CN112292157A - 细胞移植用组合物和细胞移植方法 - Google Patents
细胞移植用组合物和细胞移植方法 Download PDFInfo
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- CN112292157A CN112292157A CN201980038384.7A CN201980038384A CN112292157A CN 112292157 A CN112292157 A CN 112292157A CN 201980038384 A CN201980038384 A CN 201980038384A CN 112292157 A CN112292157 A CN 112292157A
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Abstract
本发明提供能够将肌细胞和/或心肌祖细胞适当地保持在心肌组织中、能够提高移植后的细胞的存留性和增殖性的细胞移植用组合物和细胞移植方法。本发明的细胞移植用组合物是包含蛋白质(A)的水溶液和细胞的细胞移植用组合物，其特征在于，上述细胞为心肌细胞和/或心肌祖细胞，上述蛋白质(A)的疏水度为0.2～1.2，上述蛋白质(A)具有多肽链(Y)和/或多肽链(Y’)，上述蛋白质(A)中的上述多肽链(Y)与上述多肽链(Y’)的合计个数为1～100个，上述多肽链(Y)是序列编号1所示的氨基酸序列即VPGVG序列(1)、序列编号2所示的氨基酸序列即GVGVP序列(2)、GPP序列、GAP序列和序列编号3所示的氨基酸序列即GAHGPAGPK序列(3)中的任一氨基酸序列(X)2～100个连续而成的多肽链，上述多肽链(Y’)是上述多肽链(Y)中的0.1～5％的氨基酸残基被赖氨酸残基和/或精氨酸残基置换的多肽链，上述赖氨酸残基和上述精氨酸残基的合计个数为1～100个。
Description
技术领域
本发明涉及细胞移植用组合物和细胞移植方法。
背景技术
作为心肌梗死等心力衰竭的治疗方法，再生医疗受到关注。再生医疗的目的在于，将细胞等移植到因受伤或疾病所致的损伤而使功能受损的器官或组织中，使该损伤的组织或器官的功能复原，其是具有可能成为目前难以治疗的病例的唯一治疗方法的潜在可能性的技术。成体的心肌细胞极度缺乏自我复制能力，在心肌组织受到损伤的情况下，其修复非常困难。为了修复损伤的心肌组织，进行了将通过细胞工程方法制作的包含心肌细胞的移植片或心肌片移植到患部的尝试(专利文献1)。但是，该方法具有缺乏在移植部位的定居的问题。另外，作为其他治疗方法，尝试了将骨髓来源的单核细胞、骨骼肌来源的细胞、脂肪组织来源的干细胞、由心肌采集的成心肌细胞等单一细胞利用注射器或经由冠状动脉移植到心肌组织中的基于细胞移植的治疗方法(非专利文献1)。但是，该方法具有所移植的细胞大多数不定居于心肌组织的问题。由于仅移植细胞时移植细胞在患部的存留性低，因此近年来进行了大量的与提高存留性的细胞支架材料(基体)一起进行移植的研究。例如，作为能够适用于使用干细胞等的细胞移植疗法的细胞移植疗法用材料，已知含有规定的细胞生长因子的水凝胶，其生物相容性优异，能够提高移植细胞在氧和营养的供给不充分的部位的存留性(专利文献2)。
但是，专利文献1所记载的细胞移植疗法用材料中，使用明胶等动物来源的材料作为水凝胶，因此在移植部位可能会混入可能成为感染症的原因、或可能成为引起免疫应答的原因的动物来源的过敏原物质或其他杂质等。另外，还要求提高移植细胞在移植部位的存留性、提高细胞的增殖性。
现有技术文献
专利文献
专利文献1：日本特表2007-528755号公报
专利文献2：日本特开2002-145797号公报
非专利文献
非专利文献1：Suzuki K et al.,Circulation.2004Sep 14；110(11Suppl 1)：II225-30
发明内容
发明所要解决的课题
本发明的目的在于提供能够将心肌细胞和/或心肌祖细胞适当地保持在心肌组织中、能够提高移植后的细胞的存留性和增殖性的细胞移植用组合物和细胞移植方法。
用于解决课题的手段
本发明人反复进行了深入研究，结果实现了本发明。
即，本发明涉及：一种细胞移植用组合物，其是包含蛋白质(A)的水溶液和细胞的细胞移植用组合物，其特征在于，上述细胞为心肌细胞和/或心肌祖细胞，上述蛋白质(A)的疏水度为0.2～1.2，上述蛋白质(A)具有多肽链(Y)和/或多肽链(Y’)，上述蛋白质(A)中的上述多肽链(Y)与上述多肽链(Y’)的合计个数为1～100个，上述多肽链(Y)是序列编号1所示的氨基酸序列即VPGVG序列(1)、序列编号2所示的氨基酸序列即GVGVP序列(2)、GPP序列、GAP序列和序列编号3所示的氨基酸序列即GAHGPAGPK序列(3)中的任一氨基酸序列(X)2～100个连续而成的多肽链，上述多肽链(Y’)是上述多肽链(Y)中的0.1～5％的氨基酸残基被赖氨酸残基和/或精氨酸残基置换的多肽链，上述赖氨酸残基和上述精氨酸残基的合计个数为1～100个；一种细胞移植方法，其中，将上述本发明的细胞移植用组合物移植到哺乳类(除人以外)的心肌组织中。
发明的效果
使用本发明的细胞移植用组合物和细胞移植方法将心肌细胞和/或心肌祖细胞移植到心肌组织中时，能够将心肌细胞和/或心肌祖细胞适当地保持在心肌组织中。此外，能够提高移植的细胞的存留性和增殖性。
具体实施方式
本发明的细胞移植用组合物是包含蛋白质(A)的水溶液和细胞的细胞移植用组合物，其特征在于，上述细胞为心肌细胞和/或心肌祖细胞，上述蛋白质(A)的疏水度为0.2～1.2，上述蛋白质(A)具有多肽链(Y)和/或多肽链(Y’)，上述蛋白质(A)中的上述多肽链(Y)与上述多肽链(Y’)的合计个数为1～100个，上述多肽链(Y)是序列编号1所示的氨基酸序列即VPGVG序列(1)、序列编号2所示的氨基酸序列即GVGVP序列(2)、GPP序列、GAP序列和序列编号3所示的氨基酸序列即GAHGPAGPK序列(3)中的任一氨基酸序列(X)2～100个连续而成的多肽链，上述多肽链(Y’)是上述多肽链(Y)中的0.1～5％的氨基酸残基被赖氨酸残基和/或精氨酸残基置换的多肽链，上述赖氨酸残基和上述精氨酸残基的合计个数为1～100个。
下面对本发明的细胞移植用组合物的构成进行说明。
(蛋白质(A)的水溶液)
蛋白质(A)是通过从天然物中提取、有机合成法(酶法、固相合成法和液相合成法等)和基因重组法等而得到的。关于有机合成法，可以应用“生化学实验讲座1、蛋白质化学IV(1981年7月1日、日本生化学会编、株式会社东京化学同人发行)”或“(续)生化学实验讲座2、蛋白质化学(下)(1987年5月20日、日本生化学会编、株式会社东京化学同人发行)”中记载的方法等。关于基因重组法，可以应用日本专利第3338441号公报中记载的方法等。从天然物中提取、有机合成法和基因重组法均可得到蛋白质(A)，从能够简便地变更氨基酸序列、能够低成本地大量生产的方面等出发，优选基因重组法。
本发明中的多肽链(Y)具体而言为(VPGVG)b序列、(GVGVP)c序列、(GPP)d序列、(GAP)e序列和(GAHGPAGPK)f序列(需要说明的是，b～f分别为氨基酸序列(X)的连续个数，为2～100的整数)。
在1分子蛋白质(A)中具有复数个多肽链(Y)的情况下，可以具有选自由(VPGVG)b序列、(GVGVP)c序列、(GPP)d序列、(GAP)e序列和(GAHGPAGPK)f序列组成的组中的1种，也可以具有2种以上。
另外，在蛋白质(A)中具有复数个氨基酸序列(X)的种类相同的多肽链(Y)的情况下，上述氨基酸序列(X)的连续个数在每一多肽链(Y)中可以相同、也可以不同。即，可以具有复数个上述b～f相同的多肽链(Y)，也可以具有复数个氨基酸序列(X)的连续个数b～f不同的多肽链(Y)。
