CN109776684A - 一种双特异性抗体 - Google Patents
一种双特异性抗体 Download PDFInfo
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- CN109776684A CN109776684A CN201910219509.8A CN201910219509A CN109776684A CN 109776684 A CN109776684 A CN 109776684A CN 201910219509 A CN201910219509 A CN 201910219509A CN 109776684 A CN109776684 A CN 109776684A
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- Prior art keywords
- bispecific antibody
- antigen
- chain
- binding site
- amino acid
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Abstract
本发明提供一种双特异性抗体,具体地,所述双特异性抗体为抗TNF/IL23双特异性抗体,所述双特异性抗体为人源化lgG型抗体,所述双特异性抗体包括与肿瘤坏死因子TNF‑α特异性结合的第一抗原结合部位,还包括与白细胞介素IL‑23特异性结合的第二抗原结合部位,其中所述双特异抗体还包含通过一个或多个二硫键链间连接的第一Fc链及第二Fc链,该第一Fc链和第二Fc链通过共价键或连接体分别连接到第一抗原结合部位和第二抗原结合部位上。
Description
技术领域
本发明涉及抗体领域,尤其涉及一种双特异性抗体。
背景技术
单克隆抗体是只作用于单一抗原表位的高度特异性抗体,已被广泛用于许多疾病的治疗,例如,癌症、炎症和自身免疫性疾病、感染性疾病。但是,此类治疗分子如果单独使用,没有一种能够显示出足够的药效,这是由于疾病的复杂性,如癌症或炎症性疾病通常涉及多种疾病介导的分子通路以及信号通路之间的相叉作用。在这些情况下,靶向单一的分子不能提供最佳的治疗效果,而同时阻断多个靶点或者同一靶点的多个位点的分子能够改善治疗效果。同时,使用多特异性如双特异性分子的双靶向治疗可以简化新药开发过程,因为它是单一分子。和使用多个单特异分子的联合用药相比,对于患者和医疗工作者都是更方便的。
类风湿关节炎(RA)是一种病因未明的慢性、以炎性滑膜炎为主的***性疾病。其特征是手、足小关节的多关节、对称性、侵袭性关节炎症,经常伴有关节外器官受累及血清类风湿因子阳性,可以导致关节畸形及功能丧失。RA的发病可能与遗传、感染、性激素等有关。RA关节炎的病理主要有滑膜衬里细胞增生、间质大量炎性细胞浸润,以及微血管的新生、血管翳的形成及软骨和骨组织的破坏等。
类风湿关节炎治疗的主要目的在于减轻关节炎症反应,抑制病变发展及不可逆骨质破坏,尽可能保护关节和肌肉的功能,最终达到病情完全缓解的目标。本发明提供一种双特异性抗体,对类风湿引起的腰腿关节疼痛、骨质增生、颈椎痛、坐骨神经痛、腿关节疼痛复水肿胀、肢体麻木的治疗效果显著。
发明内容
为了解决上述技术问题,本发明提供一种双特异性抗体。
本发明是以如下技术方案实现的:
一种双特异性抗体,所述双特异性抗体为抗TNF/IL23双特异性抗体,所述双特异性抗体为人源化lgG型抗体。
进一步地,所述双特异性抗体包括与肿瘤坏死因子TNF-α特异性结合的第一抗原结合部位,还包括与白细胞介素IL-23特异性结合的第二抗原结合部位,其中所述双特异抗体还包含通过一个或多个二硫键链间连接的第一Fc链及第二Fc链,该第一Fc链和第二Fc链通过共价键或连接体分别连接到第一抗原结合部位和第二抗原结合部位上。
进一步地,所述第一Fc链在如下位置包含2个氨基酸的替换,在第一Fc链上356位及379位氨基酸替换。
进一步地,所述第二Fc链在如下位置包含3个氨基酸的替换,第二Fc链上321位、407位及409位氨基酸替换。
进一步地,包含所述氨基酸替换的第一Fc链与第二Fc链更倾向于互相形成异源二聚体而不倾向于各自形成同源二聚体。
进一步地,所述第一抗原结合部位轻链可变区氨基酸序列如SEQ ID NO:1所示;所述第一抗原结合部位轻链恒定区氨基酸序列如SEQ ID NO:2所示。
