CN1057013C - 新的白细胞介素－２受体特异性免疫球蛋白 - Google Patents

新的白细胞介素－２受体特异性免疫球蛋白 Download PDF

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CN1057013C
CN1057013C CN89109618A CN89109618A CN1057013C CN 1057013 C CN1057013 C CN 1057013C CN 89109618 A CN89109618 A CN 89109618A CN 89109618 A CN89109618 A CN 89109618A CN 1057013 C CN1057013 C CN 1057013C
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卡里·L·奎因
哈罗德·E·塞里克
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Abstract

与人体IL-2受体特异性反应的类人体免疫球蛋白采用重组DNA技术制备，用于治疗T细胞介导的疾病。

Description

新的白细胞介素－２受体特异性免疫球蛋白
本发明涉及用于开发新的治疗药物的重组DNA与单克隆抗体技术的结合，更具体讲，本发明涉及对人体白细胞介素-2受体特异的非致免疫抗体的制备及其应用。
在哺乳动物中，免疫反应是由两类细胞调节的，这两类细胞可与外来物质即抗原特异地相互作用。这些细胞种类之一的B细胞是产生抗体的。第二类细胞，T-细胞，包括各种细胞亚群，这些细胞亚群在体内可控制B-细胞和各种其它造血细胞(包括T-细胞)的功能。
T-细胞产生这种控制的一种途径是通过产生称为白细胞介素-2(IL-2)的淋巴因子，原称为T-细胞生长因子。IL-2的基本功能是刺激和维持T-细胞。实际上，一些免疫学家认为IL-2可能是整个免疫反应的中心(见，Farrar，J.等，ImmunolRev。63：129-166(1982)，这里作为参考文献)。
IL-2与特异的高亲和性膜受体相互作用来发挥它的生物学作用(Greene，W.等，Progress in Hematology XIV，E.Brown，Ed，Grune和Statton，纽约(1986)，283页)。人体IL-2受体是一种复合的多链糖蛋白，其中一个链被称为Tac肽，大小约为55KD(见，Leonard，W.，等，J.Biol. Chem 260：1872(1985)，这里作为参考文献)。编码该蛋白的基因已分离出来，并预测为-272个氨基酸的肽，它包括-21个氨基酸的单肽(见，Leonard，W.，等；Nature 311：62611984)。P55 Tac蛋白质的219氨基末端氨基酸明显包括一个细胞外区(见，Leonard，W.，等，Science，230：633-639(1985)，这里用作参考文献)。
对人体IL-2受体的结构和功能的许多解释都是由于特异反应性的单克隆抗体的研究速度。具体讲，一种称为抗-Tac的小鼠单克隆抗体(Uchiyama等，J.Immunol.126：1393(1981)己表明IL-2受体可在T-细胞上检测，而且也可用单核巨噬细胞家族的细胞，肝中的星形细胞)，皮肤中的郎格罕氏细胞，当然，活化的T细胞也可以。重要的是，局部余下的T细胞，B细胞或循环的巨噬细胞不显示IL-2受体(Herrmann，等，J.Exp.Med.162：1111(1985))。
抗Tac单克隆抗体也已被用来限定需与IL-2相互作用的淋巴细胞功能并己表明了它可抑制各种T细胞功能，这包括在细胞培养中胞毒和抑制基因T淋巴细胞的增殖。基于对抗-Tac和其它抗体的研究，目前的各种疾病都与T细胞对IL-2受体的不正确表达有关，尤其是成人T细胞白血病。
最近发现，IL-2受体是T细胞介异的疾病新的治疗方法的理想目标。已建议将IL-2受体特异性抗体(如抗Tac单克隆抗体)单独便用或用作免疫结合物(例如，与蓖麻子蛋白A，同位素等结合)从而有效地除去带有IL-2受体的细胞。这些试剂理论上可消除与病症有关的表达IL-2受体的白血病细胞，某些B细胞或活化的T细胞，但可保留成熟的正常T细胞和它们的前体以确保能够进行所需的正常T细胞免疫反应。通常大多数其它T细胞特异性药物可基本上杀伤所有外周T细胞，这限制了这些药物的疗效。综上所述，使用对IL-2受体特异的适宜单克隆抗体对于自身免疫疾病，器官移植和由活化T细胞引起的任何不需要的反应具有治疗作用。实际上，已开始用例如，抗-Tac抗体进行临床试验(一般见Waldman，T.，等，Cancer Res.45：625(1985)和Waldman，T.，Science 232：727-732(1986)，这里一起用作参考文献)。
但不幸的是，使用抗-Tac和其它非人体单克隆抗体出现了一些缺点，尤其是在如下面解释的重复治疗方案中。例如，当小鼠单克隆抗体用于人体时，它们不能很好地固定补体并缺乏其它重要免疫球蛋白的功能性特征。
也许更重要的是，抗Tac和其它非人体单克隆抗体含实质伸长的氨基酸序列，当该抗体注射给人类患者时，这些氨基酸序列是致免疫的。大量研究表明，外来抗体注射后，患者对抗体产生的免疫反应是十分强烈的，该免疫反应实际在最初治疗后，基本消除了抗体的治疗作用。而且，尽管可以期望生产出越来越多的治疗各种疾病的不同的小鼠或其它抗原性(对人)的单克隆抗体，但用任何不同的非人体抗体进行第一步和第二步治疗后，甚至用于无关疗法的随后治疗可能也是无效的甚至是危险的。
虽然所谓“嵌合抗体”(例如小鼠可变区与人恒定区连接)的制备已取得一些成功。但仍保留了致免疫性问题。通常采用典型的人体单克隆抗体制备技术生产可与人体IL-2受体(如许多人体抗原)反应的人体免疫球蛋白是十分困难的。类似地，采用重组DNA技术制备所谓“人体属性”的抗体(见，欧洲专利申请公开号、0239400)得到的是不确定的结果，这部分是由于不可预测的结合亲和力。
因此，需要改良形式的对人体IL-2受体特异的类人体免疫球蛋白(在体内它们基本上是非致免疫的)，它们可以适用于治疗制剂和其它用途的方式简单而经济地制成。本发明满足了这些和其它需要。
