CN116615256A - 糖缀合物 - Google Patents
糖缀合物 Download PDFInfo
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- CN116615256A CN116615256A CN202180084465.8A CN202180084465A CN116615256A CN 116615256 A CN116615256 A CN 116615256A CN 202180084465 A CN202180084465 A CN 202180084465A CN 116615256 A CN116615256 A CN 116615256A
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- leu
- lys
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- gly
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Abstract
本文公开了使细胞结合剂例如抗体与有效载荷例如药物缀合的糖缀合物。药物通过寡糖接头缀合至细胞结合剂。本文公开的通过寡糖接头缀合的糖缀合物表现出相对于现有糖缀合物改善的性质。
Description
早先申请
本申请要求2020年10月16日提交的美国临时申请号US63/092640的优先权。所述优先权申请以其整体并出于任何和所有目的以引用方式并入本文,如同在本文中完全阐述。
技术领域
本发明涉及糖缀合物,所述糖缀合物具有与有效载荷如药物缀合的细胞结合剂如抗体。药物通过寡糖接头缀合至细胞结合剂。
背景技术
已建立抗体疗法用于靶向治疗患有癌症、免疫和血管生成病症的受试者(Carter,P.(2006)Nature Reviews Immunology 6:343-357)。使用抗体-药物缀合物(ADC)(即免疫缀合物)局部递送细胞毒性剂或细胞抑制剂(即癌症治疗中用于杀死或抑制肿瘤细胞的药物)以将药物部分递送至肿瘤以及其中的细胞内累积为目标,而这些非缀合药物剂的全身施用可能会对正常细胞产生不可接受的毒性水平(Xie等人(2006)Expert.Opin.Biol.Ther.6(3):281-291;Kovtun等人(2006)Cancer Res.66(6):3214-3121;Law等人(2006)Cancer Res.66(4):2328-2337;Wu等人(2005)Nature Biotech.23(9):1137-1145;Lambert J.(2005)Current Opin.in Pharmacol.5:543-549;Hamann P.(2005)Expert Opin.Ther.Patents 15(9):1087-1103;Payne,G.(2003)Cancer Cell 3:207-212;Trail等人(2003)Cancer Immunol.Immunother.52:328-337;Syrigos和Epenetos(1999)Anticancer Research 19:605-614)。
随着新类别的强效毒素诸如紫杉烷、刺孢霉素、美坦辛、倍癌霉素(duocarmycin)和奥瑞斯他汀(auristatin)的出现,该领域得到了发展。这些物质的低纳摩尔至皮摩尔毒性提供了超越早期毒素的显著优势。另一项技术进步涉及使用优化的接头,所述接头在细胞质中可水解,对蛋白酶具有抗性或易感性,或者对与高细胞毒性药物相关的多药耐药性外排泵具有抗性。
用于制备ADC的常见模式是将有效载荷(例如药物接头分子)缀合至抗体氨基酸赖氨酸或半胱氨酸的侧链。赖氨酸添加的动力学意味着该残基的缀合优先发生在具有高空间可及性和低pKa的赖氨酸侧链上,使得难以控制反应的位点特异性。由于在正常条件下天然型抗体中通常不存在游离半胱氨酸巯基,因此通过与半胱氨酸缀合可以提供更多的位点特异性。这允许通过例如选择性还原现有半胱氨酸或通过蛋白质工程化引入额外半胱氨酸来将游离巯基引入到抗体分子中的方法。在这两种情况下,使用例如基于马来酰亚胺加成的亲电烷基化,有效载荷可以有效地缀合至游离巯基。该方法允许有效且位点选择性地产生缀合物。然而,考虑到高产物均一性和对有效载荷的脱靶释放具有高抗性的缀合物的益处,研究一直在继续确定提供对巯基烷基化的进一步改进的缀合方法。
一种替代性缀合技术利用叠氮化物化学(N3基团,也称为叠氮基团)。特别是,叠氮基团能够与末端炔烃(铜催化的)或环炔烃(无铜,反应由环应变促进)进行选择性环加成。由与炔烃反应所产生的三唑特别耐水解和其他降解途径。该反应已证明在ADC的生产中具有实用性(参见例如WO2014/065661以及Li等人,Angew.Chem.Int.Ed.Engl.,2014年7月7日;53(28):7179-82)。也已讨论酮加羟胺或肼两者之一在ADC生产中的潜在用途(参见WO2014/065661)。
已讨论了许多用于将上述官能团引入到缀合前体中的策略。已证明产生安全有效的ADC的一种策略包括将有效载荷缀合至糖基化细胞结合剂(例如抗体)的聚糖部分缀合(参见例如WO/2018/146189)。
通过聚糖进行缀合是一种潜在的用于生成ADC的多用途策略,例如在哺乳动物或酵母细胞培养物中表达的所有IgG抗体在每个重链的Fc部分上都携带N-连接的聚糖部分。然而,这种方法带来了许多挑战。例如,聚糖通常作为同种型的复杂混合物存在,其可能包含不同水平的半乳糖基化(G0、G1、G2)和岩藻糖基化(G0F、G1F、G2F),这进而可能导致缀合化学计量的不期望的异质性。因此,现有方法通常采用一个或多个‘聚糖重塑’步骤,其中使用酶来修饰和/或添加碳水化合物部分,以便在与有效载荷缀合之前尽可能地均化聚糖结构(参见WO 2007/133855;WO2014/065661以及Li等人,Angew Chem Int Ed Engl.,2014年7月7日;53(28):7179-82)。然而,各种可能的糖部分、连接、分支、链长和可用修饰酶意味着聚糖部分可能的最终结构种类繁多。聚糖的最终大小和结构影响最终糖缀合物的许多关键性质(例如,药物-抗体比、缀合物亲水性、缀合物流体动力学等),其中许多无法可靠地先验预测。因此,对有利的聚糖构型的研究正在进行中。
一旦糖蛋白被重塑,存在若干种可能的用于与有效载荷缀合的策略。例如,已描述了许多方法,包括将均质化糖蛋白与单个或多个叠氮化物或炔烃官能化糖缩合,以产生活化的糖蛋白中间体,然后使用上述化学方法将该中间体缀合到有效载荷(更多细节参见例如WO2014/06566;Li等人,Angew Chem Int Ed Engl.,2014年7月7日;53(28):7179-82,以及其中引用的参考文献)。
已证明上述方法产生具有体内抗癌功效的糖缀合物(参见例如WO/2018/146189)。尽管如此,在一系列细胞结合剂和有效载荷方面进一步改善此类糖缀合物性质的研究仍在进行中。
发明内容
本发明人研究了一系列寡糖结构的性质,研究的目的是鉴定(1)允许有利的糖缀合物性质并(2)易于进行商业规模生产的寡糖结构。
在其研究期间,本发明人发现在细胞结合剂和有效载荷之间具有相对较短的三糖部分–GlcNAc–Gal–Sia–的糖缀合物具有一系列有利的特性。例如,与具有较大寡糖接头的类似糖缀合物相比,意外地发现这类糖缀合物:具有更高的亲水性和溶解性;显著更快的缀合动力学;体内显著更有效(尽管体外活性类似);实现药物-抗体比(“DAR”)=2的更好控制/一致性;并且显著提高受试者对治疗的耐受性。不希望受到理论束缚,本发明人相信这些性质的产生部分是由于带负电荷的唾液酸残基的存在和位置。对于一些有效载荷,发现与相同位置不带电荷的糖部分相比,这与改善的糖缀合物功效有关。
本发明人进一步确定,有利的–GlcNAc–Gal–Sia–糖缀合物可以使用容易获得的酶催化剂制备。特别是,意外地发现某些半乳糖基转移酶能够有效地将半乳糖转移到GlcNAc残基,优选地α-连接到肽骨架中的Asn残基(任选地携带α1-6岩藻糖),尽管在发现这种酶的天然系统中不发生该反应。由该反应产生的半乳糖基化寡糖也容易受到通过ST6Gal1唾液酸转移酶添加经修饰的唾液酸的影响。然后,经修饰的唾液酸残基可以有效地偶联到多种有效载荷,例如细胞毒性药物和其他治疗剂。
下文描述中阐述了一个或多个实施方案的细节。通过说明书和权利要求,其他特征、目标以及优势将为显而易见的。
附图说明
图1描绘了根据方法1的糖基化重塑和缀合。GlcNAc=α-乙酰葡糖胺,Man=甘露糖,Gal=半乳糖,Fuc=岩藻糖,Sia=唾液酸,WH=弹头分子。反应条件:(i)UDP-半乳糖、半乳糖基转移酶、MOPS缓冲液(50mM,20mM MnCl2,pH 7.2),24h;(ii)CMP-Neu5N3、ST6Gal1唾液酸转移酶、1% BSA、碱性磷酸酶、二甲胂酸盐缓冲液(50mM,pH 7.6),24小时;(iii)WH-DIBO。
图2描绘了根据方法2的糖基化重塑和缀合。GlcNAc=α-乙酰葡糖胺,Man=甘露糖,Gal=半乳糖,Fuc=岩藻糖,Sia=唾液酸,WH=弹头分子。反应条件:(i-1)糖苷内切酶S(EndoS);(i-2)糖苷内切酶S/BtFucH;(ii)UDP-半乳糖、β4GalT1、MOPS缓冲液(50mM,20mMMnCl2,pH 7.2)、1% BSA、1.3%碱性磷酸酶;(iii)CMP-Neu5N3、二甲胂酸盐缓冲液(50mM,pH 7.6)、1%BSA、1.3%碱性磷酸酶;WH-DIBO、CuSO4、抗坏血酸钠。
图3描绘了Her-WH-App1和Her-WH-App2的HIC特征。
图4描绘了Her-WH-App1和Her-WH-App2相对于基准Her2xADC的体内功效。
图5描绘了Her-WH-App1和Her-WH-App2在大鼠体内的药代动力学(PK)。
具体实施方式
在公开和描述本方法和系统之前,应理解,本方法和系统不限于不限于具体的合成方法、具体的部件或特定组成。还应理解本文使用的术语仅出于描述具体实施方案的目的并且不意图具有限制性。
除非上下文另有明确指明,否则如在本说明书和所附权利要求中所使用,单数形式“一个/种(a/an)”和“所述”包括复数个提及物。范围在本文中可表述为从“约”一个特定值和/或到“约”另一个特定值。当表述这种范围时,另一个实施方案包括从该一个特定值和/或到该另一个特定值。类似地,当通过使用先行词“约”将值表述为近似值时,应理解,特定值形成另一个实施方案。还应理解,每个范围的端点与另一端点相关和无关时,都是有意义的。
“任选”或“任选地”意指随后描述的事件或情况可发生或可未发生,并且描述包括其中所述事件或情况发生的情况和其中它未发生的情况。
贯穿本说明书的描述和权利要求,词语“包括(comprise)”和所述词语的变化形式如“包括(comprising)”和“包括(comprises)”意指“包括但不限于”并且不旨在排除例如其他添加物、部件、整数或步骤。“示例性”意指“……的实例”并且不旨在传达优选或理想实施方案的指示。“诸如”不以限制性意义使用,而是用于解释性目的。
如本文所用,“可链接(clickable)基团”是指在不使蛋白质或其他生物大分子变性的温和条件下可以与另一个可链接基团进行环加成反应的官能团。
如本文所用,“药物-抗体比率”或“DAR”是指与单个抗体或更一般的细胞结合剂缀合的药物或更一般的有效载荷的数量。DAR为1表示有一个药物与抗体缀合,DAR为2表示有两个药物与抗体缀合,依此类推。技术人员应理解某些生物缀合技术不会在给定样品中的每种抗体上安装统一数量的药物。此类情况可以由非整数DAR定义,例如1.5,表明对于给定样品,平均有1.5个药物与每种抗体缀合。
如本文所用,术语“烷基”是支链或无支链的烃基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基、庚基、辛基、壬基、癸基、十二烷基等。烷基也可以为取代的或未取代的。除非另有说明,否则术语“烷基”包括取代和未取代的烷基。烷基可以被一个或多个基团取代,所述基团包括但不限于烷氧基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤化物、羟基、酮、硝基、甲硅烷基、硫代氧基或巯基。不含碳-碳双键或三键的烷基被称为饱和烷基,而含有一个或多个此类键的烷基被称为不饱和烷基。具有双键的不饱和烷基可被称为烯基,并且具有三键的不饱和烷基可被称为炔基。除非有相反的说明,否则术语烷基包括饱和基团和不饱和基团。
本文所用的术语“环烷基”为由至少三个碳原子组成的非芳族碳基环。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基等。术语“杂环烷基”是如上文所定义的环烷基,其中环的至少一个碳原子被杂原子取代,所述杂原子例如但不限于氮、氧、硫、硒或磷。环烷基和杂环烷基可以是取代的或未取代的。除非另有说明,否则术语“环烷基”和“杂环烷基”包括取代和未取代的环烷基和杂环烷基。环烷基和杂环烷基可以被一个或多个基团取代,所述基团包括但不限于烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤化物、羟基、酮、硝基、甲硅烷基、硫代氧基或巯基。不含碳-碳双键或三键的环烷基被称为饱和环烷基,而含有一个或多个这种键的环烷基(仍不是芳族的)被称为不饱和环烷基。除非有相反的说明,否则术语环烷基包括饱和非芳族环系统和不饱和非芳族环系统。
如本文所用,否则术语“芳基”是由碳原子组成的芳环。芳基的实例包括但不限于苯基和萘基等。术语“杂芳基”是如上定义的芳基,其中环的至少一个碳原子被杂原子置换,所述杂原子例如但不限于氮、氧、硫、硒或磷。芳基和杂芳基可以是取代的或未取代的。除非另有说明,否则术语“芳基”和“杂芳基”包括取代和未取代的芳基和杂芳基。芳基和杂芳基可以被一个或多个基团取代,所述基团包括但不限于烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤化物、羟基、酮、硝基、甲硅烷基、硫代氧基或巯基。
示例性杂芳基和杂环基环包括:苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H~1,5,2-二噻嗪基、二氢呋喃并[2,3b]四氢呋喃、呋喃基、呋咕基、咪唑烷基、咪唑啉基、咪唑基、lH-吲唑基、吲哚烯基(indolenyl)、吲哚啉基、吲哚嗪基(indolizinyl)、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异吲哚啉基、异吲哚基、异喹啉基、异噻唑基、异噁唑基、亚甲基二氧基苯基、吗啉基、萘啶基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、羟吲哚基、密度基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、酚黄素基(phenoxathinyl)、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并噁唑、吡啶并咪唑、吡啶并噻唑、吡啶基(pyridinyl)、吡啶基(pyridyl)、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹啉基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、苯硫基和呫吨基。
术语“烷氧基”、“环烷氧基”、“杂环烷氧基”、“环烷氧基”、“芳氧基”和“杂芳氧基”具有前述烷基、环烷基、杂环烷基、芳基和杂芳基的含义,进一步条件是所述基团通过氧原子连接。
如本文所用,术语“空(null)”,当是指化学部分的可能身份时,表示所述基团不存在,并且两个相邻的基团彼此直接键合。举例来说,对于具有式CH3-X-CH3的一类化合物,如果X为空,则所得化合物具有式CH3-CH3。
术语“核苷酸”是指由核碱基、五碳糖(核糖或2-脱氧核糖两者之一)和一个、两个或三个磷酸基团组成的分子。在没有磷酸基团的情况下,核碱基和糖组成核苷。因此,核苷酸也可以称为单磷酸核苷、二磷酸核苷或三磷酸核苷。核碱基可以是腺嘌呤、鸟嘌呤、胞嘧啶、尿嘧啶或胸腺嘧啶。核苷酸的实例包括尿苷二磷酸(UDP)、鸟苷二磷酸(GDP)、胸苷二磷酸(TDP)、胞苷二磷酸(CDP)和胞苷单磷酸(CMP)。
如本文所用,通过符号连接的两个原子可以通过单键或双键连接。
如本文所用,术语C(x)亚烷基(其中x是数字)是指具有—(CH2)x—的未取代碳链间隔基;术语亚芳基是指芳环间隔基,并且亚杂环基是指杂环间隔基。可以进一步指定取代模式,例如亚苯基、萘、亚咪唑基等。可以进一步指定间隔基的区域化学,例如邻亚苯基、邻苯基和1,2-亚苯基都描述了苯环间隔基,其中其他基团键合到相邻碳。亚杂环基间隔基的键合排列可以使用IUPAC环编号规则来指定。举例来说,X-[1,4-亚苯基]-Y是指具有下式的化合物:
如本文所用,术语“取代的”预期包括有机化合物的所有可允许的取代基。在广义方面,可允许的取代基包括有机化合物的无环和环状、支链和非支链、碳环和杂环以及芳族和非芳族的取代基。示例性的取代基包括,例如,下文所述的那些。对于适当的有机化合物,可允许的取代基可以为一个或多个以及相同或不同的。为了本公开的目的,杂原子(诸如氮)可以具有氢取代基和/或满足杂原子化合价的本文所述有机化合物的任何可允许的取代基。本公开不旨在以任何方式受有机化合物的可允许的取代基的限制。此外,术语“取代”或“被取代”包括隐含的限制性条件,即这种取代符合被取代原子和取代基的允许化合价,并且取代产生稳定的化合物,例如化合物不会自发地经历诸如重排、环化、消除等的转化。除非特别说明,否则所谓“取代的”取代基意指取代基可以被一个或多个下列基团取代:烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、醛、氨基、羧酸、酯、醚、卤化物、羟基、酮、硝基、甲硅烷基、硫代氧基或巯基。在一个具体实例中,认为被取代的基团被质子基团取代,所述质子基团是可以根据pH被质子化或去质子化的基团。
应理解,根据本发明的某些化合物可以含有一个或多个不对称中心,因此可以制备并分离为异构体混合物,例如外消旋或非对映异构体混合物,或者对映异构体或非对映异构体纯形式。在本文所示的结构中,如果没有指定任何特定手性原子的立体化学,那么所有立体异构体都被考虑并包括在本发明的化合物中。当立体化学由代表特定构型的实心楔形或虚线指定时,则如此指定并定义该立体异构体。然而,对没有详细说明不对称中心的绝对构型的化合物的描绘不应该被认为要求所有可能的异构体必须存在于每个实施方案中。
本发明的某些化合物将包括可电离官能团,包括羧酸、磺酸、膦酸、胺等。本领域技术人员将理解,根据pH,此类基团将包含或将不包含可电离氢原子。对处于一种电离状态(例如质子化)的特定化合物的描绘不排除在不同pH下存在的其他状态(例如去质子化)。
除非另有说明,否则术语“患者”是指任何哺乳动物,包括但不限于人类。
药学上可接受的盐是保留母体化合物的所需生物活性且不产生不良毒理学效应的盐。此类盐的实例是与无机酸形成的酸加成盐,所述无机酸例如盐酸、氢溴酸、硫酸、磷酸和硝酸等;与有机酸形成的盐,所述有机酸例如乙酸、草酸、酒石酸、琥珀酸、马来酸、富马酸、葡糖酸、柠檬酸、苹果酸、甲磺酸、对甲苯磺酸、萘磺酸和聚半乳糖醛酸等;由元素阴离子形成的盐,所述阴离子诸如氯离子、溴离子和碘离子;由金属氢氧化物形成的盐,所述金属氢氧化物例如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化锂和氢氧化镁;由金属碳酸盐形成的盐,所述金属碳酸盐例如碳酸钠、碳酸钾、碳酸钙和碳酸镁;由金属碳酸氢盐形成的盐,所述金属碳酸氢盐例如碳酸氢钠和碳酸氢钾;由金属硫酸盐形成的盐,所述金属硫酸盐例如硫酸钠和硫酸钾;以及由金属硝酸盐形成的盐,所述金属硝酸盐例如硝酸钠和硝酸钾。药学上可接受的盐和非药学上可接受的盐可以使用本领域公知的方法制备,例如通过将足够碱性的化合物诸如胺与包含生理学上可接受的阴离子的合适的酸反应来制备。也可制备羧酸的碱金属(例如钠、钾或锂)或碱土金属(例如钙)盐。
公开可用来执行所公开的方法和系统的部件。本文公开用于所有方法和系统的这些和其他部件,并且应了解当公开这些部件的组合、子集、相互作用、群组等时,虽然可未明确公开这些的每个不同个别和共同组合以及排列的具体提及,但是其各自在本文中特定涵盖和描述。这适用于本申请的所有方面,包括但不限于方法中所公开的步骤。因此,如果有可执行的各种额外步骤,应了解这些额外步骤可各自对于所公开方法的任何特定实施方案或实施方案组合来执行。
本文公开了具有与细胞结合剂(“CBA”)缀合的至少一个有效载荷的糖缀合物。来自缀合反应的制备物中每个CBA的平均有效载荷数可以通过常规方法表征,例如UV、反相HPLC、HIC、质谱、ELISA测定和电泳。还可确定以p表示的CBA数量分布。通过ELISA,可确定在特定CBA制剂中p的平均值(Hamblett等人(2004)Clin.Cancer Res.10:7063-7070;Sanderson等人(2005)Clin.Cancer Res.11:843-852。
本文所述的糖缀合物组合物可以是均质的,即意味着每种细胞结合剂与相同数量的有效载荷缀合。在其他实施方案中,糖缀合物组合物可以包括缀合物的分布,即一些细胞结合剂缀合到单个有效载荷,一些细胞结合剂缀合到两个有效载荷,一些细胞结合剂缀合到三个有效载荷,等等。除非有相反的说明,否则对与一定数量的有效载荷缀合的细胞结合剂的描绘不排除还存在其他缀合物的可能性。
在一些实施方案中,本文公开的糖缀合物具有以下结构:
[[有效载荷]x—唾液酸苷—Gal—GlcNAc]y—CBA,
其中
唾液酸苷是指经修饰的唾液酸残基
Gal是指半乳糖残基;
GlcNAc是指N-乙酰葡糖胺残基,任选地在C-6位用岩藻糖糖基化;
