCATGATTCATGATGTCAGTCATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCTCCAGGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGACTATTTCTGCAGCTCATATACAAGCAGCAACAATTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA | 21 |
A03 | CAGGTCCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATACTATCAGCTGGGTGCGACAGGCCCCTGGACAAGAGCTTGAGTGGATGGGAAGGATCATCCCTATCCTTGGTATAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGATTATAGCAGCAGCTGGAACTCTATGGACGTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCCAGTCTGGGCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACATTGGTTATTATCACTATGTCTCCTGGTACCAACAACACCCGGGCAAAGCCCCCAAACTCATGATTTATGAGGACAGTAAGAGGCCCTCAGGGATTTCTAATCGTTTCTCTGGCTCCAAGTCTGGCACCACGGCCTCCCTGACCGTCTCTGGGCTCCAGGCTGAGGACGAGGCTCATTATTACTGCAGTTCTTTTACAAGTAGAAGTACTTGGGTGTTCGGCGGAGGGACCCAGCTCACCGTCCTA | 22 |
A04 | GAGGTGCAGCTGGTGCAGCCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCCTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAAGGATCATCCCTATCCTTGGTATAACAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTTCTGTGCGAGAGATCAGCGGCCGGCGAGCATGGACGTCTGGGGCCAGGGCACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCCAGTCTGAGCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATATCTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGTCCCCAAACTCATGATTCATGATGTCAGTCATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCTCCAGGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGACTATTTCTGCAGCTCATATACAAGCAGCAACAATTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA | 23 |
A05 | CAGGTCCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATACTATCACCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAAGGATCATCCCTGTCCTTGGTATAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGATTATAGCAGCAGCTGGAACTCTATGGACGTCTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCCAGTCTGGGCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATGATTTATGATGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTTCTCCGGCTCCAAGTCTGGGAACACGGCCTCCCTGACCGTCTCTGGGCTCCACGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCAGCAACAATTTTGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA | 24 |
A06 | CAGGTGCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCGGCAGCTATACTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAAGGATCATCCCTATCCTTGGTATAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGATTATAGCAGCAGCTGGAACTCTATGGACGTCTGGGGCCAAGGAACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCCAGTCTGGGCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGTGCTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATGATTTATGAGGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTTCTCTGCCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCTCCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCAGCAACAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA | 25 |
A07 | CAGGTGCAGCTGCAGGAGTCGGGCCCAGGGCTTGTGAAGCCTTCGGAGACCCTGTCCCTCACTTGCACTGTCTCTGGTGGCTCCATCAGTAGTTACTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGATTGGGTCTATCTATTACAGTGGGAGCACCAACTACAACCCCTCCCTCAAGAGTCGAGTCACCATCTCAAGAGACAAGTCGAAGAACCAGTTGTTTCTGAAGTTGAATTCTATGACCGCCGCGGACACGGCCGTCTATTATTGTGCGAGAGATGTTTGGGGCAGTGGCCAGTCATTTGACAGTTGGGGCCAGGGCACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCAATTTTATGCTGACTCAGCCCCACTCTGTGTCGGAGTCTCCGGGGAAGACGGTAACCATCTCCTGCACCCGCAGCAGTGGCAGCATTGCCAGCAACTATGTGCAGTGGTACCAGCAGCGCTTGGGCAGTTCCCCCACCACTGTGATCTATGAACATAGCCGAAGACCCTCTGGGGTCCCTGATCGGTTCTCTGCCTCCATCGACAGCTCCTCCAACTCTGCCTCCCTCACCATCTCTGGACTGAAGACTGAGGACGAGGCTGACTACTACTGTCAGTCTTATGATGTCAGCAATCGAGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA | 26 |
A08 | GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTAGCTATTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAAGCAAGATGGAAGTGAGAAATACTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTATTGTGCGAAAGCCCCGTGGTATAGCAGCTCGCCGACACCCTACGGTATGGACGTCTGGGGCCAGGGCACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAACTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAGGCGCCTGATCTATGGTGCATCCACTTTGATGAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACACCTCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA | 27 |
A10 | GAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAACACGTTACATTTGGGGGAGTTATCGGGCATACGGTATGGACGTCTGGGGCCAAGGGACAATGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCGACATCCAGATGACCCAGTCTCCATCCTCCATGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGCGCGAGTCAGAGCATTAGCAGTCATTTAAATTGGTATCAGCAGCTGCCAGGCAATGCCCCTACTCTCCTGATCTATTATGCTTCCAATTTACAAAGTGGGGTCCCATCTAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAGCCTGATGATTTTGCAACTTACTACTGTCAACAGAGTATCAGTCTCCCGTACACTTTTGGCCAGGGGACCAAGGTGGAGATCAAA | 28 |
A12 | GAGGTGCAGCTGGTGCAGCCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCCTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAAGGATCATCCCTATCCTTGGTATAACAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTTCTGTGCGAGAGATCAGCGGCCGGCGAGCATGGACGTCTGGGGCCAGGGCACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCCAGTCTGAGCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTATATCTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGTCCCCAAACTCATGATTCATGATGTCAGTCATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCTCCAGGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGACTATTTCTGCAGCTCATATACAAGCAGCAACAATTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA | 29 |
B01 | GAGGTGCAGCTGGTGCAGCCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCCTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAAGGATCATCCCTATCCTTGGTATAACAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTTCTGTGCGAGAGATCAGCGGCCGGCGAGCATGGACGTCTGGGGCCAGGGCACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCCAGTCTGGGCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATGATTTATGAGGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTACTACTGCAGCACAGTTACAAGCCTCAGCACTTATGTCTTCGGAACTGGGACCAAGCTGACCGTCCTA | 30 |
B07 | GAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAGGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCATCTGGATACACCTTCACCAGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAATAATCAACCCTAGTGGTGGTAGCACAAGCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGGCAGGAACGTATAGCAGTGGCTGGACGATTGACTACTGGGGGCAAGGGACCACGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCGATATTGTGATGACGCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTATACACTGATGGAAACACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGATTTATTACTGCATGCATAGTAAACAGTGGCCTCCCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA | 31 |
B08 | GAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGGACACTACTACTACATGGACGTCTGGGGGCAAGGGACCACGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCGATATTGTGATGACTCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAGGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTATCAGCAGAAACCTGGCCGGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCCACTTTCGGCGGAGGGACCAAGCTGGAGATCAAA | 32 |
B10 | GAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGGACACTACTACTACATGGACGTCTGGGGGCAAGGGACCACGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCGATATTGTGATGACTCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAGGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTATCAGCAGAAACCTGGCCGGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCCACTTTCGGCGGAGGGACCAAGCTGGAGATCAAA | 33 |
B11 | CAGGTGCAGCTGGTGGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGATGGGAGGGATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCGGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGGTATACAGCCTCTTCGCTACTACGGTATGGACGTCTGGGGCCAAGGAACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCCAGTCTGCGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAGTAATTATGTATACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAAACTCCTCATCTATAGGAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAGTGGTCGGGGAGTGTTCGGCGGAGGGACCCAGCTCACCGTCCTA | 34 |
B12 | CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTTATAGCGGTGGTAGCACACACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGACACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACGGCCGTGTATTACTGTGCGAGGGGGGCTGGTACCTTAAATGCTTTTGATATCTGGGGGCAAGGGACCACGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCCAGTCTGGGCTGACTCAGCCTCCCTCCACGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGCTTATAGCTATGTCTCCTGGTATCAACAACACCCAGGCAAAGCCCCCAAACTTCTCATTTATGCGGTCACTAAGAGGCCCTCGGGGGTCCCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGACTCCAGGATGAGGATGAGGCTGATTATTACTGCAGCTCTTTTGCAGGCGGCAGCACTCTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA | 35 |