本发明提供了新的用于治疗T细胞介异的人体疾病的组合物，该组合物含类人体免疫球蛋白，它们能特异地阻断人体IL-2与其受体的结合或能结合到人体IL-2受体上的P55 Tac蛋白质上。该免疫球蛋白可能有两对轻链/重链复合物，典型的是至少一对具有包括小鼠互补决定区的链，互补决定区功能性地与人体骨架区片段连接。例如，带或不带其它天然小鼠氨基酸残基的小鼠互补决定区可用来制备类人体抗体，该抗体能以比108M-1更强的亲和力与人体IL-2受体结合。
本发明的包括结合阶段及其其它衍生物的免疫球蛋白可通过各种重组DNA技术，采用转染细胞中的最终表达(优选不灭的真核细胞，如骨髓瘤或杂交瘤细胞)很容易地制备。包括编码类人体免疫球蛋白骨架区的第一序列和编码所要免疫球蛋白互补决定区的第二序列的多核苷酸可合成制备或通过将适宜的cDNA与基因组DNA片段组合来制备。
类人体免疫球蛋白可以基本上纯的形式单独使用或与胞毒剂(如放射性核素，核糖体抑制蛋白或在细胞表面有活性的胞毒剂)复合使用。所有这些化合物都可用于治疗T细胞介导的疾病。类人体免疫球蛋白或它们的复合物可制备成药用剂型，这些剂型依据服药方式而变化。
本发明还提供了研制含1或多个来自供体免疫球蛋白的互补决定区(CDR′S)和来自人体免疫球蛋白骨架区的类人体免疫球蛋白链的新方法，优选的方法包括首先将供体免疫球蛋白的骨架或可变区氨基酸序列与所收集的人体免疫球蛋白链中的相应序列比较，然后从收集物中选择较为同源的序列之一作为人体免疫球蛋白。人体免疫球蛋白或接受体免疫球蛋白序列典型地选自所收集的至少10至20个免疫球蛋白链序列，它们通常与收集的供体免疫球蛋白序列有最高的同源性。人体免疫球蛋白骨架序列典型地与供体免疫球蛋白骨架序列有约65至70％或更高的同源性。供体免疫球蛋白既可是重链也可是轻链(或二者都是)，收集的人体免疫球蛋白含同样的链。人体属性的轻链和重链可用来形成完全的人体属性免疫球蛋白或抗体，它们具有两对轻/重链，可带或不带一段或整段的人体恒定区和其它蛋白质。
在本发明的另一个实施方案中，既可与上面的比较步骤相结合也可单独独立出来，在受体免疫球蛋白链中的其它氨基酸可被CDR供体免疫球蛋白链中的氨基酸取代。更具体讲，来自供体免疫球蛋白的相应氨基酸对受体免疫球蛋白的人体骨架氨基酸的进一步选择性的取代可在免疫球蛋白中定位进行：
(a)受体免疫球蛋白的人体骨架区中的氨基酸在人体免疫球蛋白序列中的该位置是少见的而在供体免疫球蛋白中的相应氨基酸在该位置是常见的；或
(b)该氨基酸与COR之一直接相邻；或
(c)该氨基酸被预测位于三维免疫球蛋白模型中CDR的约3A°之内并能与抗原或人体属性的免疫球蛋白的CDR相互作用。
人体属性的免疫球蛋白链除包括CDR外，典型地包含至少3个来自供体免疫球蛋白的氨基酸，通常至少有一个氨基酸与供体免疫球蛋白的CDR直接相邻。重链和轻链可通过用这三个氨基酸的一或三个位置标准来确定。
当本发明的人体属性重链和轻链结合到完整的抗体中时，它们在人体中基本上是非致免疫的并基本保留了与供体免疫球蛋白一样的对抗原(如含某一抗原决定簇的蛋白质或其它化合物)的亲和力。该亲和力大约为108M-1或更高，并且可以在供体免疫球蛋白对抗原原始亲和力的大约4倍范围内变化。
图的描述
图1.比较抗-Tac重链序列(上线)和Eu重链序列(下线)。对氨基酸采用一字编码。每条线上的第一个氨基酸在左边编码两个序列中的同样氨基酸用线连接。3个CDR下面划线。其它氨基酸位置(指在人体属性的抗Tac重链中使用的抗-Tac氨基酸而不是Eu氨基酸)是由*表示的。
图2.比较抗Tac轻链序列(上线)和Eu轻链序列(下线)对氨基酸采用单字编码。每条线上的第一个氨基酸在左边编号。在两个序列中相同的氨基酸用线连接。3个CDR下面划线。其它氨基酸位置(指人体属性的抗Tac重链中采用的抗Tac氨基酸而不是Eu氨基酸)用*表示。
图3.用作人体属性的抗Tac重链可变区基因的基因核苷酸序列。编码蛋白质的部分基因的转译氨基酸序列位于核苷酸序列的下部。基因始端和末端的核苷酸TCTAGA为xbaI位点。成熟的重链序列由氨基酸#20Q起始。
图4.用作人体属性的抗Tac轻链可变区基因的基因核苷酸序列。编码蛋白质的部分基因的转译氨基酸序列位于核苷酸序列的下部。该基因始端和末端的核苷酸TCTAGA为xba I位点。成熟的轻链序列由氨基酸#21D起始。
图5.A.用于合成人体属性抗Tac重链基因的四个寡核苷酸序列，标明5′至3′。
    B.寡核苷酸的相关位置。箭头指向每个寡核苷酸的3′方向。
图6.(A)用于合成人体属性抗Tac轻链基因的四个寡核苷酸序列，标有5′至3′。(B)寡核苷酸的相关位置。箭头指向每个寡核苷酸的3′方向。标明Hind III位点在重叠的JFD2和JFD3中的位置。
图7.用于表达人体属性抗Tac重链的质粒pHUGTACl的图解。标明有关的限制位点，将重链的编码区用方框标出。免疫球蛋白(Ig)启动子的转录方向用箭头表示。EH＝重链增强子，HYg＝抗潮霉素基因。
图8.用于表达人体属性抗Tac轻链的质粒pHULTAC的图解。标明相关的限制位点，轻链的编码区用方框标出。Ig启动子的转录方向用箭头表示。
图9.将HUT 102和Jur kat细胞用抗Tac抗体和人体属性抗Tac抗体染色，随后分别用带有荧光粉的山羊抗小鼠Ig抗体或山羊抗人体Ig抗体染色标记，对这些染色细胞进行荧光细胞检测。在每个方框图中，当删去第一抗体时，用虚线表示该结果，实线表示含有第一和第二(结合的)抗体时的结果。
图10.(A)HUT 102细胞用所示的0-40ng抗Tac染色，随后用生物素化的抗-Tac染色。再后用与藻红蛋白结合的抗生物素蛋白染色，最后进行荧光细胞测量。
     (B)HUT 102细胞用所示抗体染色，然后用生物素化的抗Tac染色，再用与藻红蛋白结合的抗生物素蛋白染色，最后进行荧光细胞检测。
本发明提供一种可与人T细胞上的IL-2受体特异性反应的类似人的免疫球蛋白。这些免疫球蛋白的结合亲和力至少约为108M-1，较好的是10’M-1～1010M-1或更强，它们能够阻止IL-2与人IL-2受体的结合。类似人的免疫球蛋白应具有类似人的结构并可能具有互补性决定区(CDR′S)，CDR′S来自免疫球蛋白，特别是小鼠免疫球蛋白，它们可与P55 Tac蛋白质上的抗原决定簇特异性反应。可大量廉价生产本发明的免疫球蛋白，通过各种技术可用这些免疫球蛋白治疗人类患者T细胞介导的疾病。