Y是选自1、2、3、4、5、6、7或8的整数;
有效载荷表示共价连接到经修饰的唾液酸残基的一种或多种治疗剂;
x表示选自1-100、50-100、25-50、1-50、1-25、1-16、1-12、1-8或1-4整数
并且CBA是指细胞结合剂。
在某些实施方案中,x可以是1、2、3、4、5、6、7、8、9或10。
经修饰的唾液酸残基(或唾液酸苷)具有以下通式:
其中QQ是氢或缀合的有效载荷;
ZZ是羟基或缀合的有效载荷;
YY是羟基或缀合的有效载荷;
XX是羟基或缀合的有效载荷;并且
其中QQ、ZZ、YY和XX中的至少一者是缀合的有效载荷。
在一些实施方案中,QQ是缀合的有效载荷,并且XX、YY和ZZ中的每一个都是羟基。在其他实施方案中,ZZ是缀合的有效载荷,QQ是氢,并且XX和YY各自是羟基。在另外的实施方案中,ZZ和QQ各自是缀合的有效载荷,并且XX和YY各自是羟基。在此类情况下,ZZ和QQ可以相同或不同。
在一个实施方案中,每个CBA的平均有效载荷数量在1到4的范围内。在一些实施方案中,所述范围选自1至2、1至3、2至4、3-6或4-8。
在本发明的某些方面,糖缀合物可以具有下式:
其中:
CBA是细胞结合剂,例如肽,诸如抗体,优选地单克隆抗体;
y是DAR的量度,可以是0.5-6;优选地0.8-4,更优选地0.8-2.2,甚至更优选地0.9-2.1。在一些实施方案中,y为0.8-1.2、0.9-1.1、1.8-2.2或1.9-2.1。
Rfa是氢或岩藻糖部分;
QQ是氢或至少一个缀合的有效载荷;
ZZ是羟基或至少一个缀合的有效载荷;
YY是羟基或至少一个缀合的有效载荷;
XX是羟基或至少一个缀合的有效载荷;并且
其中QQ、ZZ、YY和XX中的至少一者是或至少一个缀合的有效载荷。
在某些情况下,糖缀合物可以包括上述2,6和2,3连接的寡糖的混合物。在其他实施方案中,糖缀合物可以基本上仅是2,6连接的寡糖,或者基本上在2,3连接的寡糖上。在一些实施方案中,糖缀合物可以是至少90%、至少95%、至少98%或至少99%的2,6-连接的寡糖,而在其他实施方案中,糖缀合物可以是至少90%、至少95%、至少98%或至少99%的2,3-连接的寡糖。
在优选的实施方案中,GlcNAc残基可以通过β-N-糖苷键结合至CBA:
在其他实施方案中,GlcNAc残基可以通过α-N-糖苷键结合至CBA。
当Rfa是岩藻糖部分时,它可以是具有下式的岩藻糖残基:
在某些实施方案中,Rfa是氢,而在其他实施方案中,Rfa是岩藻糖。在一些实施方案中,组合物可具有糖缀合物,其中至少90%、至少95%、至少98%或至少99%的糖缀合物具有Rfa的氢原子,而在其他实施方案中,组合物可具有糖缀合物,其中至少90%、至少95%、至少98%或至少99%的糖缀合物具有Rfa的岩藻糖残基。
在某些实施方案中,细胞结合剂是抗体,并且寡糖通过天冬酰胺侧链经由β-N-糖苷键缀合至抗体:
在某些情况下,根据Kabat中陈述的EU索引,GlcNAc部分缀合至抗体的天冬酰胺297(Asn297)残基处。在y为2的某些实施方案中,GlcNAc部分可以缀合至Fc结构域中的两个Asn297残基。在y为1的实施方案中,GlcNAc部分可以缀合至Fc结构域中的一个Asn297残基。当抗体通过链延长或截短两者之一经修饰时,寡糖可以缀合至未经修饰抗体中对应于Asn297的天冬酰胺残基。
本文提供了高度同质的糖缀合物,意味着每个单独的CBA具有相同的糖基化至CBA的聚糖结构。例如,在抗体的情况下,组合物中至少75%、至少80%、至少85%、至少90%、至少95%、至少97.5%或至少99%的单个抗体分子可以具有相同的聚糖结构。对于其中寡糖被糖基化至Asn297的实施方案,至少75%、至少80%、至少85%、至少90%、至少95%、至少97.5%或至少99%的抗体的特征可以在于在Asn297处具有相同的聚糖。
本文术语“抗体”以最广义使用,明确覆盖单克隆抗体、多克隆抗体、二聚体、多聚体、多特异性抗体(例如双特异性抗体)和抗体片段,只要它们表现出期望的生物学活性(Miller等人(2003)Jour,of Immunology 170:4854-4861)。抗体可以为鼠的、人的、人源化的、嵌合的、或源于其他物种的抗体。抗体是由免疫系统产生的能够识别并结合特定抗原的蛋白质。(Janeway,C,Travers,P.,Walport,M.,Shlomchik(2001)ImmunoBiology,第5版,Garland Publishing,New York)。靶抗原通常具有由多种抗体上的CDR所识别的许多结合位点,也称为表位。特异性结合不同表位的每种抗体具有不同的结构。因此,一种抗原可能有超过一种相应抗体。抗体包含全长免疫球蛋白分子或全长免疫球蛋白分子的免疫活性部分,即,含有抗原结合位点的分子,所述抗原结合位点免疫特异性结合感兴趣的靶抗原或其部分,此类靶标包括但不限于癌细胞或产生与自身免疫疾病相关的自身免疫抗体的细胞。免疫球蛋白可以是免疫球蛋白分子的任何类型/类别(例如IgG、IgE、IgM、IgD和IgA)或亚型/亚类(例如lgG1、lgG2、lgG3、lgG4、lgA1和lgA2)。免疫球蛋白可源于任何物种,包括人、鼠或兔来源。
“抗体片段”包括全长抗体的一部分,一般是它的抗原结合区或可变区。抗体片段的实例包括Fab、Fab’、F(ab')2和scFv片段;双链抗体;线性抗体;Fab表达文库产生的片段、抗独特型(抗Id)抗体、CDR(互补决定区)和免疫特异性结合癌细胞抗原、病毒抗原或微生物抗原的任何上述物质的表位结合片段、单链抗体分子;和由抗体片段形成的多特异性抗体。
如本文所用,术语“单克隆抗体”是指从基本上同源的抗体群获得的抗体,即除了可能少量存在的可能天然存在的突变之外,构成该群的单个抗体是相同的。单克隆抗体针对单个抗原位点具高度特异性。另外,与包括针对不同决定簇(表位)的不同抗体的多克隆抗体制品相反,每种单克隆抗体均是针对抗原上的单个决定簇。除其特异性之外,单克隆抗体的优点在于可以合成而不被其他抗体污染。经修饰语“单克隆”表示从基本上同质的抗体群获得的抗体的特征,并不被解释为需要通过任何特定方法产生抗体。例如,根据本公开使用的单克隆抗体可以通过首先由Kohler等人(1975)Nature 256:495描述的杂交瘤方法制备,或者可以通过重组DNA方法制备(参见,US 4816567)。单克隆抗体也可以使用Clackson等人(1991)Nature,352:624-628;Marks等人(1991)J.Mol.Biol.,222:581-597中所述的技术从噬菌体抗体库或从携带完全人类免疫球蛋白系统的转基因小鼠分离(Lonberg(2008)Curr.Opinion 20(4):450-459)。
本文中的单克隆抗体特别包括“嵌合”抗体,其中一部分重链和/或轻链与源于特定物种或属于特定抗体类别或子类的抗体中的相应序列相同或同源,而所述链的剩余部分与源于另一物种或属于另一抗体类别或子类的抗体中的相应序列相同或同源;以及此类抗体的片段,只要其展现所需生物活性即可(US 4816567;和Morrison等人(1984)Proc.Natl.Acad.Sci.USA,81:6851 -6855)。嵌合抗体包括“灵长类化”抗体,其包含来源于非人类灵长类动物(例如,旧世界猴或猿)的可变域抗原结合序列和人类恒定区序列。
本文中的“完整抗体”是包含VL和VH结构域,以及轻链恒定结构域(CL)和重链恒定结构域CH1、CH2和CH3的抗体。恒定结构域可以是天然序列恒定结构域(例如人天然序列恒定结构域)或其氨基酸序列变体。完整抗体可具有一种或多种“效应子功能”,其指归因于抗体Fc区(天然序列Fc区或氨基酸序列变体Fc区)的那些生物活性。抗体效应子功能的实例包括C1 q结合;补体依赖性细胞毒性;Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);吞噬作用;以及细胞表面受体诸如B细胞受体和BCR的下调。
根据其重链的恒定结构域的氨基酸序列,可将完整抗体分为不同的类别。完整抗体有五种主要类别:IgA、IgD、IgE、IgG和IgM,并且这些类别中的一些可进一步分为“子类别”,例如lgG1、lgG2、lgG3、lgG4、IgA和lgA2。优选IgG同种型,特别是IgG1亚型。对应于不同类别抗体的重链恒定结构域分别称为α、δ、ε、γ和μ。不同类别的免疫球蛋白的亚基结构和三维构型是熟知的。
用于降低非人抗体或抗体片段的体内免疫原性的技术包括称为“人源化”的技术。
“人源化抗体”是指包含人抗体的经经修饰可变区的至少一部分的多肽,其中该可变区的一部分,优选基本上小于完整人可变结构域的部分,已被来自非人物种的相应序列取代并且其中该经经修饰的可变区连接至另一种蛋白质的至少另一部分,优选人抗体的恒定区。表述“人源化抗体”包括其中一个或多个互补决定区(“CDR”)氨基酸残基和/或一个或多个框架区(“FW”或“FR”)氨基酸残基被啮齿类动物或其他非人抗体中类似位点的氨基酸残基取代的人抗体。表述“人源化抗体”还包括免疫球蛋白氨基酸序列变体或其片段,其包含基本上具有人免疫球蛋白氨基酸序列的FR和基本上具有非人免疫球蛋白氨基酸序列的CDR。
非人(例如鼠)抗体的“人源化”形式是嵌合抗体,其包含来自非人免疫球蛋白的最小序列。或者,从另一个角度来看,人源化抗体是人抗体,它也含有从非人(例如鼠)抗体中选择的序列来代替人序列。人源化抗体可以包含不会显著改变其结合和/或生物活性的来自相同或不同物种的保守氨基酸取代或非天然残基。此类抗体是含有源自非人免疫球蛋白的最小序列的嵌合抗体。
有一系列的人源化技术,包括‘CDR接枝’、‘引导选择’、‘去免疫化’、‘表面重整’(也称为‘镶面’)、‘复合抗体’、‘人串内容优化’和框架改组。
抗体可以是完整抗体。抗体可以是人源化抗体、去免疫抗体或表面重整抗体。抗体可以是完全人单克隆IgG1抗体,优选地IgG1,κ。
如本文所用,氨基酸编号是根据Kabat等人(1991,NIH Publication 91-3242,National Technical Information Service,Springfield,VA,下文中为“Kabat”)陈述的EU索引编号系统。“Kabat中陈述的EU索引”是指人IgG 1EU抗体的残基编号,如Kabat等人同上中所述。
在例如IgG2、IgG3和IgG4(或lgA1、lgA2、IgD、IgE、IgM等)中的取代的情况下,技术人员可以容易地使用序列比对程序诸如NCBI (http://blast.ncbi.nlm.nih.gov/Blast.cgi)将序列与IgG1进行比对,以确定所需同种型的哪些残基对应于本文所述的Kabat位置。
在一些实施方案中,根据Kabat中陈述的EU索引,有效载荷与连接到天冬酰胺残基的N-连接聚糖缀合,所述天冬酰胺残基位于对应于IgG1的297的位置。
在一些实施方案中,抗体是具有2个携带Sd(A)x部分(即y=2)的N-连接的聚糖的完整抗体。在一些实施方案中,抗体恰好具有2个携带Sd(A)x部分的N-连接聚糖。
在某些方面,单克隆抗体可用于本文公开的缀合物和方法。合适的单克隆抗体包括阿巴伏单抗(abagovomab)、阿昔单抗(abciximab)、阿比妥珠单抗(abituzumab)、阿泽奇单抗(abrezekimab)、阿利鲁单抗(abrilumab)、阿克托舒单抗(actoxumab)、阿达木单抗(adalimumab)、阿德木单抗(adecatumumab)、阿杜卡努单抗(aducanumab)、阿法库单抗(afasevikumab)、阿非莫单抗(afelimomab)、阿拉赛珠单抗(alacizumab)、阿来组单抗(alemtuzumab)、阿利库单抗(alirocumab)、阿妥莫单抗(altumomab)、阿麦妥单抗(amatuximab)、马安那莫单抗(anatumomab mafenatox)、安德利昔单抗(andecaliximab)、阿奈妥单抗(anetumab)、阿尼鲁单抗(anifrolumab)、安芦组单抗(anrukinzumab)、阿泊珠单抗(apolizumab)、阿普卢妥单抗(aprutumab)、阿西莫单抗(arcitumomab)、阿伐苏单抗(ascrinvacumab)、阿塞珠单抗(aselizumab)、阿替利珠单抗(atezolizumab)、阿度尤单抗(atidortoxumab)、阿替奴单抗(atinumab)、阿托木单抗(atorolimumab)、阿维鲁单抗(avelumab)、阿妥昔珠单抗(azintuxizumab)、巴匹组单抗(bapineuzumab)、巴利昔单抗(basiliximab)、巴维昔单抗(bavituximab)、BCD-100、贝妥莫单抗(bectumomab)、贝戈洛单抗(begelomab)、贝兰妥单抗(belantamab)、贝利木单抗(belimumab)、贝马里妥珠单抗(bemarituzumab)、贝那利珠单抗(benralizuma)、fasenramab、贝度尤单抗(berlimatoxumab)、贝迈奇单抗(bermekimab)、伯萨利单抗(bersanlimab)、柏替木单抗(bertilimumab)、贝索单抗(besilesomab)、贝伐珠单抗(bevacizumab)、贝洛托舒单抗(bezlotoxumab)、比西单抗(biciromab)、比玛卢单抗(bimagrumab)、比美吉珠单抗(bimekizumab)、泊特埃单抗(birtamimab)、比伐珠单抗(bivatuzumab)、布来鲁单抗(bleselumab)、博纳吐单抗(blinatumomab)、布隆妥维单抗(blontuvetmab)、布索组单抗(blosozumab)、伯考赛珠单抗(bococizumab)、布雷库单抗(brazikumab)、本妥昔单抗(brentuximab)、布雷奴单抗(briakinumab)、柏达鲁单抗(brodalumab)、布洛赛珠单抗(brolucizumab)、布隆妥珠单抗(brontictuzumab)、布罗索尤单抗(burosumab)、司库奇尤单抗(crysvitamab)、卡比利珠单抗(cabiralizumab)、卡米丹单抗(camidanlumab)、卡瑞利珠单抗(camrelizumab)、卡那单抗(canakinumab)、美崁珠单抗美坦辛(cantuzumabmertansine)、美崁珠单抗(cantuzumab)、卡普赛珠单抗(caplacizumab)、卡罗单抗(capromab)、卡芦单抗(carlumab)、卡罗图西单抗(carotuximab)、卡妥索单抗(catumaxomab)、CBR96、西利珠单抗(cedelizumab)、赛普利单抗(cemiplimab)、色古珠单抗(cergutuzumab)、塞妥珠单抗(certolizumab)、西卓里单抗(cetrelimab)、西妥昔单抗(cetuximab)、西碧砂塔单抗(cibisatamab)、西妥珠单抗(cirmtuzumab)、泊西他珠单抗(citatuzumab bogatox)、西妥木单抗(cixutumumab)、克拉扎珠单抗(clazakizumab)、克立昔单抗(clenoliximab)、可利维珠单抗(clivatuzumab)、钴妥珠单抗(codrituzumab)、钴非珠单抗(cofetuzumab)、库特妥单抗(coltuximab)、可那幕单抗(conatumumab)、康珠单抗(concizumab)、考韦昔单抗(cosfroviximab)、CR6261、克瑞组单抗(crenezumab)、立赞利珠单抗(crizanlizumab)、克罗特度单抗(crotedumab)、库沙珠单抗(cusatuzumab)、达西妥珠单抗(dacetuzumab)、达克珠单抗(daclizumab)、达洛妥珠单抗(dalotuzumab)、达匹利珠单抗(dapirolizumab)、达雷木单抗(daratumumab)、德屈库单抗(dectrekumab)、登西珠单抗(demcizumab)、狄宁妥珠单抗(denintuzumab mafodotin)、地舒单抗(denosumab)、狄帕土西单抗(depatuxizumab)、德尔罗妥单抗(derlotuximab)、地莫单抗(detumomab)、迪扎米珠单抗(dezamizumab)、达妥昔单抗(dinutuximab)、地利伏单抗(diridavumab)、多玛洛珠单抗(domagrozumab)、阿托度单抗(dorlimomab)、多塔利单抗(dostarlimab)、卓齐妥单抗(drozitumab)、ds-8201、杜利哥珠单抗(duligotuzumab)、杜匹鲁单抗(dupilumab)、德瓦鲁单抗(durvalumab)、度司妥单抗(dusigitumab)、杜沃珠西单抗(duvortuxizumab)、依美昔单抗(ecromeximab)、依库珠单抗(eculizumab)、埃巴单抗(edobacomab)、依决洛单抗(edrecolomab)、依法利珠单抗(efalizumab)、依芬古单抗(efungumab)、埃迪鲁单抗(eldelumab)、依来努单抗(elezanumab)、依戈妥单抗(elgemtumab)、埃洛妥珠单抗(elotuzumab)、艾西莫单抗(elsilimomab)、尹克妥珠单抗(emactuzumab)、依玛鲁单抗(emapalumab)、伊密贝珠单抗(emibetuzumab)、艾美赛珠单抗(emicizumab)、艾美赛珠单抗(hemlibra)、恩泊妥单抗(enapotamab)、埃文单抗(enavatuzumab)、因富珠单抗(enfortumab)、恩莫单抗(enlimomab)、因诺利珠单抗(enoblituzumab)、依诺凯组单抗(enokizumab)、依诺苏单抗(enoticumab)、因西珠西单抗(ensituximab)、西依匹莫单抗(epitumomab)、依帕珠单抗(epratuzumab)、依普奈珠单抗(eptinezumab)、依瑞奈尤单抗(erenumab)、厄利珠单抗(erlizumab)、厄妥索单抗(ertumaxomab)、艾达珠单抗(etaracizumab)、艾替利单抗(etigilimab)、依曲利组单抗(etrolizumab)、依维苏单抗(evinacumab)、依洛尤单抗(evolocumab)、艾韦单抗(exbivirumab)、法索单抗(fanolesomab)、法拉莫单抗(faralimomab)、发瑞西单抗(faricimab)、发雷珠单抗(farletuzumab)、法司努单抗(fasinumab)、fbta05、泛维珠单抗(felvizumab)、非扎奴单抗(fezakinumab)、菲巴妥珠单抗(fibatuzumab)、芬克拉妥珠单抗(ficlatuzumab)、芬妥木单抗(figitumumab)、非利伏单抗(firivumab)、弗兰托单抗(flanvotumab)、夫来库单抗(fletikumab)、弗特珠单抗(flotetuzumab)、芳妥珠单抗(fontolizumab)、福雷芦单抗(foralumab)、福拉韦单抗(foravirumab)、瑞玛奈珠单抗(fremanezumab)、非苏木单抗(fresolimumab)、弗洛西单抗(frovocimab)、夫卢维单抗(frunevetmab)、福拉奴单抗(fulranumab)、富珠西单抗(futuximab)、加卡奈珠单抗(galcanezumab)、加利昔单抗(galiximab)、甘妥单抗(gancotamab)、甘尼妥单抗(ganitumab)、更汀芦单抗(gantenerumab)、伽妥珠单抗(gatipotuzumab)、加维莫单抗(gavilimomab)、格迪伏单抗(gedivumab)、吉妥单抗(gemtuzumab)、吉伏组单抗(gevokizumab)、吉维单抗(gilvetmab)、瑾司鲁单抗(gimsilumab)、吉利妥昔单抗(girentuximab)、格列姆巴妥木单抗(glembatumumab)、戈利木单抗(golimumab)、加利昔单抗(gomiliximab)、戈奈单抗(gosuranemab)、古塞库单抗(guselkumab)、伊利尤单抗(ianalumab)、伊巴珠单抗(ibalizumab)、IBI308、替伊莫单抗(ibritumomab)、伊克芦库单抗(icrucumab)、艾达赛珠单抗(idarucizumab)、依法妥珠单抗(ifabotuzumab)、伊戈伏单抗(igovomab)、伊达珠单抗(iladatuzumab)、IMAB362、尹马鲁单抗(imalumab)、伊普利单抗(imaprelimab)、英西单抗(imciromab)、英加妥珠单抗(imgatuzumab)、伊克拉单抗(inclacumab)、英达西单抗(indatuximab ravtansine)、维汀-英度妥单抗(indusatumab vedotin)、依那利珠单抗(inebilizumab)、英夫利西单抗(infliximab)、伊诺莫单抗(inolimomab)、奥加伊妥珠单抗(inotuzumab)、英妥木单抗(intetumumab)、IOMAB-B、伊匹单抗(ipilimumab)、伊妥木单抗(iratumumab)、伊索妥昔单抗(isatuximab)、伊卡利单抗(iscalimab)、异妥拉明单抗(istiratumab)、伊立珠单抗(itolizumab)、伊西贝单抗(ixekizumab)、凯利昔单抗(keliximab)、拉贝珠单抗(labetuzumab)、拉诺珠单抗(lacnotuzumab)、拉地拉单抗(ladiratuzumab)、兰帕利珠单抗(lampalizumab)、拉那利尤单抗(lanadelumab)、兰洛珠单抗(landogrozumab)、拉妥昔单抗(laprituximab)、拉韦昔单抗(larcaviximab)、来瑞组单抗(lebrikizumab)、来马索单抗(lemalesomab)、棱达利珠单抗(lendalizumab)、伦韦单抗(lenvervimab)、濂溪珠单抗(lenzilumab)、乐德木单抗(lerdelimumab)、乐利单抗(leronlimab)、来索伏单抗(lesofavumab)、来利珠单抗(letolizumab)、来沙木单抗(lexatumumab)、利韦单抗(libivirumab)、利法珠单抗(lifastuzumab)、利格利珠单抗(ligelizumab)、黎罗图单抗(lilotomab