C01 | CAAATGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTATCTTTGGTACAGCAAACTATGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGTGAGAGGATACAGTTCAATATACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACAATGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCCAGTCTGGGCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAGTCAGTCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGTGGTTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATGATTTATGATGTCAGTAAGCGGCCCTCAGGGGTTTCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCGGCTCATATACAAGCGACGGGACTCTAGTATTCGGCGGAGGGACCAAGCTGACCGTCCTA | 36 |
C02 | CAGGTGCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATACTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAAGGATCATCCCTATCCTTGGTATAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGATAGGTCTTACAACTGGCTCGACCCCTGGGGCCGTGGCACCCTGGTCACCGTCTCGAGTGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGCTAGCCAGTCTGCGCTGACTCAGCCTGTCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCATCAGTGACGTTGGTGATTATAACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACTCATGATTTATGACGTCAATAATCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCTCCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGCAGCAGCACTCTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTA | 37 |
藉由ELISA量測實例1中產生的scFv對抗原GUCY2C的結合親和力。作為用於量測結合親和力的抗原,以及實例1中製備的人類GUCY2C重組抗原,使用藉由相同方法製備的猴GUCY2C重組抗原及鼠GUCY2C重組抗原,量測對每一抗原的親和力(參見圖1a)。
更具體而言,將分別融合製備的人類GUCY2C(SEQ ID NO:112)、猴GUCY2C(SEQ ID NO:114)以及小鼠GUCY2C(SEQ ID NO:113)的GUCY2C-rCD4融合蛋白質結合於Nunc MaxisorpTM96孔板中塗佈有鏈黴親和素的位置。在移除未與洗滌緩衝液組合的所有合成蛋白質之後,在每一孔中培育在培養溶液中所獲得的抗GUCY2C scFV。此後,藉由使用Eu-標籤抗體Ab讀取DELFIA增強的信號來量測親和力。
所用抗原的資訊如下:
生物體 | Uniprot ID | NCBI基因ID | NCBI參考序列 | |
Hu-GUCY2C | 智人(人類) | P25092 | 2984 | NP_004954.2 |
Mu-GUCY2C | 小家鼠(家鼠) | Q3UWA6 | 14917 | NP_001120790.1 |
Cy-GUCY2C | 長尾獼猴(食蟹獼猴) | G7PJX5 | 102130850 | XP_005570270.1 |
rCD4 | 褐家鼠 | P05540 | 24932 | NP_036837.1 |
另外,以兩種濃度(5奈莫耳/升、50奈莫耳/升)製備實例1中產生的18種scFv,且其分別用作ELISA的初級抗體,以偵測GUCY2C抗原,且藉此,量測每一純系之間的結合親和力的強度,並且以此確定排序。更具體而言,在MaxiSorb板中塗佈抗FLAG抗體且藉由添加先前獲得的scFv結合之後,藉由洗滌過程移除剩餘scFv。此處,培育及組合生物素化的人類GUCY2C-rCD4蛋白質,且接著藉由經由鏈黴親和素-Europlum顯色DELFIA增強法讀數信號來量測對抗原的親和力。
此外,藉由表面電漿子共振(SPR)分析來量測實例1中產生的18種scFv對GUCY2C抗原的親和力。更具體而言,
將蛋白質G以150微克/毫升的濃度連接至HCA晶片,且接著5毫莫耳/升scFv及抗原以40微升/秒的速率以800奈莫耳/升至12.5奈莫耳/升的各種濃度流動。在25攝氏度條件下使用MASS2(Sierra SPR-32;布魯克(Bruker))以關聯時間2分鐘及解離時間10分鐘進行SPR分析。用軟體R3分析資料。
如上量測的18種scFv(SEQ ID NO:1至18)及陽性對照組scFv(5F9 scFv-Fc;SEQ ID NO: 19)對3種抗原(人類GUCY2C、猴GUCY2C以及小鼠GUCY2C)的結合親和力及親和力排序結果展示於表6及圖1b(結合親和力,ELISA)、圖2b(親和力排序,5奈莫耳/升)以及圖2c(親和力排序,50奈莫耳/升)中:
[ 表 6]
(n.d.:未偵測)
scFv ID | 純系ID | 結合ELISA(Hu-GUCY2C-rCD4) | 結合ELISA(Cy-GUCY2C-rCD4) | 結合ELISA(Mu-GUCY2C-rCD4) | 親和力排序ELISA(5奈莫耳/升) | 親和力排序(50奈莫耳/升) | 親和力(SPR) |
A01 | 2426_01_A02 | 30194 | 28056 | 352 | 13814 | 104387 | n.d. |
A02 | 2427_01_A08 | 48333 | 60 | 74 | 33437 | 167867 | 743 nM |
A03 | 2427_01_A12 | 59173 | 7871 | 77 | 36021 | 199194 | 219 nM |
A04 | 2427_01_B02 | 50995 | 73 | 66 | 30425 | 173460 | 311 nM |
A05 | 2427_01_B07 | 43016 | 89 | 62 | 18286 | 131086 | 4394 nM |
A06 | 2427_01_C01 | 63094 | 1527 | 80 | 35080 | 185082 | 716 nM |
A07 | 2427_01_C02 | 79025 | 51086 | 17087 | 4741 | 27729 | 3731 nM |
A08 | 2432_01_D05 | 58055 | 2273 | 1276 | 8697 | 54750 | n.d. |
A10 | 2432_01_D08 | 55377 | 37187 | 82 | 81236 | 242966 | 48 nM |
A12 | 2433_01_G08 | 38220 | 56 | 53 | 28096 | 151338 | 297 nM |
B01 | 2433_01_H07 | 39417 | 4486 | 70 | 26219 | 133243 | 335 nM |
B07 | 2436_02_F10 | 68628 | 48862 | 66 | 25925 | 139097 | 293 nM |
B08 | 2436_02_F11 | 61079 | 33693 | 56 | 23307 | 152983 | n.d. |
B10 | 2436_02_G01 | 34355 | 21161 | 82 | 12521 | 104751 | 2856 nM |
B11 | 2437_02_G07 | 37532 | 23563 | 44 | 14849 | 89646 | 1329 nM |
B12 | 2437_02_G10 | 30920 | 22095 | 48 | 9592 | 77088 | 4539 nM |
C01 | 2437_02_H05 | 37474 | 21616 | 51 | 3090 | 29476 | 1148 nM |
C02 | 2437_02_H08 | 49474 | 32344 | 61 | 11013 | 86347 | 1481 nM |
C07 (陽性對照組) | 5F9 scFv | 83913 | 49221 | 41 | 133261 | 183619 | 15 nM |
如表6及圖1b中所展示,表明所有18種scFv對人類GUCY2C的結合親和力顯著高於對猴GUCY2C及小鼠GUCY2C的結合親和力,且已證實其特異性結合於人類GUCY2C。另外,如表6及圖2b以及圖2c中所展示,已證實與人類GUCY2C具有相對高親和力的scFv中存在對猴GUCY2C的親和力。當總體上判定SPR結果時,已證實A10的scFV具有相對高結合能力且對人類及猴GUCY2C具有親和力。
實例 3 :細胞結合分析
使用天然表現GUCY2C的細胞,證實實例1中產生的18種scFv是否可實際上在細胞表面上偵測GUCY2C表現。對此,使用GUCY2C陽性癌細胞、T84結腸癌細胞(ATCC® CCL248™)。使用GUCY2C陰性乳癌細胞T-47D(ATCC® HTB-133™)作為對照組。
在使用胰蛋白酶-EDTA分離兩個細胞株之後,將其置放於FACS緩衝液(1x PBS + 2% BSA)中。10微克/毫升的18種scFv及陽性對照組5F9 scFv中的每一者與T84及T-47D細胞一起在冰上培養1小時。使用5微克/毫升IgG-Fc-PE Ab(BioLegend;409304)偵測組合至細胞的scFv。用ToPro
®3(活/死染色)培養細胞,且接著用流式細胞儀染紅。使用FlowJo 10.5軟體(FlowJo LLC)使所獲得資料浮動。
圖3a中繪示所得結果。
另外,圖3b中繪示藉由流式細胞術所獲得的MFI(螢光強度平均值)。
如圖3a及圖3b中所繪示,已證實以與陽性對照組5F9相等的量結合於GUCY2C表現的T84細胞的A10 scFv(SEQ ID NO:9)及B01 scFv(SEQ ID NO:11)、B11 scFv(SEQ ID NO:15)以及B12 scFv(SEQ ID NO:16)亦展示結合可能性。
實例 4 : 製備表現抗 GUCY2C-CAR 的免疫細胞 ( NK 細胞 ) 4.1. 慢病毒產生
CAR-NK細胞為嵌合抗原受體(CAR)在NK細胞表面上表現的形式,本實例中使用的嵌合抗原受體由包括結合於GUCY2C(參見實例1及表4)的scFv多肽的細胞外域、跨膜域(CD28;由GenBank寄存編號NM_006139.4編碼)以及細胞內傳訊域(CD3ζ;由GenBank寄存編號NM_001378516.1編碼)組成(抗GUCY2C-CAR)。
藉由將表現脂染胺3000轉染套組(#L3000015,英傑(Invitrogen))及抗GUCY2C CAR(結合GUCY2C的scFv-CD28-CD3ζ)的質體處理至LentiX-293T(#632180 Clonthech)而進行轉染,且在轉染後次日起2天內,獲得上清液。使用Lenti-X濃縮器(#631232,Clonetech)濃縮病毒。將所獲得沈澱物溶解於CTS-PBS中且在-80℃下儲存。
在使用病毒RNA分離套組(#740956,Macherey-Nagel)自病毒提取RNA之後,使用Lenti-X qRT-PCR滴定套組(#631235,Takara)量測病毒滴度。
實例 4.2. 製備 NK 細胞
將iPSC(CMC-hiPSC-003,韓國疾病控制與預防中心)在mTeSR™ Plus(幹細胞技術(STEMCELL Technoology),100-0276)中培養2至3天,且在形成約500微米直徑的聚集物時,將培養溶液改變至STEMdiff™造血套組(幹細胞技術,05310)的培養基A中,藉此發生造血幹細胞(hematopoietic stem cell;HSC)分化。在培養基A中培養3天之後,其另外在相同套組的培養基B中培養9天以獲得HSC。接著,每2至3天移除一半培養溶液,且添加相同量的新培養溶液以替換所述培養溶液。
將HSC轉移至用StemSpan™ NK細胞產生套組(幹細胞技術,09960)中所包括的淋巴分化塗層材料表面處理的板,且在相同套組產品中所包括的淋巴祖細胞擴增培養基中培養14天,且每3至4天替換一半培養溶液。接著,在藉由在NK細胞分化培養基中每3至4天替換一半培養溶液而進行培養之後14天內,獲得NK細胞。
實例 4.3.iPSC 中分化的原始 NK 細胞的表面類型特性的證實
為了證實在實例4.2中獲得的iPSC中分化的原始NK細胞是否正常進行分化,且其具有表面類型特點及NK細胞固有功能(穿孔素、顆粒酶B、IFN),通過流式細胞術證實NK細胞表面標記物的表現,且證實NK細胞的凋亡過程的效應分子的表現。
具體而言,將實例4.2中獲得的iPSC中分化的原始NK細胞與圖4a至圖4b中表示的每一抗體在4℃下培育1小時,且接著用流式細胞儀(FACS)證實。另外,為了證實細胞內表現的細胞介素,使用滲透套組在細胞表面中開孔,且使用固定溶液進行固定,且接著使用圖4c中表示的抗體(TNF-α、IFN-γ、穿孔素、顆粒酶B)對其進行染色,並用流式細胞儀對其進行分析。
圖4a至圖4c中繪示所得結果。如圖4a及圖4b中所繪示,表現抗GUCY2C CAR的NK細胞展示較低CD117表現及較高CD94/NKG2D表現,且展示NK細胞的成熟表型,且已證實NK活化受體的表現較高且正常表現細胞介素受體。另外,如圖4c中所繪示,已證實作為NK細胞凋亡過程中的主要因子的IFN-γ、顆粒酶B以及穿孔素的表現在表現抗GUCY2C CAR的NK細胞中較高。
實例 4.4. 產生表現抗 GUCY2C CAR 的 NK 細胞
在如上自iPSc獲得NK細胞的過程中,在中間HSC步驟中,藉由MOI 3000用lentiboost(Sirion)處理裝載實例4.1中製備的抗GUCY2C CAR(結合GUCY2C的scFv-CD28-CD3ζ)的慢病毒,且次日,利用NK細胞,藉由所描述方法進行分化。
為了證實包含純系ID A12(SEQ ID NO:3)、D08(SEQ ID NO:9)、H07(SEQ ID NO:11)、G07(SEQ ID NO:15)或5F9(SEQ ID NO:19;陽性對照)作為結合GUCY2C的scFV在分化NK細胞中的CAR表現,以1:100使用共軛FITC的山羊抗人類Fab抗體(#31628,Invitrogn),且將其在4攝氏度下培育20分鐘。此後,用FACS緩衝液(2% FBS/PBS)洗滌,且藉由FACS分析(LSR fortessa,BD)證實表現量。
圖5中繪示所得結果。如圖5中所繪示,已證實所有分化NK細胞表現結合GUCY2C的scFV(D08、G07、A12、H07)。
實例 4.5. 表現抗 GUCY2C-CAR 的 NK 細胞的活體外細胞毒性測試
將GUCY2C基因(NM_004963.4)次選殖於pLV-EF1α-puroR質體中,且藉由參考實例4.1中所描述的方法產生慢病毒。將製備的慢病毒轉導至HT29細胞(ATCC HTB38
TM)以在細胞表面上表現其,且2天後,僅藉由以2.5微克/毫升的濃度處理嘌呤黴素來選擇表現GUCY2C的細胞。照此選擇2週後,最後獲得表現GUCY2C的HT29細胞株。使用CFSE增殖套組(賽默飛世爾(Thermo Fisher),C34554)標記照此製備的標靶細胞(HT29(ATCC HTB38
TM)或HT29-GUCY2C)。
藉由使用PB洗滌之後,將每一比率的效應細胞(表現抗GUCY2C-CAR的NK細胞)在96孔板中等分以便為100微升/孔。固定每一標靶細胞且根據E(效應細胞):T(標靶細胞)比調整NK細胞的數目,藉此準備以使得E:T比為10:1、3:1、1:1、0.5:1。接著,針對陰性對照製備僅具有標靶細胞的樣品及僅具有效應細胞的孔。將此等混合細胞在37℃培育箱中培養4小時,且接著用FACS(10% FBS/PBS)的洗滌緩衝液洗滌,且接著,最後,用DAPI-FACS緩衝液(DAPI最終工作5微克/毫升)70微升/孔製備樣品,且接著在10分鐘內,藉由FACS(Intellicyt® iQue Screener PLUS)進行分析。使用分析值,藉由以下等式,轉換裂解活性。
細胞毒性%=
圖6a(標靶細胞為HT29細胞的情況下的結果)及圖6b(標靶細胞為表現GUCY2C的HT29細胞的情況下的結果)中繪示所得結果。如圖6a及圖6b中所繪示,證實表現CAR的NK細胞的細胞毒性,其包含4種結合GUCY2C的scFV(D08、G07、A12、H07)(CAR-NK)。已證實,在標靶細胞為並不表現GUCY2C的大腸直腸癌細胞株HT29時,CAR-NK展示約20%或更小的細胞毒性,而其在過度表現HT29-GUCY2C標靶細胞株的GUCY2C中以最大量展示60%或更大的細胞毒性。已證實,取決於scFv的類型,細胞毒性值存在差異,但所有所用純系皆展示針對GUCY2C的劑量依賴性細胞毒性。
4.6 活體外表現抗 GUCY2C-CAR 的 NK 細胞的 CAR 依賴性殺死作用及 NK 固有殺死 ( CAR 非依賴性 ) 作用的證實
為了證實表現抗GUCY2C-CAR的NK細胞的活體外CAR依賴性殺死作用,藉由使用表現包含結合GUCY2C的scFV(D08)的CAR的NK細胞進行以下實驗。
具體而言,藉由與實例4.4中所描述的方法相同的方法,固定標靶細胞(HT29(ATCC HTB38
TM)或HT29-GUCY2C),且藉由FACS(Intellicyt® iQue Screener PLUS)對其進行分析。使用分析值,藉由以下等式,轉換裂解活性。
細胞毒性%=
藉由製造聚集物且接種一定量且接著藉由造血幹細胞分化培養基固定造血幹細胞且將其分化成淋巴祖細胞來進行分化。經由再次分化成NK細胞的過程獲得細胞。
圖7中繪示所得結果(GUCY2C靶向CAR-NK細胞的純系號D08)。如圖7中所繪示,在表現包含結合GUCY2C的scFV(D08)的CAR的NK細胞(GUCY2C靶向CAR-NK細胞)活體外與標靶細胞株共同培養時,證實CAR依賴性殺死作用及NK固有殺死作用(CAR-非依賴性)。換言之,藉由在圖7的GUCY2C-HT29細胞中細胞毒性隨E:T比增加(效應細胞增加)而增加的結果,已證實其具有非隨機的CAR濃度依賴性殺死作用,且藉由甚至在模擬-HT29細胞中展示細胞毒性,已證實亦存在NK固有殺死作用(CAR非依賴性)。
實例 4.7. 活體內表現抗 GUCY2C-CAR 的 NK 細胞的 CAR 依賴性殺死作用及 NK 固有殺死 ( CAR 非依賴性 ) 的證實
為了證實活體內表現抗GUCY2C-CAR的NK的CAR依賴性殺死作用及NK固有殺死(CAR非依賴性)作用,藉由使用表現包含結合GUCY2C的scFV(D08)的CAR的NK細胞進行以下實驗。
具體而言,在將CFSE染色標靶細胞株(HT29-GUCY2細胞)腹膜內注射至小鼠中之後1小時內,利用IL-2/15腹膜內注射表現包含結合GUCY2C的scFV(D08)的CAR的NK細胞以證實小鼠體內標靶細胞的減少程度。為觀察此情況,藉由等待4小時且將PBS注射至腹腔中並再次回收其的方法而獲得腹腔中的剩餘細胞,且藉由經由流式細胞術量測CFSE染料的方法觀察標靶細胞的死亡。