已知基本的抗体结构单位由四聚体组成。每个四聚体由两个相同的多肽链对组成，每一对都有一条“轻”链(大约25KD)和一条“重”链(大约50-70KD)。每条链的NH2末端开始都有一个主要负责抗原识别，含大约100-110或更多的氨基酸的可变区。每条链的COOH末端都限定一个主要负责效应子功能的恒定区。
可将轻链分为卡巴链或入链。重链则可分为γ，ν，α，δ，或ε，并将抗体的同型分别定义为IgG，IgM，IgD和IgE。在轻链和重链内，可变区和恒定区是通过一个由大约12或更多个氨基酸组成的“J”区连接起来的，重链还包括一个由大约12或更多个氨基酸组成的“D”区。(见，Fundamental Immuno-logy，Paul，W.，Ed.，第7章，131-166页，Raven Press，N.Y.(1984)，在此列为本文参考文献)。
每一重链/轻链对的可变区都形成抗体结合位点。这些链都具有相同的一般结构，即都具有由三个超可变区连接的相对保存下来的骨架区，也称为CDR′S(见：“Sequences of pro-teins of Immunological Interest”，Kabat，E.，et al.，U.S.Department of Healthand Human Services，(1983)；and Chol-thia and Lesk，J.Mol.Biol.，196：901-917(1987)，在此列为本文参考文献)。来自每对的两条链的CDR′S通过骨架区连成一线，从而结合到特定的抗原决定簇上。
本文所采用的术语“免疫球蛋白”是指一种由一种或多种实际被免疫球蛋白基因编码的多肽组成的蛋白质。被识别的免疫球蛋白基因包括κ，λ，α，γ，δ，ε和ν恒定区基因，以及无数免疫球蛋白可变区基因。免疫球蛋白除了抗体以外也可以各种形式存在，例如包括Fv，Fab，和F(ab)2，以及以单链形式存在(例如，Huston，et al.，Proc.Nat.Acad.Sci.U.S.A.85：5879-5883(1988)and Bird，et al.，Science，242：423-426(1988)在此列为本文参考文献)。(见：Hood，et al.，“Immunology”，Benjamin，N.Y.，Znd ed.(1984)，and Hunkapiller and Hood，Nature，323；15-16(1986)，在此列为本文参考文献)。
嵌合抗体为已通过遗传工程从属于不同物种的免疫球蛋白基因片段构建了其轻链和重链基因的抗体。例如，来自小鼠单克隆抗体的基因的可变(v)片段可与人恒定(c)片段，如γ1和γ3连接。因此典型的治疗用嵌合抗体是一种由来自小鼠抗体的V或抗原结合区和来自人体体的C或效应子区组成的杂交蛋白(例如，A.T.C.C.储存号为CRL 9688的菌株分泌一种抗-Tac嵌合抗体)，尽管也可使用其它哺乳动物种。
本文所采用的术语“骨架区”是指在单一物种的不同免疫球蛋白中相对保存下来的免疫球蛋白轻链和重链可变区部分(即不是CDR′S)，其定义如所引用的Kabat等人的文章中所述。本文所采用的“类似人的骨架区”是每条现有的链中至少含有大约70或更多个氨基酸残基，特别是75-85或更多个残基，与人免疫球蛋白中的骨架区相同的骨架区。
本文所采用的术语“类似人的免疫球蛋白”是指包含类似人的骨架区且其中任何存在的恒定区是基本上与人免疫球蛋白恒定区同源((即至少大约85-90％，最好是大约95％相同)的免疫球蛋白。因而，除CDR′S可能例外，类似人的免疫球蛋白的所有部分都是基本上与一种或多种天然人免疫球蛋白序列的相应部分同源的。例如，类似人的免疫球蛋白不会包含小鼠可变区/人恒定区嵌合抗体。
本发明还包括选择在类似人的免疫球蛋白链中有限数目的氨基酸的标准，为了增强包含类似人的免疫球蛋白的抗体的亲和力，应选择与在供体而不是受体的那些位置上的氨基酸相同的氨基酸。
本发明部分地基于这样一种模式，即在以前生产类似人的抗体的方法中(例如用小鼠抗体作为CDR′S源)亲和力丧失的两个动因是：
(1)当将小鼠CDR′S与人骨架结合时，骨架中接近于CDR′S的氨基酸变为人的而不是小鼠的。在不打算与理论相结合的情况下，我们认为这些改变了的氨基酸可使CDR′S略微反常，因为它们可产生不同于供体小鼠抗体的静电或疏水力，并且反常的CDR′S不可能象在供体抗体中的CDR′S一样有效地与抗原接触；
(2)同样，在原来小鼠抗体中接近于(但非部分的)CDR′S的氨基酸(即仍为部分骨架)，可与有助于亲和力的抗原接触。当将这些抗体变成类似人的抗体时，这些氨基酸丧失，因为全部骨架氨基酸都变成人的了。
为了避免这些问题，和生产对目的抗原具有很强亲和力的类似人的抗体，本发明使用下列四种标准来设计类似人的免疫球蛋白。这些标准可单个使用，必要时也可结合使用，以达到所需亲和力或其它特征。
标准I：用来自与待变成类似人的供体免疫球蛋白异常同源的特定人免疫球蛋白的骨架，或用来自许多人抗体的同感骨架作为受体。例如，小鼠重(或轻)链可变区序列与人重(或轻)链可变区在数据库(例如，National Biomedical ResearchFoundation Protein Identification Resource中的比较表明人类不同区的同源程度变化范围很大，一般从大约40％到大约60-70％。选择与供体免疫球蛋白重(轻)链可变区最为同源的人重(轻)链可变区之一作为受体免疫球蛋白，只有少数氨基酸会随着从供体免疫球蛋白变为类似人的免疫球蛋白而改变。因此，并且仍在不打算与理论相结合的情况下，认为有一个在其构象异常的CDR′S附近改变一个氨基酸的较小的机会。而且，包含类似人的免疫球蛋白链的类似人的抗体的精确轮廓可能更接近供体抗体的形状，这也减少了使CDR′S反常的机会。
一般说来，应在至少有大约10-20条不同的人重链的代表性收集物中选择3-5个最为同源的重链可变区序列之一作为受体以提供重链骨架，轻链与之类似。最好使用1-3个最为同源的可变区之一。所选受体免疫球蛋白链最好在骨架区至少约65％与供体免疫球蛋白同源。