作为构成多肽链(Y)的氨基酸序列(X)，从心肌细胞和/或心肌祖细胞(以下，在不必将它们特别区分的情况下，记载为“心肌细胞等”)的存留性和增殖性的方面出发，优选VPGVG序列(1)和/或GVGVP序列(2)。即，从心肌细胞等的存留性的方面出发，作为多肽链(Y)，优选(VPGVG)b序列和/或(GVGVP)c序列。在蛋白质(A)具有氨基酸序列(X)的种类不同的多肽链(Y)的情况下，作为多肽链(Y)，从心肌细胞等的存留性和增殖性的方面出发，优选为选自由(GPP)d序列、(GVGVP)c序列和(GAHGPAGPK)f序列组成的组中的2种以上的序列，特别优选为(GVGVP)c序列和(GAHGPAGPK)f序列。
多肽链(Y)是氨基酸序列(X)2～100个连续(上述b～f分别为2～100)而成的多肽链，从心肌细胞等的存留性和增殖性的方面出发，连续的个数优选为2～50个(上述b～f分别为2～50)，进一步优选为2～30个(上述b～f分别为2～30)。
本发明中，多肽链(Y’)是多肽链(Y)中的0.1～5％的氨基酸残基被赖氨酸残基(K)和/或精氨酸残基(R)置换的多肽链，赖氨酸残基(K)和精氨酸残基(R)的合计个数为1～100个。具体而言，多肽链(Y’)是构成多肽链(Y)的氨基酸序列(X)的一部分或全部被置换成下述氨基酸序列(X’)、且多肽链(Y)中的1～100个氨基酸残基被赖氨酸残基(K)和/或精氨酸残基(R)置换的多肽链。
氨基酸序列(X’)：氨基酸序列(X)中的20～60％的氨基酸残基被赖氨酸残基(K)和/或精氨酸残基(R)置换的氨基酸序列。
氨基酸序列(X’)中，从蛋白质(A)在水中的溶解性的方面出发，氨基酸序列(X)中的氨基酸残基的置换数(被赖氨酸残基(K)和/或精氨酸残基(R)置换的数目)优选为1～5个、进一步优选为1～4个、更进一步优选为1～3个。
另外，作为氨基酸序列(X’)，从蛋白质(A)在水中的溶解性的方面出发，优选为选自由序列编号7所示的氨基酸序列即GKGVP序列(7)、序列编号8所示的氨基酸序列即GKGKP序列(8)、序列编号9所示的氨基酸序列即GKGRP序列(9)和序列编号10所示的氨基酸序列即GRGRP序列(10)组成的组中的至少一种序列，进一步优选为选自由GKGVP序列(7)和GKGKP序列(8)组成的组中的至少一种。
是否为多肽链(Y’)可以通过将蛋白质(A)的序列中的全部的K和R置换成其他氨基酸残基(G、A、V、P或H)时是否成为多肽链(Y)来进行判断。需要说明的是，在氨基酸序列(X)为GAHGPAGPK序列(3)的情况下，由于序列中存在K，因此对判断方法进行如下变更。将蛋白质(A)的序列中的全部的K和R置换成其他氨基酸残基(G、A、V、P或H)时，若出现GAHGPAGPα这样的序列(α为G、A、V、P或H)，则进一步将α置换成K。其结果，在该序列成为多肽链(Y)的情况下，将氨基酸残基置换之前的序列判断为多肽链(Y’)。多肽链(Y’)中，从蛋白质(A)在水中的溶解性和心肌细胞等的存留性的方面出发，多肽链(Y)中被置换的氨基酸残基数优选为1～70个、进一步优选为1～30个。另外，多肽链(Y’)是多肽链(Y)中的0.1～5％的氨基酸残基被赖氨酸残基(K)和/或精氨酸残基(R)置换的多肽链，从蛋白质(A)在水中的溶解性和心肌细胞等的存留性和增殖性的方面出发，上述被置换的氨基酸残基优选为0.1～4％、进一步优选为0.5～3％。
本发明中，蛋白质(A)具有多肽链(Y)和/或多肽链(Y’)，蛋白质(A)中的多肽链(Y)和多肽链(Y’)的合计个数为1～100个。在蛋白质(A)具有氨基酸序列(X)的种类和/或连续个数不同的多肽链(Y)的情况下，分别计为1个，多肽链(Y)的个数为其合计。多肽链(Y’)也是同样的。
蛋白质(A)在1分子蛋白质(A)中具有合计1～100个的多肽链(Y)和/或多肽链(Y’)，从心肌细胞等的存留性和增殖性的方面出发，优选为1～80个、特别优选为1～60个。
蛋白质(A)中，将相同的氨基酸序列(X)反复结合的部分作为1个多肽链(Y)，将直到结合与氨基酸序列(X)不同的序列为止作为1个。例如，在(GVGVP)100GAGAGS(VPGVG)20这一序列中，多肽链(Y)为(GVGVP)100和(VPGVG)20这2个。另外，在蛋白质(A)的序列中的全部的赖氨酸残基(K)和精氨酸残基(R)被置换成其他氨基酸(G、A、V、P或H)时，将氨基酸序列(X)反复结合的部分作为1个多肽链(Y’)，将直到结合与氨基酸序列(X)不同的序列为止作为1个。例如，在(GVGVP)4GKGVP(GVGVP)3GAGAGS(GVGVP)4GKGVP(GVGVP)3这一序列中，作为多肽链(Y’)的(GVGVP)4GKGVP(GVGVP)3有2个。
本发明中，蛋白质(A)的疏水度为0.2～1.2，从蛋白质(A)在水中的溶解性的方面、胶凝的方面出发，优选为0.3～1.2、进一步优选为0.4～1.2、更进一步优选为0.45～1.2、特别优选为0.60～1.2、最优选为0.60～0.75。蛋白质(A)的疏水度表示蛋白质(A)分子的疏水性的程度，可以通过将构成蛋白质(A)分子的各氨基酸残基的数目(Mα)、各氨基酸的疏水度(Nα)和1分子蛋白质(A)中的氨基酸残基的总数(MT)代入下述数学式中而算出。需要说明的是，各氨基酸的疏水度使用非专利文献(Albert L.Leninger,David L.Nelson,Reininger的新生物化学上、广川书店、2010年9月、p.346-347)中记载的下述数值。
疏水度＝Σ(Mα×Nα)/(MT)
Mα：1分子蛋白质(A)中的各氨基酸残基数
Nα：各氨基酸的疏水度
MT：1分子蛋白质(A)中的氨基酸残基的总数
A(丙氨酸)：1.8
R(精氨酸)：-4.5
N(天冬酰胺)：-3.5
D(天冬氨酸)：-3.5
C(半胱氨酸)：2.5
Q(谷氨酰胺)：-3.5
E(谷氨酸)：-3.5
G(甘氨酸)：-0.4
H(组氨酸)：-3.2
I(异亮氨酸)：4.5
L(亮氨酸)：3.8
K(赖氨酸)：-3.9
M(蛋氨酸)：1.9
F(苯丙氨酸)：2.8
P(脯氨酸)：-1.6
S(丝氨酸)：-0.8
T(苏氨酸)：-0.7
W(色氨酸)：-0.9
Y(酪氨酸)：-1.3
V(缬氨酸)：4.2
例如，在蛋白质(A)为序列编号6所示的氨基酸序列即(GVGVP)4GKGVP(GVGVP)3序列(6)的情况下，蛋白质(A)的疏水度＝{16(G的数目)×(-0.4)+15(V的数目)×4.2+8(P的数目)×(-1.6)+1(K的数目)×(-3.9)}/40(氨基酸残基的总数)＝1.0。
本发明中，蛋白质(A)优选进一步具有GAGAGS序列(4)。蛋白质(A)具有GAGAGS序列(4)时，蛋白质(A)在生物体内更不易被分解，蛋白质(A)容易在不被分解的情况下存在至心肌细胞等充分定居于心肌组织中为止。从生物体内难分解性的方面出发，GAGAGS序列(4)优选具有序列编号4所示的氨基酸序列即GAGAGS序列(4)2～100个连续结合而成的多肽链(S)。多肽链(S)中，从生物体内难分解性的方面出发，GAGAGS序列(4)的连续数优选为2～100个、进一步优选为2～50个、更进一步优选为3～40个、特别优选为4～30个。蛋白质(A)具有多肽链(S)的情况下，蛋白质(A)在1分子中具有1个以上的多肽链(S)即可，从生物体内难分解性的方面出发，优选具有1～20个、进一步优选具有3～10个。
蛋白质(A)中，多肽链(Y)、多肽链(Y’)和多肽链(S)合计具有2个以上的情况下，多肽链与多肽链之间可以具有间隔氨基酸序列(Z)。间隔氨基酸序列(Z)是1个或2个以上的氨基酸结合而成的氨基酸序列，是在多肽链(Y)、多肽链(Y’)或多肽链(S)中不存在的氨基酸序列。从生物体内难分解性的方面出发，构成间隔氨基酸序列(Z)的氨基酸的数目优选为1～30个、进一步优选为1～15个、特别优选为1～10个。作为间隔氨基酸序列(Z)，具体而言，可以举出序列编号11所示的氨基酸序列即VAAGY序列(11)、序列编号12所示的氨基酸序列即GAAGY序列(12)和LGP序列等。