結果,如圖8中所繪示,證實活體內表現包含結合GUCY2C的scFV(D08)的CAR的NK細胞的CAR依賴性殺死作用及NK固有殺死作用(CAR非依賴性)。
實例 4.8. 表現抗 GUCY2C-CAR 的 NK 細胞的 IFN- γ 分泌能力的證實
為了證實影響表現抗GUCY2C-CAR的NK細胞的殺死能力的IFN-γ分泌能力,藉由使用表現包含結合GUCY2C的scFV(5F9、D08、G07)的CAR的NK細胞進行以下實驗。
具體而言,使用ELISA方法量測IFN-γ分泌能力,且在共同培養標靶細胞及每一NK細胞24小時後,回收上清液。在塗佈抗體以識別IFN-γ的板中培育回收的上清液,且藉由洗滌操作移除剩餘溶液。對此,藉由再次識別能夠顯色的IFN-γ抗體,量測顯色程度以證實所分泌IFN-γ。
結果,如圖9a中所繪示,已證實,在表現抗GUCY2C-CAR的NK細胞與過度表現GUCY2C的HT29-GUCY2C靶向細胞株(HT29 GCC細胞)共同培養時,顯著增加所分泌IFN-γ的量。如圖9b中所繪示,藉由在不包含CAR的原始NK(原始NK)中與HT29-GUCY2C細胞共同培養而未增加IFN-γ的量,且藉由與GUCY2C陽性癌細胞,T84細胞共同培養而證實增加IFN-γ的相對較少量。另一方面,已證實,在表現包含結合GUCY2C的scFV(5F9、D08、G07)的CAR的NK細胞與GUCY2C陽性癌細胞,T84細胞共同培養時,與不表現GUCY2C的模擬HT29細胞相比,IFN-γ量顯著增加。
實例 4.9. 在動物模型中投與表現抗 GUCY2C-CAR 的 NK 細胞時存活率的證實
為了證實在動物模型中投與表現抗GUCY2C-CAR的NK細胞時的存活率,進行以下實驗。
具體而言,在移植HT29-GUCY2C-Luc細胞i.p.(2.5x10
6個細胞)至NOG小鼠(DO)中之後,在第3天,將各組與表現相同量的HT29細胞(IVIS總通量)的小鼠分離,且一起投與CAR NK及細胞介素。以1x10
7個細胞的量腹膜內投與GUCY2C-CAR NK細胞,且細胞介素的濃度投與為hIL-2(Novartis Proleukin)/10微克(ip,4次/週)、hIL-15(Peprotech)/3微克(ip,qd)。接著,證實每一實驗組的存活率及存活日。
[表7]
組 | No. | 死亡日 | ||
G1(HT29-Luc,ip,媒劑+測試樣品2) | 1 | 2021-12-14 | 66 | |
2 | 2021-12-14 | 66 | ||
3 | 2021-12-13 | 65 | ||
4 | 2021-12-14 | 66 | ||
5 | 2021-12-14 | 66 | ||
6 | 2021-12-14 | 66 | ||
G2(HT29-Luc,ip,測試樣品1+測試樣品2) | 1 | 95 | ||
2 | 2021-12-31 | 83 | ||
3 | 95 | |||
4 | 2021-12-27 | 79 | ||
5 | 2021-12-14 | 66 | ||
6 | 2021-12-30 | 82 |
結果,如表7及圖10中所展示,已證實與對照組相比,CAR-NK細胞投與組的存活率顯著較高,且CAR-NK細胞投與組的存活日比對照組更長,因為對照組的平均存活日為66天,且CAR-NK細胞投與組為82.5天。
無
圖1a為示意性地繪示使用ELISA量測scFv對GUCY2C的結合親和力的過程的示意圖。
圖1b為繪示藉由ELISA量測的scFv對3種GUCY2C(人類GUCY2C、猴GUCY2C以及小鼠GUCY2C)的結合親和力的圖表。
圖2a為示意性地繪示使用ELISA量測scFv對GUCY2C的親和力排序的過程的示意圖。
圖2b及圖2c繪示量測藉由ELISA量測的scFV對GUCY2C的親和力排序的結果,且圖2b繪示5奈莫耳/升下scFv的結果,且圖2c繪示50奈莫耳/升下scFv的結果。
圖3a繪示針對scFv的GUCY2C細胞的細胞結合分析的結果。
圖3b為繪示作為scFv的GUCY2C細胞的細胞結合分析的結果而獲得的MFI(螢光強度平均值)的圖表。
圖4a為繪示藉由流式細胞術證實iPSC中分化的原始NK細胞的NK細胞表面標記物的表現的結果的圖表。
圖4b為繪示證實iPSC中分化的原始NK細胞的NK細胞表面標記物的表現的結果的圖表。
圖4c為繪示證實iPSC中分化的原始NK細胞的NK細胞凋亡過程的效應分子的表現的結果的圖表。
圖5為繪示引入抗GUCY2C CAR的NK細胞中的抗GUCY2C CAR的表現量的圖表。
圖6a為繪示針對不表現GUCY2C的標靶細胞的抗GUCY2C-CAR表現的NK細胞的細胞毒性的圖表。
圖6b為繪示針對表現GUCY2C的標靶細胞的抗GUCY2C-CAR表現的NK細胞的細胞毒性的圖表。
圖7為繪示針對不表現GUCY2C的標靶細胞及活體外表現GUCY2C的標靶細胞的抗GUCY2C-CAR表現的NK細胞的CAR依賴性殺死能力的圖表。
圖8為繪示抗GUCY2C-CAR表現的NK細胞及活體內CD19靶向CAR-NK細胞的CAR依賴性殺死能力的圖表。
圖9a為證實在抗GUCY2C-CAR表現的NK細胞與表現GUCY2C的標靶細胞共同培養時所分泌IFN-γ量顯著增加的圖表。在圖表中,「無NK」為未用NK細胞處理的實驗組且對應於值0。
圖9b為證實在包括結合GUCY2C的scFV(5F9、D08、G07)的CAR-NK細胞與作為GUCY2C陽性癌細胞的T84細胞共同培養時IFN-γ量顯著增加的圖表。在圖表中,「無NK」為未用NK細胞處理的實驗組且對應於值0。
圖10為將投與抗GUCY2C-CAR表現的NK細胞時的存活率與對照組(媒劑投與組)的存活率進行比較的圖表。
<![CDATA[<110> LG化學股份有限公司]]> <![CDATA[<120> 鳥苷酸環化酶2C結合多肽以及其應用]]> <![CDATA[<130> OPP20221099TW]]> <![CDATA[<150> KR 10-2021-0045510]]> <![CDATA[<151> 2021-04-07]]> <![CDATA[<160> 115]]> <![CDATA[<170> koPatentIn 3.0]]> <![CDATA[<210> 1]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 1]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Glu Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Gln Trp Leu Gln Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Ala Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu 130 135 140 Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln 145 150 155 160 Ser Leu Leu Lys Lys Ser Asp Gly Asn Thr Tyr Leu Ser Trp Tyr His 165 170 175 Gln Arg Pro Gly Gln Ser Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn 180 185 190 Arg Asp Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Asp Thr 195 200 205 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Thr Glu Asp Val Gly Ile 210 215 220 Tyr Tyr Cys Met Gln Gly Ser His Trp Pro Pro Thr Phe Gly Gln Gly 225 230 235 240 Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 2]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 2]]> Glu Val Gln Leu Val Gln Pro Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Leu Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asp Gln Arg Pro Ala Ser Met Asp Val Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Ala Ser Gln Ser Glu Leu Thr Gln Pro Ala Ser Val Ser 130 135 140 Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser 145 150 155 160 Asp Val Gly Gly Tyr Ile Tyr Val Ser Trp Tyr Gln Gln His Pro Gly 165 170 175 Lys Val Pro Lys Leu Met Ile His Asp Val Ser His Arg Pro Ser Gly 180 185 190 Val Ser Asn Arg Phe Ser Gly Ser Arg Ser Gly Asn Thr Ala Ser Leu 195 200 205 Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser 210 215 220 Ser Tyr Ala Gly Ser Asn Asn Tyr Val Phe Gly Thr Gly Thr Lys Val 225 230 235 240 Thr Val Leu <![CDATA[<210> 3]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合]]>成的_GUCY2C-結合 scFv <![CDATA[<400> 3]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Thr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Glu Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Tyr Ser Ser Ser Trp Asn Ser Met Asp Val Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Ala Ser Gln Ser Gly Leu Thr Gln Pro Pro Ser 130 135 140 Ala Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr 145 150 155 160 Ser Ser Asp Ile Gly Tyr Tyr His Tyr Val Ser Trp Tyr Gln Gln His 165 170 175 Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Glu Asp Ser Lys Arg Pro 180 185 190 Ser Gly Ile Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Thr Thr Ala 195 200 205 Ser Leu Thr Val Ser Gly Leu Gln Ala Glu Asp Glu Ala His Tyr Tyr 210 215 220 Cys Ser Ser Phe Thr Ser Arg Ser Thr Trp Val Phe Gly Gly Gly Thr 225 230 235 240 Gln Leu Thr Val Leu 245 <![CDATA[<210> 4]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 4]]> Glu Val Gln Leu Val Gln Pro Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Leu Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asp Gln Arg Pro Ala Ser Met Asp Val Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Ala Ser Gln Ser Glu Leu Thr Gln Pro Ala Ser Val Ser 130 135 140 Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser 145 150 155 160 Asp Val Gly Gly Tyr Ile Tyr Val Ser Trp Tyr Gln Gln His Pro Gly 165 170 175 Lys Val Pro Lys Leu Met Ile His Asp Val Ser His Arg Pro Ser Gly 180 185 190 Val Ser Asn Arg Phe Ser Gly Ser Arg Ser Gly Asn Thr Ala Ser Leu 195 200 205 Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser 210 215 220 Ser Tyr Thr Ser Ser Asn Asn Tyr Tyr Phe Gly Thr Gly Thr Lys Val 225 230 235 240 Thr Val Leu <![CDATA[<210> 5]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 5]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Thr Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Val Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Tyr Ser Ser Ser Trp Asn Ser Met Asp Val Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Ala Ser Gln Ser Gly Leu Thr Gln Pro Arg Ser 130 135 140 Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr 145 150 155 160 Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His 165 170 175 Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys Arg Pro 180 185 190 Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala 195 200 205 Ser Leu Thr Val Ser Gly Leu His Ala Glu Asp Glu Ala Asp Tyr Tyr 210 215 220 Cys Ser Ser Tyr Ala Gly Ser Asn Asn Phe Val Phe Gly Thr Gly Thr 225 230 235 240 Lys Val Thr Val Leu 245 <![CDATA[<210> 6]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 6]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Gly Ser Tyr 20 25 30 Thr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Tyr Ser Ser Ser Trp Asn Ser Met Asp Val Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Ala Ser Gln Ser Gly Leu Thr Gln Pro Arg Ser 130 135 140 Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr 145 150 155 160 Ser Ser Asp Val Gly Ala Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His 165 170 175 Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Glu Val Ser Lys Arg Pro 180 185 190 Ser Gly Val Pro Asp Arg Phe Ser Ala Ser Lys Ser Gly Asn Thr Ala 195 200 205 Ser Leu Thr Val Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr 210 215 220 Cys Ser Ser Tyr Ala Gly Ser Asn Asn Trp Val Phe Gly Gly Gly Thr 225 230 235 240 Lys Leu Thr Val Leu 245 <![CDATA[<210> 7]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 7]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Arg Asp Lys Ser Lys Asn Gln Leu Phe Leu 65 70 75 80 Lys Leu Asn Ser Met Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Asp Val Trp Gly Ser Gly Gln Ser Phe Asp Ser Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Ala Ser Asn Phe Met Leu Thr Gln Pro His Ser Val 130 135 140 Ser Glu Ser Pro Gly Lys Thr Val Thr Ile Ser Cys Thr Arg Ser Ser 145 150 155 160 Gly Ser Ile Ala Ser Asn Tyr Val Gln Trp Tyr Gln Gln Arg Leu Gly 165 170 175 Ser Ser Pro Thr Thr Val Ile Tyr Glu His Ser Arg Arg Pro Ser Gly 180 185 190 Val Pro Asp Arg Phe Ser Ala Ser Ile Asp Ser Ser Ser Asn Ser Ala 195 200 205 Ser Leu Thr Ile Ser Gly Leu Lys Thr Glu Asp Glu Ala Asp Tyr Tyr 210 215 220 Cys Gln Ser Tyr Asp Val Ser