不管如何选择受体免疫球蛋白，都可通过在类似人的免疫球蛋白链的骨架中选择少量与在供体而不是受体的那些位置上的氨基酸相同的氨基酸而获得较高的亲和力。下列标准限定什么氨基酸可如此选择。较好的是，在符合这些标准之一的大多数或全部氨基酸位置上，实际上应选择供体氨基酸。
标准II：如果在人受体免疫球蛋白骨架中的某一氨基酸是异常的(即，“稀有的”，如本文所用的，它表明在代表性数据库中并不大于10％的人重(轻)链V区序列的那个位置上出现的氨基酸)，并且如果在那个位置上的供体氨基酸对人序列是典型的(即，“普通的”，如本文所用的，它表明在代表性数据库中至少约25％序列上出现的氨基酸)，则可选择供体氨基酸而不是受体氨基酸。这个标准有助于确保人骨架中的某一典型氨基酸不破坏抗体结构。而且，通过用来自对人抗体恰好是典型的供体抗体的氨基酸取代异常氨基酸，可使类似人的抗体的免疫原性变小。
标准III：在类似人的免疫球蛋白链中与3个CDR′S直接相邻的位置上，可选择供体氨基酸而不是受体氨基酸。这些氨基酸极有可能与CDR′S中的氨基酸相互作用，若从受体中选择，则会使供体CDR′S反常并减小亲和力。而且，相邻的氨基酸可直接与抗原相互作用(Amit et al.Science 233，747-753(1986)，在此列为本文参考文献)并且从供体中选择这些氨基酸可利于保持所有抗原在原始抗体中提供亲和力的接触。
标准IV：一个典型的原始供体抗体的三维模型显示出某些CDR′S外的氨基酸与CDR′S接近并具有通过氢键、范德华力、疏水作用等与CDR′S中的氨基酸相互作用的良好可能性。在那些氨基酸位置上，可选择供体氨基酸而不是受体免疫球蛋白氨基酸。符合这一标准的氨基酸一般应在CDR′S中某些位点的大约3埃单位内具有一个侧链原子并且必须含有能够借助所建立的化学力(如上面所列举的)与CDR原子相互作用的原子。建立象抗体这样的蛋白质模型的计算机程序一般可以找到并为本领域技术人员熟知的(见，Loew et al.Int.J.Quant.Chem.，Quant.Biol.Symp.，15：55-66(1988)；Bruccoleri et al.，Nature，335，564-568(1988)；Chothia et al.，Science，233：755-758(1986)，所有这些都列为本文参考文献)。这些参考文献不构成部分发明。实际上，因为所有抗体都具有相似的结构，所以必要的话可以采用已知抗体的结构，这可从Brookhaven蛋白质资料库中得到，作为其它抗体的大致模型。可以使用商业上可得到的计算机程序在计算机监示器上显示这些模型，计算原子间的距离，和估计不同氨基酸相互作用的可能性(见，Ferrin etal.，J.Mol.Graphics，6：13-27(1988))。
类似人的抗体一般至少具有三个优于小鼠或在某些情况下优于用于人类治疗的嵌合抗体的潜在优点：
1)因为效应子部分是人，所以它可与人免疫系统的其它部分更好地相互作用(例如，通过补体依赖性细胞毒性(CDC)或抗体依赖性细胞毒性(ADCC)更有效地破坏靶细胞)。
2)人免疫系统不应将类似人的抗体的骨架或恒定区识别为补来物，因此对这种注射用抗体的抗体反应应小于对全部外源小鼠抗体或部分外源嵌合抗体的抗体反应。
3)据报导注射用小鼠抗体在人循环中的半衰期比正常抗体的半衰期短得多(D.Shaw et al.，J.Immunol.，138：4534-4538(1987))。注射用类似人的抗体可能具有与天然存在的人抗体更加类似的半衰期，因而使得所给的常用剂量少而低。
一方面，本发明涉及编码重链和/或轻链CDR′S的重组DNA片段，CDR′S来自能与人IL-2受体上的所需抗原决定簇结合的免疫球蛋白，例如抗Tac单克隆抗体。编码这些区的DNA片段将与编码合适的类似人的骨架区的DNA片段连接。图1和图2分别给出了优选的DNA序列，它们在表达时编码含有抗Tac重链和轻链超可变区(具有类似人的骨架区)的多肽链。由于密码子简并性和非关键氨基酸取代，其它DNA序列可容易地取代那些序列，如下所述。
DNA片段一般还应包括一个可操作地连接到类似人的抗体编码序列上的表达控制DNA序列，包括自然联合或异源启动子区。表达控制序列最好是在载体中能够转化或转染真核宿主细胞的真核启动子系统，但也可使用原核宿主的控制序列。一旦载体已插入到合适的宿主中，就可在适合于核苷酸序列高水平表达的条件下供养宿主，根据需要，可收集并纯化轻链，重链，轻/重链二聚体或完整抗体，结合片段或其它免疫球蛋白形式。
可按照众所周知的方法从各种人细胞，但最好是不灭的B细胞中分离人恒定区DNA序列(见，Kabat op. Cit.和Wp87/02671)。同样可从能够与人IL-2受体结合的单克隆抗体中得到产生本发明免疫球蛋白的CDR′S，该CDR′S来源于任何合适的哺乳动物(包括小鼠，大鼠，兔子)或能够通过众所周知的方法产生抗体的其它脊椎动物。DNA序列合适的来源细胞和用于免疫球蛋白表达和分泌的宿主细胞可从许多地方得到，例如美国典型培养物保藏中心(“Cotalogue时Cell Linesand Hybridomas，”Fifth edition(1985)Rockville，Maryland，U.S.A.，在此列为本文参考文献)。
除了本文具体描述的类似人的免疫球蛋白以外，可利用各种本领域技术人员熟知的重组DNA技术设计并生产其它“基本同源的”改良免疫球蛋白。例如，从图3和图4的序列看，骨架区可在一级结构水平变化，如几个氨基酸被取代，末端或中间加入或删除几个氨基酸等等。而且，可单独或结合使用各种不同的人骨架区作为本发明类似人的免疫球蛋白的基础。一般说来，可以通过各种众所周知的技术，如位点针对性诱变(见，Gillman and Smith，Gene8：81-97(1979)和Roberts，S.et al.Nature 328：731-734(1987)，这两篇文章均列为本文参考文献)容易地完成基因的修饰。