在蛋白质(A)中的两末端的各多肽链(Y)、多肽链(Y’)和多肽链(S)的N和/或C末端可以具有末端氨基酸序列(T)。末端氨基酸序列(T)是1个或2个以上的氨基酸结合而成的氨基酸序列，是在多肽链(Y)、多肽链(Y’)或多肽链(S)中不存在的氨基酸序列。从生物体内难分解性的方面出发，构成末端氨基酸序列(T)的氨基酸的数目优选为1～100个、进一步优选为1～50个、特别优选为1～40个。作为末端氨基酸序列(T)，具体而言，可以举出序列编号13所示的氨基酸序列即MDPVVLQRRDWENPGVTQLNRLAAHPPFASDPM序列(13)等。
蛋白质(A)中，除了上述末端氨基酸序列(T)以外，为了容易进行所表达的蛋白质(A)的纯化或检测，还可以在蛋白质(A)的N和/或C末端具有含有特殊氨基酸序列的蛋白质或肽(以下将它们称为“纯化标签”)。作为纯化标签，利用亲和纯化用的标签。作为这样的纯化标签，有谷胱甘肽-S-转移酶(GTS)、麦芽糖结合蛋白(MBP)、HQ标签、Myc标签、HA标签、FLAG标签、由聚组氨酸构成的6×His标签、V5标签、Xpress标签、AU1标签、T7标签、VSV-G标签、DDDDK标签、S标签、CruzTag09TM、CruzTag22TM、CruzTag41TM、Glu-Glu标签、Ha.11标签和KT3标签等。
下面示出各纯化标签(i)与识别结合该标签的配体(ii)的组合的一例。
(i-1)谷胱甘肽-S-转移酶(GTS)(ii-1)谷胱甘肽
(i-2)麦芽糖结合蛋白(MBP)(ii-2)直链淀粉
(i-3)HQ标签(ii-3)镍
(i-4)Myc标签(ii-4)抗Myc抗体
(i-5)HA标签(ii-5)抗HA抗体
(i-6)FLAG标签(ii-6)抗FLAG抗体
(i-7)6×His标签(ii-7)镍或钴
作为上述纯化标签序列的导入方法，可以举出在表达用载体中的编码蛋白质(A)的核酸的5’或3’末端插入编码纯化标签的核酸的方法、或使用市售的纯化标签导入用载体的方法等。
关于1分子蛋白质(A)中的多肽链(Y)和多肽链(Y’)的合计含量(重量％)，从与心肌细胞等的相互作用的方面、以及心肌细胞等的存留性和增殖性的方面出发，以蛋白质(A)的分子量为基准，优选为10～90重量％、进一步优选为20～80重量％。
蛋白质(A)中的多肽链(Y)和多肽链(Y’)的合计含量可以通过确定氨基酸序列而求出。具体而言，可以通过下述的测定方法求出。
<多肽链(Y)和多肽链(Y’)的合计含量的测定方法>
使用岛津制作所公司制造的肽测序仪(蛋白质测序仪)PPSQ-33A确定氨基酸序列。根据所确定的氨基酸序列利用下述数学式(1)求出多肽链(Y)和多肽链(Y’)的合计含量。
多肽链(Y)和多肽链(Y’)的合计含量＝Σ(γ×β)/Σ(α×β)×100 (1)
α：蛋白质(A)中的各氨基酸残基的数目
β：各氨基酸的分子量
γ：多肽链(Y)和多肽链(Y’)中的各氨基酸的个数
关于1分子蛋白质(A)中的氨基酸序列(X)和氨基酸序列(X’)的合计含量(重量％)，从心肌细胞等的存留性和增殖性的方面出发，以蛋白质(A)的分子量为基准，优选为10～90重量％、进一步优选为20～80重量％。
蛋白质(A)中的氨基酸序列(X)和氨基酸序列(X’)的合计含量可以利用蛋白质测序仪来求出。具体而言，可以通过下述测定方法求出。
<氨基酸序列(X)和氨基酸序列(X’)的含量的测定方法>
从能够在特定氨基酸残基处切断的切断方法中选用两种以上，将蛋白质(A)分解至30个残基以下的程度。之后，利用高效液相色谱法(HPLC)将蛋白质(A)的片段分离后，利用蛋白质测序仪读取氨基酸序列。由所得到的氨基酸序列进行肽图谱分析，确定蛋白质(A)的全序列。之后，利用下述记载的测定式测定氨基酸序列(X)和氨基酸序列(X’)的合计含量。
氨基酸序列(X)和氨基酸序列(X’)的合计含量(％)＝[{氨基酸序列(X)的分子量}×{氨基酸序列(X)的数目}+{氨基酸序列(X’)的分子量}×{氨基酸序列(X’)的数目}]/{蛋白质(A)的分子量}×100
从蛋白质(A)在水中的溶解性和心肌细胞等的存留性和增殖性的方面出发，1分子蛋白质(A)中的GAGAGS序列(4)与氨基酸序列(X)和氨基酸序列(X’)的合计的序列数的比例{GAGAGS序列(4):氨基酸序列(X)和氨基酸序列(X’)的合计}优选为4:1～1:20、进一步优选为4:1～1:10。
从心肌细胞等的存留性和增殖性的方面出发，蛋白质(A)的分子量优选为15～200kDa、进一步优选为15～100kDa。需要说明的是，蛋白质(A)的分子量是通过利用SDS-PAGE(SDS聚丙烯酰胺凝胶电泳)法将测定样品分离并将泳动距离与标准物质进行比较的方法求出的。
以下例示出一部分优选的蛋白质(A)。
(1)氨基酸序列(X)为GVGVP序列(2)的蛋白质
(1-1)具有GVGVP序列(2)连续而成的多肽链(Y1)中的1个氨基酸残基被赖氨酸残基(K)置换的多肽链(Y’1)的蛋白质(A1)，进一步优选为具有作为(GVGVP)4GKGVP(GVGVP)3序列(6)的多肽链(Y’2)和作为(GAGAGS)4序列(5)的多肽链(S1)的蛋白质(A2)；具有多肽链(Y’2)和作为(GAGAGS)2序列(14)的多肽链(S2)的蛋白质(A4)；以及具有多肽链(Y’2)、多肽链(S1)和多肽链(S2)的蛋白质(A5)。具体而言，为下述蛋白质：分子量约80kDa的序列编号15所示的氨基酸序列即序列(15)的蛋白质(SELP8K、疏水度0.62)，其具有下述结构：在具有12个多肽链(S1)[GAGAGS序列(4)4个连续而成的(GAGAGS)4序列(5)]和13个多肽链(Y’2)[GVGVP序列(2)8个连续而成的多肽链(Y2)中的缬氨酸残基(V)中的1个被置换成赖氨酸残基(K)的(GVGVP)4GKGVP(GVGVP)3序列(6)]且它们交替地进行化学结合而形成的结构上化学结合1个多肽链(S2)[GAGAGS序列(4)2个连续而成的(GAGAGS)2序列(14)]；分子量约82kDa的序列编号16所示的氨基酸序列即序列(16)的蛋白质(SELP0K、疏水度0.72)等，其具有下述结构：分别具有17个多肽链(S2)[GAGAGS序列(4)2个连续而成的(GAGAGS)2序列(14)]和多肽链(Y’2)[(GVGVP)4GKGVP(GVGVP)3序列(6)]且它们交替地进行化学结合。
(1-2)具有GVGVP序列(2)连续而成的多肽链(Y1)的蛋白质(A6)，进一步优选为具有GVGVP序列(2)2个连续而成的多肽链(Y1)和GAGAGS序列(4)6个连续而成的多肽链(S3)的蛋白质(A7)，具体而言，为分子量约93kDa的序列编号17所示的氨基酸序列即序列(17)的蛋白质(SLP4.1、疏水度0.47)，其具有多肽链(Y1)和多肽链(S3)结合而成的氨基酸嵌段(L-1)29个反复进行化学结合而成的结构。
(2)氨基酸序列(X)为VPGVG序列(1)的蛋白质
(2-1)具有VPGVG序列(1)4个连续而成的多肽链(Y3)和VPGVG序列(1)8个连续而成的多肽链(Y4)的蛋白质(A8)，进一步优选为具有VPGVG序列(1)4个连续而成的多肽链(Y3)、VPGVG序列(1)8个连续而成的多肽链(Y4)和GAGAGS序列(4)的蛋白质(A9)，具体而言，为分子量约220kDa的序列编号18所示的氨基酸序列即序列(18)的蛋白质(ELP1.1、疏水度1.12)，其具有在多肽链(Y3)上结合GAGAGS序列(4)、进一步结合多肽链(Y4)而成的氨基酸嵌段(L-2)40个反复进行化学结合而成的结构。