进一步地,所述第一抗原结合部位重链可变区氨基酸序列如SEQ ID NO:3所示;所述第一抗原结合部位重链恒定区氨基酸序列如SEQ ID NO:4所示。
进一步地,所述第二抗原结合部位轻链可变区氨基酸序列如SEQ ID NO:5所示;所述第二抗原结合部位轻链恒定区氨基酸序列如SEQ ID NO:6所示。
进一步地,所述第二抗原结合部位重链可变区氨基酸序列如SEQ ID NO:7所示;所述第二抗原结合部位重链恒定区氨基酸序列如SEQ ID NO:8所示。
本发明的有益效果是:
单克隆抗体是只作用于单一抗原表位的高度特异性抗体,已被广泛用于许多疾病的治疗,例如,癌症、炎症和自身免疫性疾病、感染性疾病。但是,此类治疗分子如果单独使用,没有一种能够显示出足够的药效,这是由于疾病的复杂性,如癌症或炎症性疾病通常涉及多种疾病介导的分子通路以及信号通路之间的相叉作用。在这些情况下,靶向单一的分子不能提供最佳的治疗效果,而同时阻断多个靶点或者同一靶点的多个位点的分子能够改善治疗效果。同时,使用多特异性如双特异性分子的双靶向治疗可以简化新药开发过程,因为它是单一分子。和使用多个单特异分子的联合用药相比,对于患者和医疗工作者都是更方便的。
本发明还提供一种包含所述双特异性抗体的设备,所述设备提供的缓释层可以在用药后较长时间内持续释放药物,长效作用,血药浓度长时间恒定维持在有效浓度,减少“峰谷”现象;减少给药次数,对半衰期短或需频繁给药的药物,可以改善病人的顺应性;采用经皮给药可以不经过肝脏的“首过效应”和胃肠道的破坏,且皮肤间层还有储存作用,使药物浓度曲线平缓,避免了“峰谷现象”,提供可预定的和较长的作用时间,维持稳定持久的血药浓度,毒性和不良反应小,使用方便。
附图说明
图1是本实施例提供的一种双特异性抗体的示意图;
图2是本实施例提供的特种给药设备的示意图
图3是本实施例提供的特种给药设备的俯视图。
其中:1-设备本体,2-免疫药物层,3-中药药物层,4-缓释层,5-粘性区。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将对本发明作进一步地详细描述。下述实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的设备、原料、试剂等,如无特殊说明,均为可从常规商业途径购买得到的设备、原料、试剂。
实施例1:
一种特种给药设备,如图2所示,所述设备包括设备本体1,免疫药物层2,中药药物层3以及缓释层4,所述设备本体1为U型,外边缘凸出,外边缘设置有粘性区5,可以粘贴至人体任意位置,所述设备本体1由防水材料制成,所述免疫药物层与中药药物层之间设置有防水支撑层,如图3虚线所示,虚线内为免疫药物层2,虚线外为中药药物层3,所述设备本体1直径为4-10cm,具体可根据患处面积定制。
实施例2:
本发明缓释层的制备方法如下:将0.5%(w/v)中等分子量的壳聚糖溶液溶解于1%(w/v)乙酸中至终浓度为0.1%,获得第一分散液。向第一分散液中加入干粉质量相当于壳聚糖溶液中壳聚糖干粉质量的30%的3,4-二羟基肉桂酸,之后加入质量比为第一分散液0.01%的硬质胺后获得第二分散液,向所述第二分散液中加入固化剂,所述固化剂为甘羟铝,质量比为第二分散液的5.7%,加入固化基材,所述固化基材为不完全中和型NP-700聚丙烯酸钠,质量比为第二分散液的26%,加入固化调节剂,所述固化调节剂为酒石酸,质量比为第二分散液的12.1%,加入增稠剂和络合剂,所述增粘剂为60%聚乙烯吡咯烷酮PVPK90和40%羟甲基纤维素钠CMC-Na组成的混合物,所述混合物质量比为第二分散液的5.8%,络合剂为乙二胺四乙酸二钠,质量比为第二分散液的2.2%。上述过程于65℃下进行,将所有成分搅拌均匀后倒入模具,冷却后制成缓释层,所述缓释层呈凝胶状,厚度为2mm,能够紧密贴合人体皮肤,具有生物大分子穿透能力,但同时能起到一定生物大分子滞留效果,使得缓释层具有较强的药物穿透效果和缓释效果,3,4-二羟基肉桂酸具有较强的皮肤渗透能力,能够穿透角质层运送有效量的药液至皮下,使药液在皮下弥散分布,有效作用时间长,药物吸收率更高。
经皮给药可以不经过肝脏的“首过效应”和胃肠道的破坏,且皮肤间层还有储存作用,使药物浓度曲线平缓,避免了“峰谷现象”,提供可预定的和较长的作用时间,维持稳定持久的血药浓度,毒性和不良反应小,使用方便。
实施例3:
本发明参考WO2013060867中描述的一种大规模生产异二聚体双特异抗体的方法,该方法先还原两种混合的同源二聚体形式抗体,然后通过在这两种同源二聚体抗体的Fc区引入不对称氨基酸突变从而促使不同抗体的Fab臂发生交换,最后通过氧化铰链区的链间二硫键形成稳定的双特异抗体。
本发明所述免疫药物层中放置有抗TNF/IL23双特异性抗体,所述双特异性抗体为人源化lgG型抗体,所述双特异性抗体包括与肿瘤坏死因子TNF-α特异性结合的第一抗原结合部位,还包括与白细胞介素IL-23特异性结合的第二抗原结合部位,其中所述双特异抗体包含通过一个或多个二硫键链间连接的第一Fc链及第二Fc链,该第一Fc链和第二Fc链通过共价键或连接体分别连接到第一抗原结合部位和第二抗原结合部位上,并且第一Fc链和第二Fc链在如下位置包含5个氨基酸的替换:
重链恒定区为人IgG1,在第一Fc链上356位及379位氨基酸替换,第二Fc链上321位、407位及409位氨基酸的替换,包含上述氨基酸替换的第一Fc链与第二Fc链更倾向于互相形成异源二聚体而不倾向于各自形成同源二聚体,具体地,第一Fc链T356L及D379Q替换,第二Fc链L321E、Y407K及I409V替换。
进一步地,所述第一抗原结合部位轻链可变区氨基酸序列如SEQ ID NO:1所示;轻链恒定区氨基酸序列如SEQ ID NO:2所示;重链可变区氨基酸序列如SEQ ID NO:3所示;重链恒定区氨基酸序列如SEQ ID NO:4所示。所述第二抗原结合部位轻链可变区氨基酸序列如SEQ ID NO:5所示;轻链恒定区氨基酸序列如SEQ ID NO:6所示;重链可变区氨基酸序列如SEQ ID NO:7所示;重链恒定区氨基酸序列如SEQ ID NO:8所示。通过PCR的方法分别扩增轻链可变区以及轻链恒定区,重链可变区以及重链恒定区。本申请中所有PCR反应均使用NEB公司的Phusion超保真DNA聚合酶(F-530L)。PCR引物根据碱基互补原则以及酶切位点的需要进行常规设计,双特异性抗体参考常规方法合成,上述抗体注射入免疫药物层中。
实施例4:
本发明所述中药药物层中放置有中药配伍如下:
黄芪30份,党参15份,白术8份,当归15份,白芍6份,杜仲6份,桑寄生6份,川牛膝10份,独活9份,防风7.5份,鸡血藤15份,千年健10份,金刚刺10份,枸杞子32份,土茯苓25份,萆蘇19份,蒲公英12份,紫花地丁25份,白花蛇舌草25份,黄柏5份,生地黄8份,丹参20份,薏苡仁30份,桃仁15份,红花10份,熟地黄10份,川芎15份,赤芍6份,制南星6份,白芥子6份,制僵蚕10份,地龙10份,露蜂房10份,威灵仙19份,路路通15份,生马钱子23份,生草乌15份,生南星25份,冰片2份,林麝麝香一份。
将黄芪,党参,白术,当归,白芍,杜仲,桑寄生,川牛膝,独活,防风,鸡血藤,千年健,金刚刺,枸杞子,土茯苓,萆蘇,蒲公英,紫花地丁切碎,剩余成分研磨至80目,将香油放入锅内加热,将黄芪,党参,白术,当归,白芍,杜仲,桑寄生,川牛膝,独活,防风,鸡血藤,千年健,金刚刺,枸杞子,土茯苓,萆蘇,蒲公英,紫花地丁同时入锅,文火煎炸,药料炸至黄褐色时,取出药料,去渣滤净得药油;将药油放入干净的铜锅内,加热至120℃左右,将剩余成分加入锅中搅拌,水气散尽,松散为度,急住火,沉淀后取上清液,注射入中药药物层。
实施例5:
辅助治疗类风湿性关节炎的设备的治疗效果
(1)风湿引起的腰腿关节疼痛
诊断标准:由风湿引起的腰腿关节疼痛,主要症状为腰腿关节局部有明显的红、肿、热、痛及触痛,疼痛无定处,呈游走性。
痊愈的标准为:风湿引起的腰腿关节疼痛的主要表现症状完全消失。
有效的标准为:风湿引起的腰腿关节疼痛的主要表现症状减轻。
无效的标准为:风湿引起的腰腿关节疼痛的主要表现症状没有改变。
(2)骨质增生
诊断标准:通过骨科检查,患者的骨关节边缘上增生骨质,疼痛难忍。
痊愈的标准为:患者的骨关节边缘上增生骨质完全消失,无疼痛。
有效的标准为:患者的骨关节边缘上增生骨质减小,疼痛减轻。
无效的标准为:患者的骨关节边缘上增生骨质没有改变,疼痛无好转。
(3)颈椎痛
诊断标准:颈椎痛主要症状为颈椎酸痛,肩膀疼痛或发硬、头晕、耳鸣、四肢发麻。
痊愈的标准为:颈椎痛主要表现症状完全消失。
有效的标准为:颈椎痛主要表现症状减轻。
无效的标准为:颈椎痛主要表现症状没有改变。
(4)坐骨神经痛