Asn Arg Val Phe Gly Gly Gly Thr Lys 225 230 235 240 Leu Thr Val Leu <![CDATA[<210> 8]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 8]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ala Pro Trp Tyr Ser Ser Ser Pro Thr Pro Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Ala Ser Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Arg Arg Leu Ile Tyr Gly Ala Ser Thr 180 185 190 Leu Met Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 9]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 9]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Arg Tyr Ile Trp Gly Ser Tyr Arg Ala Tyr Gly Met Asp 100 105 110 Val Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Ala Ser Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Met Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser His Leu Asn Trp Tyr Gln 165 170 175 Gln Leu Pro Gly Asn Ala Pro Thr Leu Leu Ile Tyr Tyr Ala Ser Asn 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Gln Gln Ser Ile Ser Leu Pro Tyr Thr Phe Gly Gln Gly 225 230 235 240 Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 10]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 10]]> Glu Val Gln Leu Val Gln Pro Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Leu Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asp Gln Arg Pro Ala Ser Met Asp Val Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Ala Ser Gln Ser Glu Leu Thr Gln Pro Ala Ser Val Ser 130 135 140 Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser 145 150 155 160 Asp Val Gly Gly Tyr Ile Tyr Val Ser Trp Tyr Gln Gln His Pro Gly 165 170 175 Lys Val Pro Lys Leu Met Ile His Asp Val Ser His Arg Pro Ser Gly 180 185 190 Val Ser Asn Arg Phe Ser Gly Ser Arg Ser Gly Asn Thr Ala Ser Leu 195 200 205 Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ser 210 215 220 Ser Tyr Thr Ser Ser Asn Asn Tyr Val Phe Gly Thr Gly Thr Lys Val 225 230 235 240 Thr Val Leu <![CDATA[<210> 11]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 11]]> Glu Val Gln Leu Val Gln Pro Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Leu Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Asp Gln Arg Pro Ala Ser Met Asp Val Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Ala Ser Gln Ser Gly Leu Thr Gln Pro Ala Ser Val Ser 130 135 140 Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser 145 150 155 160 Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly 165 170 175 Lys Ala Pro Lys Leu Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly 180 185 190 Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu 195 200 205 Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser 210 215 220 Thr Val Thr Ser Leu Ser Thr Tyr Val Phe Gly Thr Gly Thr Lys Leu 225 230 235 240 Thr Val Leu <![CDATA[<210> 12]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 12]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Arg Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Thr Tyr Ser Ser Gly Trp Thr Ile Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Ala Ser Asp Ile Val Met Thr Gln Ser Pro Leu 130 135 140 Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser 145 150 155 160 Ser Gln Ser Leu Val Tyr Thr Asp Gly Asn Thr Tyr Leu Asn Trp Phe 165 170 175 Gln Gln Arg Pro Gly Gln Ser Pro Arg Arg Leu Ile Tyr Lys Val Ser 180 185 190 Asn Arg Asp Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly 210 215 220 Ile Tyr Tyr Cys Met His Ser Lys Gln Trp Pro Pro Thr Phe Gly Gly 225 230 235 240 Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 13]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 13]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly His Tyr Tyr Tyr Met Asp Val Trp Gly Gln Gly Thr Thr 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Ala Ser Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser 130 135 140 Val Ser Pro Gly Glu Gly Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser 145 150 155 160 Val Ser Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro 165 170 175 Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn 210 215 220 Asn Trp Pro Ser Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 225 230 235 <![CDATA[<210> 14]]> <![CDATA[<211> 238]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 14]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly His Tyr Tyr Tyr Met Asp Val Trp Gly Gln Gly Thr Thr 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Ala Ser Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser 130 135 140 Val Ser Pro Gly Glu Gly Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser 145 150 155 160 Val Ser Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro 165 170 175 Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn 210 215 220 Asn Trp Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 225 230 235 <![CDATA[<210> 15]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 15]]> Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Gly Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ile Gln Pro Leu Arg Tyr Tyr Gly Met Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Ala Ser Gln Ser Ala Leu Thr Gln Pro Pro 130 135 140 Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly 145 150 155 160 Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr Trp Tyr Gln Gln Leu 165 170 175 Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Arg Asn Asn Gln Arg Pro 180 185 190 Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala 195 200 205 Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr 210 215 220 Cys Ala Ala Trp Asp Asp Ser Leu Ser Gly Arg Gly Val Phe Gly Gly 225 230 235 240 Gly Thr Gln Leu Thr Val Leu 245 <![CDATA[<210> 16]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 16]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Tyr Ser Gly Gly Ser Thr His Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg His Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Gly Ala Gly Thr Leu Asn Ala Phe Asp Ile Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Ala Ser Gln Ser Gly Leu Thr Gln Pro Pro Ser Thr Ser 130 135 140 Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser 145 150 155 160 Asp Val Gly Ala Tyr Ser Tyr Val Ser Trp Tyr Gln Gln His Pro Gly 165 170 175 Lys Ala Pro Lys Leu Leu Ile Tyr Ala Val Thr Lys Arg Pro Ser Gly 180 185 190 Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu 195 200 205 Thr Val Ser Gly Leu Gln Asp Glu Asp Glu Ala Asp Tyr Tyr Cys Ser 210 215 220 Ser Phe Ala Gly Gly Ser Thr Leu Val Phe Gly Gly Gly Thr Lys Leu 225 230 235 240 Thr Val Leu <![CDATA[<210> 17]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 17]]> Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Gly Tyr Ser Ser Ile Tyr Tyr Tyr Tyr Gly Met Asp Val Trp 100 105 110 Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Ala Ser Gln Ser Gly Leu Thr Gln Pro 130 135 140 Arg Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr 145 150 155 160 Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln 165 170 175 Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys 180 185 190 Arg Pro Ser Gly Val Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn 195 200 205 Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp 210 215 220 Tyr Tyr Cys Gly Ser Tyr Thr Ser Asp Gly Thr Leu Val Phe Gly Gly 225 230 235 240 Gly Thr Lys Leu Thr Val Leu 245 <![CDATA[<210> 18]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 18]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Thr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Ser Tyr Asn Trp Leu Asp Pro Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Ala Ser Gln Ser Ala Leu Thr Gln Pro Val Ser Val Ser 130 135 140 Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ile Ser 145 150 155 160 Asp Val Gly Asp Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly 165 170 175 Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly 180 185 190 Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu 195 200 205 Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser 210 215 220 Ser Tyr Thr Ser Ser Ser Thr Leu Val Phe Gly Gly Gly Thr Lys Leu 225 230 235 240 Thr Val Leu <![CDATA[<210> 19]]> <![CDATA[<211> 250]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv]]> <![CDATA[<400> 19]]> Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Gly Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Lys Thr Trp Pro Arg 85 90 95 Thr Phe Gly Gln Gly Thr Asn Val Glu Ile Lys Ala Ser Gly Gly Gly 100 105 110 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Glu Leu Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys 130 135 140 Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Phe Gly Gly Ser Phe 145 150 155 160 Ser Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu 165 170 175 Glu Trp Ile Gly Glu Ile Asn His Arg Gly Asn Thr Asn Asp Asn Pro 180 185 190 Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln 195 200 205 Phe Ala Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr 210 215 220 Tyr Cys Ala Arg Glu Arg Gly Tyr Thr Tyr Gly Asn Phe Asp His Trp 225 230 235 240 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 245 250 <![CDATA[<210> 20]]> <![CDATA[<211> 738]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 20]]> caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60 tcctgcaagg catctggata caccttcacc agctactata tgcactgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaata atcaacccta gtggtggtag cacaagctac 180 gcacaggagt tccagggcag agtcaccatg accagggaca cgtccacgag cacagtctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagatggg 300 cagtggcttc aatttgacta ctggggccaa ggaaccctgg tcaccgtctc gagtggtgga 360 ggcggttcag gcggaggtgg ctctggcggt ggcgctagcg atattgtgat gacacagtct 420 ccactctccc tgcccgtcac ccttgggcag ccggcctcca tctcctgcag gtctagtcaa 480 agcctcctaa aaaagagtga tgggaacacc tacttgagtt ggtatcacca gaggccaggc 540 caatctccac ggcgcctaat ttataaggtt tctaatcggg actctggggt cccagacaga 600 ttcagcggca gtgggtcaga cactgatttc actctgaaaa tcagcagagt ggagactgag 660 gatgttggaa tttattactg catgcaaggt tcacactggc ctccgacgtt cggccaaggg 720 accaaggtgg aaatcaaa 738 <![CDATA[<210> 21]]> <![CDATA[<211> 729]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 21]]> gaggtgcagc tggtgcagcc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccctcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat aacaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt atttctgtgc gagagatcag 300 cggccggcga gcatggacgt ctggggccag ggcaccctgg tcaccgtctc gagtggtgga 360 ggcggttcag gcggaggtgg ctctggcggt ggcgctagcc agtctgagct gactcagcct 420 gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagcagt 480 gacgttggtg gttatatcta tgtctcctgg taccaacagc acccaggcaa agtccccaaa 540 ctcatgattc atgatgtcag tcatcggccc tcaggggttt ctaatcgctt ctctggctcc 600 aggtctggca acacggcctc cctgaccatc tctgggctcc aggctgagga cgaggctgac 660 tatttctgca gctcatatgc aggcagcaac aattatgtct tcggaactgg gaccaaggtc 720 accgtccta 729 <![CDATA[<210> 22]]> <![CDATA[<211> 735]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 22]]> caggtccagc tggtgcaatc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatacta tcagctgggt gcgacaggcc 120 cctggacaag agcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattat 300 agcagcagct ggaactctat ggacgtctgg ggccagggaa ccctggtcac cgtctcgagt 360 ggtggaggcg gttcaggcgg aggtggctct ggcggtggcg ctagccagtc tgggctgact 420 cagcctccct ccgcgtccgg gtctcctgga cagtcagtca ccatctcctg cactggaacc 480 agcagtgaca ttggttatta tcactatgtc tcctggtacc aacaacaccc gggcaaagcc 540 cccaaactca tgatttatga ggacagtaag aggccctcag ggatttctaa tcgtttctct 600 ggctccaagt ctggcaccac ggcctccctg accgtctctg ggctccaggc tgaggacgag 660 gctcattatt actgcagttc ttttacaagt agaagtactt gggtgttcgg cggagggacc 720 cagctcaccg tccta 735 <![CDATA[<210> 23]]> <![CDATA[<211> 729]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 23]]> gaggtgcagc tggtgcagcc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccctcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat aacaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt atttctgtgc gagagatcag 300 cggccggcga gcatggacgt ctggggccag ggcaccctgg tcaccgtctc gagtggtgga 360 ggcggttcag gcggaggtgg ctctggcggt ggcgctagcc agtctgagct gactcagcct 420 gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagcagt 480 gacgttggtg gttatatcta tgtctcctgg taccaacagc acccaggcaa agtccccaaa 540 ctcatgattc atgatgtcag tcatcggccc tcaggggttt ctaatcgctt ctctggctcc 600 aggtctggca acacggcctc cctgaccatc tctgggctcc aggctgagga cgaggctgac 660 tatttctgca gctcatatac aagcagcaac aattattact tcggaactgg gaccaaggtc 720 accgtccta 729 <![CDATA[<210> 24]]> <![CDATA[<211> 735]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 24]]> caggtccagc tggtgcaatc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatacta tcacctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatccctg tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattat 300 agcagcagct ggaactctat ggacgtctgg ggccagggaa ccctggtcac cgtctcgagt 360 ggtggaggcg gttcaggcgg aggtggctct ggcggtggcg ctagccagtc tgggctgact 420 cagcctcgct cagtgtccgg gtctcctgga cagtcagtca ccatctcctg cactggaacc 480 agcagtgatg ttggtggtta taactatgtc tcctggtacc aacagcaccc aggcaaagcc 540 cccaaactca tgatttatga tgtcagtaag cggccctcag gggtccctga tcgcttctcc 600 ggctccaagt ctgggaacac ggcctccctg accgtctctg ggctccacgc tgaggatgag 660 gctgattatt actgcagctc atatgcaggc agcaacaatt ttgtcttcgg aactgggacc 720 aaggtcaccg tccta 735 <![CDATA[<210> 25]]> <![CDATA[<211> 735]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 25]]> caggtgcagc tggtgcaatc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcggc agctatacta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattat 300 agcagcagct ggaactctat ggacgtctgg ggccaaggaa ccctggtcac cgtctcgagt 360 ggtggaggcg gttcaggcgg aggtggctct ggcggtggcg ctagccagtc tgggctgact 420 cagcctcgct cagtgtccgg gtctcctgga cagtcagtca ccatctcctg cactggaacc 480 agcagtgatg ttggtgctta taactatgtc tcctggtacc aacagcaccc aggcaaagcc 540 cccaaactca tgatttatga ggtcagtaag cggccctcag gggtccctga tcgcttctct 600 gcctccaagt ctggcaacac ggcctccctg accgtctctg ggctccaggc tgaggatgag 660 gctgattatt actgcagctc atatgcaggc agcaacaatt gggtgttcgg cggagggacc 720 aagctgaccg tccta 735 <![CDATA[<210> 26]]> <![CDATA[<211> 732]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 26]]> caggtgcagc tgcaggagtc gggcccaggg cttgtgaagc cttcggagac cctgtccctc 60 acttgcactg tctctggtgg ctccatcagt agttactact ggagctggat ccggcagccc 120 ccagggaagg gactggagtg gattgggtct atctattaca gtgggagcac caactacaac 180 ccctccctca agagtcgagt caccatctca agagacaagt cgaagaacca gttgtttctg 240 aagttgaatt ctatgaccgc cgcggacacg gccgtctatt attgtgcgag agatgtttgg 300 ggcagtggcc agtcatttga cagttggggc cagggcaccc tggtcaccgt ctcgagtggt 360 ggaggcggtt caggcggagg tggctctggc ggtggcgcta gcaattttat gctgactcag 420 ccccactctg tgtcggagtc tccggggaag acggtaacca tctcctgcac ccgcagcagt 480 ggcagcattg ccagcaacta tgtgcagtgg taccagcagc gcttgggcag ttcccccacc 540 actgtgatct atgaacatag ccgaagaccc tctggggtcc ctgatcggtt ctctgcctcc 600 atcgacagct cctccaactc tgcctccctc accatctctg gactgaagac tgaggacgag 660 gctgactact actgtcagtc ttatgatgtc agcaatcgag tgttcggcgg agggaccaag 720 ctgaccgtcc ta 732 <![CDATA[<210> 27]]> <![CDATA[<211> 738]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 27]]> gaggtgcagc tgttggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180 gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcgctgtat 240 ctgcaaatga acagcctgag agctgaggac acggctgtgt attattgtgc gaaagccccg 300 tggtatagca gctcgccgac accctacggt atggacgtct ggggccaggg caccctggtc 360 accgtctcga gtggtggagg cggttcaggc ggaggtggct ctggcggtgg cgctagcgac 420 atccagatga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 480 acttgccagg cgagtcagga cattagcaac tatttaaatt ggtatcagca gaaaccaggg 540 aaagccccta ggcgcctgat ctatggtgca tccactttga tgagtggggt cccatcaagg 600 ttcagcggca gtggatctgg gacagatttc actctcacca tcagcagtct gcaacctgaa 660 gattttgcaa cttactactg tcaacagagt tacagtacac ctctcacttt cggcggaggg 720 accaaggtgg aaatcaaa 738 <![CDATA[<210> 28]]> <![CDATA[<211> 738]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 28]]> gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaacacgt 300 tacatttggg ggagttatcg ggcatacggt atggacgtct ggggccaagg gacaatggtc 360 accgtctcga gtggtggagg cggttcaggc ggaggtggct ctggcggtgg cgctagcgac 420 atccagatga cccagtctcc atcctccatg tctgcatctg taggagacag agtcaccatc 480 acttgccgcg cgagtcagag cattagcagt catttaaatt ggtatcagca gctgccaggc 540 aatgccccta ctctcctgat ctattatgct tccaatttac aaagtggggt cccatctagg 600 ttcagtggca gtggatctgg gacagatttc actctcacca tcagcagtct gcagcctgat 660 gattttgcaa cttactactg tcaacagagt atcagtctcc cgtacacttt tggccagggg 720 accaaggtgg agatcaaa 738 <![CDATA[<210> 29]]> <![CDATA[<211> 729]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 29]]> gaggtgcagc tggtgcagcc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccctcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat aacaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt atttctgtgc gagagatcag 300 cggccggcga gcatggacgt ctggggccag ggcaccctgg tcaccgtctc gagtggtgga 360 ggcggttcag gcggaggtgg ctctggcggt ggcgctagcc agtctgagct gactcagcct 420 gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagcagt 480 gacgttggtg gttatatcta tgtctcctgg taccaacagc acccaggcaa agtccccaaa 540 ctcatgattc atgatgtcag tcatcggccc tcaggggttt ctaatcgctt ctctggctcc 600 aggtctggca acacggcctc cctgaccatc tctgggctcc aggctgagga cgaggctgac 660 tatttctgca gctcatatac aagcagcaac aattatgtct