另外，蛋白质(A)可以为与序列(15)的蛋白质、序列(16)的蛋白质、序列(17)的蛋白质或序列(18)的蛋白质具有同源性的蛋白质。
该同源性优选为80％以上、更优选为90％以上、进一步优选为95％以上。
作为蛋白质(A)的水溶液中的水没有特别限定，优选经灭菌的水。作为灭菌方法，可以举出通过了具有0.2μm以下的孔径的微滤膜的水、通过了超滤膜的水、通过了反渗透膜的水和利用高压釜在121℃加热20分钟而进行了加热灭菌的离子交换水等。
(细胞)
如上所述，本发明的细胞移植用组合物可以提高心肌细胞和/或心肌祖细胞在心肌中的存留性和增殖性。
作为心肌祖细胞，例如可以举出在细胞表面表达GFRA2(神经秩蛋白(Neurturin)受体)、PDGFRA(血小板衍生生长因子受体α)或KDR(含激酶插入域蛋白受体)蛋白的细胞。
心肌细胞和/或心肌祖细胞优选来自哺乳类。
另外，心肌细胞和/或心肌祖细胞优选来自干细胞。
干细胞可以是从组织中分离出的这些干细胞，也可以是经传代培养的这些干细胞。作为干细胞没有特别限定，可以举出小鼠胚胎干细胞、小鼠间充质干细胞、小鼠多能干细胞、人胚胎干细胞、人间充质干细胞、人多能干细胞等，从操作容易性和安全性的方面出发，优选人多能干细胞，作为进行细胞移植的对象，从免疫排斥的方面出发，优选哺乳类，进一步优选人。
从干细胞分化成心肌细胞和/或心肌祖细胞的方法没有特别限制，例如可以通过(Funakoshi,S.et al.Sci Rep 8,19111(2016))所记载的方法实施而获得心肌细胞和/或心肌祖细胞。
本发明的细胞移植用组合物可以不包含动物来源的血清等。在不包含动物来源的血清等时，推测可以降低抗原性。
另外，由于本发明的细胞移植用组合物中包含的蛋白质(A)具有生物来源的序列，因此推测其生物相容性高。此外，由于蛋白质(A)能够利用大肠杆菌等细菌低成本地大量生产，因此能够容易地制造。
另外，本发明的细胞移植用组合物中包含的蛋白质(A)不容易受到体内的蛋白酶的分解，因此具有持续性，能够长期存在于生物体内。
本发明的细胞移植用组合物中，以上述细胞移植用组合物的合计重量为基准，上述细胞移植用组合物中的上述蛋白质(A)的浓度优选为1～20重量％、更优选为2～20重量％、进一步优选为10～20重量％。
细胞移植用组合物中的蛋白质(A)的浓度以细胞移植用组合物的合计重量为基准为1～20重量％时，细胞移植用组合物的粘度充分提高。因此，能够使心肌细胞等适当地定居于心肌组织，提高心肌细胞等的存留性。
特别是在细胞移植用组合物中的蛋白质(A)的浓度以细胞移植用组合物的合计重量为基准为10～20重量％的情况下，当细胞移植用组合物被加热至约37℃时，流动性消失，形成具有不会由于自重而发生形状变化的程度的固化度的凝胶。细胞移植用组合物发生胶凝时，能够防止心肌细胞等的分散，能够进一步提高心肌细胞等的存留性。
需要说明的是，该胶凝时，无需使细胞移植用组合物中含有交联剂等胶凝剂，仅利用细胞移植用组合物即可进行胶凝。另外，本发明的细胞移植用组合物优选不包含交联剂等胶凝剂。
本发明的细胞移植用组合物中，以上述细胞移植用组合物的合计液量为基准，细胞移植用组合物中的心肌细胞和/或心肌祖细胞的含有浓度优选为1×105～1×109个/mL。
细胞移植用组合物中的心肌细胞等的含有浓度以细胞移植用组合物的合计液量为基准小于1×105个/mL时，心肌细胞等的数目过少，因此不容易充分得到将细胞移植到心肌组织中的效果。
细胞移植用组合物中的心肌细胞等的含有浓度以细胞移植用组合物的合计液量为基准大于1×109个/mL时，心肌细胞等过剩，难以提高向心肌中移植的心肌细胞等的存留性。另外，在这样的含有浓度的情况下，从成本效率的方面出发不经济。
(其他成分)
本发明的细胞移植用组合物可以进一步包含无机盐和磷酸(盐)。
作为无机盐，可以举出氯化钠、氯化钾、氯化钙、氯化镁、硫酸钠、硫酸钾、硫酸钙、硫酸镁、碳酸氢钠、碳酸氢钾、碳酸氢钙和碳酸氢镁等。需要说明的是，磷酸盐不包含在无机盐中。
从心肌细胞等的存留性和增殖性的方面出发，本发明的细胞移植用组合物中的盐的含量(重量％)以细胞移植用组合物的合计重量为基准优选为0～1.3重量％、进一步优选为0.5～1.3重量％、更进一步优选为0.7～1.1重量％、特别优选为0.85～0.95重量％。
磷酸(盐)是指磷酸和/或磷酸盐。作为本发明的细胞移植用组合物中的磷酸(盐)，可以举出磷酸和磷酸盐。作为盐，可以举出碱金属盐和碱土金属盐，具体而言可以举出钠盐、钾盐、钙盐和镁盐等。
从蛋白质(A)的溶解性的方面出发，本发明的细胞移植用组合物中的磷酸(盐)的含量(重量％)以细胞移植用组合物的合计重量为基准优选为0～0.30重量％、进一步优选为0.10～0.30重量％、更进一步优选为0.12～0.28重量％、特别优选为0.14～0.26重量％。
另外，细胞移植用组合物可以进一步包含生长因子。
在细胞移植用组合物包含生长因子的情况下，生长因子的种类优选根据患部和对象疾病的种类来确定。
作为生长因子，可以举出表皮生长因子(Epidermal growth factor：EGF)、胰岛素样生长因子(Insulin-like growth factor：IGF)、转化生长因子(Transforming growthfactor：TGF)、神经生长因子(Nerve growth factor：NGF)、脑源性神经营养因子(Brain-derived neurotrophic factor：BDNF)、血管内皮细胞生长因子(Vesicular endothelialgrowth factor：VEGF)、粒细胞集落刺激因子(Granulocyte-colony stimulating factor：G-CSF)、粒细胞-巨噬细胞集落刺激因子(Granulocyte-macrophage-colony stimulatingfactor：GM-CSF)、血小板衍生生长因子(Platelet-derived growth factor：PDGF)、促红细胞生成素(Erythropoietin：EPO)、血小板生成素(Thrombopoietin：TPO)、碱性成纤维细胞生长因子(basic fibroblast growth factor：bFGF或FGF2)、肝细胞生长因子(Hepatocytegrowth factor：HGF)等。
从细胞增殖的方面出发，细胞移植用组合物中的生长因子的浓度以细胞移植用组合物的合计重量为基准优选为0.003～9.1重量％、进一步优选为0.003～6.25重量％。
细胞移植用组合物可以进一步包含公知的分化因子、激素、趋化因子、细胞因子、细胞粘附分子、趋化因子、酶、酶抑制剂、辅酶、矿物、脂肪、脂质、糖类、抗生素、炎症抑制剂、免疫抑制剂、缓冲物质、稳定剂和维生素等。
从组织亲和性的方面出发，细胞移植用组合物的pH优选为5～9、进一步优选为6～8。pH的调整可以通过添加公知的缓冲物质等进行调整。
接着对本发明的细胞移植用组合物的使用方法进行说明。
本发明的细胞移植用组合物可以用于心肌细胞移植治疗法。
即，作为使用本发明的细胞移植用组合物的对象的组织为心肌组织。
另外，作为使用本发明的细胞移植用组合物的对象疾病没有特别限定，可以举出心肌梗死、心绞痛、心肌病、心肌炎等。
即，本发明的细胞移植用组合物在心肌细胞移植治疗法中的使用为本发明的一个方式，本发明的细胞移植用组合物在用于治疗选自由心肌梗死、心绞痛、心肌病和心肌炎组成的组中的至少一种疾病的心肌细胞移植治疗法中的使用也是本发明的一个方式。
接着对使用本发明的细胞移植用组合物的心肌移植方法进行说明。
本发明的细胞移植方法的特征在于，将上述本发明的细胞移植用组合物移植到哺乳类的心肌组织中。