此外，可以生产只含一部分抗体一级结构的多肽片段，该片段具有一种或多种免疫球蛋白活性(例如，补体结合活性)。还因为象许多基因一样，免疫球蛋白相关基因含有独立的功能区，每个功能区都具有一种或多种截然不同的生物学活性，可将这些基因与来自其它基因的功能区融合(如，酶，见1987年12月15日提交的共同转让的U.S.S.N.132,387，在此列为本文参考文献)以生产具有新特性的融合蛋白(例如免疫毒素)。
能够最终表达所需类似人的抗体的本发明的核酸序列可从各种不同的多核苷酸(基因组或CDNA，RNA，合成寡核甘酸等)和成分(如V.J.D，和C区)，以及通过各种不同的技术制成。连接合适的基因组序列是目前最常用的生产方法，但也可利用CDNA序列(见，欧洲专利公开0239400号和Reichmann，L.，et al.，Nature 332：323-327(1988)，这两篇文章均列为本文参考文献)。
如前所述，当DNA序列被可操作地连接到(即定位以确保起作用的)表达控制序列上以后，它将在宿主中得以表达。这些表达载体一般可作为游离基团或作为宿主染色体DNA的一个整合部分在宿主体内复制。表达载体通常含有选择标记物，例如四环素或新霉素，以便检测那些用所需DNA序列转化的细胞(见，例如美国专利4,704,362，在此列为本文参考文献)。
大肠杆菌是一种特别适用于克隆本发明的DNA序列的原核宿主。其它适用的微生物宿主包括杆菌，例如枯草杆菌，和其它肠道细菌属，例如沙门氏菌属，沙雷氏菌属，及各种假单胞菌属的菌种。在这些原核宿主中，人们也可以制造表达载体，该载体一般应含有与宿主细胞一致的表达控制序列(如复制起点)。此外，应具有一定数量的各种众所周知的启动子，例如乳糖启动子系统，色氨酸(trp)启动子系统，B-内酰胺酶启动子系统，或来自λ噬菌体的启动子系统。这些启动子将控制表达，有时也可与操纵子序列一起控制表达，并具有用于开始并完成转录和转译的核糖体结合位点序列等。
也可用其它微生物，如酵母进行表达。酵母属是理想的宿主，其具有含表达控制序列的合适载体，例如启动子，包括3-磷酸甘油酸激酶或其它糖酵解酶，和复制起点，终止序列等。
除微生物之外，也可用哺乳动物组织细胞培养物表达和生产本发明的多肽(见，Winnacker，“From Genes toClones，”VCH Publishers，N.Y.，N.Y.(1987)，在此列为本文参考文献)，真核细胞是最为理想的，因为在本领域中已培育了许多能够分泌完整免疫球蛋白的合适的宿主细胞系，包括CHO细胞系，各种COS细胞系，Hela细胞，骨髓瘤细胞系等，但较好的是转化的B细胞或杂交瘤。这些细胞的表达载体可包括表达控制序列，例如复制起点，启动子，增强子(Queen，C.，et al.，Immunol.Rev. 89：49-68(1986)，在此列为本文参考文献)，必要的加工信息位点，例如核糖体结合位点，RNA拼接位点，多聚腺苷酸化位点，和转录终止子序列。优选的表达控制序列是得自免疫球蛋白基因，SV40，腺病毒，牛乳头状瘤病毒等的启动子。
含有感兴趣的DNA片段(如重链和轻链编码序列和表达控制序列)的载体可通过众所周知的方法被转移到宿主细胞中，所用方法依宿主细胞类型的不同而改变。例如，对原核细胞通常采用氯化钙转染而对其它细胞宿主可采用磷酸钙处理或电击。(见，Maniatis，et al.，Molecular Cloning：A LaboratoryManual，Cold Spring Harbor Press，(1982)，在此列为本文参考文献。)
表达后，可按照本领域的标准方法，包括硫酸铵沉淀，亲和柱，柱层析，凝胶电泳等纯化整个抗体，其二聚体，轻链和重链，或本发明的其它免疫球蛋白形式(见，Scopes，R.，ProteinPurification，Springer-Verlag，N.Y.(1982))。为了药用，至少约90-95％同源的基本上纯的免疫球蛋白是较好的，98-99％或更多同源性最好。一旦部分纯化或按要求纯化到同源，则可在治疗上(包括体外)或在显象和演示测定方法，免疫荧光染色等方面采用这些多肽(见，Immunolo-glcal Methods，Vols，I and II，Lefkovits and Pernis，eds.，Academic Press，New York，N.Y.(1979 and 1981))。
本发明的抗体可分别用于治疗T细胞介导的病症。一般说来，在鉴别出与疾病相关的细胞带有IL-2受体时，能够阻止IL-2与人IL-2受体结合的类似人的抗体是适宜的(见，U.S.S.N.085,707，题为“Treating Human Malign-ancies and Disorders，”在此列为本文参考文献)。
例如适于治疗的典型病症包括移植病毒宿主疾病和在经历器官移植(如心，肺，肾，肝等)的患者中移植排斥。其它疾病包括自身免疫疾病，如I型糖尿病，多发性硬化，类风湿性关节炎，系统性红斑狼疮，和重症肌无力。
本发明的类似人的抗体也可与其它抗体，特别是可与在引起疾病细胞上的其它标记物反应的人单克隆抗体结合起来使用。例如，适宜的T细胞标记物可包括那些聚集到所谓“分化丛”(“Clustersof Differentiation”)中的标记物，“分化丛”是由First International Leukocyte Different-iation Workshop命名的(Leukocyte Typing，Bernard，et al.，Eds.，Springer-VerlagN.Y.(1984)，在此列本文参考文献)。
这些抗体也可用作单独给药的组合物，这些组合物与化学治疗剂或免疫抑制剂一起给药。这些药剂一般包括环孢多肽A或嘌呤类似物(如，甲氨蝶呤，6-巯基嘌呤等)，但也可利用许多本领域技术人员熟知的其它药剂(如环磷酰胺，泼尼松等)。
本发明的一个较好药用组合物包括将主题抗体用于免疫毒素，免疫毒素的特征在于其两个组分，且主要用于在体外或体内杀死所选择的细胞。其成分之一为细胞毒性剂。当它被吸附或吸收时通常使细胞致死。已知为“传递载体”的第二个成分负责将毒性剂传递至特定的细胞类型，如包括癌细胞在内的细胞。这两种成分通常是按各种熟知的化学方法中的任何一种将其化学结合在一起。例如，当细胞毒性剂为一蛋白质，第二成分为一完整的免疫球蛋白时，可利用异双官能交联剂如SPDP、碳化二亚胺、戊二醛等将它们连接在一起。各种免疫毒素的生产方法是现有技术中熟知的，例如可从下处查到：“Monoclonal Antibody-Toxin Conjugates：Aiming the Magic Bullet，”Thorpe等，Monoclonal Antibodies in ClinicalMedicine，Academic Press，168-190页(1982)，该文章在此引用以作参考。