satetraxetan)、林妥珠单抗(lintuzumab)、里瑞卢单抗(lirilumab)、洛迪赛珠单抗(lodelcizumab)、洛吉维单抗(lokivetmab)、龙卡司珠单抗(loncastuximab)、洛妥珠美坦辛(lorvotuzumab)、罗沙珠单抗(losatuxizumab)、路卡珠单抗(lucatumumab)、鲁利珠单抗(lulizumab)、鲁昔单抗(lumiliximab)、卢姆力土珠单抗(lumretuzumab)、阿汀-鲁帕妥单抗(lupartumab amadotin)、鲁吉珠单抗(lutikizumab)、马帕木单抗(mapatumumab)、马捷珠单抗(margetuximab)、马塔西单抗(marstacimab)、马司莫单抗(maslimomab)、马妥珠单抗(matuzumab)、玛弗利木单抗(mavrilimumab)、美泊利单抗(mepolizumab)、美替木单抗(metelimumab)、米拉珠单抗(milatuzumab)、明瑞莫单抗(minretumomab)、米吉珠单抗(mirikizumab)、美洼珠单抗(mirvetuximab soravtansine)、米妥莫单抗(mitumomab)、莫都珠单抗(modotuximab)、莫加木珠单抗(mogamulizumab)、莫那利单抗(monalizumab)、莫罗木单抗(morolimumab)、莫孙内珠单抗(mosunetuzumab)、莫维组单抗(motavizumab)、莫塞妥莫单抗(moxetumomab)、莫罗单抗(muromonab)-CD3、他那可单抗(nacolomab tafenatox)、那美芦单抗(namilumab)、他那莫单抗(naptumomab)、那妥昔单抗(naratuximab)、纳那妥单抗(narnatumab)、那他珠单抗(natalizumab)、纳维西单抗(navicixizumab)、那韦伏单抗(navivumab)、那西塔单抗(naxitamab)、奈巴库单抗(nebacumab)、奈昔单抗(necitumumab)、奈莫利珠单抗(nemolizumab)、NEOD001、奈瑞莫单抗(nerelimomab)、奈斯维单抗(nesvacumab)、尼塔奇单抗(netakimab)、尼妥珠单抗(nimotuzumab)、尼塞韦单抗(nirsevimab)、纳武单抗(nivolumab)、诺莫单抗(nofetumomab)、奥托萨昔单抗(obiltoxaximab)、阿托珠单抗(obinutuzumab)、奥卡土珠单抗(ocaratuzumab)、奥克莱珠单抗(ocrelizumab)、奥度莫单抗(odulimomab)、奥法木单抗(ofatumumab)、奥拉单抗(olaratumab)、奥雷可鲁单抗(oleclumab)、奥仑达利珠单抗(olendalizumab)、奥洛组单抗(olokizumab)、奥马珠单抗(omalizumab)、omburtamab、OMS721、阿那妥单抗(onartuzumab)、欧土希珠单抗(ontuxizumab)、奥瓦利单抗(onvatilimab)、奥匹努单抗(opicinumab)、莫奥珠单抗(oportuzumab)、奥戈伏单抗(oregovomab)、奥替苏单抗(orticumab)、奥昔组单抗(otelixizumab)、奥替利单抗(otilimab)、特乐土珠单抗(otlertuzumab)、奥塞芦单抗(oxelumab)、奥扎奈珠单抗(ozanezumab)、奥利组单抗(ozoralizumab)、帕昔单抗(pagibaximab)、帕利珠单抗(palivizumab)、潘瑞卢单抗(pamrevlumab)、帕尼单抗(panitumumab)、潘科曼单抗(pankomab)、帕巴库单抗(panobacumab)、巴萨妥珠单抗(parsatuzumab)、帕考珠单抗(pascolizumab)、束妥昔珠单抗(pasotuxizumab)、帕替组单抗(pateclizumab)、帕曲妥单抗(patritumab)、PDR001、帕博利珠单抗(pembrolizumab)、培妥莫单抗(pemtumomab)、培拉凯珠单抗(perakizumab)、帕妥珠单抗(pertuzumab)、培克珠单抗(pexelizumab)、吡帝里单抗(pidilizumab)、平尼土珠单抗(pinatuzumab)、平妥莫单抗(pintumomab)、普拉鲁单抗(placulumab)、洛扎利珠单抗(plozalizumab)、泊咖丽珠单抗(pogalizumab)、波拉珠单抗(polatuzumab)、泊奈组单抗(ponezumab)、珀韦昔单抗(porgaviximab)、普尼珠单抗(prasinezumab)、普瑞利珠单抗(prezalizumab)、普立昔单抗(priliximab)、瑞托萨昔单抗(pritoxaximab)、普立木单抗(pritumumab)、PRO 140、奎利珠单抗(quilizumab)、拉寇图单抗(racotumomab)、雷德图单抗(radretumab)、雷韦单抗(rafivirumab)、雷泮赛珠单抗(ralpancizumab)、拉莫西鲁单抗(ramucirumab)、雷奈维单抗(ranevetmab)、雷珠单抗(ranibizumab)、拉瓦加利单抗(ravagalimab)、雷夫利珠单抗(ravulizumab)、雷昔库单抗(raxibacumab)、瑞法奈珠单抗(refanezumab)、瑞加韦单抗(regavirumab)、瑞拉利单抗(relatlimab)、壬托鲁单抗(remtolumab)、瑞替珠单抗(reslizumab)、利妥木单抗(rilotumumab)、利努苏单抗(rinucumab)、利散吉珠单抗(risankizumab)、利妥昔单抗(rituximab)、利伐巴珠单抗(rivabazumab)、罗妥木单抗(robatumumab)、罗来度单抗(roledumab)、若奇单抗(romilkimab)、罗莫单抗(romosozumab)、隆利组单抗(rontalizumab)、罗斯蛮珠单抗(rosmantuzumab)、罗伐辟珠单抗(rovalpituzumab tesirine)、罗维珠单抗(rovelizumab)、洛利昔珠单抗(rozanolixizumab)、卢利珠单抗(ruplizumab)、SA237、沙西珠单抗(sacituzumab)、沙玛立珠单抗(samalizumab)、山罗塔单抗(samrotamab)、沙利姆单抗(sarilumab)、萨特利珠单抗(satralizumab)、沙妥莫单抗(satumomab)、司库奇尤单抗(secukinumab)、塞鲁单抗(selicrelumab)、司里班妥单抗(seribantumab)、瑟托萨昔单抗(setoxaximab)、塞曲苏单抗(setrusumab)、司韦单抗(sevirumab)、SGN-CD19a、SHP647、西罗珠单抗(sibrotuzumab)、西法木单抗(sifalimumab)、司妥昔单抗(siltuximab)、辛妥珠单抗(simtuzumab)、西利珠单抗(siplizumab)、瑟曲单抗(sirtratumab)、西鲁库单抗(sirukumab)、索飞珠单抗(sofituzumab)、索拉珠单抗(solanezumab)、索利托单抗(solitomab)、索耐珠单抗(sonepcizumab)、松妥组单抗(sontuzumab)、斯巴达珠单抗(spartalizumab)、司他芦单抗(stamulumab)、硫索单抗(sulesomab)、舒他伏单抗(suptavumab)、苏替莫单抗(sutimlimab)、舒维组单抗(suvizumab)、苏托舒单抗(suvratoxumab)、他巴鲁单抗(tabalumab)、他卡妥珠单抗(tacatuzumab)、他度组单抗(tadocizumab)、塔妥珠单抗(talacotuzumab)、他利珠单抗(talizumab)、坦妥维单抗(tamtuvetmab)、他尼组单抗(tanezumab)、托西莫单抗(taplitumomab)、塔曲妥单抗(tarextumab)、塔伏利单抗(tavolimab)、替非组单抗(tefibazumab)、替莫单抗(telimomab)、替利妥珠单抗(telisotuzumab)、替尼他单抗(tenatumomab)、替奈昔单抗(teneliximab)、替利组单抗(teplizumab)、tepoditamab、替妥木单抗(teprotumumab)、特度鲁单抗(tesidolumab)、特土罗单抗(tetulomab)、特折鲁单抗(tezepelumab)、TGN1412、替布利珠单抗(tibulizumab)、替加组单抗(tigatuzumab)、替曲吉珠单抗(tildrakizumab)、替加妥珠单抗(timigutuzumab)、替莫鲁单抗(timolumab)、替米古妥珠单抗(tiragotumab)、替雷利珠单抗(tislelizumab)、替雷珠单抗(tisotumab)、TNX-650、托珠单抗(tocilizumab)、托木妥昔单抗(tomuzotuximab)、托利珠单抗(toralizumab)、托萨托舒单抗(tosatoxumab)、托西莫单抗(tositumomab)、托韦妥单抗(tovetumab)、曲罗芦单抗(tralokinumab)、曲妥珠单抗(trastuzumab)、TRBS07、曲利组单抗(tregalizumab)、度伐鲁单抗(tremelimumab)、曲戈卢单抗(trevogrumab)、西莫白介素单抗(tucotuzumab)、妥韦单抗(tuvirumab)、优利妥昔单抗(ublituximab)、优隆单抗(ulocuplumab)、巫瑞卢单抗(urelumab)、乌珠单抗(urtoxazumab)、乌司奴单抗(ustekinumab)、乌托米卢单抗(utomilumab)、瓦达斯土西单抗(vadastuximab)、vanalimabmab、万多妥珠单抗(vandortuzumab)、凡提土单抗(vantictumab)、凡努西珠单抗(vanucizumab)、伐利昔单抗(vapaliximab)、伐瑞沙枯单抗(varisacumab)、瓦利卢单抗(varlilumab)、伐利组单抗(vatelizumab)、维得利珠单抗(vedolizumab)、维妥珠单抗(veltuzumab)、维帕莫单抗(vepalimomab)、维森库单抗(vesencumab)、维西珠单抗(visilizumab)、沃巴利珠单抗(vobarilizumab)、伏洛昔单抗(volociximab)、封勒罗利单抗(vonlerolizumab)、伏派利单抗(vopratelimab)、伏妥土珠单抗(vorsetuzumab mafodotin)、伏妥莫单抗(votumumab)、伏那吉珠单抗(vunakizumab)、珍妥珠单抗(xentuzumab)、XMAB-5574、扎鲁木单抗(zalutumumab)、扎木单抗(zanolimumab)、扎妥昔单抗(zatuximab)、辛诺枯图珠单抗(zenocutuzumab)、齐拉木单抗(ziralimumab)、佐贝珠西单抗(zolbetuximab)以及佐莫单抗(zolimomab)。
上文所述的缀合化学允许本文所述的糖基化细胞结合剂与多种有效载荷缀合。例如,在一些实施方案中,有效载荷是或包括治疗剂(例如治疗性蛋白质、脂质或核酸)、标记物或成像剂(例如放射性核素、荧光团或染料)、药物、抗生素、疫苗、免疫抑制剂、佐剂或保护剂。
一类优选的有效载荷包括药物(在本文中也称为“药物部分”),其中药物与细胞结合剂的缀合允许药物以高精度递送至靶细胞。
药物分子可以是药物或前药。在一些实施方案中,药物选自由以下组成的组:药物活性化合物,特别是低至中等分子量的化合物(例如约200至约2500Da,优选地约300至约1750Da)。在一些实施方案中,药物可以是以下一种或多种:细胞毒素、免疫调节剂、抗病毒剂、抗细菌剂、肽和寡核苷酸。示例性药物包括秋水仙碱、长春花生物碱、蒽环类药物、喜树碱、多柔比星、柔红霉素、紫杉烷、吡啶并苯二氮(PDD)、刺孢霉素和其他烯-二炔类化合物、微管溶素(tubulysin)、依沙替康(exatecan)、伊立替康、抑制性肽、鹅膏蕈碱(amanitin)、脱三角梅蛋白(deBouganin)、倍癌霉素、美坦辛或奥瑞斯他汀、长春花生物碱、蒽环类药物、紫杉烷、鹅膏蕈碱,特别是长春花生物碱、蒽环类药物、喜树碱、紫杉烷、微管溶素、鹅膏蕈碱、美坦辛和奥瑞斯他汀。
为避免疑问,药物可能不是吡咯并苯二氮(PBD),即包含以下子结构的化合物:
其中任何原子可以进一步被任何官能团取代。
在优选的实施方案中,药物部分通过接头部分(所谓的‘药物-接头’有效载荷)缀合至本文所述的糖基化细胞结合剂,产生具有下式的缀合物,其中一种或多种药物连接至相同的唾液酸苷:
[[药物接头]z—唾液酸苷—Gal—GlcNAc]z—CBA,
其中如上定义的唾液酸苷上位置QQ、XX、YY和ZZ中的一个或多个是接头有效载荷,并且z在每种情况下独立地选自1、2、3、4、5、6、7或8。在一些实施方案中,多个药物可以缀合到同一接头上,所述接头缀合到唾液酸苷,从而具有下式:
[[药物]z-接头—唾液酸苷—Gal—GlcNAc]z—CBA。
在其他实施方案中,多个药物可以缀合到同一接头上,并且多个接头可以缀合到唾液酸苷上,从而具有下式:
[[[药物]z-接头]z—唾液酸苷—Gal—GlcNAc]z—CBA。
在某些实施方案中,接头可以包括从1,3偶极体和应变环炔或应变反式环烯之间的环加成反应获得的环系统。
因此,在一些示例性实施方案中,有效载荷连接至唾液酸苷的QQ位置,因此:
其中L是接头。在一些示例性实施方案中,有效载荷连接至唾液酸苷的ZZ位置,因此:
在其他实施方案中,有效载荷(例如药物)连接至唾液酸苷的位置QQ和位置ZZ。有效载荷和接头可以相同或不同。
多种细胞毒性化合物可以用作有效载荷。在一些实施方案中,有效载荷包括DNA损伤剂、微管蛋白聚合抑制剂(也可称为微管抑制剂或微管去稳定剂、拓扑异构酶抑制剂、RNA剪接抑制剂或RNA聚合酶抑制剂。如本文所用,DNA损伤剂不包括如上定义的吡咯并苯二氮化合物。在一些实施方案中,缀合物可以包含至少两种选自上述类别的不同药剂。例如,缀合物可以包含多种DNA损伤剂或多种微管抑制剂。在一些情况下,缀合物可以包含至少一种DNA损伤剂和至少一种微管抑制剂。在其他实施方案中,缀合物可以包含至少一种DNA损伤剂和至少一种拓扑异构酶抑制剂。在其他实施方案中,缀合物可以包含至少一种微管抑制剂和至少一种拓扑异构酶抑制剂。在其他实施方案中,缀合物可以包含至少一种微管抑制剂、至少一种DNA损伤剂和至少一种拓扑异构酶抑制剂。
合适的DNA损伤剂包括烯二炔化合物、多柔比星化合物、倍癌霉素化合物,合适的微管抑制剂包括多拉司他汀(dolastatin)化合物、紫杉烷、长春花生物碱、美坦辛化合物、微管溶素化合物、艾日布林(eribulin)化合物和念珠藻素(crytophycin)化合物。合适的拓扑异构酶抑制剂包括喜树碱化合物和片螺素化合物。
其他类型的有效载荷也可以被缀合,包括免疫刺激剂。
在一些实施方案中,有效载荷可以包括烯二炔抗肿瘤抗生素,其示例性成员包括卡奇霉素(calicheamicin)、石狮霉素(shishijimicin)、钩霉素(uncialamycin)、新抑癌蛋白(neocarzinostatin)、埃斯佩拉霉素(esperamicin)、达内霉素(dynemicin)和高尔夫霉素(golfomycin)。
在某些情况下,有效载荷可包括具有下式的卡奇霉素化合物:
其中Rch1或Rch2中的一个是与末端唾液酸苷缀合的接头。当不是接头时,Rch1可以是H、-S-S-CH3、C(O)CH3或任何足够不稳定的可以被裂解以产生游离巯基的基团。当不是接头时,Rch2可以是H、C1-4烷基或C(O)C1-4烷基。
在一些情况下,有效载荷可包括具有下式的石狮霉素化合物:
其中Rsh1、Rsh2或Rsh3中的一个是与末端唾液酸苷缀合的接头。当不是接头时,Rsh1可以是H、-S-S-CH3、C(O)CH3或任何足够不稳定的可以被裂解以产生游离巯基的基团。当不是接头时,Rsh2可以是H、C1-4烷基或C(O)C1-4烷基。当不是接头时,Rsh3可以是H。
在一些情况下,有效载荷可以包括具有下式的钩霉素化合物:
其中Run1、Run2、Run3、Run4或Run5中的一个是与末端唾液酸苷缀合的接头,并且其余都是H。
在一些情况下,有效载荷可以包括具有下式的新抑癌蛋白化合物:
其中Rne1、Rne2、Rne3、Rne4或Rne5中的一个是与末端唾液酸苷缀合的接头,并且其余都独立地是H或C1-4烷基。
在一些情况下,有效载荷可以包括具有下式的埃斯佩拉霉素(esparamicin)化合物:
其中Res1、Res2、Res3、Res4、Res4、Res5、Res6、Res7或Res8中的一个是与末端唾液酸苷缀合的接头。当不是接头时,Res1可以是H、-S-S-CH3、C1-4烷基、C(O)CH3或任何足够不稳定的可被裂解以产生游离巯基的基团。当不是接头时,Res2、Res3、Res4、Res4、Res5、Res6、Res7和Res8独立地是H、C1-4烷基或C(O)C1-4烷基。
在某些情况下,有效载荷可以是具有下式的达内霉素化合物:
其中Rdy1、Rdy2、Rdy3、Rdy4、Rdy4、Rdy5或Rdy6中的一个是与末端唾液酸苷缀合的接头,并且其余都独立地是H或C1-4烷基。
在其他情况下,有效载荷可以包括具有下式的高尔夫霉素化合物:
其中Rgo是与末端唾液酸苷缀合的接头。
在一些实施方案中,有效载荷可以是多拉司他汀化合物,例如多拉司他汀10或多拉司他汀15类似物。在某些实施方案中,多拉司他汀化合物可以是奥瑞斯他汀,例如具有下式:
其中Rau1和Rau2中的一个是与末端唾液酸苷缀合的接头,并且另一个选自H和C1-4烷基。
在其他实施方案中,有效载荷可以包括具有下式的柔红霉素或多柔比星化合物:
其中Rdox是H或ORd7,X是O或NRd8两者之一,并且其中Rd1、Rd2、Rd3、Rd4、Rd4、Rd5、Rd6、Rd7或Rd8中的一个是与末端唾液酸苷缀合的接头,并且其余都独立地选自H和C1-4烷基。
在其他情况下,有效载荷可以包括安丝菌素衍生物,例如具有下式的美登素(mertansine)化合物:
其中Rme是与末端唾液酸苷缀合的接头。
在其他实施方案中,有效载荷可以包括长春花生物碱,例如具有下式的长春新碱/长春碱化合物:
其中Rv是CH3或C(O)H;
Rv1是OH、OAc或与末端唾液酸苷缀合的接头;
Rv2是OH、OCH3或与末端唾液酸苷缀合的接头;并且
Rv3不存在或者是与末端唾液酸苷缀合的接头。
在其他实施方案中,有效载荷可以包括具有下式的艾日布林化合物:
其中Rer是与末端唾液酸苷缀合的接头。
在其他实施方案中,有效载荷可以包括具有下式的喜树碱化合物:
其中Rc1是H或末端唾液酸苷的接头;
Rc2是H、CH2CH3或末端唾液酸苷的接头;
Rc3是H、OH、CH3;或末端唾液酸苷的接头;
Rc4是H或F;并且
Rc5是NH2或末端唾液酸苷的接头。
可包含在有效载荷中的其他化合物是具有下式的倍癌霉素化合物:
其中Rdu1是H或末端唾液酸苷的接头;并且
Rdu2是C1-8烷基、OC1-8烷基苯基、4-羟基苯基或末端唾液酸苷的接头。
在一些实施方案中,有效载荷包括具有下式的紫杉烷化合物:
其中Rtx1是–C(O)Ph、-C(O)OtBu或末端唾液酸苷的接头;
Rtx2是H或末端唾液酸苷的接头;
Rtx3是–C(O)CH3、OMe或末端唾液酸苷的接头;
Rt4是苯基或–CH=C(CH3)2。
在一些实施方案中,有效载荷包括具有下式的念珠藻素化合物:
其中Xcr是O或NH;
RCR2是H或CH3;并且
Rcr3是末端唾液酸苷的接头。
在一些情况下,有效载荷可以包括其他微管蛋白抑制剂(例如哈米特林(hemiasterlin)、HTI-286)、秋水仙碱、圆皮海绵内酯、根薯酮内酯A、根薯酮内酯B、根薯酮内酯AF、
根薯酮内酯AJ、根薯酮内酯AI-环氧化物、月桂内酯(laulimalide)、埃博霉素A或埃博霉素B。
接头将有效载荷与末端唾液酸苷结合,在一些实施方案中,可描绘如下:
其中有效载荷如上文所定义,Het表示杂环系统,L1从Het到有效载荷选自空或子接头,L2从Het到唾液酸苷选自空或子接头,x1是选自1、2、3、4、5、6、7或8的整数;x2是选自1、2、3、4、5、6、7或8的整数;并且x3是选自1、2、3、4、5、6、7或8的整数。对于其中一个接头包含多个有效载荷(即x1、x2或x3中的至少一者>1)的实施方案,有效载荷可以相同或不同。
对于特征为连接到同一唾液酸苷的多个接头-有效载荷部分的实施方案(即,QQ、XX、YY和ZZ中的至少两者是缀合的有效载荷),有效载荷的身份、Het、L1、L2、x1、x2和x3可以相同或不同。
示例性杂环系统包括稠合多环杂环系统。
其中H1表示杂环,并且A表示碳环或杂环,优选地在环骨架中具有8个原子的环。示例性8原子环包括环辛烷、环辛烯、氮杂环辛烷、氮杂环辛烯、2-氮杂环辛酮及其不饱和衍生物。在一些实施方案中,8原子环可以稠合到一个或多个芳环上。
由H1表示的杂环可以由(a)1,3偶极体或1,2,4,5四嗪两者之一与(b)应变炔烃或应变烯烃两者之一之间的环加成反应形成。优选的应变炔烃包括环辛炔,并且优选的应变烯烃包括反式环辛烯。杂环包括但不限于三唑、1,2哒嗪、噁唑、异噁唑、噁二唑以及此类环的饱和和部分不饱和的类似物。