作为本发明的细胞移植方法中的哺乳类没有特别限定，可以为人、小鼠、大鼠、猪、猴等。
本发明的细胞移植方法中，向心肌组织中移植的细胞数优选为1×103～1×108个。
所移植的细胞数小于1×103个时，移植的细胞数少，因此不容易充分得到细胞移植的效果。
所移植的细胞数大于1×108个时，细胞过剩，难以提高移植到心肌中的细胞的存留性。另外，在这样的细胞数的情况下，从成本效率的方面出发不经济。
[实施例]
以下通过实施例和比较例进一步说明本发明，但本发明并不限定于此。以下，只要没有特别指定，％表示重量％、份表示重量份。
<制造例1>
οSELP8K的生产
依据日本专利第4088341号公报的实施例记载的方法，制作编码SELP8K的质粒pPT0345。
将所制作的质粒转化到大肠杆菌中，得到SELP8K生产株。
使用在30℃下生长得到的SELP8K生产株的过夜培养液，接种在250ml烧瓶中的LB培养基50ml中。加入卡那霉素使最终浓度为50μg/ml，一边在30℃进行搅拌(200rpm)一边对该培养液进行培养。在培养液达到OD600＝0.8(使用吸光度计UV1700：岛津制作所制)时，将40ml转移到事先加温至42℃的烧瓶中，在同样的温度下培养约2小时。将该培养体在冰上冷却，测定培养液的OD600。通过离心分离收集大肠杆菌。为了从收集的大肠杆菌中取出蛋白质，进行超声波破碎(4℃、30秒×10次)来溶菌。
将由该大肠杆菌产生的蛋白质供于十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)后，转移至聚偏二氟乙烯膜上。然后，使用兔抗SELP8K抗体作为一次抗体、使用抗兔IgG HRP标记抗体(GE Healthcare公司制造)作为二次抗体来进行蛋白质印迹分析。该产物的表观分子量为约80kDa。因此可知，SELP8K生产株生成了表观分子量80kDa的具有兔抗SELP8K抗体反应性的SELP8K。
οSELP8K的纯化
通过菌体溶解、利用离心分离除去不溶性碎片以及亲和层析从大肠杆菌生物质中纯化出上述得到的SELP8K。如此，得到分子量约80kDa的蛋白质(A-1)(SELP8K)。
οSELP8K的鉴定
按照下述程序对所得到的蛋白质(A-1)进行鉴定。
使用兔抗SELP8K抗体和针对C末端序列的6×His标签的兔抗6×His抗体(Roland公司制造)，通过蛋白质印迹法进行分析。表观分子量80kDa的蛋白质条带对各抗体显示出抗体反应性。另外，将所得到的蛋白质供于氨基酸分析，结果该产物富含甘氨酸(43.7％)、丙氨酸(12.3％)、丝氨酸(5.3％)、脯氨酸(11.7％)和缬氨酸(21.2％)。另外，该产物包含1.5％的赖氨酸。下述表1中示出了经纯化的产物的组成与由合成基因序列推测出的预测理论组成的相关关系。
因此确认到，蛋白质(A-1)为序列(15)的蛋白质，其中在具有13个(GVGVP)4GKGVP(GVGVP)3序列(6)和12个(GAGAGS)4序列(5)且它们交替地进行化学结合而形成的结构上化学结合(GAGAGS)2序列(14)。
[表1]
<制造例2>
在制造例1中，使用“编码SELP0K的质粒pPT0364”来代替“编码SELP8K的质粒pPT0345”，除此以外同样地得到分子量约82kDa的序列(16)的蛋白质(A-2)。
<制造例3>
在制造例1中，使用“编码SLP4.1的pSY1398-1”来代替“编码SELP8K的质粒pPT0345”，除此以外同样地得到分子量约93kDa的序列(17)的蛋白质(A-3)。
<制造例4>
在制造例1中，使用“编码ELP1.1的质粒pPT0102-1”来代替“编码SELP8K的质粒pPT0345”，除此以外同样地得到分子量约220kDa的序列(18)的蛋白质(A-4)。
<比较制造例1>
在制造例1中，使用“编码SLP4.1.3返质粒pPT0102”来代替“编码SELP8K的质粒pPT0345”，除此以外同样地得到分子量约150kDa的序列编号19所示的氨基酸序列即序列(19)的蛋白质(A’-1)。
<移植细胞的制作方法>
使用PiggyBac转座子载体系统(System-Biosciences公司)，在来自健康者的人多能干细胞株中在CAG启动子下插入荧光素酶基因，由此制作出稳定表达荧光素酶的人多能干细胞。利用(Funakoshi,S.et al.Sci Rep 8,19111(2016))中记载的方法由该细胞株分化诱导人多能干细胞。在分化诱导后第20天使用流式细胞仪分离提取心肌细胞，由此制作包含移植用的心肌细胞的溶液。
<实施例1>
在包含移植用的心肌细胞的溶液中加入上述蛋白质(A-1)和水，按照蛋白质(A-1)的浓度为10重量％、且移植用的心肌细胞的含有浓度为5×107个/mL的方式制备实施例1的细胞移植用组合物。
<实施例2～4>
除了使用蛋白质(A-2)～蛋白质(A-4)来代替蛋白质(A-1)以外，与实施例1同样地制备实施例2～4的细胞移植用组合物。
<比较例1>
在包含移植用的心肌细胞的溶液中加入水，按照移植用的心肌细胞的含有浓度为5×107个/mL的方式制备比较例1的细胞移植用组合物。
<比较例2>
除了使用蛋白质(A’-1)来代替蛋白质(A-1)以外，与实施例1同样地制备比较例2的细胞移植用组合物。
<心肌细胞向小鼠中的移植>
使用注射器将各实施例和各比较例的细胞移植用组合物20μL(细胞数1×106个)注入到心肌梗死模型小鼠的心肌组织中。注入1小时后，使用注射器对各小鼠进行荧光素的腹腔内给药，使用IVIS(活体成像系统，In vivo imaging system)对小鼠心肌组织中的荧光素酶的发光强度进行检测。
<细胞移植后的心肌细胞的存留性评价(细胞移植后第0天)>
使用下式由检测到的发光强度计算出细胞移植后第0天的心肌细胞的存留性。将结果记载于表2。
[细胞移植后第0天的心肌细胞的存留性]＝[荧光素酶的发光强度]/[比较例1的荧光素酶的发光强度]
需要说明的是，表2中的“细胞移植后第0天的心肌细胞的存留性(相对值)”是将注入了比较例1的细胞移植用组合物的小鼠中的“细胞移植后第0天的荧光素酶发光强度”设为1.0的情况下的相对比。
<细胞移植后的心肌细胞的增殖性评价(移植第0天～第84天)>
之后对注入了各实施例和各比较例的细胞移植用组合物的小鼠进行饲养，在第3、5、7、14、28、56和84天使用注射器进行荧光素的腹腔内给药，使用IVIS(活体成像系统)对小鼠心肌组织中的荧光素酶的发光强度进行检测。
使用下式由检测到的发光强度计算出细胞移植后的心肌细胞的增殖性。将结果记载于表3。
[细胞移植后的心肌细胞的增殖性]＝[荧光素酶的发光强度]/[细胞移植后第0天的荧光素酶的发光强度]
需要说明的是，表3中的“细胞移植后的心肌细胞的增殖性(相对值)”是将注入了各实施例和各比较例的细胞移植用组合物的小鼠中的“细胞移植第0天的荧光素酶发光强度”设为1.0的情况下的相对比。
由表2可知，在使用实施例1～4的细胞移植用组合物时，与使用比较例1和2的细胞移植用组合物的情况相比，细胞移植后的心肌细胞的存留性评价显著高。
另外，由表3可知，在使用实施例1～4的细胞移植用组合物时，与使用比较例1和2的细胞移植用组合物的情况相比，细胞移植后的心肌细胞的增殖性评价高。
因此可知，使用本发明的细胞移植用组合物时，能够将心肌细胞保持于心肌组织中，并且细胞的增殖性高。
工业实用性
本发明的细胞移植用组合物和细胞移植方法能够将心肌细胞等适当地保持于心肌组织中，能够提高移植细胞的存留性和增殖性。因此，本发明的细胞移植用组合物和细胞移植方法对于心肌梗死等以心脏功能不完善为特征的疾病是有效的。
SEQUENCE LISTING
<110> 国立大学法人京都大学(KYOTO UNIVERSITY)
三洋化成工业株式会社(SANYO CHEMICAL INDUSTRIES, LTD.)