诊断标准:由腰椎间盘脱出症引起的坐骨神经痛,主要症状为坐骨神经通路及其分布区内疼痛,自臀部沿大腿后侧、小腿外侧向远端放射。
痊愈的标准为:坐骨神经痛主要表现症状完全消失。
有效的标准为:坐骨神经痛主要表现症状减轻。
无效的标准为:坐骨神经痛主要表现症状没有改变。
(5)腿关节复水肿胀
诊断标准:由风湿、类风湿引起的腿关节复水肿胀,主要症状为腿关节疼痛复水肿胀。
痊愈的标准为:腿关节疼痛复水肿胀症状完全消失。
有效的标准为:腿关节疼痛复水肿胀症状减轻。
无效的标准为:腿关节疼痛复水肿胀症状没有改变。
(6)肢体麻木
诊断标准:由风湿、类风湿引起的肢体麻木,主要症状为肢体麻木。
痊愈的标准为:肢体麻木症状完全消失。
有效的标准为:肢体麻木症状减轻。
无效的标准为:肢体麻木症状没有改变。
经过998例患者的临床使用,其中472例患者为风湿引起的腰腿关节疼痛,115例为骨质增生,98例为颈椎痛,有101例坐骨神经痛,116例为腿关节疼痛复水肿胀,96例为肢体麻木。年龄最大的84岁,年龄最小的为23岁,男性患者347名,女性为651名,每贴48小时更换一次,30日为一疗程。850例贴2个疗程后有效;有578例贴13个疗程后周期后痊愈;其余未痊愈,但是症状有减轻趋势;总治愈率为57.9%。
以上所揭露的仅为本发明较佳实施例而已,当然不能以此来限定本发明之权利范围,因此依本发明权利要求所作的等同变化,仍属本发明所涵盖的范围。
序列表
<110> 蔡毓旻
<120> 一种双特异性抗体
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<170> SIPOSequenceListing 1.0
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Glu Met Arg
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<212> PRT
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<223> 第一抗原结合部位重链可变区氨基酸序列
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Glu His Asp Glu Gln Gly Glu Val Pro Trp Lys Met Gln Cys Asp Leu
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Leu Ile Pro Val Pro Met Asp Asp Ile Phe Leu Tyr Phe Tyr Ile Met
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Phe Gly Met Met Arg Ser Gly Pro Met Gln Asp Tyr Cys Val Cys Val
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Ile Phe Arg Lys Tyr Trp Ser Glu Cys Gln Glu Met Gly Trp Met Val
85 90 95
Pro Asp Lys Gly Asn Met Leu Phe Glu Tyr Val Phe Asn Leu
100 105 110
<210> 4
<211> 330
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 第一抗原结合部位重链恒定区氨基酸序列
<400> 4
Trp Met Lys Cys His Ser Ser Glu Asn Asn Lys Glu Arg Phe Phe Phe
1 5 10 15
Phe His Pro Arg Pro Ala Trp Thr Ile Asp Glu Ser Ala Ser Gln Thr
20 25 30
Lys Thr Cys His Ala Phe Val Asp Trp Pro Pro Pro Arg Phe Cys Glu
35 40 45
Asn Ser Ser Asp Lys Ile Gln Gln Ala Met Lys Ile Arg His Trp Thr
50 55 60