在一些实施方案中,例如(x2和x3=1),杂环系统可以具有下式:
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其中x如上文所定义,RH1选自H、C1-4烷基、芳基、C1-4烷芳基,并且可以与L1或L2一起形成环;
RH2选自H、C1-4烷基、芳基、C1-4烷芳基,并且表示单键或双键。
在某些实施方案中,A环可具有下式:
其中RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’独立地选自空、H、F、Cl、Br、I、C1-4烷基、C1-4烷氧基、芳基;并且其中RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’中的任一个可以是L1或L2;气化站RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’中的任何两者或更多者可以一起形成环;例如RA1和RA2以及RA3和RA4各自可以一起形成芳环,而RA1’、RA2’、RA3’和RA4’各自为空;
当RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’中的一个是L1或L2时,W可以是CH2CH2。当RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’都不是L1或L2时,W可以是具有下式的基团:
其中L1/2表示L1或L2两者之一。
前提条件为当W、RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’中的一个包括L1时,W、RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’都不包括L2;并且
当W、RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’中的一个包括L2时,W、RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’都不包括L1。
在一些实施方案中,A环可以具有下式:
虽然上文没有描述,但是应该理解,如果L1连接到8原子环上,L2将连接到杂环上,反之亦然。
在一些实施方案中,L2可以为空或者具有下式的基团:
—L21—L22—L23—L24—L25—L26—,
其中:
L21键合到杂环系统,并且选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR21、OC(=O)、OC(=O)NR21、NR21C(=O)、NR21C(=O)O、NR21C(=O)、NR21C(=O)NR21、OC(=O)O,其中R21在每种情况下选自H和C1-4烷基;
L22选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR22、OC(=O)、OC(=O)NR22、NR22C(=O)、NR22C(=O)、NR22C(=O)O、NR22C(=O)NR22、OC(=O)O,其中R22在每种情况下选自H和C1-4烷基;
L23选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、S、聚(乙烯)、聚(缩醛);聚(甘油)、O、NR23、OC(=O)、OC(=O)NR23、NR23C(=O)、NR23C(=O)、NR23C(=O)O、NR23C(=O)NR23、OC(=O)O,其中R23在每种情况下选自H和C1-4烷基;
L24选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR24、OC(=O)、OC(=O)NR24、NR24C(=O)、NR24C(=O)、NR24C(=O)O、NR24C(=O)NR24、OC(=O)O,其中R24在每种情况下选自H和C1-4烷基;
L25选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR25、OC(=O)、OC(=O)NR25、NR25C(=O)、NR25C(=O)、NR25C(=O)O、NR25C(=O)NR25、OC(=O)O,其中R25在每种情况下选自H和C1-4烷基;
L26键合到唾液酸苷,并且选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR26、OC(=O)、OC(=O)NR26、NR26C(=O)、NR26C(=O)、NR26C(=O)O、NR26C(=O)NR26、OC(=O)O,其中R26在每种情况下选自H和C1-4烷基。
在某些实施方案中,L21、L22、L23、L24、L25和L26中的任何两者或更多者可以一起形成环。
本领域技术人员理解,对L21、L22、L23、L24、L25和L26中的每一个选择零会产生L2为空的实施方案。
在某些实施方案中,L26是NHC(O)NH,而在其他实施方案中,L26是杂环基或杂芳基,例如三唑、1,2哒嗪、噁唑、异噁唑、噁二唑及其饱和和部分不饱和的类似物。
在某些实施方案中,L21是亚芳基,例如1,4-亚苯基。
在一些实施方案中,L21为空、OC(O)NH、C1-8亚烷基,优选地C1-3亚烷基或亚芳基,例如1,4-亚苯基,L22为空或C1-8亚烷基,优选地C1-3亚烷基,L23为空、C(=O)NH、NHC(=O)、NHC(=O)O或OC(=O)NH;L24为空或聚(乙烯),L25为空或C1-8亚烷基,优选地C1-3亚烷基,并且L26为空或杂环基或杂芳基,例如三唑、1,2哒嗪、噁唑、异噁唑、噁二唑及其饱和和部分不饱和的类似物。
在某些实施方案中,L21是OC(O)NH,并且L22、L23、L24、L25和L26中的每一个都为空。
举例来说,对x、L21、L22、L23、L24、L25和L26的某些选择将产生具有以下部分结构的实施方案:
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其中L1、有效载荷、Rh2、A、QQ、ZZ、YY和XX如上文所定义。如上所述,QQ、ZZ、YY和XX中的超过一个可以是缀合的有效载荷,具有相同或不同的有效载荷以及相同或不同的接头。
在一些实施方案中,L1可以为空,或者是具有下式的基团:
—L11—L12—L13—L14—L15—L16—,
其中:
L11键合到杂环系统,并且选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR11、OC(=O)、OC(=O)NR11、NR11C(=O)、NR11C(=O)、NR11C(=O)NR11、OC(=O)O,其中R11在每种情况下选自H和C1-4烷基;
L12选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR12、OC(=O)、OC(=O)NR12、NR12C(=O)、NR12C(=O)、NR12C(=O)NR12、OC(=O)O,其中R12在每种情况下选自H和C1-4烷基;
L13选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR13、OC(=O)、OC(=O)NR13、NR13C(=O)、NR13C(=O)、NR13C(=O)NR13、OC(=O)O,其中R13在每种情况下选自H和C1-4烷基;
L14选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR14、OC(=O)、OC(=O)NR14、NR14C(=O)、NR14C(=O)、NR14C(=O)NR14、OC(=O)O,其中R14在每种情况下选自H和C1-4烷基;
L15选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR15、OC(=O)、OC(=O)NR15、NR15C(=O)、NR15C(=O)、NR15C(=O)NR15、OC(=O)O,其中R15在每种情况下选自H和C1-4烷基;
L16键合到有效载荷,并且选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR16、OC(=O)、OC(=O)NR16、NR16C(=O)、NR16C(=O)、NR16C(=O)NR16、OC(=O)O,其中R16在每种情况下选自H和C1-4烷基。
在某些实施方案中,L11、L12、L13、L14、L15和L16中的任何两者或更多者可以一起形成环。
L13可以是支链C1-8亚烷基、亚芳基、杂芳基或杂环基。举例来说,L13可以是具有下式的苯基:
其中y1是化合价允许的任何取代数。在以上示例性式中,x1可以是1、2、3、4或5。技术人员认识到其他可能的L13基团将产生不同的x1可能性。在其他情况下,L13可以是支链亚烷基,例如具有下式的亚甲基:
或具有下式的次甲基:
在一些实施方案中,L13可以包括聚合基团,例如具有下式的聚(甘油):
或者
具有下式的聚缩醛:
其中y为1-1,000;并且
R456选自氢或式(456)的部分:
并且R456是式456的部分的次数少于30次。
可裂解的L1基团将包含在环境条件下经历键断裂的至少一个官能团。可裂解基团包括酸敏感性基团、氧化还原敏感性基团和酶可裂解基团,例如蛋白酶可裂解基团。示例性酸敏感性基团包括席夫碱/亚胺、腙、硼酸酯和缩醛。示例性氧化还原敏感性基团包括硫代缩醛、草酸酯、二硫化物、肽和联硒化物基团。示例性酶可裂解基团包括肽片段Val-Lys、Val-Ala、Val-Arg、Phe-Lys和Val-Cit。
在一些情况下,L1可以包括自分解间隔区。自分解间隔基是指与选择性可裂解基团键合的化学部分,其中可裂解基团的活化导致一系列反应,最终从间隔基释放有效载荷。示例性自分解间隔基包括对氨基苯甲醇、对羟基苯甲醇、2-氨基咪唑-5-甲醇部分、邻或对氨基苯甲醇缩醛、氨基丁酸酰胺、1,2-二氨基乙烯、1,3-二氨基丙烯。
在一些实施方案中,L1可以包含自分解间隔基、可裂解基团和任选的附加接头,例如具有下式的缀合物:
其中RSIP是一个或多个自分解间隔基,RCL是可裂解基团,并且RL1当存在时是附加接头,x1.5是选自1、2、3、4、5、6、7和8的整数;并且x1.6是选自1、2、3、4、5、6、7和8的整数。
当有效载荷包括可官能化胺或醇基团时,有效载荷可以通过氨基甲酸酯、碳酸酯、膦酸酯或磺酸酯基团键合到L1或RSIP,例如
在下文描述的实施方案中,x1.5、x1.6和x3都被选择为1。在本发明的范围内还考虑了那些变量大于1的实施方案。
X是有效载荷中的氧或氮原子,并且Xz是O、NH或NC1-4烷基。上文描绘的苄基自分解间隔基可进一步被吸电子基团如硝基、氟、三氟甲基等取代一次或多次。Rea1和Rea2可以独立地选自H、C1-4烷基或(CH2CH2O)nCH2CH2OH,其中n为0、1、2或3。
举例来说,有效载荷的奥瑞斯他汀家族(部分描绘的结构)可以通过仲胺官能团(即,Rau1形成接头,并且Rau2是氢)缀合:
在一些情况下,RCL是肽基残基,例如,
其中z是1或0,z1是1或0,RCC是H、肽基、C1-6烷基、环烷基、芳基、杂芳基或杂环基,Raa1/Raa2和Raa3独立地选自H、任选被苯基取代的C1-6烷基、COOH、NH2、COHNH2、NHC(O)NH2。在某些实施方案中,z1是0并且Raa1是异丙基并且Raa2是(-CH2)4NH2、(-CH2)3NHC(O)NH2、(-CH2)3NHC(NH)NH2或CH3。在其他情况下,z1是0,Raa1是苄基,并且Raa2是(-CH2)4NH2。在另外的实施方案中,z1是1,Raa1是异丙基,Raa2是(-CH2)3NHC(O)NH2,并且Raa3是(-CH2)COOH。
肽基残基可以具有下式:
其中Rcc、z、z1、Raa1、Raa2、Raa3、RSIP如上文所定义。
在一些情况下,RSIP可以是具有下式的4-氨基苯甲醇,当z1为0时,举例如下:
或
当z1为1时,RSIP可以是4-氨基苯甲醇。
在一些情况下,RCL是具有下式的肽基团:
在其他实施方案中,RCL可以是葡糖酸残基,例如:
在其他实施方案中,可裂解基团可以是二硫化物:
其中Rds1和Rds2独立地选自H和C1-4烷基。在某些情况下,Rds1和Rds2都是氢,或者Rds1和Rds2都是甲基。在其他情况下,Rds1是氢,并且Rds2是C1-4烷基。
当有效载荷包括酮或醛时,可裂解基团可以包括腙:
腙的水解被认为释放了具有其原始羰基的有效载荷。举例来说,可以使用腙连接的多柔比星有效载荷:
包含羧酸官能团的有效载荷也可以通过腙连接:
其中Rhy表示H或C1-4烷基,优选地甲基。
举例来说,长春新碱型有效载荷可以与腙缀合:
RL1可以由下式表示:
其中
RL1A选自空、C1-10亚烷基、芳基、—(CH2CH2O)a—;
RL1B选自空、NHC(O)O、NHC(O)NH、OC(O)NH、O、NRzz,其中Rzz为H或C1-4烷基、NHC(O)、C(O)NH、C1-10亚烷基、芳基、—(CH2CH2O)a—;
RL1C选自空、C1-10亚烷基、芳基、—(CH2CH2O)a—;
RL1D选自空、NHC(O)O、NHC(O)NH、OC(O)NH、O、NRzz,其中Rzz为H或C1-4烷基、NHC(O)、C(O)NH、C1-10亚烷基、芳基、—(CH2CH2O)a—;
RL1E选自空、NHC(O)O、NHC(O)NH、OC(O)NH、O、NRzz,其中Rzz是H或C1-4烷基、NHC(O)、C(O)NH、C1-10亚烷基;芳基、—(CH2CH2O)a—;
其中在每种情况下,a独立地选自1、2、3、4、5、6、7、8、9或10。在其他实施方案中,a可以是1-50、10-100、5-10、5-25、25-50或50-100;
a1选自1、2、3或4;并且
a2选自1、2、3、4、5、6、7或8。
在一些情况下,RL1可以具有下式:
其中RL1A、RL1B、RL1C、RL1D和a1如上文所定义。
在一些情况下,RL1可以具有下式:
其中RL1A和a1如上文所定义。
制备方法
本文公开的糖缀合物可以通过在具有下式的糖缀合物前体之间进行环加成反应来制备:
其中Rfa、y和CBA如上文所定义;
Q是H或L2—Aq;
Z是OH或L2—Az;
Y是OH或L2—Ay;并且
X是OH或L2—Ax;其中
L2如上文所定义,并且Aq、Ax、Ay和Az各自是可链接基团,条件是Aq、Ax、Ay和Az中的至少一者是存在的,
其中有效载荷前体具有下式:
其中有效载荷和L1如上文所定义,并且Ap是糖缀合物前体中Aq、Ax、Ay和Az中的一个的互补可链接基团。
如本文所用,“可链接基团”是指在与细胞结合剂相容的条件下将经历环加成反应的官能团,即不会使聚合物链变性或断裂。互补是指糖缀合物前体和有效载荷前体中可链接基团之间的关系。一对互补的可链接基团将包括应变环状系统和1,3偶极体或四嗪。应变环状系统包括具有下式的环辛炔和反式环辛烯:
其中W1是炔烃或反式双键两者之一,例如,
其中RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’独立地选自空、H、F、Cl、Br、I、C1-4烷基、C1-4烷氧基、芳基;并且其中RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’中的任一个可以是L1或L2,前提条件为当RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’中的一个是L1或L2时,其余RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’都不是L1或L2;其中RA1、RA1'、RA2、RA2'、RA3、RA3'、RA4和RA4'中的任何两者或更多者可以一起形成环;例如,RA1和RA2以及RA3和RA4可以各自一起形成芳环,而RA1'、RA2'、RA3'和RA4'各自为空;
当RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’中的一个是L1或L2时,W可以是CH2CH2。当RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’都不是L1或L2时,W可以是具有下式的基团:
其中L1/2表示L1或L2两者之一。
在某些情况下,应变环状系统具有下式:
在一些情况下,应变环状系统是具有下式的反式环辛烯:
合适的1,3偶极体和四嗪包括:
(叠氮化物)、/>(重氮化物)、/>(硝酮)、/>(氧化偶氮化物)、(氧化腈)、/>(悉尼酮)以及/>(四嗪),
其中RH1和RH2如上文所定义。
在一些实施方案中,当糖缀合物前体包含四嗪时,有效载荷前体包含反式环辛烯,反之亦然,即糖缀合物前体包含反式环辛烯,有效载荷前体包含四嗪。当糖缀合物前体包含叠氮化物、重氮化物、硝酮、氧化偶氮化物、氧化腈或悉尼酮时,有效载荷前体可以包含环辛炔,反之亦然。通过利用不同对的Aq、Ax、Ay、Az和Ap基团之间的不同反应性,单个唾液酸苷残基可以高度可控地缀合到多个有效载荷。
糖缀合物前体和有效载荷前体之间的反应优选地在水性缓冲溶液中进行,例如磷酸盐、缓冲盐水(例如磷酸盐缓冲盐水、tris缓冲盐水)、柠檬酸盐、HEPES、tris和甘氨酸。优选地,缓冲溶液是磷酸盐缓冲盐水(PBS)或tris缓冲液。
该反应可以在约4℃至约50℃,更优选地约10℃至约45℃,甚至更优选地约20℃至约40℃,最优选地约30℃至约37℃范围的温度下进行。反应可以在约5至约9范围、优选地约5.5至约8.5范围、更优选地约6至约8范围内的pH下进行。最优选地,反应在约7至约8范围内的pH下进行。
在某些情况下,第一化合物可以包括上述2,6连接和2,3连接的糖缀合物前体的混合物。在其他实施方案中,糖缀合物前体可以基本上仅是2,6连接的寡糖,或者基本上在2,3连接的寡糖上。在一些实施方案中,糖缀合物前体可以是至少90%、至少95%、至少98%或至少99%的2,6-连接的寡糖,而在其他实施方案中,糖缀合物前体可以是至少90%、至少95%、至少98%或至少99%的2,3-连接的寡糖。
在优选的实施方案中,糖缀合物前体中的寡糖可以通过β-N-糖苷键结合至CBA:
/>
在某些实施方案中,细胞结合剂是抗体,并且寡糖通过天冬酰胺侧链经由β-N-糖苷键缀合至抗体:
在某些情况下,根据Kabat中陈述的EU索引,GlcNAc部分缀合至抗体的天冬酰胺297(Asn297)残基处。在y为2的某些实施方案中,GlcNAc部分可以缀合至Fc结构域中的两个Asn297残基。在y为1的实施方案中,GlcNAc部分可以缀合至Fc结构域中的一个Asn297残基。当抗体通过链延长或截短两者之一经修饰时,寡糖可以缀合至未经修饰抗体中对应于Asn297的天冬酰胺残基。
在某些实施方案中,糖缀合物前体的特征在于Q=L2—Aq,并且X、Y、Z中的每一个都是OH。在某些实施方案中,糖缀合物前体的特征在于Q=H、Z=L2—Az,并且X和Y都是OH。在又其他实施方案中,糖缀合物前体的特征在于Q=L2—Aq、Z=L2—Az,并且X和Y都是OH。在此类情况下,Aq和Az可以相同或不同。例如,Aq可以包含四嗪,而Az可以包含1,3偶极体,例如叠氮化物,反之亦然。在其他情况下,Aq可以包含反式环辛烯,而Az可以包含环辛炔。
糖缀合物前体可以通过使具有下式的二糖受体糖基化来获得:
其中Rfa、y和CBA如上文所定义,唾液酸苷供体具有下式:
其中Q、Z、Y和X如上文所定义,并且P*是核苷酸,例如尿苷磷酸、鸟苷磷酸或和胞苷磷酸。除非有相反的说明,否则术语“磷酸酯”包括任何数量的连续磷酸酯键,例如单磷酸酯、二磷酸酯、三磷酸酯等。在优选的实施方案中,唾液酸苷供体具有下式:
二糖受体和唾液酸苷供体可以在足以形成糖缀合物前体的条件和时间下通过至少一种唾液酸转移酶接触。唾液酸转移酶可以来源于哺乳动物、鱼类、两栖动物、鸟类、无脊椎动物或细菌。在一个实施方案中,唾液酸转移酶是α-(2,3)-唾液酸转移酶。在另一个实施方案中,唾液酸转移酶是α-(2,6)-唾液酸转移酶。在又一个实施方案中,唾液酸转移酶是α-(2,8)-唾液酸转移酶。在一个优选的实施方案中,唾液酸转移酶是α-(2,6)-唾液酸转移酶,优选地β-半乳糖苷α-(2,6)-唾液酸转移酶1(ST6Gal 1)。在一个优选的实施方案中,唾液酸转移酶是哺乳动物唾液酸转移酶。在其他实施方案中,唾液酸转移酶大鼠β-半乳糖苷α-2,6-唾液酸转移酶1(ST6Gal 1);多杀性巴氏杆菌(Pasteurella multocida)α-(2,3)-唾液酸转移酶;或CMP-N-乙酰神经氨酸-β-半乳糖胺-α-2,3-唾液酸转移酶(ST3Gal IV)。
唾液酸苷供体的糖基化可以在合适的缓冲溶液中进行,例如磷酸盐、缓冲盐水(例如磷酸盐缓冲盐水、tris缓冲盐水)、柠檬酸盐、HEPES、tris和甘氨酸。合适的缓冲液是本领域已知的。优选地,缓冲液是磷酸盐缓冲盐水(PBS)或tris缓冲液。糖基化优选地在约4℃至约50℃范围内,更优选地在约10℃至约45℃范围内,甚至更优选地在约20℃至约40℃范围内,最优选地在约30℃至约37℃范围内的温度下进行。糖基化可在约5至约9范围内,优选地在约5.5至约8.5范围内,更优选地在约6至约8范围内的pH下进行。最优选地,糖基化在约7至约8范围内的pH下进行。
在一些实施方案中,二糖受体可以通过β-N-糖苷键连接到CBA:
在某些实施方案中,细胞结合剂是抗体,并且二糖受体通过天冬酰胺侧链经由β-N-糖苷键缀合至抗体:
在某些情况下,根据Kabat中陈述的EU索引,GlcNAc部分缀合至抗体的天冬酰胺297(Asn297)残基处。在y为2的某些实施方案中,GlcNAc部分可以缀合至Fc结构域中的两个Asn297残基。在y为1的实施方案中,GlcNAc部分可以缀合至Fc结构域中的一个Asn297残基。当抗体通过链延长或截短两者之一经修饰时,寡糖可以缀合至未经修饰抗体中对应于Asn297的天冬酰胺残基。
二糖受体可以通过一种方法来制备,所述方法包括重塑抗体以得到具有下式的截短的N-聚糖受体的步骤:
其中Rfa、y和CBA如上文所定义,以及用半乳糖供体使截短的N-聚糖受体糖基化的步骤。
在一些实施方案中,截短的N-聚糖受体可以通过β-N-糖苷键连接到CBA:
在某些实施方案中,细胞结合剂是抗体,并且GlcNAc残基(具有或没有C-6岩藻糖)通过天冬酰胺侧链经由β-N-糖苷键缀合至抗体:
在一些优选的情况下,当Rfa是岩藻糖,优选地L-岩藻糖,甚至更优选地α-L-岩藻糖时,表征GlcNAc受体。
在某些情况下,根据Kabat中陈述的EU索引,GlcNAc残基缀合至抗体的天冬酰胺297(Asn297)残基处。在y为2的某些实施方案中,GlcNAc残基可以缀合至Fc结构域中的两个Asn297残基。在y为1的实施方案中,GlcNAc残基可以缀合至Fc结构域中的Asn297残基之一。当抗体通过链延长或截短两者之一经修饰时,寡糖可以缀合至未经修饰抗体中对应于Asn297的天冬酰胺残基。
截短的N-聚糖受体可以通过重塑如本文公开的任何合适的抗体来获得。在一些实施方案中,使用内切糖苷酶,例如分类为EC3.2.1.96的内切糖苷酶来进行重塑。在一些实施方案中,内切糖苷酶包括内切-β-N-乙酰葡糖胺糖苷酶D(内切糖苷酶D、糖苷内切酶-D或糖苷内切酶-D)、内切-β-N-乙酰葡糖胺糖苷酶H(内切糖苷酶H、糖苷内切酶-H或糖苷内切酶-H)、内切糖苷酶S(糖苷内切酶S、糖苷内切酶-S或糖苷内切酶-S)、内切-β-N-乙酰葡糖胺糖苷酶M(内切糖苷酶M、糖苷内切酶-M或糖苷内切酶-M)、内切-β-N-乙酰葡糖胺糖苷酶LL(内切糖苷酶LL、糖苷内切酶LL(EndoLL)、糖苷内切酶-LL或糖苷内切酶-LL)、内切-β-N-乙酰葡糖胺糖苷酶F1(内切糖苷酶F1、糖苷内切酶-F1或糖苷内切酶-F1)、内切-β-N-乙酰葡糖胺糖苷酶F2(内切糖苷酶F2、糖苷内切酶-F2或糖苷内切酶-F2)和内切-β-N-乙酰葡糖胺糖苷酶F3(内切糖苷酶F3、糖苷内切酶-F3或糖苷内切酶-F3)。
在一些实施方案中,在重塑步骤中可以使用两种或更多种类型的内切糖苷酶的组合。例如,几种内切糖苷酶可以是具有不同底物特异性的内切糖苷酶的组合,所述内切糖苷酶被分类为EC3.2.1.96。示例性组合包括内切糖苷酶D和内切糖苷酶S;糖苷内切酶S和糖苷内切酶LL;糖苷内切酶D和糖苷内切酶LL;糖苷内切酶D和糖苷内切酶H;糖苷内切酶S和糖苷内切酶H;内切糖苷酶F1和内切糖苷酶F2;糖苷内切酶F1和糖苷内切酶F3;糖苷内切酶F2和糖苷内切酶F3;糖苷内切酶D、糖苷内切酶S和糖苷内切酶LL;内切糖苷酶D、内切糖苷酶S和内切糖苷酶H,以及内切糖苷酶D、内切糖苷酶S和内切糖苷酶F1。
重塑可以在合适的缓冲溶液中进行,例如磷酸盐、缓冲盐水(例如磷酸盐缓冲盐水、tris缓冲盐水)、柠檬酸盐、HEPES、tris和甘氨酸。合适的缓冲液是本领域已知的。优选地,缓冲液是磷酸盐缓冲盐水(PBS)或tris缓冲液。重塑优选地在约4℃至约50℃范围内,更优选地在约10℃至约45℃范围内,甚至更优选地在约20℃至约40℃范围内,最优选地在约30℃至约37℃范围内的温度下进行。重塑可在约5至约9范围内,优选地在约5.5至约8.5范围内,更优选地在约6至约8范围内的pH下进行。最优选地,所述方法在约7至约8范围内的pH下进行。
在一些实施方案中,可以重塑抗体,使得GlcNAc残基(具有或没有C-6岩藻糖)与Asn297连接(在一条或两条重链上),并且抗体上不存在其他聚糖结构。
截短的N-聚糖受体可以根据常规技术纯化,或者可以直接用于半乳糖基化。如上所述的二糖受体可以通过将截短的N-聚糖受体、半乳糖供体和半乳糖转移酶组合来制备。合适的半乳糖基供体包括半乳糖基核苷酸,包括UDP-半乳糖。
本文公开的糖缀合物可以以含有糖缀合物和药学上可接受的载体的药物组合物的形式提供给有需要的患者。药学上可接受的载体可以是任何合适的药学上可接受的载体。它可以是一种或多种相容性固体或液体填充剂、稀释剂、其他赋形剂或适用于向人或兽医患者施用的包封物质(例如,生理学上可接受的载体或药理学上可接受的载体)。
组合物可以添加药学上可接受的赋形剂。例如,缓冲剂(包括例如乙酸的盐形式、柠檬酸的盐形式、硼酸的盐形式和磷酸的盐形式)、防腐剂(诸如苯扎氯铵、氯丁醇、对羟基苯甲酸酯和硫柳汞)。
适用于肠胃外施用的组合物方便地包含本发明组合物的无菌水性制剂,其优选地与接受者的血液等渗。这种水性制剂可以根据已知的方法使用合适的分散剂或湿润剂和悬浮剂来配制。无菌可注射制剂还可以是在无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬剂,例如在1,3-丁二醇中的溶液。可采用的可接受的媒介物和溶剂为水、林格氏溶液(Ringer's solution)和等渗氯化钠溶液。此外,无菌的不挥发性油通常用作溶剂或混悬介质。为此,可采用任何温和不挥发性油,诸如合成的单甘油酯或二甘油酯。此外,脂肪酸(诸如油酸)可用于可注射液的制备。适用于口服、皮下、静脉内、肌内等施用的载体制剂可见于Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pa.。
本发明的药物组合物的制备及其各种施用途径可以根据本领域熟知的方法进行。参见例如Remington:The Science and Practice of Pharmacy,Mack Publishing Co.,第20版,2000;以及Sustained and Controlled Release Drug Delivery Systems,J.R.Robinson编,Marcel Dekker,Inc.,New York,1978。可用于本发明的递送系统包括延时释放、延迟释放和持续释放的递送系统,使得本发明组合物的递送发生在待治疗部位致敏之前,并有足够的时间引起该部位致敏。本发明的组合物可以与其他治疗剂或疗法结合使用。此类系统可以避免重复施用本发明的组合物,从而增加受试者和医生的便利性,并且可能特别适用于本发明的某些组合物。
许多类型的释放递送系统是可获得的,并且是本领域普通技术人员已知的。合适的释放递送系统包括基于聚合物的系统,例如聚(丙交酯-乙交酯)、共聚草酸酯、聚己内酯、聚酯酰胺、聚原酸酯、聚羟基丁酸和聚酸酐。含有药物的前述聚合物的微胶囊描述于例如美国专利号5,075,109中。递送系统还包括非聚合物系统,其为脂质,包括甾醇诸如胆固醇、胆固醇酯和脂肪酸或中性脂肪诸如甘油一酯、甘油二酯和甘油三酯;水凝胶释放系统;硅橡胶(sylastic)系统;基于肽的系统;蜡涂层;使用常规粘合剂和赋形剂的压制片剂;部分融合的植入物;等等。具体实例包括但不限于:(a)侵蚀系统,其中活性组合物以一种形式包含在基质中,如美国专利号4,452,775、4,667,014、4,748,034和5,239,660中所述;和(b)扩散系统,其中活性组分以受控的速率从聚合物中渗透出来,如美国专利号3,832,253和3,854,480中所述。此外,可以使用基于泵的硬件递送系统,其中一些适于植入。
通常,本文公开的糖缀合物以合适的包装提供,例如小瓶、小袋、安瓿和/或任何适于治疗或检测方法的容器。试剂盒组分可以以浓缩物(包括冻干组合物)的形式提供,其可以在使用前进一步稀释,或者它们可以以使用浓度提供。
实施例
以下实施例仅用于说明本发明,并不旨在以任何方式限制本发明的范围。
试剂和材料
除非另有说明,否则所有化学品均来自Sigma。胞苷-5’-(5-乙酰氨基-9-叠氮基-3,5,9-三脱氧-β-D-甘油基-D-半乳糖-2-非呋喃吡喃糖酸单磷酸)(CMP-Neu5Ac9N3)和重组大鼠α-(2,6)-唾液酸转移酶(GFP-ST6Gal I)根据先前的报告(http://dx.doi.org/10.1002/anie.201307095)制备。
内切-BCN-PEG4-酸可以根据WO 2016/053107第142页中描述的程序制备,并且也可以从许多商业供应商处获得。
内切-BCN-PEG4
实施例1:可链接有效载荷的合成
如下将含有单个伯胺基团的细胞毒性弹头(本文称为WH-NH2)与内切-BCN-PEG4缀合。
将WH-NH2(600mg,1.0当量)、内切-BCN-PGE4-酸(1.2当量)和EDCl-HCl(1.2当量)溶于DCM(15体积,2% MeOH)中,并在0-5℃下搅拌。反应完成后,用纯化水(10体积)淬灭反应。分离水层,用盐水洗涤有机层,用硫酸钠干燥并减压浓缩,得到粗制WH-NH-内切-BCN-PEG4(650mg,93.2%,73.57% HPLC纯度)。
通过RP-HPLC(C18,MeCN:H2O)纯化粗制WH-NH-内切-BCN-PEG4(400mg),合并含有产物的级分并冻干,得到呈白色固体的WH-NH-内切-BCN-PEG4(130mg,33%,94.61%HPLC纯度)。
WH-NH-内切-BCN-PEG4
实施例2:CMP-Neu5N3和CMP-Neu9N3的合成。
将唾液酸醛缩酶(0.2U/μL,5μL)和CMP-唾液酸合成酶(0.2U/μL,5μL)添加到N-叠氮乙酰基-D-甘露糖胺(5mg,0.019mmol)于tris-HCl缓冲液(100mM,pH 8.9,20mM MgCl2,1.9mL)中的含有丙酮酸钠(10.5mg,0.095mmol)和CTP(10mg,0.019mmol)的混合物中。将试管在37℃下温育,并通过TLC(EtOH:NH4HCO3水溶液(1M)7:3,v:v)监测反应进程,5小时后表明反应完成。添加EtOH(3mL),通过离心去除沉淀,并在减压下浓缩上清液。将残余物重新溶解在蒸馏水(500μL)中,随后冻干,以提供粗物质,将其应用于Biogel细P-2柱(50*1cm,用0.1M NH4HCO3在4℃下在黑暗中洗脱)。通过TLC检测产物,合并合适的级分并冻干,以提供呈无定形白色固体形式的CMP-Neu5N3(10.1mg,81%)。
1H NMR(300MHz,d2o)δ7.82(d,J=7.5Hz,1H,H-6,cyt),5.97(d,J=7.6Hz,1H,H-5,cyt),5.84(d,J=4.2Hz,1H,H-1,rib),4.18(dd,J=7.4,4.4Hz,2H,H-2+H-3,rib),4.14–4.04(m,4H,H-4+H-5rib,H-6Neu),4.04–3.97(m,1H,H-4),3.95(s,2H,N3CH2CO),3.87(t,J=10.2Hz,1H,H-5),3.82–3.74(m,1H,H-8),3.72(m,1H,H-9a),3.49(d,J=11.8Hz,1H,H-9b),3.30(d,J=9.5Hz,1H,H-7),2.36(dd,J=13.3,4.6Hz,1H,H-3eq),1.51(td,J=12.0,5.6Hz,1H,H-3ax)。HRMS(ESI):C20H30N7O16P[M-H]-m/z计算值:654.1414;实测值:653.9477。
CMP-Neu9N3按照报告的程序制备。将CTP(126mg,0.24mmol)添加到5-乙酰氨基-9-叠氮基-3,5,9-三脱氧-D-甘油-D-半乳糖-2-壬磺酸(50mg,0.15mmol)于含有MgCl2(20mM)的Tris-HCl缓冲液(0.1M,9mL,pH 8.9)中的溶液中。添加来自脑膜炎奈瑟菌(N.meningitis)的重组CMP-唾液酸合成酶(4.0U)和来自酿酒酵母(S.cererisiae)的无机焦磷酸酶(2.0U),并且将反应混合物在37℃下振荡温育。通过TLC(异丙醇:20mM NH4OH,4:1,v:v)监测反应进程,3h后指示反应完成。添加乙醇(80mL),并将混合物置于冰上2h,之后离心。倾析上清液,将沉淀(主要是无机盐)再悬浮于EtOH(30mL)中,在冰上冷却1h并离心。将合并的乙醇提取物在真空中浓缩,得到粗产物(168mg)。将乙醇(1.8mL)缓慢添加到溶解在H2O(0.2mL)中的物质中,并且立即发生沉淀。将混合物在冰上保持2h。接下来,在离心后移除上清液,并在超细Biogel P-2柱上干燥并纯化白色沉淀,用0.1M NH4HCO3在4℃下洗脱。通过UV和TLC(如上)检测合适的级分,收集,在真空中浓缩(浴温<25℃)并冻干,以得到CMP-Neu9N3(60mg,62%)。1H NMR(含有0.1M NH4HCO3的D2O,600MHz):δ7.82(d,1H,J5,6=7.8Hz,H-6,cyt),5.97(d,1H,J5,6=7.8Hz,H-5,cyt),5.82(d,1H,J1,2=4.8Hz,H-1rib),4.17(t,1H,J=4.8),4.13(t,1H,J=4.8Hz),4.08(m,3H,),3.99(d,1H,J=12.0Hz),3.90(m,2H),3.78(t,1H),3.49(dd,1H,J=2.4,13.2Hz,H-9a),3.35(dd,1H,J=6.0,13.2Hz,H-9b),3.31(dd,1H,J=9.6Hz),2.33(dd,1H,J3eq,4=4.8Hz,J3eq,3ax=13.2Hz,H-3eq),1.90(s,3H,Me),1.55(ddd,1H,J3ax,P=6.0Hz,J3ax,3eq=13.2Hz,J3ax,4=12.0Hz,H-3ax);13C NMR(含有0.1MNH4HCO3的D2O,600MHz):δ174.2,170.4,166.0,160.7,141.4,96.5,88.8,82.9,74.2,71.5,69.3,69.1,67.4,64.9,53.0,51.7,41.0,22.0;ESI-MS:C20H28N7O15P2-[M+H]-计算值:m/z:638.1470;实测值638.1421。
实施例3:聚糖重塑
分析由胰蛋白酶消化抗体产生的糖肽
通过Speed Vac(Savant SC 110)干燥IgG抗体的等分试样,并将其再溶解在碳酸氢铵缓冲液(50mM,pH 8.4)中,并在100℃下加热5分钟,以使糖蛋白变性。将混合物冷却至室温后,添加胰蛋白酶(胰蛋白酶/IgG=1/30,w/w),并将溶液在37℃下温育22h,之后将其加热至100℃持续5分钟以使胰蛋白酶失活。将该溶液通过C18反相柱,用5%乙酸水溶液洗涤,并用2-丙醇/5%乙酸(20-100%)梯度洗脱,得到糖肽,使该糖肽经历装备有XBridge-BEH酰胺-HILIC柱(Waters,Milford,MA,USA;2.1×150mm,3.5μm粒度)的LCMS-IT-TOF质谱仪(Shimadzu)。在20℃下以0.16ml/min的流速进行这些分离,流动相A由100mM甲酸铵水溶液组成(用甲酸调节至pH 3.4-3.6)并且流动相B为纯ACN。
天然完整IgG分析
在之前的分析中,使用ZEBA旋转柱对样品进行脱盐,稀释至2mg/ml,注射0.5uL(=1ug)。使用配备AcquityC18 2.1x 50mm的Agilent 1290Infinity LC运行/注射样品,梯度为20-40% B(=70% IPA/20% ACN/10% H2O/0.1% FA)对比A(H2O中的0.1% FA),在70℃下10分钟。检测器是Agilent 6560Ion Mobility Q-TOF LC/MS,其中出于此目的,仅使用了Q-TOF功能。使用Agilent’s Bioconfirm软件进行运行后分析和解卷积。
用于使用App2修饰IgG的一般程序(图2)
糖苷内切酶S.处理
使用从酿脓链球菌克隆并在大肠杆菌中作为与几丁质结合结构域的融合体过表达的糖苷内切酶S进行IgG聚糖的修饰。(New England BioLabs)。向30mM组氨酸、200mM山梨醇和0.02%吐温-20中的IgG抗体(10mg/mL)中添加10mM Tris、25mM NaCl、2.5mM EDTA、2.5mM CaCl2、25mM乙酸钠中的糖苷内切酶S(0.13mL,100kU/mL)。将所得溶液在37℃下温育约48小时,随后进行蛋白A琼脂糖凝胶柱(GE Healthcare)纯化,进行交换缓冲液并浓缩至1.2mL含有20mM MnCl2的50mM MOPS。
IgG的半乳糖基化
通过将β-1,4-半乳糖基转移酶(200μg/mL)添加到50mM MOPS、20mM MnCl2、10mMUDP-半乳糖、pH 7.2、80μg/mL BSA、85U/mL小牛小肠碱性磷酸酶中的糖苷内切酶S处理产生的物质中,并在37℃下温育70h,实现了携带截短的N-聚糖的IgG的半乳糖基化。为了确保完全半乳糖基化,向反应中添加额外等份试样的UDP-半乳糖和半乳糖基转移酶,并在37℃下再温育24h。使用蛋白A琼脂糖凝胶柱纯化半乳糖基化IgG,并使用Amicon 10kDa截止自旋浓缩器(Millipore)将溶液在50mM二甲胂酸盐(pH 7.6)中交换。
IgG的唾液酸化
在pH 7.6的50mM二甲胂酸盐、14mg/mL IgG、8mM CMP-Neu5N3、90μg/ml BSA、90U/mL小牛肠碱性磷酸酶和0.4mg/mL GFP-ST6Gal I中进行半乳糖基化IgG的唾液酸化,并在37℃下温育4天,随后进行蛋白A琼脂糖凝胶柱纯化,并将缓冲液交换成50mM二甲胂酸盐。如先前所述,使用Shimadzu LCMS-IT-TOF质谱仪通过LC-MS监测唾液酸化的程度。在每48小时温育后,使用Amicon 10kDa截止自旋浓缩器将样品与50mM二甲胂酸盐(pH7.6)进行缓冲液交换以去除ST6Gal I抑制剂CMP,并将额外等分试样的CMP-Neu5N3和α2-6唾液酸转移酶添加回到该洗涤的制剂中。
关键的发现是野生型人β4GalT1半乳糖基转移酶将半乳糖残基转移到α1-6岩藻糖基化GlcNAc残基上的意外能力。该反应在自然界中不会发生。此外,发现所得二糖可通过由ST6Gal1唾液酸转移酶添加叠氮基经修饰的唾液酸来进一步经修饰。
实施例4:与可链接有效载荷的缀合
通过添加7.5摩尔当量的WH-NH-内切-BCN-PEG4(实施例1)(在DMA中的10mM储备液)和DMA,将实施例3的pH 7.6 50mM二甲胂酸盐缓冲液中的10mg/ml Her2缀合至20%v/v的最终共溶剂水平。将缀合反应在20℃水浴中温育过夜,并且然后通过PLRP纯化。PLRP的DAR达到1.8。
所得糖缀合物在本文中称为‘Her-App2’。
实施例5:双触角抗体药物缀合物的制备
根据Li等人2014(Angew.Chem.Int.Ed.Engl.,2014年7月7日;53(28):7179-82)中所述的方法对赫赛汀抗体上N连接的寡糖进行重塑。参见图1。通过添加20摩尔当量的WH-NH-内切-BCN-PEG4(实施例1)(在DMA中的10mM储备液,图1中提供的结构)和DMA,使50mM二甲胂酸盐缓冲液pH 7.6中的9.2mg/ml重塑Her2(实施例3)缀合至20%v/v的最终共溶剂水平。将缀合反应在20℃水浴中温育66小时。PLRP的DAR达到1.4。
所得糖缀合物在本文中称为‘Her-App1’。
重组唾液酸转移酶ST6Gal1对抗体Fc区双触角N-聚糖的α(1,3)-臂和α(1,6)-臂的活性可以通过控制CMP-唾液酸和抗体的比率来区分。这可能导致ADC具有DAR2或DAR4。然而,需要小心控制所需的反应化学计量,这会影响批次之间的产品再现性。
实施例6:糖缀合物性质
物理性质
通过疏水作用色谱(HIC)分析Her-App1和Her-App2。使用柱MabPac HIC-丁基,5μm,4.6x100mm柱(Thermo,#882558,批号01425138,序列号001303)和MabPac HIC-丁基,5μm,4.6x 10mm保护柱(Thermo,#882559,批号1425011)进行此分析。流动相A为1.5M(NH4)2SO4、25mM NaPO4(pH 7.4),流动相B为80%25mM NaPO4(pH 7.4)、20% CH3CN。以每分钟0.8ml运行测定,并且柱温为25℃。使用10μl样品以1mg/ml进行分析。
HIC显示了两个ADC之间的明显差异,Her-App1分离成多种疏水物质,而Her-App2作为一个更亲水性峰洗脱(参见图4)。
鉴于Her-App2具有比Her-App1少得多的糖残基(比较图2和3)的事实,Her-App2相对于Her-App1的亲水性增加初看是令人惊讶的。糖残基是非常亲水的部分,表明具有更多糖残基的缀合物将具有更高的亲水性。事实并非如此,这表明ADC的抗体、寡糖和药物接头元件之间发生了更复杂的相互作用。
与Her2的体外结合
Her2是赫赛汀抗体的同源抗原。通过ELISA测定Her-App1和Her-App2的结合。在室温下用0.5μg/mL重组人Her2包被Maxisorp ELISA板,之后用3% BSA封闭。在66.6和0.016nM之间的检测缓冲液(0.1% BSA/0.05%吐温)中以四分稀释制备样品滴定。然后将样品在抗原包被板上温育1小时。将与HRP缀合的小鼠抗人抗体用于检测(Sanquin M1328),并温育1小时,之后洗涤并添加检测剂TMB持续10分钟,之后用HCl终止反应。在Spectramax板读取器上在450nm下获得结合吸光度数据。
为了进行比较,还评估了Her2与‘Her-C220’[一种非缀合形式的赫赛汀,其中4个链间半胱氨酸中的3个已被V(重链中)或S(轻链中)两者之一取代]和B12[一种抗HIV-1蛋白的非缀合单克隆抗体;在此处用作对照]的结合。
ADC/抗体 | IC50(nM) |
Her-App1 | 0.23 |
Her-App2 | 0.38 |
Her2-C220 | 0.17 |
B12 | 未结合 |
两个ADC以相似的亲和力结合至Her2。
体外细胞毒性