<120> 细胞移植用组合物和细胞移植方法(a composition for celltransplantation and a method for cell transplantation)
<130> 587-PCT
<150> JP 2018-111976
<151> 2018-06-12
<160> 19
<170> PatentIn version 3.5
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<223> 氨基酸序列(Amino acid sequence)(Z)
<400> 12
Gly Ala Ala Gly Tyr
1 5
<210> 13
<211> 33
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 氨基酸序列(Amino acid sequence)(T)
<400> 13
Met Asp Pro Val Val Leu Gln Arg Arg Asp Trp Glu Asn Pro Gly Val
1 5 10 15
Thr Gln Leu Asn Arg Leu Ala Ala His Pro Pro Phe Ala Ser Asp Pro
20 25 30
Met
<210> 14
<211> 12
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 多肽链(Polypeptide chain)(S)
<400> 14
Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser
1 5 10
<210> 15
<211> 884
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> SELP8K
<400> 15
Met Asp Pro Val Val Leu Gln Arg Arg Asp Trp Glu Asn Pro Gly Val
1 5 10 15
Thr Gln Leu Asn Arg Leu Ala Ala His Pro Pro Phe Ala Ser Asp Pro
20 25 30
Met Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
35 40 45
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
50 55 60
Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
65 70 75 80
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
85 90 95
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
100 105 110
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
115 120 125
Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
130 135 140
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
145 150 155 160
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
165 170 175
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
180 185 190
Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
195 200 205
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
210 215 220
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
225 230 235 240
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
245 250 255
Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
260 265 270
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
275 280 285
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
290 295 300
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
305 310 315 320
Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
325 330 335
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
340 345 350
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
355 360 365
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
370 375 380
Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
385 390 395 400
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
405 410 415
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
420 425 430
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
435 440 445
Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
450 455 460
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
465 470 475 480
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
485 490 495
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
500 505 510
Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
515 520 525
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
530 535 540
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
545 550 555 560
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
565 570 575
Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
580 585 590
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
595 600 605
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
610 615 620
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
625 630 635 640
Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
645 650 655
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
660 665 670
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
675 680 685
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
690 695 700
Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
705 710 715 720
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
725 730 735
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
740 745 750
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
755 760 765
Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
770 775 780
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
785 790 795 800
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
805 810 815
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
820 825 830
Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
835 840 845
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
850 855 860
Ala Gly Ala Met Asp Pro Gly Arg Tyr Gln Asp Leu Arg Ser His His
865 870 875 880
His His His His
<210> 16
<211> 948
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> SELP0K
<400> 16
Met Asp Pro Val Val Leu Gln Arg Arg Asp Trp Glu Asn Pro Gly Val
1 5 10 15
Thr Gln Leu Asn Arg Leu Ala Ala His Pro Pro Phe Ala Ser Asp Pro
20 25 30
Met Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly
35 40 45
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
50 55 60
Pro Gly Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
65 70 75 80
Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
85 90 95
Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
100 105 110
Gly Val Gly Val Pro Gly Lys Gly Val Pro Gly Val Gly Val Pro Gly
115 120 125
Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly
130 135 140
Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
145 150 155 160
Val Gly Val Pro Gly Val Gly Val Pro Gly Lys Gly Val Pro Gly Val
165 170 175
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
180 185 190
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val
195 200 205
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Lys Gly
210 215 220
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
225 230 235 240
Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
260 265 270
Pro Gly Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
275 280 285
Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
290 295 300
Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
305 310 315 320
Gly Val Gly Val Pro Gly Lys Gly Val Pro Gly Val Gly Val Pro Gly
325 330 335
Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly
340 345 350
Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
355 360 365
Val Gly Val Pro Gly Val Gly Val Pro Gly Lys Gly Val Pro Gly Val
370 375 380
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
385 390 395 400
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val
405 410 415
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Lys Gly
420 425 430
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
435 440 445
Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly
450 455 460
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
465 470 475 480
Pro Gly Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
485 490 495
Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
500 505 510
Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
515 520 525
Gly Val Gly Val Pro Gly Lys Gly Val Pro Gly Val Gly Val Pro Gly
530 535 540
Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly
545 550 555 560
Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
565 570 575
Val Gly Val Pro Gly Val Gly Val Pro Gly Lys Gly Val Pro Gly Val
580 585 590
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
595 600 605
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val
610 615 620
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Lys Gly
625 630 635 640
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
645 650 655
Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly
660 665 670
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
675 680 685
Pro Gly Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
690 695 700
Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
705 710 715 720
Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
725 730 735
Gly Val Gly Val Pro Gly Lys Gly Val Pro Gly Val Gly Val Pro Gly
740 745 750
Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly
755 760 765
Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
770 775 780
Val Gly Val Pro Gly Val Gly Val Pro Gly Lys Gly Val Pro Gly Val
785 790 795 800
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
805 810 815
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val
820 825 830
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Lys Gly
835 840 845
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
850 855 860
Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly
865 870 875 880
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
885 890 895
Pro Gly Lys Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
900 905 910
Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
915 920 925
Ser Gly Ala Met Asp Pro Gly Arg Tyr Gln Asp Leu Arg Ser His His
930 935 940
His His His His
945
<210> 17
<211> 1384
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> SLP4.1
<400> 17
Met Asp Pro Val Val Leu Gln Arg Arg Asp Trp Glu Asn Pro Gly Val
1 5 10 15
Thr Gln Leu Asn Arg Leu Ala Ala His Pro Pro Phe Ala Ser Asp Pro
20 25 30
Met Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
35 40 45
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
50 55 60
Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
65 70 75 80
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
85 90 95
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
100 105 110
Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
115 120 125
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
130 135 140
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
145 150 155 160
Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly
165 170 175
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
180 185 190
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
195 200 205
Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly
210 215 220
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
225 230 235 240
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly
245 250 255
Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly
260 265 270
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
275 280 285
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
290 295 300
Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
305 310 315 320
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
325 330 335
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val
340 345 350
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
355 360 365
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
370 375 380
Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val
385 390 395 400
Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
405 410 415
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
420 425 430
Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
435 440 445
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
450 455 460
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
465 470 475 480
Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
485 490 495
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
500 505 510