各种细胞毒性剂均适用于免疫毒素，细胞毒性剂可包括：放射性核素，如碘-131、钇-90、铼-188和铋-212；各种化学疗剂，如长春花碱酰胺、氨甲蝶呤、阿霉素和顺氯氨铂；以及细胞毒性蛋白，如商陆抗病毒蛋白、假单胞菌外毒素A、蓖麻蛋白、白喉毒素、蓖麻蛋白A链等核蛋白体抑制蛋白，或在细胞表面具有活性的试剂，如磷脂酶(如磷脂酶C)〔一般见，Commonly assigned
U.S.S.N.07/290,968 filed onDecember 28，1988)，“Chimeric Texins”，Olsnes and phil，pharmac.Ther.25：355-381(1982)，以及“Monoclonal Antibodiesfor Cancer Detection and Therapy，”eds，Baldwin and Byers，pp159-179，224-226，Academic Press(1985)，所有这些文献均在此引用以作参考〕。
免疫毒素的传递成分包括本发明的类似人体免疫球蛋白。最好使用完整的免疫球蛋白或其结合片段，如Fab，免疫毒素中的抗体一般为同型的人IgM或IgG，但根据需要也可使用其它哺乳动物的恒定区。
本发明的类似人体抗体和其药用组合物主要用于非肠道给药，即皮下、肌内或静脉内给药。用于非肠道给药的组合物通常包括溶解在一种可接受载体(优选水溶性载体)内的抗体溶液或其鸡尾酒液。各种水溶性载体，如水、缓冲水、0.4％盐水、0.3％甘氨酸等，均可使用。这些溶液无菌，且一般无颗粒物。可采用常规的、熟知的灭菌技术对这些组合物进行灭菌。组合物中也可含有达到近似生理条件所需要的可作药用的辅助剂，如pH调节和缓冲剂、毒性调节剂等，例如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。这些配方中抗体的浓度可广泛改变，即从小于约0.5％(重量)，通常在或至少约1％，直至大于15％或20％，这主要取决于液体体积、粘度以及所选择的具体服用方式。
因此，用于肌内注射的一种典型药用组合物可含有1ml无菌的缓冲水及50mg抗体。用于静脉内输液的一种典型组合物可含有250ml无菌Ringer氏溶及150mg抗体，非肠道给药的组合物的实际制备方法是本领域熟练技术人员所知道的，或是明显的。其详细情况可见Remington′s PharmaceuticalScience，15th ed.，Mack PublishingCompany，Easton，Pennsylvania(1980)，该文章在此引用以作参考。
本发明的抗体可被冷冻保藏，且在使用前在合适的载体上被重新组配。这一技术已被证明对于常规的免疫球蛋白是有效的。现有技术中已知的冷冻及重建技术均可使用。本领域技术人员知道，冷冻和重新组配可导致抗体活性的不同程度丧失(例如，使用常规的系统的免疫球蛋白，IgM抗体具有比IgG抗体更大程度的活性丧失)，因此必须对用量进行调节以补偿损失。
可服用含有本发明类似人抗体或其混合物的组合物以用于预防或治疗。对于治疗用途，是给已患有疾病的病人服用足以治疗或至少部分抑制该疾病量的组合物。足以达到这一目的的量被称作“有效治疗剂量”，该用途的有效量取决于感染的程度以及患者自身免疫系统的所处的状态，但一般为每剂量约1-200mg抗体，更常用的剂量为5-25mg/患者。必须注意，本发明的物质一般可在严重的疾病状态(即危及生命或潜在的危及生命)情况下使用。在这些情况下，为了将过量物质减少至最低程度以及使“外源物质”排斥反应的可能性降低(通过本发明的类似人抗体达到)，主治医师可能且感到有必要给患者服用实际过量的这些抗体。
对于预防目的，是给未处在疾病状态的患者服用含有本发明抗体或其混合物的组合物，以增强患者的抵抗力。这种用量被定义为“预防有效剂量”。对于这一用途，精确的用途同样取决于患者的健康状况及总体免疫水平，但一般为每剂量0.1-25mg，尤其是每个患者0.5-2.5mg，一个较好的预防应用就是防止肾移植排斥反应。
组合物的单个或复合服法可按主治医师所选定的剂量和方式进行。在任何情况下，药用配方应提供足以有效治疗患者的定量抗体。
本发明的类似人抗体可进一步在体外找到各种用途。例如，该抗体可用于T-细胞分型、用于分离带有特定的IL-2受体或该受体的片段的细胞、用于制备疫苗等。
用于诊断目的，该抗体可被标记或不被标记。未标记的抗体可与其它的标记抗体(第二抗体)结合使用，该抗体与类似人体抗体反应，如针对于人免疫球蛋白恒定区的特异抗体。或者，可直接标记抗体。各种标记物均可使用。如放射性核素、荧光物质、酶、酶底物、酶辅助因子、酶抑制剂、配位体(尤其是半抗原)等。各种免疫检测法均可得到。且对于本领域熟练技术人员来说均是熟知的。
药盒也可与主抗体结合使用，以保护或检测细胞活性，或检测所选择的抗原的存在。因此，一般是以单独冷冻在容器中或与特异地针对所需细胞类型的补助抗体一起冷冻在容器中的形式提供本发明的主抗体组合物。与一标记物或毒素连接的抗体或未连接的抗体包括在药盒中，药盒中还带有缓冲液，如Tris、磷酸盐、碳酸盐等，稳定剂，杀生物剂，惰性蛋白如血清白蛋白等，以及一份使用说明。这些物质的含量一般低于活性抗体重量的5％，且一般总重量至少约为抗体浓度的0.001％(wt)。该药盒中通常还需要包括一种膨胀剂或赋形剂，以稀释活性成分，其中赋形剂可以占组合物总重量的1-99％的量存在。当使用能够与嵌合抗体结合的第二抗体进行检测时，它通常被装在一个单独的瓶中。第二抗体通常与一标记物连接，且按上述抗体配方的类似方式配剂。
下面的例子是用于说明而不是进行限定。
                实  验类似人轻链和重链基因的设计