测定Her-App1和Her-App2针对Her2+ve N87细胞的体外细胞毒性。使用“解冻并进行”细胞毒性测定来确定细胞毒性,从低温储存中取出N87细胞,并在EDGE板上以5×104个细胞/mL(5×103个细胞/孔)接种,然后在37℃/5% CO2/绝对湿度下温育至少2小时。使用最终阴性对照,从500nM到0.4768pM一式两份制备测试和对照样品的11点1/4系列滴定。将滴定的样品添加到含有细胞的EDGE板中,并在37℃/5% CO2/绝对湿度下温育5天。添加Celltiter Aqueous One溶液,并将板在37℃/5% CO2/绝对湿度下温育最后一次,然后使用SpectraMax板读取器测量490nm处的吸光度。
为了进行比较,还评估了‘Her2xADC’[Her2-C220缀合至替丝瑞林的C220残基]和B12-C220-SG3249[B12抗体缀合至替丝瑞林的C220残基]的细胞毒性。
ADC | IC50(pM) |
Her-WH-App1 | 24.7 |
Her-WH-App2 | 21.7 |
Her2xADC | 17.9 |
B12-C220-SG3249 | 2994 |
发现Her-App1和Her-App2彼此具有相似的细胞毒性,并且与基准Her2xADC也具有相似的细胞毒性。用非Her2结合B12对照ADC观察到明显更少的细胞杀伤。
体内功效
在乳腺癌Her2+ve BT474异种移植物模型中测量Her-App1和Her-App2缀合物的体内功效。为了进行比较,还评估了‘Her2xADC’的体内功效。
在研究的第1天雌性严重联合免疫缺陷小鼠(Fox Chase CB17/Icr-Prkdcscid/IcrIcoCrl,Charles River)为10周龄,并且体重(BW)范围为16.1g至21.8g。在肿瘤植入当天,每只测试小鼠接受1mm3 BT474片段皮下植入右侧,并且监测肿瘤生长,直到平均大小接近100至150mm3的目标范围。使用卡尺在两个维度上测量肿瘤,并且使用下式计算体积:
肿瘤体积(mm3)=w2 x 1/2
其中w=肿瘤的宽度并且l=肿瘤的长度(mm)。假设1mg等于1mm3的肿瘤体积,可估计肿瘤重量。
肿瘤植入后三十六天,指定为研究的第1天,将动物分组,每组由十只小鼠组成,小鼠的个体肿瘤体积为75至172mm3,并且组平均肿瘤体积为119–121mm3。在研究的第1天,经由尾静脉注射以单次注射(qd x 1)静脉内(i.v.)施用药物。给药体积为每20克体重0.2mL(10mL/kg),并且针对每只个别动物的体重按比例调整。每周使用卡尺测量肿瘤两次,并且当肿瘤达到1000mm3的终点体积时或研究结束时(第59天)(以先到者为准),对每只动物实施安乐死。结果在图4中示出。
Her2xADC和Her-App1的最小有效剂量(MED)>0.6mg/kg,而Her-App2的MED被确定为0.3mg/kg。
耐受性:大鼠毒理学研究
在单次静脉给药大鼠耐受性研究中评估Her2xADC、Her-App1和Her-App2。
雄性Sprague Dawley大鼠(n=3/组)在第1天接受4mg/kg的Her-App1、2mg/kg的Her-App2或4mg/kg的Her-App1给药,在给药后第21天进行尸检。通过临床病理学活体取样(第8天和第21天的血液)和药代动力学重复取样,对体重和食物消耗量进行频繁监测。尸检时,对所选器官进行肉眼观察,称重并保留以进行可能的组织病理学检查。
评估1.5mg/kg的Her2xADC,对雄性Sprague Dawley大鼠进行单次静脉注射与总体体重增加减少(总体体重增加减少39%)相关,与食物消耗量减少相关。白细胞数量在第8天减少(-61%),在第21天有恢复的迹象。尸检时,观察到胸腺、脾脏、睾丸和前列腺/精囊重量减少,并且肾上腺重量增加。
Her-App1在4mg/kg时耐受性差,导致3只动物中有2只在给药后11天提前安乐死。这些动物的体重增加显著减少,给药后没有预期的体重增加。几个血液学参数在第8天显著降低(网织红细胞(-93%)、白细胞(-86%)和血小板(-66%)),没有恢复的迹象。
Her-App2在2和4mg/kg时具有良好的临床耐受性。体重增加量呈剂量依赖性减少(4mg/kg时,总体体重增加减少55%),与食物消耗量减少一致。几个血液学参数在第8天降低(网织红细胞(-52%)、白细胞(-68%)和血小板(-22%)),在第21天有恢复的迹象。尸检时,发现胸腺、肝脏和脾脏重量出现剂量依赖性减少,肺重量增加,其中两只动物在4mg/kg剂量下出现肾脏苍白。
Her2xADC的最大耐受剂量(MTD)为1.5mg/kg(测试的最高剂量)。
Her-App1的最大耐受剂量(MTD)低于4mg/kg。
Her-App2的最大耐受剂量(MTD)为4mg/kg。
治疗指数
ADC的治疗指数(TI)可以通过首先确定MED和MTD的人体等效剂量并且然后将MTD的HED除以MED的HED来计算,如下所示:
MED:小鼠的最小有效剂量 MTD:最大耐受剂量
HED:人体当量剂量 TI:治疗指数
Her-App2的治疗指数显示为Her-PL1603-App1的至少两倍。
Her-App2的治疗指数显示为Her2xADC的约6倍。
Her-App1和Her-App2在大鼠体内的药代动力学(PK)
给药后1、3、6、48、72、168、336和480h,获取以2和/或4mg/kg单剂量的Her-App1和Her-App2给药的大鼠的血浆样品。如Zammarchi Blood vol 131(10),1094-1105 2018中所述,分析样品的总人IgG和WH缀合的IgG。
图5A示出了总IgG和WH-IgG(即弹头缀合的IgG)在4mg时Her2-App1的可比较的PK曲线,这表明缀合物高度稳定。
图5B示出了总IgG和WH-IgG在2和4mg时Her2-App2的可比较的PK曲线,这表明缀合物高度稳定。
关于性质的进一步评论
如以上实施例1-4中所述的‘方法2’的另一个优点在于它更容易将DAR控制为2。在使用完整聚糖的早期方法中,更难以将DAR控制为2,需要小心控制反应条件。
此外,方法2消除了Fc(γ)受体活性,这对于许多ADC应用是有利的。
实施例7–附加缀合
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美坦辛DIBO
长春碱DIBO
将DMF中的美坦辛DIBO或长春碱-DIBO添加到pH 7.6二甲胂酸盐缓冲液中的实施例3的重塑抗体中。将混合物在室温下置于振荡器中2h,通过在7KDa截止Zeba旋转柱(Thermo Scientific)中用二甲胂酸盐缓冲液或PBS缓冲液洗涤来去除过量的DIBO试剂。
缀合
根据上述实施例4中描述的一般程序,将上述美坦辛和长春碱药物接头中的每一种缀合至Her2抗体。在每种情况下,通过天然完整IgG分析观察到修饰的完整转化(即DAR=2)。
实施例8
方案1.酯酶可裂解和可点击PCTX的合成.试剂和条件:a)琥珀酰酐,吡啶,3h(92%);b)三(乙二醇)-1,8-二胺,CH2Cl2中的三乙胺,3h(95%);c)HATU,于DMF中的DIPEA,24h(90%)。
4-(((1S,2R)-1-苯甲酰氨基-3-(((4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-二乙酰氧基-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-9-基)氧基)-3-氧代-1-苯基丙-2-基)氧基)-4-氧代丁酸(8-2)
将8-1(0.05g,0.06mmol)和琥珀酸酐(0.076g,0.76mmol)于1.2ml吡啶中的反应混合物在室温下搅拌3h。3h后,将吡啶在真空中蒸发至干。然后用2ml水处理残余物,搅拌20分钟,并过滤。然后将所得沉淀溶解在丙酮中,缓慢添加水,并收集产物的细晶体。这产生0.048g(86%)的8-2。
1H NMR(DMSO-d6,500MHz):δ12.25(br s,1H),9.19(d,1H),7.94-8.00(d,2H),7.81-7.85(d,2H),7.70-7.73(m,1H),7.63-7.66(m,2H),7.49-7.56(m,1H),7.45-7.50(m,2H),7.40-7.44(m,4H),7.11-7.21(m,1H),6.27(s,1H),5.76-5.83(t,1H),5.73(s,1H),5.50-5.54(t,1H),5.40(d,1H),5.34(d,1H),4.88-4.90(d,2H),4.61(s,1H),4.08-4.11(m,1H),3.97-4.02(m,2H),3.56(d,1H),2.57-2.63(t,2H),2.27-2.37(m,1H),2.22(s,3H),2.09(s,3H),1.76-1.83(m,1H),1.74(s,3H),1.58-1.65(t,1H),1.48(s,3H),1.21(s,1H),0.95-1.00(d,6H)。
13C NMR 134,131.9,130,129.2,129.20,129.09,128.85,128.09,127.93,84.15,75.76,75.11,75,75.14,71.41,71,55.34,54.43,46.51,40.28,37.11,37,34.86,34.86,29.28,29,26.74,23.11,22.05,21.16,14.39,10.63,10.33。MALDI HRMS C51H55NO17 m/z[M+Na+]976.35;实测值976.346。
碳酸双环[6.1.0]壬-4-炔-9-基甲基(4-硝基苯基)酯(8-3)
向((1R,8S,9r)-双环[6.1.0]壬-4-炔-9-基甲醇(100mg,0.66mmol)于CH2Cl2(10mL)中的溶液中添加吡啶(134.70μL,1.66mmol)和氯甲酸4-硝基苯酯(200mg,1mmol)。在室温下搅拌3h后,用饱和氯化铵溶液(10mL)淬灭反应混合物,并用CH2Cl2(3×10mL)提取。使用MgSO4干燥有机层,并在真空中浓缩。通过硅胶柱色谱(EtOAc:己烷,1:5)进一步纯化残余物,得到呈白色固体的所需产物8-3(162mg,77%)。
1H NMR(CDCl3,500MHz):δ8.28(d,2H),7.40(d,2H),4.31(d,2H),2.15-2.5(m,6H),1.35-1.45(m,2H),0.64-0.75(m,3H).13C NMR(150MHz,CDCl3):δ155.6,152.5,145.3,125.3,121.7,98.7,68.0,29.0,21.3,20.5,17.2。
(2-(2-(2-氨基乙氧基)乙氧基)乙基)氨基甲酸((1R,8S,9r)-双环[6.1.0]壬-4-炔-9-基甲酯(8-4)
将Et3N(339μL,1.945mmol)添加到8-3(150mg,0.389mmol)和三(乙二醇)-1,8-二胺(569μL,3.89mmol)于CH2Cl2(10mL)中的搅拌溶液中。将反应混合物搅拌3h,之后在减压下去除溶剂。通过在latrobead上进行快速色谱(MeOH/CH2Cl2,5%至25%,v/v)纯化残余物,得到呈淡黄色液体的化合物8-4(116mg,92%)。
1H NMR(CDCl3,500MHz):δ5.48(br s,NH),4.15(d,2H),3.5-3.75(m,8H),3.4(brs,2H),2.9(br s,2H),2.5(br s,2NH2),2.16-2.36(m,6H),1.5-1.65(m,2H),1.2-1.44(m和s,3H),0.79-1.00(m,2H)13C NMR(150MHz,CDCl3):δ98.8,73.4,70.3,70.2,70.1,62.7,41.7,40.8,29.1,21.4,20.1,17.8.MALDI HRMS C17H28N2O4 m/z计算值(M+H)+325.2124,实测值:325.2122。
二乙酸(4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((19R)-19-((S)-苯甲酰氨基(苯基)甲基)-1-(双环[6.1.0]壬-4-炔-9-基)-3,14,17-三氧代-2,7,10,18-四氧杂-4,13-二氮杂二十碳烷-20-酰基)氧基)-12-(苯甲酰氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(8-5)
将8-2(5mg,0.0052mmol)和8-4(2.1mg,0.0062mmol)的混合物溶解在无水DMF(1ml)中。依次添加N,N-二异丙基乙胺(2.73μL,0.0157mmol)和1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(HATU,3mg,0.00786mmol),并将反应混合物在室温下搅拌2h。在室温下搅拌反应2h后,TLC显示反应完全。在减压下蒸发溶剂,并且通过硅胶色谱使用EtOAc己烷(5至15%,v/v)作为流动相来纯化粗产物,得到呈白色固体的纯8-5(6.5mg,98%)。
1H NMR(CDCl3,500MHz):δ8.15(d,1H),7.83(d,1H),7.63(t,1H),7.52(dt,2H),7.48–7.37(m,3H),7.32(s,1H),6.30(s,1H),6.25–6.13(m,1H),5.69(d,1H),5.46(d,0H),5.31(s,0H),5.03–4.92(m,0H),4.32(d,1H),4.21(d,1H),4.13(q,1H),3.96(d,1H),3.81(d,1H),3.60(d,4H),3.48(s,1H),3.37(s,2H),2.77(t,1H),2.54(d,2H),2.44(s,1H),2.39(d,1H),2.35–2.28(m,1H),2.24(s,2H),2.15(d,1H),2.06(s,1H),1.93(s,2H),1.69(s,2H),1.64(s,4H),1.50(dd,3H),1.33–1.20(m,5H),1.14(s,2H),0.93–0.85(m,1H),0.73(s,1H)。
13C NMR(150MHz,CDCl3):δ130.22,127.36,133.70,128.72,131.85,126.78,129.00,128.43,75.61,71.74,53.19,75.08,74.37,84.43,72.10,76.42,76.42,69.23,45.60,70.23,69.77,39.36,40.73,43.72,29.44,35.13,30.76,22.68,33.27,35.47,21.39,21.39,35.48,14.82,35.57,9.62,23.39,9.62,18.63,17.32,33.28,22.68,31.61,29.66,26.80,22.13,14.12,22.87,23.69。MALDI HRMS C68H81N3O20 m/z计算值(M+Na)+1282.54,实测值:1282.534。
缀合
根据上述实施例4中描述的一般程序,将上述可链接药物接头(化合物8-5)缀合到Her2抗体。通过天然完整IgG分析观察到修饰的完全转化(即DAR=2)。
实施例9
B.制备化合物11
C.制备可点击紫杉醇衍生物16
乙酸1-(4-甲氧基苯基)-2-(2-甲基丙-1-烯-1-基)-4-氧代氮杂环丁烷-3-基酯(9-1)
在N2下,向4-甲氧基苯胺(6.14g,50mmol)于无水CH2Cl2(50ml)中的溶液中添加3-甲基丁-2-烯醛(4.62g,55mmol)和分子筛(5g)。然后将混合物在室温下搅拌4h。完全反应后,过滤以去除分子筛,并在真空下去除溶剂。在-78℃下,将残余物溶解于具有TEA(7.58g75mmol)的无水CH2Cl2(50ml)中。在10分钟内,向所述溶剂中添加乙酸2-氯-2-氧代乙酯(8.16g,60mmol)。然后使反应缓慢升温至室温。12h后,将溶剂用饱和NH4Cl溶剂洗涤,然后用CH2Cl2(50ml*3)提取水相。用盐水洗涤合并的有机相,用MgSO4干燥,浓缩,并通过硅胶柱使用EA:Hex(20:1至4:1)纯化,得到产率为69%的浅黄色固体。
乙酸(2S,3R)-1-(4-甲氧基苯基)-2-(2-甲基丙-1-烯-1-基)-4-氧代氮杂环丁烷-3-基酯(9-1(+))
向乙酸1-(4-甲氧基苯基)-2-(2-甲基丙-1-烯-1-基)-4-氧代氮杂环丁烷-3-基酯(9-1)(14.50g,50mmol)于180ml 0.2M磷酸钠缓冲液(pH=7.4)与20ml乙腈的混合物中的溶液中添加10g‘PS Amano’脂肪酶,并将混合物在50℃下剧烈搅拌。48h后,1H NMR显示起始材料的转化率为50%。通过硅藻土过滤反应混合物并将其用EA(250ml*3)提取。将合并的有机相用Na2SO4干燥并浓缩。通过硅胶柱使用EA:Hex(20:1至4:1)纯化粗产物,得到呈白色固体的乙酸(2S,3R)-1-(4-甲氧基苯基)-2-(2-甲基丙-1-烯-1-基)-4-氧氮杂环丁烷-3-基酯(1(+)),产率48%(97%ee)。使用相同条件使所述产物再次与“PS Amano”(一半为5g)反应,进一步纯化,两步产率为43%(98.9%ee)。
(3R,4S)-3-羟基-1-(4-甲氧基苯基)-4-(2-甲基丙-1-烯-1-基)氮杂环丁烷-2-酮(9-2)
在0℃下,向氢氧化钾(0.09g,1.6mmol)于1ml水和3ml THF中的溶液中添加乙酸(2S,3R)-1-(4-甲氧基苯基)-2-(2-甲基丙-1-烯-1-基)-4-氧代氮杂环丁烷-3-基酯(9-1(+))(0.289g,1mmol)。然后使混合物升温至室温并搅拌3h。完成后,用盐水洗涤溶剂,并用EA(5ml*2)提取。用无水Na2SO4干燥合并的有机层,浓缩并通过硅胶柱使用EA:Hex(4:1至1:1)纯化,得到呈白色固体的(3R,4S)-3-羟基-1-(4-甲氧基苯基)-4-(2-甲基丙-1-烯-1-基)氮杂环丁烷-2-酮(9-2)(产率98%)。
(3R,4S)-1-(4-甲氧基苯基)-4-(2-甲基丙-1-烯-1-基)-3-((三异丙基甲硅烷基)氧基)氮杂环丁烷-2-酮(9-3)
向(3R,4S)-3-羟基-1-(4-甲氧基苯基)-4-(2-甲基丙-1-烯-1-基)氮杂环丁烷-2-酮(9-2)(2.47g,1mmol)于DMF(10ml)中的溶液中添加Et3N(1.5g,1.5mmol)、4-二甲基氨基吡啶(1.22g,1mmol)。然后在10分钟时段内添加TIPSCl(2.12g,1.1mmol)。室温下搅拌3h。完成后,添加EA(50ml),用水(10ml*3)和盐水洗涤溶剂。用无水Na2SO4干燥有机层,浓缩并通过硅胶柱使用EA:Hex(30:1至8:1)纯化,得到呈白色固体的(3R,4S)-1-(4-甲氧基苯基)-4-(2-甲基丙-1-烯-1-基)-3-((三异丙基甲硅烷基)氧基)氮杂环丁烷-2-酮(9-3)(产率97%)。
(3R,4S)-4-(2-甲基丙-1-烯-1-基)-3-((三异丙基甲硅烷基)氧基)氮杂环丁烷-2-酮(9-4)
在0℃下在30分钟时段内向(3R,4S)-1-(4-甲氧基苯基)-4-(2-甲基丙-1-烯-1-基)-3-((三异丙基甲硅烷基)氧基)氮杂环丁烷-2-酮(9-3)(2.19g,6mmol)于乙腈(30ml)中的溶液中逐滴添加硝酸铈(IV)铵(10.15g,18.5mmol)于H2O中的溶液。然后在1h时段内添加另外的H2O(35ml)。完成后,用200ml H2O稀释混合物,并用EA(200ml)提取。将有机层用饱和NaHCO3(100ml)、饱和NaHSO3(100ml)处理,并再次用饱和NaHCO3(100ml)处理。用盐水洗涤,用无水Na2SO4干燥,在真空下浓缩。然后通过硅胶柱使用EA:Hex(10:1至3:1)纯化粗产物,得到产率为63%产率的呈无色固体的(3R,4S)-4-(2-甲基丙-1-烯-1-基)-3-((三异丙基甲硅烷基)氧基)氮杂环丁烷-2-酮(9-4)。
(3R,4S)-1-丙烯酰基-4-(2-甲基丙-1-烯-1-基)-3-((三异丙基甲硅烷基)氧基)氮杂环丁烷-2-酮(9-5)
在氮气氛围下在0℃下向(3R,4S)-4-(2-甲基丙-1-烯-1-基)-3-((三异丙基甲硅烷基)氧基)氮杂环丁烷-2-酮(9-4)(29.7mg,0.1mmol)于无水CH2Cl2(2ml)中的溶液中添加Et3N(0.07ml,0.5mmol)和4-二甲基氨基吡啶(12.2mg,0.1mmol)。然后添加丙烯酰氯(27mg,0.3mmol)。搅拌16h。完成后,添加10ml EA,并将溶剂用饱和NH4Cl溶剂、水洗涤,然后用盐水洗涤。将有机相用无水Na2SO4干燥,在真空下浓缩。然后通过硅胶柱使用EA:Hex(30:1至6:1)纯化粗产物,得到产率为62%的呈无色油状的(3R,4S)-1-丙烯酰基-4-(2-甲基丙-1-烯-1-基)-3-((三异丙基甲硅烷基)氧基)氮杂环丁烷-2-酮(9-5)。
4-甲基苯磺酸戊-4-烯-1-基酯(6)
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在0℃下,向戊-4-烯-1-醇(0.86g,10mmol)于吡啶(5ml)中的溶液中添加4-甲苯磺酰氯(4.19g,22mmol)。搅拌6h。完成后,添加10ml EA,并用1M HCl和5% NaHCO3洗涤混合物,以去除吡啶。然后将有机层用盐水处理,用无水Na2SO4干燥,在真空下浓缩。然后通过硅胶柱使用EA:Hex(20:1至4:1)纯化粗产物,得到产率为88%的呈无色油状的4-甲基苯磺酸戊-4-烯-1-基酯(9-6)。
5-叠氮基戊-1-烯(9-7)