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
515 520 525
Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly
530 535 540
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
545 550 555 560
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
565 570 575
Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly
580 585 590
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
595 600 605
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly
610 615 620
Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly
625 630 635 640
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
645 650 655
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro
660 665 670
Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
675 680 685
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
690 695 700
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val
705 710 715 720
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
725 730 735
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
740 745 750
Ser Gly Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val
755 760 765
Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
770 775 780
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
785 790 795 800
Ala Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
805 810 815
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
820 825 830
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
835 840 845
Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
850 855 860
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
865 870 875 880
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
885 890 895
Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly
900 905 910
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
915 920 925
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
930 935 940
Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly
945 950 955 960
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
965 970 975
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly
980 985 990
Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly
995 1000 1005
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser
1010 1015 1020
Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val Gly
1025 1030 1035
Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala
1040 1045 1050
Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
1055 1060 1065
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Val
1070 1075 1080
Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser Gly
1085 1090 1095
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala
1100 1105 1110
Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
1115 1120 1125
Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly Ser
1130 1135 1140
Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
1145 1150 1155
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser
1160 1165 1170
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala Gly
1175 1180 1185
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala
1190 1195 1200
Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
1205 1210 1215
Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ala
1220 1225 1230
Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
1235 1240 1245
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala
1250 1255 1260
Gly Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly
1265 1270 1275
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser
1280 1285 1290
Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
1295 1300 1305
Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Ala
1310 1315 1320
Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
1325 1330 1335
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala
1340 1345 1350
Gly Ala Gly Ser Gly Val Gly Val Pro Gly Val Gly Val Pro Met
1355 1360 1365
Asp Pro Gly Arg Tyr Gln Asp Leu Arg Ser His His His His His
1370 1375 1380
His
<210> 18
<211> 2690
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> ELP 1.1
<400> 18
Met Asp Pro Val Val Leu Gln Arg Arg Asp Trp Glu Asn Pro Gly Val
1 5 10 15
Thr Gln Leu Asn Arg Leu Ala Ala His Pro Pro Phe Ala Ser Asp Pro
20 25 30
Met Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
35 40 45
Val Pro Gly Val Gly Gly Ala Gly Ala Gly Ser Val Pro Gly Val Gly
50 55 60
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
65 70 75 80
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
85 90 95
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
100 105 110
Val Gly Val Pro Gly Val Gly Gly Ala Gly Ala Gly Ser Val Pro Gly
115 120 125
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
130 135 140
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
145 150 155 160
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
165 170 175
Pro Gly Val Gly Val Pro Gly Val Gly Gly Ala Gly Ala Gly Ser Val
180 185 190
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
195 200 205
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
210 215 220
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
225 230 235 240
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Gly Ala Gly Ala Gly
245 250 255
Ser Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
260 265 270
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
275 280 285
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
290 295 300
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Gly Ala Gly
305 310 315 320
Ala Gly Ser Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
325 330 335
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
340 345 350
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
355 360 365
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Gly
370 375 380
Ala Gly Ala Gly Ser Val Pro Gly Val Gly Val Pro Gly Val Gly Val
385 390 395 400
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
405 410 415
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
420 425 430
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
435 440 445
Gly Gly Ala Gly Ala Gly Ser Val Pro Gly Val Gly Val Pro Gly Val
450 455 460
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
465 470 475 480
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
485 490 495
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
500 505 510
Gly Val Gly Gly Ala Gly Ala Gly Ser Val Pro Gly Val Gly Val Pro
515 520 525
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
530 535 540
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
545 550 555 560
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
565 570 575
Val Pro Gly Val Gly Gly Ala Gly Ala Gly Ser Val Pro Gly Val Gly
580 585 590
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
595 600 605
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
610 615 620
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
625 630 635 640
Val Gly Val Pro Gly Val Gly Gly Ala Gly Ala Gly Ser Val Pro Gly
645 650 655
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
660 665 670
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
675 680 685
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
690 695 700
Pro Gly Val Gly Val Pro Gly Val Gly Gly Ala Gly Ala Gly Ser Val
705 710 715 720
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
725 730 735
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
740 745 750
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
755 760 765
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Gly Ala Gly Ala Gly
770 775 780
Ser Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
785 790 795 800
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
805 810 815
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
820 825 830
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Gly Ala Gly
835 840 845
Ala Gly Ser Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
850 855 860
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
865 870 875 880
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
885 890 895
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Gly
900 905 910
Ala Gly Ala Gly Ser Val Pro Gly Val Gly Val Pro Gly Val Gly Val
915 920 925
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
930 935 940
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
945 950 955 960
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
965 970 975
Gly Gly Ala Gly Ala Gly Ser Val Pro Gly Val Gly Val Pro Gly Val
980 985 990
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
995 1000 1005
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
1010 1015 1020
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
1025 1030 1035
Val Pro Gly Val Gly Gly Ala Gly Ala Gly Ser Val Pro Gly Val
1040 1045 1050
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
1055 1060 1065
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
1070 1075 1080
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
1085 1090 1095
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Gly Ala Gly Ala
1100 1105 1110
Gly Ser Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
1115 1120 1125
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
1130 1135 1140
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
1145 1150 1155
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
1160 1165 1170
Val Gly Gly Ala Gly Ala Gly Ser Val Pro Gly Val Gly Val Pro
1175 1180 1185
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
1190 1195 1200
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
1205 1210 1215
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
1220 1225 1230
Gly Val Gly Val Pro Gly Val Gly Gly Ala Gly Ala Gly Ser Val
1235 1240 1245
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
1250 1255 1260
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
1265 1270 1275
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
1280 1285 1290
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Gly
1295 1300 1305
Ala Gly Ala Gly Ser Val Pro Gly Val Gly Val Pro Gly Val Gly
1310 1315 1320
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
1325 1330 1335
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
1340 1345 1350
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
1355 1360 1365
Val Pro Gly Val Gly Gly Ala Gly Ala Gly Ser Val Pro Gly Val
1370 1375 1380
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
1385 1390 1395
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
1400 1405 1410
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
1415 1420 1425
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Gly Ala Gly Ala
1430 1435 1440
Gly Ser Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
1445 1450 1455
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
1460 1465 1470
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
1475 1480 1485
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
1490 1495 1500
Val Gly Gly Ala Gly Ala Gly Ser Val Pro Gly Val Gly Val Pro
1505 1510 1515
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
1520 1525 1530
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