tcggaactgg gaccaaggtc 720 accgtccta 729 <![CDATA[<210> 30]]> <![CDATA[<211> 729]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 30]]> gaggtgcagc tggtgcagcc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccctcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat aacaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt atttctgtgc gagagatcag 300 cggccggcga gcatggacgt ctggggccag ggcaccctgg tcaccgtctc gagtggtgga 360 ggcggttcag gcggaggtgg ctctggcggt ggcgctagcc agtctgggct gactcagcct 420 gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagcagt 480 gatgttggtg gttataacta tgtctcctgg taccaacagc acccaggcaa agcccccaaa 540 ctcatgattt atgaggtcag taatcggccc tcaggggttt ctaatcgctt ctctggctcc 600 aagtctggca acacggcctc cctgaccatc tctgggctcc aggctgagga cgaggctgat 660 tactactgca gcacagttac aagcctcagc acttatgtct tcggaactgg gaccaagctg 720 accgtccta 729 <![CDATA[<210> 31]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 31]]> gaggtgcagc tggtgcagtc tggggctgag gtgaagaggc ctgggtcctc ggtgaaggtc 60 tcctgcaagg catctggata caccttcacc agctactata tgcactgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaata atcaacccta gtggtggtag cacaagctac 180 gcacagaagt tccagggcag agtcaccatg accagggaca cgtccacgag cacagtctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc ggcaggaacg 300 tatagcagtg gctggacgat tgactactgg gggcaaggga ccacggtcac cgtctcgagt 360 ggtggaggcg gttcaggcgg aggtggctct ggcggtggcg ctagcgatat tgtgatgacg 420 cagtctccac tctccctgcc cgtcaccctt ggacagccgg cctccatctc ctgcaggtct 480 agtcaaagcc tcgtatacac tgatggaaac acctacttga attggtttca gcagaggcca 540 ggccaatctc caaggcgcct aatttataag gtttctaacc gggactctgg ggtcccagac 600 agattcagcg gcagtgggtc aggcactgat ttcacactga aaatcagcag ggtggaggct 660 gaggatgttg ggatttatta ctgcatgcat agtaaacagt ggcctcccac tttcggcgga 720 gggaccaagg tggaaatcaa a 741 <![CDATA[<210> 32]]> <![CDATA[<211> 714]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 32]]> gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaggacac 300 tactactaca tggacgtctg ggggcaaggg accacggtca ccgtctcgag tggtggaggc 360 ggttcaggcg gaggtggctc tggcggtggc gctagcgata ttgtgatgac tcagtctcca 420 gccaccctgt ctgtgtctcc aggggaagga gccaccctct cctgcagggc cagtcagagt 480 gttagcagca acttagcctg gtatcagcag aaacctggcc gggctcccag gctcctcatc 540 tatggtgcat ccaccagggc cactggtatc ccagccaggt tcagtggcag tgggtctggg 600 acagagttca ctctcaccat cagcagcctg cagtctgaag attttgcagt ttattactgt 660 cagcagtata ataactggcc cagtttcggc ggagggacca agctggagat caaa 714 <![CDATA[<210> 33]]> <![CDATA[<211> 714]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 33]]> gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaggacac 300 tactactaca tggacgtctg ggggcaaggg accacggtca ccgtctcgag tggtggaggc 360 ggttcaggcg gaggtggctc tggcggtggc gctagcgata ttgtgatgac tcagtctcca 420 gccaccctgt ctgtgtctcc aggggaagga gccaccctct cctgcagggc cagtcagagt 480 gttagcagca acttagcctg gtatcagcag aaacctggcc gggctcccag gctcctcatc 540 tatggtgcat ccaccagggc cactggtatc ccagccaggt tcagtggcag tgggtctggg 600 acagagttca ctctcaccat cagcagcctg cagtctgaag attttgcagt ttattactgt 660 cagcagtata ataactggcc cactttcggc ggagggacca agctggagat caaa 714 <![CDATA[<210> 34]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 34]]> caggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag gacttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240 atggagctga gcggcctgag atctgaggac acggccgtgt attactgtgc gagaggtata 300 cagcctcttc gctactacgg tatggacgtc tggggccaag gaaccctggt caccgtctcg 360 agtggtggag gcggttcagg cggaggtggc tctggcggtg gcgctagcca gtctgcgctg 420 actcagccac cctcagcgtc tgggaccccc gggcagaggg tcaccatctc ttgttctgga 480 agcagctcca acatcggaag taattatgta tactggtacc agcagctccc aggaacggcc 540 cccaaactcc tcatctatag gaataatcag cggccctcag gggtccctga ccgattctct 600 ggctccaagt ctggcacctc agcctccctg gccatcagtg ggctccggtc cgaggatgag 660 gctgattatt actgtgcagc atgggatgac agcctgagtg gtcggggagt gttcggcgga 720 gggacccagc tcaccgtcct a 741 <![CDATA[<210> 35]]> <![CDATA[<211> 729]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 35]]> caggtgcagc tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac acactacgca 180 gactccgtga agggccgatt caccatctcc agacacaatt ccaagaacac gctgtatctt 240 caaatgaaca gcctgagagc tgaggacacg gccgtgtatt actgtgcgag gggggctggt 300 accttaaatg cttttgatat ctgggggcaa gggaccacgg tcaccgtctc gagtggtgga 360 ggcggttcag gcggaggtgg ctctggcggt ggcgctagcc agtctgggct gactcagcct 420 ccctccacgt ccgggtctcc tggacagtca gtcaccatct cctgcactgg aaccagcagt 480 gacgttggtg cttatagcta tgtctcctgg tatcaacaac acccaggcaa agcccccaaa 540 cttctcattt atgcggtcac taagaggccc tcgggggtcc ctgatcgctt ctctggctcc 600 aagtctggca acacggcctc cctgaccgtc tctggactcc aggatgagga tgaggctgat 660 tattactgca gctcttttgc aggcggcagc actctggtgt tcggcggagg gaccaagctg 720 accgtccta 729 <![CDATA[<210> 36]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 36]]> caaatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactat 180 gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgt gagaggatac 300 agttcaatat actactacta cggtatggac gtctggggcc aagggacaat ggtcaccgtc 360 tcgagtggtg gaggcggttc aggcggaggt ggctctggcg gtggcgctag ccagtctggg 420 ctgactcagc ctcgctcagt gtccgggtct cctggacagt cagtcaccat ctcctgcact 480 ggaaccagca gtgatgttgg tggttataac tatgtctcct ggtaccaaca gcacccaggc 540 aaagccccca aactcatgat ttatgatgtc agtaagcggc cctcaggggt ttctgatcgc 600 ttctctggct ccaagtctgg caacacggcc tccctgacca tctctgggct ccaggctgag 660 gacgaggctg attattactg cggctcatat acaagcgacg ggactctagt attcggcgga 720 gggaccaagc tgaccgtcct a 741 <![CDATA[<210> 37]]> <![CDATA[<211> 729]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_GUCY2C-結合 scFv 編碼序列]]> <![CDATA[<400> 37]]> caggtgcagc tggtgcaatc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agctatacta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180 gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagatagg 300 tcttacaact ggctcgaccc ctggggccgt ggcaccctgg tcaccgtctc gagtggtgga 360 ggcggttcag gcggaggtgg ctctggcggt ggcgctagcc agtctgcgct gactcagcct 420 gtctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccatcagt 480 gacgttggtg attataacta tgtctcctgg taccaacagc acccaggcaa agcccccaaa 540 ctcatgattt atgacgtcaa taatcggccc tcaggggttt ctaatcgctt ctctggctcc 600 aagtctggca acacggcctc cctgaccatc tctgggctcc aggctgagga cgaggctgat 660 tattactgca gctcatatac aagcagcagc actctggtat tcggcggagg gaccaagctg 720 accgtccta 729 <![CDATA[<210> 38]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H1]]> <![CDATA[<400> 38]]> Gly Tyr Thr Phe Thr Ser Tyr Tyr 1 5 <![CDATA[<210> 39]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H1]]> <![CDATA[<400> 39]]> Gly Gly Thr Leu Ser Ser Tyr Ala 1 5 <![CDATA[<210> 40]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H1]]> <![CDATA[<400> 40]]> Gly Gly Thr Phe Ser Ser Tyr Thr 1 5 <![CDATA[<210> 41]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H1]]> <![CDATA[<400> ]]> 41 Gly Gly Thr Phe Gly Ser Tyr Thr 1 5 <![CDATA[<210> 42]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> ]]> 人工序列 <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H1]]> <![CDATA[<400> 42]]> Gly Gly Ser Ile Ser Ser Tyr Tyr 1 5 <![CDATA[<210> 43]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H1]]> <![CDATA[<400> 43]]> Gly Phe Thr Phe Ser Ser Tyr Trp 1 5 <![CDATA[<210> 44]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H1]]> <![CDATA[<400> 44]]> Gly Gly Thr Phe Ser Ser Tyr Ala 1 5 <![CDATA[<210> 45]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H1]]> <![CDATA[<400> 45]]> Gly Phe Thr Phe Ser Ser Tyr Ser 1 5 <![CDATA[<210> 46]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H2]]> <![CDATA[<400> 46]]> Ile Asn Pro Ser Gly Gly Ser Thr 1 5 <![CDATA[<210> 47]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H2]]> <![CDATA[<400> 47]]> Ile Ile Pro Ile Leu Gly Ile Thr 1 5 <![CDATA[<210> 48]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H2]]> <![CDATA[<400> 48]]> Ile Ile Pro Ile Leu Gly Ile Ala 1 5 <![CDATA[<210> 49]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H2]]> <![CDATA[<400> 49]]> Ile Ile Pro Val Leu Gly Ile Ala 1 5 <![CDATA[<210> 50]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H2]]> <![CDATA[<400> 50]]> Ile Tyr Tyr Ser Gly Ser Thr 1 5 <![CDATA[<210> 51]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H2]]> <![CDATA[<400> 51]]> Ile Lys Gln Asp Gly Ser Glu Lys 1 5 <![CDATA[<210> 52]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H2]]> <![CDATA[<400> 52]]> Ile Ile Pro Ile Phe Gly Thr Ala 1 5 <![CDATA[<210> 53]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H2]]> <![CDATA[<400> 53]]> Ile Tyr Ser Gly Gly Ser Thr 1 5 <![CDATA[<210> 54]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H3]]> <![CDATA[<400> 