Asp Arg Tyr Asp Ser Leu Trp Ala Arg Gln Tyr Lys Lys Tyr Leu Tyr
65 70 75 80
Gly Cys Ser Tyr Tyr Gly Val Gln Gly Pro Met Thr Pro Ser Met His
85 90 95
Ile Ile Ala Ile Cys Ala Met Val Arg Phe Met Pro Trp Gln Glu Asn
100 105 110
Phe Ser Ala Ala Pro Cys Asp Trp Arg Pro Gln Pro His Lys Thr Met
115 120 125
Ile Ser Pro Phe Tyr Met Gln Pro Tyr Ala Asn Ala Arg Phe Ala Pro
130 135 140
Lys Trp Ile Ser Gln Cys Leu Ala Ala Glu Arg Cys Phe Lys Ala Ile
145 150 155 160
Gln Tyr Lys Glu Gly Arg Asp Gly Tyr Lys Phe Gln Gly Gln Arg Glu
165 170 175
Leu Leu Lys Gly Tyr Asp Tyr Leu Ile Trp Glu His Thr Ala Met Cys
180 185 190
Gly Arg Asp Phe Arg His Val Asn Ala Thr Ser Asp Asp Gln Pro Cys
195 200 205
His Trp Thr Thr Arg Phe Leu Lys Gln Ile Asn Leu Trp Gly Tyr Arg
210 215 220
Thr Leu Lys Val Lys Lys Arg Asp Asn Lys Lys Pro Lys Trp His His
225 230 235 240
Ser His Leu Trp Gln Gly Phe Pro Asp Tyr His Gly Ala Glu Trp Val
245 250 255
Trp Gln Asp Gln Thr Tyr Val Trp Ile Cys Lys Thr Tyr Thr Thr Tyr
260 265 270
Leu Met Ile Lys Gln Asn Ile Val Ile Glu Leu Val Asn Gln Asn Phe
275 280 285
Phe Ile Glu Arg Phe Ser Val Ile Ala Met Ala Arg Pro Tyr Lys Ile
290 295 300
His Arg Trp Leu Tyr Trp Trp Arg Met Pro Trp His Asn Lys Tyr Ala
305 310 315 320
His Gly Gly His Met Val Gly Cys Tyr Arg
325 330
<210> 5
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 第二抗原结合部位轻链可变区氨基酸序列
<400> 5
Thr Phe Thr Leu Gln Lys Ile Arg Cys Gly Leu Asp Pro Pro Asn Arg
1 5 10 15
Asp Ser Asn His Cys Met Asp Ala Ser Tyr Asp Gln His Pro Lys Gln
20 25 30
Ser Ile Gln Tyr Arg Met Ser Gln Asp Ile Ala Gln Arg Ser Ile Tyr
35 40 45
Cys Pro Tyr Pro Ala Tyr Tyr Trp Tyr Pro Tyr Glu Trp Asp Ile Pro
50 55 60
Leu Tyr Ala Val Gln Trp Ser Cys His Asn Gly Arg Gln Asn Trp Arg
65 70 75 80
Val Trp Met Cys Trp Gly Pro Glu Val Trp Ser Gly Phe Leu Tyr Cys
85 90 95
Ala Pro Met Glu Tyr Asp Met Ile Lys Asn Pro Trp
100 105
<210> 6