1535 1540 1545
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
1550 1555 1560
Gly Val Gly Val Pro Gly Val Gly Gly Ala Gly Ala Gly Ser Val
1565 1570 1575
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
1580 1585 1590
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
1595 1600 1605
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val
1610 1615 1620
Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Gly
1625 1630 1635
Ala Gly Ala Gly Ser Val Pro Gly Val Gly Val Pro Gly Val Gly
1640 1645 1650
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
1655 1660 1665
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
1670 1675 1680
Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
1685 1690 1695
Val Pro Gly Val Gly Gly Ala Gly Ala Gly Ser Val Pro Gly Val
1700 1705 1710
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
1715 1720 1725
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
1730 1735 1740
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
1745 1750 1755
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Gly Ala Gly Ala
1760 1765 1770
Gly Ser Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
1775 1780 1785
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
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2120 2125 2130
Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
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Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
2150 2155 2160
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2165 2170 2175
Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro
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2240 2245 2250
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2270 2275 2280
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Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
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Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly
2345 2350 2355
Val Pro Gly Val Gly Gly Ala Gly Ala Gly Ser Val Pro Gly Val
2360 2365 2370
Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly Val
2375 2380 2385
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2390 2395 2400
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Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Gly Ala Gly Ala
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Gly Ser Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
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Val Gly Val Pro Gly Val Gly Val Pro Gly Val Gly Val Pro Gly
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2600 2605 2610
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2615 2620 2625
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2630 2635 2640
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2645 2650 2655
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2660 2665 2670
Met Asp Pro Gly Arg Tyr Gln Asp Leu Arg Ser His His His His
2675 2680 2685
His His
2690
<210> 19
<211> 1534
<212> PRT
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1 5 10 15
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35 40 45
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50 55 60
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100 105 110
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115 120 125
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130 135 140
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145 150 155 160
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195 200 205
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210 215 220
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260 265 270
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
275 280 285
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290 295 300
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Lys Gly Val Pro Gly Lys
305 310 315 320
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
325 330 335
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340 345 350
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
355 360 365
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
370 375 380
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385 390 395 400
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405 410 415
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420 425 430
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
435 440 445
Ala Gly Ala Gly Ser Gly Lys Gly Val Pro Gly Lys Gly Val Pro Gly
450 455 460
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
465 470 475 480
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485 490 495
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500 505 510
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515 520 525
Gly Lys Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
530 535 540
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625 630 635 640
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675 680 685
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690 695 700
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
705 710 715 720
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Lys Gly
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820 825 830
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
835 840 845
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850 855 860
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865 870 875 880
Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
885 890 895
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980 985 990
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
995 1000 1005
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1010 1015 1020
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Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser
1040 1045 1050
Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
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Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser
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1085 1090 1095
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala
1100 1105 1110
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1115 1120 1125
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1130 1135 1140
Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Lys Gly Val Pro
1145 1150 1155
Gly Lys Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala
1160 1165 1170
Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
1175 1180 1185
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala
1190 1195 1200
Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
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Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
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Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala
1310 1315 1320
Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly
1325 1330 1335
Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala
1340 1345 1350
Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Lys Gly Val Pro
1355 1360 1365
Gly Lys Gly Val Pro Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala
1370 1375 1380
Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
1385 1390 1395
Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala
1400 1405 1410
Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly
1415 1420 1425
Ala Gly Ala Gly Ser Gly Lys Gly Val Pro Gly Lys Gly Val Pro
1430 1435 1440
Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
1445 1450 1455
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser
1460 1465 1470
Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly
1475 1480 1485
Ala Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala Gly Ala Gly Ser
1490 1495 1500
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Asp Pro Gly Arg Tyr Gln Asp Leu Arg Ser His His His His His
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His
Claims (15)
1.一种细胞移植用组合物，其是包含蛋白质(A)的水溶液和细胞的细胞移植用组合物，其特征在于，
所述细胞为心肌细胞和/或心肌祖细胞，
所述蛋白质(A)的疏水度为0.2～1.2，
所述蛋白质(A)具有多肽链(Y)和/或多肽链(Y’)，
所述蛋白质(A)中的所述多肽链(Y)与所述多肽链(Y’)的合计个数为1～100个，
所述多肽链(Y)是序列编号1所示的氨基酸序列即VPGVG序列(1)、序列编号2所示的氨基酸序列即GVGVP序列(2)、GPP序列、GAP序列和序列编号3所示的氨基酸序列即GAHGPAGPK序列(3)中的任一氨基酸序列(X)2～100个连续而成的多肽链，
所述多肽链(Y’)是所述多肽链(Y)中的0.1～5％的氨基酸残基被赖氨酸残基和/或精氨酸残基置换的多肽链，所述赖氨酸残基和所述精氨酸残基的合计个数为1～100个。
2.如权利要求1所述的细胞移植用组合物，其中，所述蛋白质(A)进一步具有序列编号4所示的氨基酸序列即GAGAGS序列(4)2～100个连续结合而成的多肽链(S)。
3.如权利要求2所述的细胞移植用组合物，其中，
1分子所述蛋白质(A)中的所述GAGAGS序列(4)与所述氨基酸序列(X)和氨基酸序列(X’)的合计的序列数的比例、即GAGAGS序列(4):氨基酸序列(X)和氨基酸序列(X’)的合计为4:1～1:20，
所述氨基酸序列(X’)是氨基酸序列(X)中的20％～60％的氨基酸残基被赖氨酸残基和/或精氨酸残基置换的氨基酸序列。
4.如权利要求1～3中任一项所述的细胞移植用组合物，其中，由SDS-PAGE、即SDS聚丙烯酰胺凝胶电泳法得到的所述蛋白质(A)的分子量为15kDa～200kDa。
5.如权利要求1～4中任一项所述的细胞移植用组合物，其中，所述蛋白质(A)为具有多肽链(Y’1)的蛋白质(A1)，所述多肽链(Y’1)是所述氨基酸序列(X)为所述GVGVP序列(2)的多肽链(Y1)中的1个氨基酸残基被赖氨酸残基置换的多肽链。
6.如权利要求2～5中任一项所述的细胞移植用组合物，其中，所述蛋白质(A)是具有多肽链(S1)和多肽链(Y’2)的蛋白质(A2)，所述多肽链(S1)为序列编号5所示的氨基酸序列即(GAGAGS)4序列(5)，所述多肽链(Y’2)为序列编号6所示的氨基酸序列即(GVGVP)4GKGVP(GVGVP)3序列(6)。
7.如权利要求1～6中任一项所述的细胞移植用组合物，其中，以所述细胞移植用组合物的合计重量为基准，所述蛋白质(A)的浓度为1重量％～20重量％。
8.如权利要求1～7中任一项所述的细胞移植用组合物，其中，以所述细胞移植用组合物的合计液量为基准，所述细胞的含有浓度为1×105个/mL～1×109个/mL。
9.如权利要求1～8中任一项所述的细胞移植用组合物，其中，所述细胞来自干细胞。
10.如权利要求1～9中任一项所述的细胞移植用组合物，其中，所述细胞来自哺乳类。
11.如权利要求1～10中任一项所述的细胞移植用组合物，其中，所述细胞来自人多能干细胞。
12.如权利要求1～11中任一项所述的细胞移植用组合物，其用于心肌细胞移植治疗法。
13.如权利要求1～12中任一项所述的细胞移植用组合物，其用于选自由心肌梗死、心绞痛、心肌病和心肌炎组成的组中的至少一种疾病。
14.一种细胞移植方法，其中，将权利要求1～13中任一项所述的细胞移植用组合物移植到除人以外的哺乳类的心肌组织中。
15.如权利要求14所述的细胞移植方法，其中，移植到所述心肌组织中的细胞数为1×103个～1×108个。
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| JP2018-111976 | 2018-06-12 | ||
| JP2018111976 | 2018-06-12 | ||
| PCT/JP2019/018606 WO2019239751A1 (ja) | 2018-06-12 | 2019-05-09 | 細胞移植用組成物及び細胞移植方法 |
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| JP2002145797A (ja) * | 2000-11-10 | 2002-05-22 | Seishi Yoneda | ヒドロゲルからなる細胞移植療法用材料 |
| WO2012172887A1 (ja) * | 2011-06-13 | 2012-12-20 | 国立大学法人大阪大学 | 心疾患治療薬および心疾患治療用細胞シート |
| JP2018000861A (ja) * | 2016-07-08 | 2018-01-11 | 田畑 泰彦 | 細胞移植用組成物及びそれを含む細胞移植用溶液 |
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| JP3338441B2 (ja) | 1988-11-09 | 2002-10-28 | プロテイン ポリマー テクノロジーズ，インコーポレイティド | 組換え的に調製された官能的な合成タンパク質ポリマー |
| US5817303A (en) | 1995-05-05 | 1998-10-06 | Protein Polymer Technologies, Inc. | Bonding together tissue with adhesive containing polyfunctional crosslinking agent and protein polymer |
| US9587222B2 (en) | 2003-08-01 | 2017-03-07 | Cellseed Inc. | Three-dimensional tissue structure |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002145797A (ja) * | 2000-11-10 | 2002-05-22 | Seishi Yoneda | ヒドロゲルからなる細胞移植療法用材料 |
| WO2012172887A1 (ja) * | 2011-06-13 | 2012-12-20 | 国立大学法人大阪大学 | 心疾患治療薬および心疾患治療用細胞シート |
| JP2018000861A (ja) * | 2016-07-08 | 2018-01-11 | 田畑 泰彦 | 細胞移植用組成物及びそれを含む細胞移植用溶液 |
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| EP3811983A4 (en) | 2022-03-16 |
| US11648279B2 (en) | 2023-05-16 |
| JPWO2019239751A1 (ja) | 2021-08-05 |
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| JP7241358B2 (ja) | 2023-03-17 |
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