54]]> Asp Gly Gln Trp Leu Gln Phe Asp Tyr 1 5 <![CDATA[<210> 55]]> <![CDATA[<211> 9]]> <![CDATA[<212> PR]]>T <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H3]]> <![CDATA[<400> 55]]> Asp Gln Arg Pro Ala Ser Met Asp Val 1 5 <![CDATA[<210> 56]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H3]]> <![CDATA[<400> 56]]> Asp Tyr Ser Ser Ser Trp Asn Ser Met Asp Val 1 5 10 <![CDATA[<210> 57]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H3]]> <![CDATA[<400> 57]]> Asp Val Trp Gly Ser Gly Gln Ser Phe Asp Ser 1 5 10 <![CDATA[<210> 58]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H3]]> <![CDATA[<400> 58]]> Ala Pro Trp Tyr Ser Ser Ser Pro Thr Pro Tyr Gly Met Asp Val 1 5 10 15 <![CDATA[<210> 59]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<21]]>3> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 合成的_CDR-H3]]> <br/> <br/> <br/><![CDATA[<400> 59]]> <br/><![CDATA[Thr Arg Tyr Ile Trp Gly Ser Tyr Arg Ala Tyr Gly Met Asp Val 1 5 10 15 <![CDATA[<210> 60]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H3]]> <![CDATA[<400> 60]]> Gly Thr Tyr Ser Ser Gly Trp Thr Ile Asp Tyr 1 5 10 <![CDATA[<210> 61]]> <![CDATA[<211> ]]>8 <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H3]]> <![CDATA[<400> 61]]> Gly His Tyr Tyr Tyr Met Asp Val 1 5 <![CDATA[<210> 62]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H3]]> <![CDATA[<400> 62]]> Gly Ile Gln Pro Leu Arg Tyr Tyr Gly Met Asp Val 1 5 10 <![CDATA[<210> 63]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H3]]> <![CDATA[<400> 63]]> Gly Ala Gly Thr Leu Asn Ala Phe Asp Ile 1 5 10 <![CDATA[<210> 64]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H3]]> <![CDATA[<400> 64]]> Gly Tyr Ser Ser Ile Tyr Tyr Tyr Tyr Gly Met Asp Val 1 5 10 <![CDATA[<210> 65]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H3]]> <![CDATA[<400> 65]]> Asp Arg Ser Tyr Asn Trp Leu Asp Pro 1 5 <![CDATA[<210> 66]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L1]]> <![CDATA[<400> 66]]> Gln Ser Leu Leu Lys Lys Ser Asp Gly Asn Thr Tyr 1 5 10 <![CDATA[<210> 67]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L1]]> <![CDATA[<400> 67]]> Ser Ser Asp Val Gly Gly Tyr Ile Tyr 1 5 <![CDATA[<210> 68]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L1]]> <![CDATA[<400> 68]]> Ser Ser Asp Ile Gly Tyr Tyr His Tyr 1 5 <![CDATA[<210> 69]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L1]]> <![CDATA[<400> 69]]> Ser Ser Asp Val Gly Gly Tyr Asn Tyr 1 5 <![CDATA[<210> 70]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L1]]> <![CDATA[<400> 70]]> Ser Ser Asp Val Gly Ala Tyr Asn Tyr 1 5 <![CDATA[<210> 71]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L1]]> <![CDATA[<400> 71]]> Ser Gly Ser Ile Ala Ser Asn Tyr 1 5 <![CDATA[<210> 72]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L1]]> <![CDATA[<400> 72]]> Gln Asp Ile Ser Asn Tyr 1 5 <![CDATA[<210> 73]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L1]]> <![CDATA[<400> 73]]> Gln Ser Ile Ser Ser His 1 5 <![CDATA[<210> 74]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L1]]> <![CDATA[<400> 74]]> Gln Ser Leu Val Tyr Thr Asp Gly Asn Thr Tyr 1 5 10 <![CDATA[<210> 75]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L1]]> <![CDATA[<400> 75]]> Gln Ser Val Ser Ser Asn 1 5 <![CDATA[<21]]>0> 76]]> <br/><![CDATA[<211> 8]]> <br/><![CDATA[<212> PRT]]> <br/><![CDATA[<213> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 合成的_CDR-L1]]> <br/> <br/> <br/><![CDATA[<400> 76]]> <br/><![CDATA[Ser Ser Asn Ile Gly Ser Asn Tyr 1 5 <![CDATA[<210> 77]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L1]]> <![CDATA[<400> 77]]> Ser Ser Asp Val Gly Ala Tyr Ser Tyr 1 5 <![CDATA[<210> 78]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L1]]> <![CDATA[<400> 78]]> Ile Ser Asp Val Gly Asp Tyr Asn Tyr 1 5 <![CDATA[<210> 79]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L2]]> <![CDATA[<400> 79]]> Lys Val Ser 1 <![CDATA[<210> 80]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L2]]> <![CDATA[<400> 80]]> Asp Val Ser 1 <![CDATA[<210> 81]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L2]]> <![CDATA[<400> 81]]> Glu Asp Ser 1 <![CDATA[<210> 82]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L2]]> <![CDATA[<400> 82]]> Glu Val Ser 1 <![CDATA[<210> 83]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L2]]> <![CDATA[<400> 83]]> Glu His Ser 1 <![CDATA[<210> 84]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L2]]> <![CDATA[<400> 84]]> Gly Ala Ser 1 <![CDATA[<210> 85]]> <![CDATA[<211> ]]> 3 <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L2]]> <![CDATA[<400> 85]]> Tyr Ala Ser 1 <![CDATA[<210> 86]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L2]]> <![CDATA[<400> 86]]> Arg Asn Asn 1 <![CDATA[<210> 87]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L2]]> <![CDATA[<400> 87]]> Ala Val Thr 1 <![CDATA[<210> 88]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L2]]> <![CDATA[<400> 88]]> Asp Val Asn 1 <![CDATA[<210> 89]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 89]]> Met Gln Gly Ser His Trp Pro Pro Thr 1 5 <![CDATA[<210> 90]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 90]]> Ser Ser Tyr Ala Gly Ser Asn Asn Tyr Val 1 5 10 <![CDATA[<210> 91]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 91]]> Ser Ser Phe Thr Ser Arg Ser Thr Trp Val 1 5 10 <![CDATA[<210> 92]]> <![CDATA[<21]]>1> 10]]> <br/><![CDATA[<212> PRT]]> <br/><![CDATA[<213> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 合成的_CDR-L3]]> <br/> <br/> <br/><![CDATA[<400> 92]]> <br/><![CDATA[Ser Ser Tyr Thr Ser Ser Asn Asn Tyr Tyr 1 5 10 <![CDATA[<210> 93]]> <![CDATA[<211]]>> 10]]> <br/><![CDATA[<212> PRT]]> <br/><![CDATA[<213> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 合成的_CDR-L3]]> <br/> <br/> <br/><![CDATA[<400> 93]]> <br/><![CDATA[Ser Ser Tyr Ala Gly Ser Asn Asn Phe Val 1 5 10 <![CDATA[<210> 94]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 94]]> Ser Ser Tyr Ala Gly Ser Asn Asn Trp Val 1 5 10 <![CDATA[<210> 95]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 95]]> Gln Ser Tyr Asp Val Ser Asn Arg Val 1 5 <![CDATA[<210> 96]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 96]]> Gln Gln Ser Tyr Ser Thr Pro Leu Thr 1 5 <![CDATA[<210> 97]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序]]>列 <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 97]]> Gln Gln Ser Ile Ser Leu Pro Tyr Thr 1 5 <![CDATA[<210> 98]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 98]]> Ser Ser Tyr Thr Ser Ser Asn Asn Tyr Val 1 5 10 <![CDATA[<210> 99]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 99]]> Ser Thr Val Thr Ser Leu Ser Thr Tyr Val 1 5 10 <![CDATA[<210> 100]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 100]]> Met His Ser Lys Gln Trp Pro Pro Thr 1 5 <![CDATA[<210> 101]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-]]>L3 <![CDATA[<400> 101]]> Gln Gln Tyr Asn Asn Trp Pro Ser 1 5 <![CDATA[<210> 102]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 102]]> Gln Gln Tyr Asn Asn Trp Pro Thr 1 5 <![CDATA[<210> 103]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 103]]> Ala Ala Trp Asp Asp Ser Leu Ser Gly Arg Gly Val 1 5 10 <![CDATA[<210> 104]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 104]]> Ser Ser Phe Ala Gly Gly Ser Thr Leu Val 1 5 10 <![CDATA[<210> 105]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 105]]> Gly Ser Tyr Thr Ser Asp Gly Thr Leu Val 1 5 10 <![CDATA[<210> 106]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 106]]> Ser Ser Tyr Thr Ser Ser Ser Thr Leu Val 1 5 10 <![CDATA[<210> 107]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H1]]> <![CDATA[<400> 107]]> Gly Gly Ser Phe Ser Gly Tyr Tyr 1 5 <![CDATA[<210> 108]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H2]]> <![CDATA[<400> 108]]> Ile Asn His Arg Gly Asn Thr 1 5 <![CDATA[<210> 109]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-H3]]> <![CDATA[<400> 109]]> Glu Arg Gly Tyr Thr Tyr Gly Asn Phe Asp His 1 5 10 <![CDATA[<210> 110]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L1]]> <![CDATA[<400> 110]]> Gln Ser Val Ser Arg Asn 1 5 <![CDATA[<210> 111]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_CDR-L3]]> <![CDATA[<400> 111]]> Gln Gln Tyr Lys Thr Trp Pro Arg Thr 1 5 <![CDATA[<210> 112]]> <![CDATA[<211> 430]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_Hu-GUCY2C]]> <![CDATA[<400> 112]]> Met Lys Thr Leu Leu Leu Asp Leu Ala Leu Trp Ser Leu Leu Phe Gln 1 5 10 15 Pro Gly Trp Leu Ser Phe Ser Ser Gln Val Ser Gln Asn Cys His Asn 20 25 30 Gly Ser Tyr Glu Ile Ser Val Leu Met Met Gly Asn Ser Ala Phe Ala 35 40 45 Glu Pro Leu Lys Asn Leu Glu Asp Ala Val Asn Glu Gly Leu Glu Ile 50 55 60 Val Arg Gly Arg