利用人抗体Eu的序列(Sequences of Proteinsof lmmunological lnterest，Kabat，E.，等，U.S.Dept of Health and Hum an Services1983)为类似人抗体提供构架，因为抗-Tac重链的氨基酸序列与该抗体重链的同源性要超过National BiomedicalFoundation Protein Identification Resource中的任何其它重链序列。
为了选择类似人重链的序列，将抗-Tac重链序列(see，commonly assigned U.S.S.N.′s186,862和223,037，在此引用以作参考)与Eu重链序列匹配(图1)，在每一位置，选择Eu氨基酸用于类似人的序列，除非该位置落入以下类别，在此情况下选择抗-Tac氨基酸：
(1)该位置落入互补决定区(CDR)，如Kabat等所述。(氨基酸31-35，50-66，99-106)；
(2)对于在该位置的人重链Eu氨基酸异常，而对于该位置的人重链抗-Tac氨基酸正常(氨基酸27，93，95，98，107-109，111)
(3)在抗-Tac重链的氨基酸序列中，该位置紧邻CDR((氨基酸30和67)；
(4)抗-Tac抗体的三维模型指出该氨基酸结构上靠近抗原结合区(氨基酸48和68)。有些氨基酸落入一个以上的上述类型，但只在其中之一列出。
为了选择类似人轻链的序列，将抗-Tac轻链序列与Eu轻链序列匹配(图2)。在每一位置选择Eu氨基酸，除非该位置又落入类型1-4之一(在分类定义中用轻链取代重链)：
(1)CDRs(氨基酸24-34，50-56，89-97)。
(2)比Eu更典型的抗-Tac氨基酸(氨基酸48和63)
(3)邻近CDRs(无氨基酸；在所有这些位置Eu和抗-Tac己经相同)。
(4)可能三维接近结合区(氨基酸60)。
所选择的重链(图3)和轻链(图4)基因的实际核苷酸序列如下：
(1)编码如上所述的选择氨基酸序列的核甘酸序列。？
(2)这些编码序列的5′端，该核苷酸序列编码  前导(信号)序列，即抗体MOPC63的轻链前导序列和抗体PCH108A的重链前导序列(Kabat等)。选择这些前导序列作为抗体的代表。
(3)3′端编码序列，该核苷酸序列为鼠轻链J5片段和鼠重链J2片段后面的序列，它们为抗-Tac序列的一部分。之所以包括这些序列是因为它们含有拼接供体信号。
(4)在该序列的每一端是-xbaI位点，它能够在xbaI位点切割，且将一载体克隆进xbaI位点。
类似人轻链和重链基因的构建
为合成重链，利用Applied Biosystems 380BDNA合成仪合成4个寡核苷酸HFS12，HES13，HES14和HES15。其中有两种寡核苷酸为每条重链的一部分，且每种寡核苷酸与其下一个重叠约20个核苷酸，以便退火(图5B)。这些寡核苷酸一起包括了整个类似人重链(图3)，另外还在每一末端带有额外核苷酸，以允许位xbaI位点进行切割。用聚丙烯酰胺凝胶纯化这些寡核苷酸。
按标准方法(见Maniatis等的文章)，利用ATP和T4多核苷酸激酶将每种寡核苷酸磷酸化。为了让磷酸化的寡核苷酸退火，将每种寡核甘酸以3.75μm的浓度与40μl TA(33mM Tris 乙酸，pH7.9，66mM乙酸钾，10mM乙酸镁)一起悬浮，于95℃加热4分钟，然后缓慢冷却至4℃。为了通过合成寡核苷酸的反义链来从寡核苷酸合成完整基因，加进最终体积为100μl的以下成分：
10μl退火的寡核苷酸
0.16mM的每种脱氧核糖核苷酸
0.5mM ATP
0.5mM DTT
100μg/ml BSA
3.5μg/ml T4g43蛋白(DNA多聚酶)
25μg/ml T4g44/62蛋白(多聚酶辅助蛋白)
25μg/ml 45蛋白(多聚酶辅助蛋白)
于37℃将该混合物保温30分钟。然后加入10μT4DNA连接酶，于37℃继续保温30分钟。于70℃将反应保温15分钟使多聚酶和连接酶灭活。为了用xbaI消化基因，向反应物中加入50μl2xTA(含有200μg/ml BSA和1mMDTT)、43μl水及5μl的50μxbaI。37℃保温3小时后进行凝胶电泳。从凝胶上纯化出431bp xbaI片段，利用标准方法将其克隆进质粒pUc19的xbaI位点。纯化四个质粒分离物，利用双脱氧法测定其序列。其中之一具有正确的序列(图3)。
为了合成轻链，合成四个寡核苷酸JFD1，JFD2，JFD3和JFD4(图6A)。其中有两个寡核苷酸为每条轻链的一部分，且每个寡核苷酸与其下一个重叠约20个核苷酸，以便能够退火(图6B)。这些寡核苷酸一起包括了整个类似人的轻链(图4)，并在每一末端还带有几个额外的核苷酸，以便允许在xbaI位点进行切割。用聚丙烯酰胺凝胶纯化寡核苷酸。
分两部分从这些寡核苷酸合成轻链基因，将JFD1和JFD2各0.5μg结合在20μl序列酶缓冲液(40mM Tris-HCl，pH7.5，20mM氯化镁，50mM氯化钠)中，于70℃加热3分钟，然后慢慢冷至23℃，以便让寡核苷酸退火。JFD3和JFD4按同样方式处理，向每一反应中加入10mMDTT和0.5mM每种脱氧核糖核苷酸，及6.5μ序列酶(USBiochemicals)，至最终体积为24μl。然后于37℃保温1小时，以合成寡核苷酸的反义链。向每一反应物中加入xbaI和Hind III以消化DNA(在JFD2和JFD3重叠的部分有一个Hird III位点，因此在每种合成的DNA中也有一个Hind III位点；图6B)。将反应物进行聚丙烯酰胺凝胶电泳，纯化xba I-Hind III片段，且按标准方法将其克隆至pUC18。利用双脱氧法分析每个片段的几个质粒分离物的序列，选择正确的分离物。表达类似人轻链和重链的质粒的构建
从已插入重链xbaI片段的pUC19质粒中分离出重链xbaI片段，利用标准方法将其按正确方向插入载体pVν1(see，Commonly assigned U.S.S.N.223,037)的xbaI位点，产生质粒pHuGTAC1(图7)。当将该质粒转染进合适的宿主细胞时它能够高水平地表达完整的重链。