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 第二抗原结合部位轻链恒定区氨基酸序列
<400> 6
Cys Lys Trp Lys Trp Tyr His Ala His Gly Trp Ser Tyr Asp Ser Gly
1 5 10 15
Asp Thr Met Met Thr Trp Val His Trp Val His Ser Glu Ala Ile Asp
20 25 30
Asn Arg Lys Ala Glu Val Ser Gln Phe Val Met Gly Val Trp Gln Pro
35 40 45
Pro Lys Ala Ser Val Asp Glu Gly Ile Arg Leu Ile Cys Asn Pro Met
50 55 60
Glu His Glu Val Lys Arg Leu Leu Val Lys Ser Thr Pro Gln Gln Lys
65 70 75 80
Gly His Met Phe Gln Met Asn Glu Lys Glu His Cys Leu Gln Gln Thr
85 90 95
Glu Lys Gln Phe Ile Arg Gly His Trp Leu Thr Asp Glu Ser Ile His
100 105 110
Met
<210> 7
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 第二抗原结合部位重链可变区氨基酸序列
<400> 7
Ser Ser Met Pro Ala Val Met Glu Glu Arg Arg Asn Ser Gln Arg Ala
1 5 10 15
Val Gln His Cys Pro Ser Tyr Thr Ile Arg Leu His Thr Ser Arg Tyr
20 25 30
Tyr Ala Thr Arg Gly Ser Arg Gln Cys Leu Val Tyr Asp Cys Pro Ala
35 40 45
Tyr Met Cys Ile Ala Gly Gly Trp Tyr Leu Arg Ala Gln Glu Leu Pro
50 55 60
Leu Val Leu Asn Trp Phe Val Asn Ile Trp Leu Glu Cys Thr Trp Gly
65 70 75 80
Cys Asn Trp Phe Lys Thr Pro Trp Gln Gly Tyr Pro His Arg Phe Gln
85 90 95
Lys Cys Gln Asp Ser Met Cys Asp Ala Phe Arg Ala
100 105
<210> 8
<211> 332
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<223> 第二抗原结合部位重链恒定区氨基酸序列
<400> 8
Asp Cys Ser Thr Lys Gln Gly Gln Glu Pro Thr Met Asn Gln Val Cys
1 5 10 15
His Trp His Val Glu Leu Thr Glu Asp His Glu Glu Ile Asp Met Glu
20 25 30
Asn Arg Pro Glu Glu Val Lys Arg Trp Ser Cys His Ala Asn Met Val
35 40 45
His Leu Phe Val Cys Ser Pro Tyr Trp Ile Trp Trp Ser Gln Tyr Asp
50 55 60
Gln Cys Asp Glu Tyr Lys His Glu Ala Phe Trp Tyr Thr Asn Arg Ile
65 70 75 80
Lys Thr Cys Arg Glu Tyr Ala Val Phe Arg Gly Leu Gly Leu Phe Tyr
85 90 95
Tyr Lys Phe Ile Lys Arg Thr Trp Pro Ala Arg Gln Ser Phe Glu Gln
100 105 110
Met Asp Gly Val Val His Val Ile Asn Met Asp Glu Asn Arg Gln Asp
115 120 125