Leu Gln Asn Ala Gly Leu Asn Val Thr Val Asn Ala 65 70 75 80 Thr Phe Met Tyr Ser Asp Gly Leu Ile His Asn Ser Gly Asp Cys Arg 85 90 95 Ser Ser Thr Cys Glu Gly Leu Asp Leu Leu Arg Lys Ile Ser Asn Ala 100 105 110 Gln Arg Met Gly Cys Val Leu Ile Gly Pro Ser Cys Thr Tyr Ser Thr 115 120 125 Phe Gln Met Tyr Leu Asp Thr Glu Leu Ser Tyr Pro Met Ile Ser Ala 130 135 140 Gly Ser Phe Gly Leu Ser Cys Asp Tyr Lys Glu Thr Leu Thr Arg Leu 145 150 155 160 Met Ser Pro Ala Arg Lys Leu Met Tyr Phe Leu Val Asn Phe Trp Lys 165 170 175 Thr Asn Asp Leu Pro Phe Lys Thr Tyr Ser Trp Ser Thr Ser Tyr Val 180 185 190 Tyr Lys Asn Gly Thr Glu Thr Glu Asp Cys Phe Trp Tyr Leu Asn Ala 195 200 205 Leu Glu Ala Ser Val Ser Tyr Phe Ser His Glu Leu Gly Phe Lys Val 210 215 220 Val Leu Arg Gln Asp Lys Glu Phe Gln Asp Ile Leu Met Asp His Asn 225 230 235 240 Arg Lys Ser Asn Val Ile Ile Met Cys Gly Gly Pro Glu Phe Leu Tyr 245 250 255 Lys Leu Lys Gly Asp Arg Ala Val Ala Glu Asp Ile Val Ile Ile Leu 260 265 270 Val Asp Leu Phe Asn Asp Gln Tyr Phe Glu Asp Asn Val Thr Ala Pro 275 280 285 Asp Tyr Met Lys Asn Val Leu Val Leu Thr Leu Ser Pro Gly Asn Ser 290 295 300 Leu Leu Asn Ser Ser Phe Ser Arg Asn Leu Ser Pro Thr Lys Arg Asp 305 310 315 320 Phe Ala Leu Ala Tyr Leu Asn Gly Ile Leu Leu Phe Gly His Met Leu 325 330 335 Lys Ile Phe Leu Glu Asn Gly Glu Asn Ile Thr Thr Pro Lys Phe Ala 340 345 350 His Ala Phe Arg Asn Leu Thr Phe Glu Gly Tyr Asp Gly Pro Val Thr 355 360 365 Leu Asp Asp Trp Gly Asp Val Asp Ser Thr Met Val Leu Leu Tyr Thr 370 375 380 Ser Val Asp Thr Lys Lys Tyr Lys Val Leu Leu Thr Tyr Asp Thr His 385 390 395 400 Val Asn Lys Thr Tyr Pro Val Asp Met Ser Pro Thr Phe Thr Trp Lys 405 410 415 Asn Ser Lys Leu Pro Asn Asp Ile Thr Gly Arg Gly Pro Gln 420 425 430 <![CDATA[<210> 113]]> <![CDATA[<211> 430]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_Mu-GUCY2C]]> <![CDATA[<400> 113]]> Met Thr Ser Leu Leu Gly Leu Ala Val Arg Leu Leu Leu Phe Gln Pro 1 5 10 15 Ala Leu Met Val Phe Trp Ala Ser Gln Val Arg Gln Asn Cys Arg Asn 20 25 30 Gly Ser Tyr Glu Ile Ser Val Leu Met Met Asp Asn Ser Ala Tyr Lys 35 40 45 Glu Pro Met Gln Asn Leu Arg Glu Ala Val Glu Glu Gly Leu Asp Ile 50 55 60 Val Arg Lys Arg Leu Arg Glu Ala Asp Leu Asn Val Thr Val Asn Ala 65 70 75 80 Thr Phe Ile Tyr Ser Asp Gly Leu Ile His Lys Ser Gly Asp Cys Arg 85 90 95 Ser Ser Thr Cys Glu Gly Leu Asp Leu Leu Arg Glu Ile Thr Arg Asp 100 105 110 His Lys Met Gly Cys Ala Leu Met Gly Pro Ser Cys Thr Tyr Ser Thr 115 120 125 Phe Gln Met Tyr Leu Asp Thr Glu Leu Asn Tyr Pro Met Ile Ser Ala 130 135 140 Gly Ser Tyr Gly Leu Ser Cys Asp Tyr Lys Glu Thr Leu Thr Arg Ile 145 150 155 160 Leu Pro Pro Ala Arg Lys Leu Met Tyr Phe Leu Val Asp Phe Trp Lys 165 170 175 Val Asn Asn Ala Ser Phe Lys Pro Phe Ser Trp Asn Ser Ser Tyr Val 180 185 190 Tyr Lys Asn Gly Ser Glu Pro Glu Asp Cys Phe Trp Tyr Leu Asn Ala 195 200 205 Leu Glu Ala Gly Val Ser Tyr Phe Ser Glu Val Leu Asn Phe Lys Asp 210 215 220 Val Leu Arg Arg Ser Glu Gln Phe Gln Glu Ile Leu Thr Gly His Asn 225 230 235 240 Arg Lys Ser Asn Val Ile Val Met Cys Gly Thr Pro Glu Ser Phe Tyr 245 250 255 Asp Val Lys Gly Asp Leu Gln Val Ala Glu Asp Thr Val Val Ile Leu 260 265 270 Val Asp Leu Phe Ser Asn His Tyr Phe Glu Glu Asn Thr Thr Ala Pro 275 280 285 Glu Tyr Met Asp Asn Val Leu Val Leu Thr Leu Pro Ser Glu Gln Ser 290 295 300 Thr Ser Asn Thr Ser Val Ala Glu Arg Phe Ser Ser Gly Arg Ser Asp 305 310 315 320 Phe Ser Leu Ala Tyr Leu Glu Gly Thr Leu Leu Phe Gly His Met Leu 325 330 335 Gln Thr Phe Leu Glu Asn Gly Glu Asn Val Thr Gly Pro Lys Phe Ala 340 345 350 Arg Ala Phe Arg Asn Leu Thr Phe Gln Gly Phe Ala Gly Pro Val Thr 355 360 365 Leu Asp Asp Ser Gly Asp Ile Asp Asn Ile Met Ser Leu Leu Tyr Val 370 375 380 Ser Leu Asp Thr Arg Lys Tyr Lys Val Leu Met Lys Tyr Asp Thr His 385 390 395 400 Lys Asn Lys Thr Ile Pro Val Ala Glu Asn Pro Asn Phe Ile Trp Lys 405 410 415 Asn His Lys Leu Pro Asn Asp Val Pro Gly Leu Gly Pro Gln 420 425 430 <![CDATA[<210> 114]]> <![CDATA[<211> 430]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_Cy-GUCY2C]]> <![CDATA[<400> 114]]> Met Lys Thr Leu Leu Leu Asp Leu Val Leu Trp Ser Leu Leu Phe Gln 1 5 10 15 Pro Glu Trp Leu Tyr Leu Thr Ser Gln Val Ser Gln Asn Cys His Asn 20 25 30 Gly Ser Tyr Glu Ile Ser Val Leu Met Met Asp Asn Ser Ala Phe Ala 35 40 45 Glu Pro Leu Glu Asn Val Glu Asp Ala Val Asn Glu Gly Leu Glu Ile 50 55 60 Val Arg Gly Arg Leu Gln Asn Ala Gly Leu Asn Val Thr Val Asn Ala 65 70 75 80 Ser Phe Met Tyr Ser Asp Gly Leu Ile His Asn Ser Gly Asp Cys Arg 85 90 95 Ser Ser Thr Cys Glu Gly Leu Asp Leu Leu Arg Lys Ile Ser Asn Ala 100 105 110 Lys Arg Met Gly Cys Val Leu Met Gly Pro Ser Cys Thr Tyr Ser Thr 115 120 125 Phe Gln Met Tyr Leu Asp Thr Glu Leu Ser Tyr Pro Met Ile Ser Ala 130 135 140 Gly Ser Phe Gly Leu Ser Cys Asp Tyr Lys Glu Thr Leu Thr Arg Leu 145 150 155 160 Met Ser Pro Ala Arg Lys Leu Thr Tyr Phe Leu Val Asn Phe Trp Lys 165 170 175 Thr Asn Asp Leu Pro Phe Lys Thr Tyr Ser Trp Ser Thr Ser Tyr Val 180 185 190 Tyr Lys Asn Gly Thr Glu Ser Glu Asp Cys Phe Trp Tyr Leu Asn Ala 195 200 205 Leu Glu Ala Ser Val Ser Tyr Phe Ser His Glu Leu Ser Phe Lys Leu 210 215 220 Val Leu Arg Gln Asp Lys Glu Phe Gln Asp Ile Leu Met Asp His Asn 225 230 235 240 Arg Lys Ser Asn Val Ile Val Met Cys Gly Asp Pro Gln Phe Leu Tyr 245 250 255 Lys Leu Lys Gly Asp Arg Ala Val Ala Glu Asp Ile Val Ile Ile Leu 260 265 270 Val Asp Leu Phe Asn Asp Gln Tyr Phe Glu Asp Asn Val Thr Ala Pro 275 280 285 Asp Tyr Met Lys Asn Val Leu Val Leu Thr Gln Ser Pro Gly Asn Ser 290 295 300 Leu Leu Asn Ser Ser Phe Ser Arg Asn Leu Ser Pro Thr Lys Arg Asp 305 310 315 320 Phe Ala Leu Ala Tyr Leu Asn Gly Ile Leu Leu Phe Gly His Met Leu 325 330 335 Lys Thr Phe Leu Glu Asn Gly Glu Asn Ile Thr Thr Pro Lys Phe Ala 340 345 350 His Ala Phe Arg Asn Leu Thr Phe Glu Gly Tyr Asp Gly Pro Val Thr 355 360 365 Leu Asp Asp Trp Gly Asp Val Asp Ser Thr Met Val Leu Leu Tyr Thr 370 375 380 Ser Val Asp Thr Lys Lys Tyr Lys Val Leu Leu Thr Tyr Asp Thr His 385 390 395 400 Val Asn Gln Thr Asn Pro Val Asp Met Ser Pro Thr Phe Thr Trp Lys 405 410 415 Asn Ser Lys Leu Pro Asn Asp Ile Thr Asp Arg Gly Pro Gln 420 425 430 <![CDATA[<210> 115]]> <![CDATA[<211> 182]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成的_rCD4]]> <![CDATA[<400> 115]]> Thr Ser Ile Thr Ala Tyr Lys Ser Glu Gly Glu Ser Ala Glu Phe Ser 1 5 10 15 Phe Pro Leu Asn Leu Gly Glu Glu Ser Leu Gln Gly Glu Leu Arg Trp 20 25 30 Lys Ala Glu Lys Ala Pro Ser Ser Gln Ser Trp Ile Thr Phe Ser Leu 35 40 45 Lys Asn Gln Lys Val Ser Val Gln Lys Ser Thr Ser Asn Pro Lys Phe 50 55 60 Gln Leu Ser Glu Thr Leu Pro Leu Thr Leu Gln Ile Pro Gln Val Ser 65 70 75 80 Leu Gln Phe Ala Gly Ser Gly Asn Leu Thr Leu Thr Leu Asp Arg Gly 85 90 95 Ile Leu Tyr Gln Glu Val Asn Leu Val Val Met Lys Val Thr Gln Pro 100 105 110 Asp Ser Asn Thr Leu Thr Cys Glu Val Met Gly Pro Thr Ser Pro Lys 115 120 125 Met Arg Leu Ile Leu Lys Gln Glu Asn Gln Glu Ala Arg Val Ser Arg 130 135 140 Gln Glu Lys Val Ile Gln Val Gln Ala Pro Glu Ala Gly Val Trp Gln 145 150 155 160 Cys Leu Leu Ser Glu Gly Glu Glu Val Lys Met Asp Ser Lys Ile Gln 165 170 175 Val Leu Ser Lys Gly Leu 180
Claims (17)
- 一種鳥苷酸環化酶2C結合多肽,包括以下各者: 重鏈可變區,包括用選自由SEQ ID NO:38至44組成的族群的胺基酸序列表示的重鏈CDR1(下文中為CDR-H1)、用選自由SEQ ID NO:45至53組成的族群的胺基酸序列表示的CDR-H2以及用選自由SEQ ID NO:54至65組成的族群的胺基酸序列表示的CDR-H3; 輕鏈可變區,包括用選自由SEQ ID NO:66至78組成的族群的胺基酸序列表示的輕鏈CDR1(下文中為CDR-L1)、用選自由SEQ ID NO:79至88組成的族群的胺基酸序列表示的CDR-L2以及用選自由SEQ ID NO:89至106組成的族群的胺基酸序列表示的CDR-L3; 或所述重鏈可變區及所述輕鏈可變區的組合。
- 如請求項1所述的鳥苷酸環化酶2C結合多肽,其中所述鳥苷酸環化酶2C結合多肽為單鏈可變片段(single chain variable fragment,scFv)。
- 如請求項2所述的鳥苷酸環化酶2C結合多肽,用選自由SEQ ID NO:1至18組成的族群的胺基酸序列表示。
- 一種鳥苷酸環化酶2C結合抗體,包括如請求項1所述的鳥苷酸環化酶2C結合多肽或其抗原結合片段。
- 一種融合蛋白質,包括如請求項1所述的鳥苷酸環化酶2C結合多肽及免疫球蛋白的Fc域。
- 如請求項5所述的融合蛋白質,其中所述鳥苷酸環化酶2C結合多肽用選自由SEQ ID NO:1至18組成的族群的胺基酸序列表示。
- 一種嵌合抗原受體,其為包括細胞外域、跨膜域以及細胞內傳訊域的嵌合抗原受體,其中所述細胞外域包括如請求項2所述的鳥苷酸環化酶2C結合單鏈可變片段。
- 如請求項7所述的嵌合抗原受體,其中所述鳥苷酸環化酶2C結合單鏈可變片段用選自由SEQ ID NO:1至18組成的族群的胺基酸序列表示。
- 一種免疫細胞,表現如請求項7或請求項8所述的嵌合抗原受體。
- 如請求項9所述的免疫細胞,其中所述免疫細胞為T細胞、腫瘤浸潤淋巴細胞、自然殺手(Natural killer,NK)細胞、T細胞受體(T cell receptor,TCR)表現細胞、樹突狀細胞或自然殺手-T細胞。
- 一種多核苷酸,編碼如請求項1至請求項3中任一項所述的多肽、包括所述多肽的融合蛋白質或包括所述多肽的嵌合抗原受體。
- 如請求項11所述的多核苷酸,用選自由SEQ ID NO:20至37組成的族群的核酸序列表示。
- 一種用於偵測鳥苷酸環化酶2C的組成物,包括如請求項1至請求項3中任一項所述的多肽、包括所述多肽的融合蛋白質或包括所述多肽的嵌合抗原受體。
- 一種用於診斷癌症的組成物,包括如請求項1至請求項3中任一項所述的多肽、包括所述多肽的融合蛋白質或包括所述多肽的嵌合抗原受體。
- 如請求項14所述的用於診斷癌症的組成物,其中所述癌症表現鳥苷酸環化酶2C。
- 一種用於預防或治療癌症的醫藥組成物,包括: 如請求項1至請求項3中任一項所述的鳥苷酸環化酶2C結合多肽, 多核苷酸,編碼所述鳥苷酸環化酶2C結合多肽, 重組載體,包括編碼所述鳥苷酸環化酶2C結合多肽的所述多核苷酸, 嵌合抗原受體,包括所述鳥苷酸環化酶2C結合多肽, 多核苷酸,編碼所述嵌合抗原受體; 重組載體,包括編碼所述嵌合抗原受體的所述多核苷酸;以及 免疫細胞,包括編碼所述嵌合抗原受體或表現所述嵌合抗原受體的多核苷酸。
- 如請求項16所述的用於預防或治療癌症的醫藥組成物,其中所述癌症表現鳥苷酸環化酶2C。
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