从已插入轻链xbaI-Hind III片段的pUC18质粒中分离出轻链xbaI-Hind III片段，用xbaI切割载体质粒pVk1(See，Commonly assigned U.S.S.N.223,037)，去磷酸化，按标准方法与两个片段连接。所需反应产物具有环状形式：载体-xbaI-片段1-HindIII-片段2-xbaI-载体。利用限制图谱和序列分析来分析几个质粒分离物。选择具有以上形式的分离物。因此，该质粒pHuLTAC(图8)含有完整的类似人轻链(图4)，当转染进适当的宿主细胞时，该质粒将高水平地表达轻链。类似人抗体的合成及亲和力
将质粒pHuGTACl和pHULTAC转染进鼠Sp2/0细胞，根据对霉酚酸和/或潮霉素的抗性按标准方法选择整合了质粒的细胞，该抗性由质粒上的gpt和hyg基因提供(图7，8)，为了检验这些细胞分泌与IL-2受体结合的抗体，将细胞上清液与已知表达IL-2受体的HUT-102细胞一起保温。冲洗之后，将细胞与结合荧光素的山羊抗人抗体一起保温，冲洗，于FACSCAN细胞荧光仪上分析荧光。结果(图9A)清楚地表明，类似人抗体与这些细胞结合，不与不表达IL-2受体的Jurkat F细胞(图9D)结合。作为对照，也使用原始鼠抗-Tac抗体给这些细胞染色(图9B，C)，产生类似结果。
为了进一步实验，将产生类似人抗体的细胞注射进小鼠，收集产生的腹水，通过山羊抗人免疫球蛋白抗体亲和柱将类似人的抗体纯化至基本均质〔该亲和柱按标准方法在Affigel-10支持物(Bco-Rad Laboratories，Inc.，RichimondCA)上制备〕。为了测定类似人抗体相对于原始抗Tac抗体的亲和性，进行竞争性结合实验。将约5×10’HUT-102细胞与已知量(10-40ng)的抗-Tac抗体和类似人的抗-Tac抗体一起于4℃保温10分钟。然后向细胞中加入100ng生物素化的抗-Tac，于4℃保温30分钟。该抗-Tac的量已被预先测定，它足以饱和细胞上的结合位点，但并不大量过量。然后用含有0.1％叠氮化钠的磷酸盐缓冲盐水2ml洗涤细胞两次。将细胞与250ng与藻红素连接的抗生物素蛋白一起于4℃保温30分钟，该抗生物素蛋白与已经结合于细胞上的生物素化的抗-Tac结合。如上法再次洗涤细胞，固定在含1％仲甲醛的PBS中，于FACSCAN细胞荧光仪上分析荧光。
在第一步通过增加作为竞争物的抗-Tac抗体的量(10-40ng)来减少能在第二步与细胞结合的生物素化的抗-Tac的量，从而减少了在最后一步结合的与藻红素连接的抗生物素蛋白的量，减少了荧光(图10A)。用等量(20ng)的抗-Tac和类似人抗-Tac作为竞争物使荧光减少约相同程度(图10B)。它表明这些抗体具有近似相同的亲和性。因为如果一个的亲和性更大，它将更有效地与生物素化的抗-Tac竞争，从而使荧光更加减少。类似人的抗体的生物学性质
为了有效地用于治疗人类疾病，类似人的抗体应能够破坏体内表达IL-2受体的T-细胞，该抗体破坏靶细胞的机制之一就是抗体依赖的细胞介导的细胞毒性，简称为ADCC(FundamentalImmunology，Paul，W.，Ed.，Raven Press，New York(1984)，at Pg.691)，其中抗体在靶细胞与效应细胞(如巨噬细胞，它能够溶解靶细胞)之间形成一桥。为了测定类似人的抗体及原始鼠抗-Tac抗体是否能介导ADCC，利用标准方法进行铬释放检测。具体地说，就是将表达IL-2受体的人白血病HUT-102细胞与’1Cr一起保温以让细胞吸收这一放射性核素。然后将HUT-102细胞与过量的抗-Tac或类似人抗-Tac抗体一起保温。再将HUT-102细胞与30∶1或100∶1的效应细胞一起保温4小时，该效应细胞为正常纯化的人外周血单核细胞，它已通过与人重组IL-2一起保温20小时而被活化。测定释放的’1Cr(它表明HUT-102靶细胞溶解)，且减去本底。(表1)。结果表明，在每种比率的效应细胞中，抗-Tac不溶解大量的靶细胞(低于5％)，而类似人的抗体则大量溶解靶细胞(高于20％)。因此，在治疗T-细胞白血病或其它T-细胞介导的疾病方面，类似人的抗体比原始小鼠抗体更加有效。
                  表    1
           ADCC后释放的’1Cr百分数
                                    效应细胞与靶细胞比值抗体                                   30∶1          100∶1抗-Tac                                 4％            ＜1％类似人的抗-Tac                         24％           23％
从上述可知，本发明类似人的免疫球蛋白比其它人IL-2受体专一的抗体具有许多优点。当抗-Tac鼠单克隆抗体相比较，本发明的类似人的免疫球蛋白可更经济地生产，且实际含有较少的外源氨基酸序列。这种在注射进病人体内后减少抗原性的可能代表了明显的治疗改进。
为了便于清楚和理解，虽然通过说明和实施例对本发明进行了叙述。但很明显，某些改动和改进都在所附权利要求的保护范围之内。

Claims (4)

1.一种生产人体属性的免疫球蛋白链的方法，该链具有来自人受体免疫球蛋白的骨架区和来自能够结合到抗原上的供体免疫球蛋白的互补决定区(CDR′s)，所说的方法包括在免疫球蛋白中的某一位置上用来自供体免疫球蛋白的相应氨基酸取代受体免疫球蛋白的至少一个非CDR骨架氨基酸，其中：
(a)受体免疫球蛋白的人骨架区中的氨基酸对于人免疫球蛋白序列中的所述位置来说是少见的，而供体免疫球蛋白中的相应的氨基酸对于所述位置来说是常见的；或
(b)该氨基酸与CDR′s之一直接相邻；或
(c)预计该氨基酸具有一个能与抗原或与人体属性免疫球蛋白的CDR′s相互作用的侧链原子。
2.根据权利要求1的方法，其中所述非CDR骨架氨基酸中至少有3个被来自选自标准(a)、(b)或(c)的供体免疫球蛋白的氨基酸所取代。
3.根据权利要求2的方法，其中至少一个由供体取代的氨基酸与CDR直接相邻。
4.权利要求1-3任一项的方法，其中所述人体属性免疫球蛋白的成熟的轻和重可变区蛋白质序列是与图3和图4中的成熟蛋白质序列同源的。
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