Lys Ala Ser Asp Cys Ser Ala Pro His Pro Lys Ala Arg Val Pro Asn
130 135 140
Gly Thr Ile Val Ala Ile Leu Lys Ile Ser Glu Cys Leu Phe Glu Thr
145 150 155 160
Leu Tyr Trp Glu Lys Val Leu His Thr Tyr Ser Phe Gly Gln Leu Gly
165 170 175
Tyr Asp Val Leu Trp Ile Pro Glu Pro Gln Thr Pro Ala Asp Asn Asn
180 185 190
Ala Phe Gln Ile Ala Tyr Val Ile Ala Tyr Lys His Arg Trp Gly His
195 200 205
Thr Leu Ala Glu His Cys Trp Met Gly Glu Asn Lys Met Cys Asp Thr
210 215 220
Leu Val Ala Asp Val Thr Asp Asp Asn Met Asn His His Phe Ile Trp
225 230 235 240
Glu Arg Val Asn Arg His Glu Leu Lys Gln Cys Ser Pro Thr Gly Ala
245 250 255
Asp Cys Ser Glu Gly Arg Asp Trp Asn Gln Leu Thr Ala Val Ala Met
260 265 270
His Tyr Ile Val Asn Ala Arg Gln Ser Lys Tyr Lys Cys Cys Arg Ser
275 280 285
Val Ala Trp Cys Leu Val Gly His Cys Arg Leu Ile Glu Gly Phe Pro
290 295 300
Val Arg Glu Ala Met Met His Val Thr Lys Asn Ser Tyr Arg Lys Ala
305 310 315 320
Pro Cys Pro Asn Ser Glu Trp Gly Cys Ser His Pro
325 330
Claims (9)
1.一种双特异性抗体,其特征在于,所述双特异性抗体为抗TNF/IL23双特异性抗体,所述双特异性抗体为人源化lgG型抗体。
2.根据权利要求1所述双特异性抗体,其特征在于,所述双特异性抗体包括与肿瘤坏死因子TNF-α特异性结合的第一抗原结合部位,还包括与白细胞介素IL-23特异性结合的第二抗原结合部位,其中所述双特异抗体还包含通过一个或多个二硫键链间连接的第一Fc链及第二Fc链,该第一Fc链和第二Fc链通过共价键或连接体分别连接到第一抗原结合部位和第二抗原结合部位上。
3.根据权利要求1-2任一所述的双特异性抗体,其特征在于,所述第一Fc链在如下位置包含2个氨基酸的替换,在第一Fc链上356位及379位氨基酸替换。
4.根据权利要求1-3任一所述的双特异性抗体,其特征在于,所述第二Fc链在如下位置包含3个氨基酸的替换,第二Fc链上321位、407位及409位氨基酸替换。
5.根据权利要求1-4所述的双特异性抗体,其特征在于,包含所述氨基酸替换的第一Fc链与第二Fc链更倾向于互相形成异源二聚体而不倾向于各自形成同源二聚体。
6.根据权利要求5所述双特异性抗体,其特征在于,所述第一抗原结合部位轻链可变区氨基酸序列如SEQ ID NO:1所示;所述第一抗原结合部位轻链恒定区氨基酸序列如SEQ IDNO:2所示。
7.根据权利要求6所述双特异性抗体,其特征在于,所述第一抗原结合部位重链可变区氨基酸序列如SEQ ID NO:3所示;所述第一抗原结合部位重链恒定区氨基酸序列如SEQ IDNO:4所示。
8.根据权利要求7所述双特异性抗体,其特征在于,所述第二抗原结合部位轻链可变区氨基酸序列如SEQ ID NO:5所示;所述第二抗原结合部位轻链恒定区氨基酸序列如SEQ IDNO:6所示。
9.根据权利要求8所述双特异性抗体,其特征在于,所述第二抗原结合部位重链可变区氨基酸序列如SEQ ID NO:7所示;所述第二抗原结合部位重链恒定区氨基酸序列如SEQ IDNO:8所示。
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