在室温下,向4-甲基苯磺酸戊-4-烯-1-基酯(9-6)(2.40g,10mmol)于DMF(10ml)中的溶液中添加叠氮化钠(1.05g,15mmol)。搅拌24h。一旦完成,将溶液用H2O(30ml)淬灭,然后用乙醚(10ml*3)提取。将合并的有机层用盐水处理,用无水Na2SO4干燥,缓慢浓缩,以去除乙醚。然后将粗产物直接用于下一步骤。
戊-4-烯-1-胺(9-8)
在0℃下,向5-叠氮戊-1-烯(9-7)(1.11g,10mmol)于乙醚(10ml)中的溶液中添加PPh3(2.62g,10mmol)。搅拌1h。然后添加H2O(2ml),使溶液升温至室温并再搅拌12h。一旦完成,就将溶液用冰水(10ml)淬灭,并将混合物用CH2Cl2(10ml*2)提取。将合并的有机层用盐水处理,用无水Na2SO4干燥,缓慢浓缩,以去除CH2Cl2。然后将粗产物直接用于下一步骤。
戊-4-烯-1-基氨基甲酸叔丁酯(9-9)
在室温下,向戊-4-烯-1-胺(9-8)(0.85g,10mmol)于CH2Cl2(10ml)中的溶液中添加Et3N(2.5g,25mmol)和Boc-酸酐(3.27g,15mmol)。搅拌6h。完成后,将溶剂用饱和NH4Cl、水洗涤,然后用盐水洗涤。将有机相用无水Na2SO4干燥,在真空下浓缩。然后通过硅胶柱使用EA:Hex(16:1至4:1)纯化粗产物,在总共3个步骤中得到产率为51%的呈无色油状的戊-4-烯-1-基氨基甲酸叔丁酯(9-9)。
(叔丁氧基羰基)(戊-4-烯-1-基)氨基甲酸叔丁酯(9-10)
向戊-4-烯-1-基氨基甲酸叔丁酯(9-9)(1.85g,10mmol)于乙腈(15ml)中的溶液中添加4-二甲基氨基吡啶(0.24g,2mmol)。然后在50℃下添加Boc-酸酐(2.4g,11mmol)。搅拌24h。再添加一定量的Boc-酸酐(1.2g,5.5mmol),并且然后再反应24h。完成后,在真空下去除溶剂,并通过硅胶柱使用EA:Hex(20:1至5:1)直接纯化,得到产率为82%的呈无色油状的(叔丁氧基羰基)(戊-4-烯-1-基)氨基甲酸叔丁酯(9-10)。
(叔丁氧羰基)((E)-6-((2S,3R)-2-(2-甲基丙-1-烯-1-基)-4-氧代-3-((三异丙基甲硅烷基)氧基)氮杂环丁烷-1-基)-6-氧代己-4-烯-1-基)氨基甲酸叔丁酯(9-11)
向(3R,4S)-1-丙烯酰基-4-(2-甲基丙-1-烯-1-基)-3-((三异丙基甲硅烷基)氧基)氮杂环丁烷-2-酮(9-5)(25mg,0.07mmol)于CH2Cl2(3ml)中的溶液中添加(叔丁氧基羰基)(戊-4-烯-1-基)氨基甲酸叔丁酯(9-10)(60.89mg,0.21mmol)和Grubbs催化剂M720(2mg,4%*0.07mmol)。然后使溶剂升温至50℃,使CH2Cl2回流。搅拌48h。完成后,在真空下去除溶剂,并通过硅胶柱使用EA:Hex(15:1至3:1)直接纯化,得到产率为91%的呈无色油状的(叔丁氧基羰基)((E)-6-((2S,3R)-2-(2-甲基丙-1-烯-1-基)-4-氧代-3-((三异丙基甲硅烷基)氧代)氮杂环丁烷-1-基)-6-氧代己-4-烯-1-基)氨基甲酸叔丁酯(9-11)。
二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-4,9,11-三羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-12)
向10-脱乙酰基浆果赤霉素(54.5mg,0.1mmol)于THF(1ml)中的溶液中添加氯化铈(III)七水合物(1.86mg,0.005mmol),然后在0℃下添加乙酸酐(1ml,1mmol)。使反应缓慢回到室温。搅拌4h。完成后,将溶液用冰水(10ml)淬灭,并将混合物用乙酸乙酯(2ml*2)提取。将合并的有机层用盐水处理,用无水Na2SO4干燥,在真空下浓缩。然后通过硅胶柱使用EA:Hex(30:1至6:1)纯化粗产物,得到产率为91%的呈白色固体的二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-4,9,11-三羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-12)。
二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-9,11-二羟基-4a,8,13,13-四甲基-5-氧代-4-((三乙基甲硅烷基)氧基)-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-13)
在氮气氛围下向二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-4,9,11-三羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-12)(0.293g,0.5mmol)于无水CH2Cl2(5ml)中的溶液中添加4-二甲基氨基吡啶(0.184g,1.5mmol)。然后逐滴添加氯三乙基硅烷(0.151g,1mmol)。在室温下搅拌2h。完成后,用水和1M HCl处理。然后将有机层用盐水洗涤,用无水Na2SO4干燥,在真空下浓缩。然后通过硅胶柱使用EA:Hex(4:1至1:1)纯化粗产物,得到产率为77%的呈白色固体的二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-9,11-二羟基-4a,8,13,13-四甲基-5-氧代-4-((三乙基甲硅烷基)氧基)-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-13)。
二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-9-(((2R,3S)-3-((E)-6-(双(叔丁氧基羰基)氨基)己-2-烯酰胺基)-5-甲基-2-((三异丙基甲硅烷基)氧基)己-4-烯酰基)氧基)-11-羟基-4a,8,13,13-四甲基-5-氧代-4-((三乙基甲硅烷基)氧基)-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-14)
向二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-9,11-二羟基-4a,8,13,13-四甲基-5-氧代-4-((三乙基甲硅烷基)氧基)-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-13)(50mg,0.07mmol)和(叔丁氧基羰基)((E)-6-((2S,3R)-2-(2-甲基丙-1-烯-1-基)-4-氧代-3-((三异丙基甲硅烷基)氧基)氮杂环丁烷-1-基)-6-氧代己-4-烯-1-基)氨基甲酸叔丁酯(9-11)(433mg,0.7mmol)的混合物中添加无水THF(1ml)。然后将溶剂冷却至-78℃。将THF(0.7ml,7mmol)中的1.0M LiHMDS逐滴添加到所述系统中,搅拌1h。完成后,将溶剂用饱和NH4Cl(5ml)直接淬灭,并且然后用水、盐水洗涤。然后通过硅胶柱使用EA:Hex(4:1至1:1)纯化粗产物,得到产率为89%的呈白色固体的二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-9-(((2R,3S)-3-((E)-6-(双(叔丁氧基羰基)氨基)己-2-烯酰胺基)-5-甲基-2-((三异丙基甲硅烷基)氧基)己-4-烯酰基)氧基)-11-羟基-4a,8,13,13-四甲基-5-氧代-4-((三乙基甲硅烷基)氧基)-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-14)。
二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-9-(((2R,3S)-3-((E)-6-(双(叔丁氧基羰基)氨基)己-2-烯酰胺基)-2-羟基-5-甲基己-4-烯酰基)氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-15)
在0℃下向二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-9-(((2R,3S)-3-((E)-6-(双(叔丁氧基羰基)氨基)己-2-烯酰胺基)-5-甲基-2-((三异丙基甲硅烷基)氧基)己-4-烯酰基)氧基)-11-羟基-4a,8,13,13-四甲基-5-氧代-4-((三乙基甲硅烷基)氧基)-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-14)(50mg,0.038mmol)于2ml 1:1(v/v,吡啶:乙腈)中的溶液中添加0.5ml HF/py.(7:3)。然后使反应物升温至室温并搅拌24h。完成后,将溶剂用饱和NaHCO3(5ml)直接淬灭,然后用乙酸乙酯(10ml*2)提取。将合并的有机相用饱和硫酸铜(5ml)和盐水洗涤,用无水Na2SO4干燥,在真空下浓缩。然后通过硅胶柱使用EA:Hex(4:1至1:1)纯化粗产物,得到产率为90%的呈白色固体的二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-9-(((2R,3S)-3-((E)-6-(双(叔丁氧基羰基)氨基)己-2-烯酰胺基)-2-羟基-5-甲基己-4-烯酰基)氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-15)。
二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-9-(((2R,3S)-3-((E)-6-(((((1R,8S,9s)-双环[6.1.0]壬-4-炔-9-基)甲氧基)羰基)氨基)己-2-烯酰胺基)-2-羟基-5-甲基己-4-烯酰基)氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-16)
在氮气氛围下向二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-9-(((2R,3S)-3-((E)-6-(双(叔丁氧基羰基)氨基)己-2-烯酰胺基)-2-羟基-5-甲基己-4-烯酰基)氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-15)(5mg,0.005mmol)于CH2Cl2(0.2ml)中的溶液中添加0.2ml TFA。然后将溶剂搅拌15分钟。ESI显示所有化合物15都是二去保护的Boc基团。然后在真空下去除CH2Cl2和TFA。将残余物溶解在0.5ml DMF中,添加Et3N(0.1ml)使pH=8~9。添加碳酸((1R,8S,9s)-双环[6.1.0]壬-4-炔-9-基)甲基(4-硝基苯基)酯(3mg,0.01mmol)。搅拌24h。完成后,添加2ml乙酸乙酯,将混合物用水(2ml*3)、盐水洗涤。将有机相用无水Na2SO4干燥,在真空下浓缩。然后通过硅胶柱使用EA:Hex(3:1至1:1)纯化粗产物,得到呈白色固体的二乙酸(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12-(苯甲酰氧基)-9-(((2R,3S)-3-((E)-6-(((((1R,8S,9s)-双环[6.1.0]壬-4-炔-9-基)甲氧基)羰基)氨基)己-2-烯酰胺基)-2-羟基-5-甲基己-4-烯酰基)氧基)-4,11-二羟基-4a,8,13,13-四甲基-5-氧代-3,4,4a,5,6,9,10,11,12,12a-十氢-1H-7,11-甲烷环癸并[3,4]苯并[1,2-b]氧杂环丁烯-6,12b(2aH)-二基酯(9-16)。
缀合
根据上述实施例4中描述的一般程序,将上述可链接药物接头(化合物9-16)缀合到Her2抗体。通过天然完整IgG分析观察到修饰的完全转化(即DAR=2)。
------------------------------------------------
所附权利要求书的组合物和方法的范围不受本文所述的具体组合物和方法的限制,这些具体组合物和方法旨在说明权利要求的几个方面,并且功能等同的任何组合物和方法都旨在落入权利要求的范围内。对除本文所示和所述的那些以外的组合物和方法的各种修改均旨在落入所附权利要求的范围内。此外,尽管仅仅具体地描述了本文公开的一些代表性组合物和方法步骤,但所述组合物和方法步骤的其他组合也均旨在落入所附权利要求的范围内,即使没有具体地叙述也是如此。因此,步骤、元件、组件或成分的组合可能在本文中明确提及或较少提及,然而步骤、元件、组件和成分的其他组合也包括在内,即使没有明确陈述。本文所用的术语“包含”及其变形与术语“包括”及其变形同义地使用并且是开放的、非限制性术语。尽管本文使用术语“包含”和“包括”来描述各种实施方案,但可使用术语“基本上由……组成”和“由……组成”来代替“包含”和“包括”,以提供本发明更加具体的实施方案,并且也做了公开。除了在实施例中或者在另外指出的情况下,应至少理解说明书和权利要求书中使用的表示成分的量、反应条件等的所有数字,而不试图将等同原则的应用限制为权利要求的范围,应根据有效数字的数目和普通舍入方法来解释。
序列表部分描述
SEQ ID NO.1:
MIHTNLKKKFSCCVLVFLLFAVICVWKEKKKGSYYDSFKLQTKEFQVLKSLGKLAMGSDSQSVSSSSTQDPHRGRQTLGSLRGLAKAKPEASFQVWNKDSSSKNLIPRLQKIWKNYLSMNKYKVSYKGPGPGIKFSAEALRCHLRDHVNVSMVEVTDFPFNTSEWEGYLPKESIRTKAGPWGRCAVVSSAGSLKSSQLGREIDDHDAVLRFNGAPTANFQQDVGTKTTIRLMNSQLVTTEKRFLKDSLYNEGILIVWDPSVYHSDIPKWYQNPDYNFFNNYKTYRKLHPNQPFYILKPQMPWELWDILQEISPEEIQPNPPSSGMLGIIIMMTLCDQVDIYEFLPSKRKTDVCYYYQKFFDSACTMGAYHPLLYEKNLVKHLNQGTDEDIYLLGKATLPGFRTIHC
SEQ ID NO.2:
MRLREPLLSGSAAMPGASLQRACRLLVAVCALHLGVTLVYYLAGRDLSRLPQLVGVSTPLQGGSNSAAAIGQSSGELRTGGARPPPPLGASSQPRPGGDSSPVVDSGPGPASNLTSVPVPHTTALSLPACPEESPLLVGPMLIEFNMPVDLELVAKQNPNVKMGGRYAPRDCVSPHKVAIIIPFRNRQEHLKYWLYYLHPVLQRQQLDYGIYVINQAGDTIFNRAKLLNVGFQEALKDYDYTCFVFSDVDLIPMNDHNAYRCFSQPRHISVAMDKFGFSLPYVQYFGGVSALSKQQFLTINGFPNNYWGWGGEDDDIFNRLVFRGMSISRPNAVVGRCRMIRHSRDKKNEPNPQRFDRIAHTKETMLSDGLNSLTYQVLDVQRYPLYTQITVDIGTPS
SEQ ID NO.3:
MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQVQKGLPSIDSLHYLSENSKKEFKEELSKAGQESQKVKEILAKAQQADKQAQELAKMKIPEKIPMKPLHGPLYGGYFRTWHDKTSDPTEKDKVNSMGELPKEVDLAFIFHDWTKDYSLFWKELATKHVPKLNKQGTRVIRTIPWRFLAGGDNSGIAEDTSKYPNTPEGNKALAKAIVDEYVYKYNLDGLDVDVEHDSIPKVDKKEDTAGVERSIQVFEEIGKLIGPKGVDKSRLFIMDSTYMADKNPLIERGAPYINLLLVQVYGSQGEKGGWEPVSNRPEKTMEERWQGYSKYIRPEQYMIGFSFYEENAQEGNLWYDINSRKDEDKANGINTDITGTRAERYARWQPKTGGVKGGIFSYAIDRDGVAHQPKKYAKQKEFKDATDNIFHSDYSVSKALKTVMLKDKSYDLIDEKDFPDKALREAVMAQVGTRKGDLERFNGTLRLDNPAIQSLEGLNKFKKLAQLDLIGLSRITKLDRSVLPANMKPGKDTLETVLETYKKDNKEEPATIPPVSLKVSGLTGLKELDLSGFDRETLAGLDAATLTSLEKVDISGNKLDLAPGTENRQIFDTMLSTISNHVGSNEQTVKFDKQKPTGHYPDTYGKTSLRLPVANEKVDLQSQLLFGTVTNQGTLINSEADYKAYQNHKIAGRSFVDSNYHYNNFKVSYENYTVKVTDSTLGTTTDKTLATDKEETYKVDFFSPADKTKAVHTAKVIVGDEKTMMVNLAEGATVIGGSADPVNARKVFDGQLGSETDNISLGWDSKQSIIFKLKEDGLIKHWRFFNDSARNPETTNKPIQEASLQIFNIKDYNLDNLLENPNKFDDEKYWITVDTYSAQGERATAFSNTLNNITSKYWRVVFDTKGDRYSSPVVPELQILGYPLPNADTIMKTVTTAKELSQQKDKFSQKMLDELKIKEMALETSLNSKIFDVTAINANAGVLKDCIEKRQLLKK
SEQ ID NO.4:
HHHHHHWSHPQFEKGGGSGGGSGGSSAWSHPQFEKFQVLKSLGKLAMGSDSQSVSSSSTQDPHRGRQTLGSLRGLAKAKPEASFQVWNKDSSSKNLIPRLQKIWKNYLSMNKYKVSYKGPGPGIKFSAEALRCHLRDHVNVSMVEVTDFPFNTSEWEGYLPKESIRTKAGPWGRCAVVSSAGSLKSSQLGREIDDHDAVLRFNGAPTANFQQDVGTKTTIRLMNSQLVTTEKRFLKDSLYNEGILIVWDPSVYHSDIPKWYQNPDYNFFNNYKTYRKLHPNQPFYILKPQMPWELWDILQEISPEEIQPNPPSSGMLGIIIMMTLCDQVDIYEFLPSKRKTDVCYYYQKFFDSACTMGAYHPLLYEKNLVKHLNQGTDEDIYLLGKATLPGFRTIHC
SEQ ID NO.5:
HHHHHHHHHHRDLSRLPQLVGVSTPLQGGSNSAAAIGQSSGELRTGGARPPPPLGASSQPRPGGDSSPVVDSGPGPASNLTSVPVPHTTALSLPACPEESPLLVGPMLIEFNMPVDLELVAKQNPNVKMGGRYAPRDCVSPHKVAIIIPFRNRQEHLKYWLYYLHPVLQRQQLDYGIYVINQAGDTIFNRAKLLNVGFQEALKDYDYTCFVFSDVDLIPMNDHNAYRCFSQPRHISVAMDKFGFSLPYVQYFGGVSALSKQQFLTINGFPNNYWGWGGEDDDIFNRLVFRGMSISRPNAVVGRCRMIRHSRDKKNEPNPQRFDRIAHTKETMLSDGLNSLTYQVLDVQRYPLYTQITVDIGTPS
SEQ ID NO.6:
EEKTVQVQKGLPSIDSLHYLSENSKKEFKEELSKAGQESQKVKEILAKAQQADKQAQELAKMKIPEKIPMKPLHGPLYGGYFRTWHDKTSDPTEKDKVNSMGELPKEVDLAFIFHDWTKDYSLFWKELATKHVPKLNKQGTRVIRTIPWRFLAGGDNSGIAEDTSKYPNTPEGNKALAKAIVDEYVYKYNLDGLDVDVEHDSIPKVDKKEDTAGVERSIQVFEEIGKLIGPKGVDKSRLFIMDSTYMADKNPLIERGAPYINLLLVQVYGSQGEKGGWEPVSNRPEKTMEERWQGYSKYIRPEQYMIGFSFYEENAQEGNLWYDINSRKDEDKANGINTDITGTRAERYARWQPKTGGVKGGIFSYAIDRDGVAHQPKKYAKQKEFKDATDNIFHSDYSVSKALKTVMLKDKSYDLIDEKDFPDKALREAVMAQVGTRKGDLERFNGTLRLDNPAIQSLEGLNKFKKLAQLDLIGLSRITKLDRSVLPANMKPGKDTLETVLETYKKDNKEEPATIPPVSLKVSGLTGLKELDLSGFDRETLAGLDAATLTSLEKVDISGNKLDLAPGTENRQIFDTMLSTISNHVGSNEQTVKFDKQKPTGHYPDTYGKTSLRLPVANEKVDLQSQLLFGTVTNQGTLINSEADYKAYQNHKIAGRSFVDSNYHYNNFKVSYENYTVKVTDSTLGTTTDKTLATDKEETYKVDFFSPADKTKAVHTAKVIVGDEKTMMVNLAEGATVIGGSADPVNARKVFDGQLGSETDNISLGWDSKQSIIFKLKEDGLIKHWRFFNDSARNPETTNKPIQEASLQIFNIKDYNLDNLLENPNKFDDEKYWITVDTYSAQGERATAFSNTLNNITSKYWRVVFDTKGDRYSSPVVPELQILGYPLPNADTIMKTVTTAKELSQQKDKFSQKMLDELKIKEMALETSLNSKIFDVTAINANAGVLKDCIEKRQLLKKHHHHHHHHHH
SEQ ID NO.7:
FQVLKSLGKLAMGSDSQSVSSSSTQDPHRGRQTLGSLRGLAKAKPEASFQVWNKDSSSKNLIPRLQKIWKNYLSMNKYKVSYKGPGPGIKFSAEALRCHLRDHVNVSMVEVTDFPFNTSEWEGYLPKESIRTKAGPWGRCAVVSSAGSLKSSQLGREIDDHDAVLRFNGAPTANFQQDVGTKTTIRLMNSQLVTTEKRFLKDSLYNEGILIVWDPSVYHSDIPKWYQNPDYNFFNNYKTYRKLHPNQPFYILKPQMPWELWDILQEISPEEIQPNPPSSGMLGIIIMMTLCDQVDIYEFLPSKRKTDVCYYYQKFFDSACTMGAYHPLLYEKNLVKHLNQGTDEDIYLLGKATLPGFRTIHC
SEQ ID NO.8:
RDLSRLPQLVGVSTPLQGGSNSAAAIGQSSGELRTGGARPPPPLGASSQPRPGGDSSPVVDSGPGPASNLTSVPVPHTTALSLPACPEESPLLVGPMLIEFNMPVDLELVAKQNPNVKMGGRYAPRDCVSPHKVAIIIPFRNRQEHLKYWLYYLHPVLQRQQLDYGIYVINQAGDTIFNRAKLLNVGFQEALKDYDYTCFVFSDVDLIPMNDHNAYRCFSQPRHISVAMDKFGFSLPYVQYFGGVSALSKQQFLTINGFPNNYWGWGGEDDDIFNRLVFRGMSISRPNAVVGRCRMIRHSRDKKNEPNPQRFDRIAHTKETMLSDGLNSLTYQVLDVQRYPLYTQITVDIGTPS
SEQ ID NO.9:
EEKTVQVQKGLPSIDSLHYLSENSKKEFKEELSKAGQESQKVKEILAKAQQADKQAQELAKMKIPEKIPMKPLHGPLYGGYFRTWHDKTSDPTEKDKVNSMGELPKEVDLAFIFHDWTKDYSLFWKELATKHVPKLNKQGTRVIRTIPWRFLAGGDNSGIAEDTSKYPNTPEGNKALAKAIVDEYVYKYNLDGLDVDVEHDSIPKVDKKEDTAGVERSIQVFEEIGKLIGPKGVDKSRLFIMDSTYMADKNPLIERGAPYINLLLVQVYGSQGEKGGWEPVSNRPEKTMEERWQGYSKYIRPEQYMIGFSFYEENAQEGNLWYDINSRKDEDKANGINTDITGTRAERYARWQPKTGGVKGGIFSYAIDRDGVAHQPKKYAKQKEFKDATDNIFHSDYSVSKALKTVMLKDKSYDLIDEKDFPDKALREAVMAQVGTRKGDLERFNGTLRLDNPAIQSLEGLNKFKKLAQLDLIGLSRITKLDRSVLPANMKPGKDTLETVLETYKKDNKEEPATIPPVSLKVSGLTGLKELDLSGFDRETLAGLDAATLTSLEKVDISGNKLDLAPGTENRQIFDTMLSTISNHVGSNEQTVKFDKQKPTGHYPDTYGKTSLRLPVANEKVDLQSQLLFGTVTNQGTLINSEADYKAYQNHKIAGRSFVDSNYHYNNFKVSYENYTVKVTDSTLGTTTDKTLATDKEETYKVDFFSPADKTKAVHTAKVIVGDEKTMMVNLAEGATVIGGSADPVNARKVFDGQLGSETDNISLGWDSKQSIIFKLKEDGLIKHWRFFNDSARNPETTNKPIQEASLQIFNIKDYNLDNLLENPNKFDDEKYWITVDTYSAQGERATAFSNTLNNITSKYWRVVFDTKGDRYSSPVVPELQILGYPLPNADTIMKTVTTAKELSQQKDKFSQKMLDELKIKEMALETSLNSKIFDVTAINANAGVLKDCIEKRQLLKK
SEQUENCE LISTING
<110> 乔治亚大学研究基金会(University of Georgia Research Foundation,Inc)
<120> 糖缀合物
<130> P23111910WP
<150> US63/092640
<151> 2020-10-16
<160> 9
<170> PatentIn version 3.5
<210> 1
<211> 406
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体(synthetic construct)
<400> 1
Met Ile His Thr Asn Leu Lys Lys Lys Phe Ser Cys Cys Val Leu Val
1 5 10 15
Phe Leu Leu Phe Ala Val Ile Cys Val Trp Lys Glu Lys Lys Lys Gly
20 25 30
Ser Tyr Tyr Asp Ser Phe Lys Leu Gln Thr Lys Glu Phe Gln Val Leu
35 40 45
Lys Ser Leu Gly Lys Leu Ala Met Gly Ser Asp Ser Gln Ser Val Ser
50 55 60
Ser Ser Ser Thr Gln Asp Pro His Arg Gly Arg Gln Thr Leu Gly Ser
65 70 75 80
Leu Arg Gly Leu Ala Lys Ala Lys Pro Glu Ala Ser Phe Gln Val Trp
85 90 95
Asn Lys Asp Ser Ser Ser Lys Asn Leu Ile Pro Arg Leu Gln Lys Ile
100 105 110
Trp Lys Asn Tyr Leu Ser Met Asn Lys Tyr Lys Val Ser Tyr Lys Gly
115 120 125
Pro Gly Pro Gly Ile Lys Phe Ser Ala Glu Ala Leu Arg Cys His Leu
130 135 140
Arg Asp His Val Asn Val Ser Met Val Glu Val Thr Asp Phe Pro Phe
145 150 155 160
Asn Thr Ser Glu Trp Glu Gly Tyr Leu Pro Lys Glu Ser Ile Arg Thr
165 170 175
Lys Ala Gly Pro Trp Gly Arg Cys Ala Val Val Ser Ser Ala Gly Ser
180 185 190
Leu Lys Ser Ser Gln Leu Gly Arg Glu Ile Asp Asp His Asp Ala Val
195 200 205
Leu Arg Phe Asn Gly Ala Pro Thr Ala Asn Phe Gln Gln Asp Val Gly
210 215 220
Thr Lys Thr Thr Ile Arg Leu Met Asn Ser Gln Leu Val Thr Thr Glu
225 230 235 240
Lys Arg Phe Leu Lys Asp Ser Leu Tyr Asn Glu Gly Ile Leu Ile Val
245 250 255
Trp Asp Pro Ser Val Tyr His Ser Asp Ile Pro Lys Trp Tyr Gln Asn
260 265 270
Pro Asp Tyr Asn Phe Phe Asn Asn Tyr Lys Thr Tyr Arg Lys Leu His
275 280 285
Pro Asn Gln Pro Phe Tyr Ile Leu Lys Pro Gln Met Pro Trp Glu Leu
290 295 300
Trp Asp Ile Leu Gln Glu Ile Ser Pro Glu Glu Ile Gln Pro Asn Pro
305 310 315 320
Pro Ser Ser Gly Met Leu Gly Ile Ile Ile Met Met Thr Leu Cys Asp
325 330 335
Gln Val Asp Ile Tyr Glu Phe Leu Pro Ser Lys Arg Lys Thr Asp Val
340 345 350
Cys Tyr Tyr Tyr Gln Lys Phe Phe Asp Ser Ala Cys Thr Met Gly Ala
355 360 365
Tyr His Pro Leu Leu Tyr Glu Lys Asn Leu Val Lys His Leu Asn Gln
370 375 380
Gly Thr Asp Glu Asp Ile Tyr Leu Leu Gly Lys Ala Thr Leu Pro Gly
385 390 395 400
Phe Arg Thr Ile His Cys
405
<210> 2
<211> 398
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体(synthetic construct)
<400> 2
Met Arg Leu Arg Glu Pro Leu Leu Ser Gly Ser Ala Ala Met Pro Gly
1 5 10 15
Ala Ser Leu Gln Arg Ala Cys Arg Leu Leu Val Ala Val Cys Ala Leu
20 25 30
His Leu Gly Val Thr Leu Val Tyr Tyr Leu Ala Gly Arg Asp Leu Ser
35 40 45
Arg Leu Pro Gln Leu Val Gly Val Ser Thr Pro Leu Gln Gly Gly Ser
50 55 60
Asn Ser Ala Ala Ala Ile Gly Gln Ser Ser Gly Glu Leu Arg Thr Gly
65 70 75 80
Gly Ala Arg Pro Pro Pro Pro Leu Gly Ala Ser Ser Gln Pro Arg Pro
85 90 95
Gly Gly Asp Ser Ser Pro Val Val Asp Ser Gly Pro Gly Pro Ala Ser
100 105 110
Asn Leu Thr Ser Val Pro Val Pro His Thr Thr Ala Leu Ser Leu Pro
115 120 125
Ala Cys Pro Glu Glu Ser Pro Leu Leu Val Gly Pro Met Leu Ile Glu
130 135 140
Phe Asn Met Pro Val Asp Leu Glu Leu Val Ala Lys Gln Asn Pro Asn
145 150 155 160
Val Lys Met Gly Gly Arg Tyr Ala Pro Arg Asp Cys Val Ser Pro His
165 170 175
Lys Val Ala Ile Ile Ile Pro Phe Arg Asn Arg Gln Glu His Leu Lys
180 185 190
Tyr Trp Leu Tyr Tyr Leu His Pro Val Leu Gln Arg Gln Gln Leu Asp
195 200 205
Tyr Gly Ile Tyr Val Ile Asn Gln Ala Gly Asp Thr Ile Phe Asn Arg
210 215 220
Ala Lys Leu Leu Asn Val Gly Phe Gln Glu Ala Leu Lys Asp Tyr Asp
225 230 235 240
Tyr Thr Cys Phe Val Phe Ser Asp Val Asp Leu Ile Pro Met Asn Asp
245 250 255
His Asn Ala Tyr Arg Cys Phe Ser Gln Pro Arg His Ile Ser Val Ala
260 265 270
Met Asp Lys Phe Gly Phe Ser Leu Pro Tyr Val Gln Tyr Phe Gly Gly
275 280 285
Val Ser Ala Leu Ser Lys Gln Gln Phe Leu Thr Ile Asn Gly Phe Pro
290 295 300
Asn Asn Tyr Trp Gly Trp Gly Gly Glu Asp Asp Asp Ile Phe Asn Arg
305 310 315 320
Leu Val Phe Arg Gly Met Ser Ile Ser Arg Pro Asn Ala Val Val Gly
325 330 335
Arg Cys Arg Met Ile Arg His Ser Arg Asp Lys Lys Asn Glu Pro Asn
340 345 350
Pro Gln Arg Phe Asp Arg Ile Ala His Thr Lys Glu Thr Met Leu Ser
355 360 365
Asp Gly Leu Asn Ser Leu Thr Tyr Gln Val Leu Asp Val Gln Arg Tyr
370 375 380
Pro Leu Tyr Thr Gln Ile Thr Val Asp Ile Gly Thr Pro Ser
385 390 395
<210> 3
<211> 995
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体(synthetic construct)
<400> 3
Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala
1 5 10 15
Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn
20 25 30
Thr Val Lys Ala Glu Glu Lys Thr Val Gln Val Gln Lys Gly Leu Pro
35 40 45
Ser Ile Asp Ser Leu His Tyr Leu Ser Glu Asn Ser Lys Lys Glu Phe
50 55 60
Lys Glu Glu Leu Ser Lys Ala Gly Gln Glu Ser Gln Lys Val Lys Glu
65 70 75 80
Ile Leu Ala Lys Ala Gln Gln Ala Asp Lys Gln Ala Gln Glu Leu Ala
85 90 95
Lys Met Lys Ile Pro Glu Lys Ile Pro Met Lys Pro Leu His Gly Pro
100 105 110
Leu Tyr Gly Gly Tyr Phe Arg Thr Trp His Asp Lys Thr Ser Asp Pro
115 120 125
Thr Glu Lys Asp Lys Val Asn Ser Met Gly Glu Leu Pro Lys Glu Val
130 135 140
Asp Leu Ala Phe Ile Phe His Asp Trp Thr Lys Asp Tyr Ser Leu Phe
145 150 155 160
Trp Lys Glu Leu Ala Thr Lys His Val Pro Lys Leu Asn Lys Gln Gly
165 170 175
Thr Arg Val Ile Arg Thr Ile Pro Trp Arg Phe Leu Ala Gly Gly Asp
180 185 190
Asn Ser Gly Ile Ala Glu Asp Thr Ser Lys Tyr Pro Asn Thr Pro Glu
195 200 205
Gly Asn Lys Ala Leu Ala Lys Ala Ile Val Asp Glu Tyr Val Tyr Lys
210 215 220
Tyr Asn Leu Asp Gly Leu Asp Val Asp Val Glu His Asp Ser Ile Pro
225 230 235 240
Lys Val Asp Lys Lys Glu Asp Thr Ala Gly Val Glu Arg Ser Ile Gln
245 250 255
Val Phe Glu Glu Ile Gly Lys Leu Ile Gly Pro Lys Gly Val Asp Lys
260 265 270
Ser Arg Leu Phe Ile Met Asp Ser Thr Tyr Met Ala Asp Lys Asn Pro
275 280 285
Leu Ile Glu Arg Gly Ala Pro Tyr Ile Asn Leu Leu Leu Val Gln Val
290 295 300
Tyr Gly Ser Gln Gly Glu Lys Gly Gly Trp Glu Pro Val Ser Asn Arg
305 310 315 320
Pro Glu Lys Thr Met Glu Glu Arg Trp Gln Gly Tyr Ser Lys Tyr Ile
325 330 335
Arg Pro Glu Gln Tyr Met Ile Gly Phe Ser Phe Tyr Glu Glu Asn Ala
340 345 350
Gln Glu Gly Asn Leu Trp Tyr Asp Ile Asn Ser Arg Lys Asp Glu Asp
355 360 365
Lys Ala Asn Gly Ile Asn Thr Asp Ile Thr Gly Thr Arg Ala Glu Arg
370 375 380
Tyr Ala Arg Trp Gln Pro Lys Thr Gly Gly Val Lys Gly Gly Ile Phe
385 390 395 400
Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Gln Pro Lys Lys Tyr
405 410 415
Ala Lys Gln Lys Glu Phe Lys Asp Ala Thr Asp Asn Ile Phe His Ser
420 425 430
Asp Tyr Ser Val Ser Lys Ala Leu Lys Thr Val Met Leu Lys Asp Lys
435 440 445
Ser Tyr Asp Leu Ile Asp Glu Lys Asp Phe Pro Asp Lys Ala Leu Arg
450 455 460
Glu Ala Val Met Ala Gln Val Gly Thr Arg Lys Gly Asp Leu Glu Arg
465 470 475 480
Phe Asn Gly Thr Leu Arg Leu Asp Asn Pro Ala Ile Gln Ser Leu Glu
485 490 495
Gly Leu Asn Lys Phe Lys Lys Leu Ala Gln Leu Asp Leu Ile Gly Leu
500 505 510
Ser Arg Ile Thr Lys Leu Asp Arg Ser Val Leu Pro Ala Asn Met Lys
515 520 525
Pro Gly Lys Asp Thr Leu Glu Thr Val Leu Glu Thr Tyr Lys Lys Asp
530 535 540
Asn Lys Glu Glu Pro Ala Thr Ile Pro Pro Val Ser Leu Lys Val Ser
545 550 555 560
Gly Leu Thr Gly Leu Lys Glu Leu Asp Leu Ser Gly Phe Asp Arg Glu
565 570 575
Thr Leu Ala Gly Leu Asp Ala Ala Thr Leu Thr Ser Leu Glu Lys Val
580 585 590
Asp Ile Ser Gly Asn Lys Leu Asp Leu Ala Pro Gly Thr Glu Asn Arg
595 600 605
Gln Ile Phe Asp Thr Met Leu Ser Thr Ile Ser Asn His Val Gly Ser
610 615 620
Asn Glu Gln Thr Val Lys Phe Asp Lys Gln Lys Pro Thr Gly His Tyr
625 630 635 640
Pro Asp Thr Tyr Gly Lys Thr Ser Leu Arg Leu Pro Val Ala Asn Glu
645 650 655
Lys Val Asp Leu Gln Ser Gln Leu Leu Phe Gly Thr Val Thr Asn Gln
660 665 670
Gly Thr Leu Ile Asn Ser Glu Ala Asp Tyr Lys Ala Tyr Gln Asn His
675 680 685
Lys Ile Ala Gly Arg Ser Phe Val Asp Ser Asn Tyr His Tyr Asn Asn
690 695 700
Phe Lys Val Ser Tyr Glu Asn Tyr Thr Val Lys Val Thr Asp Ser Thr
705 710 715 720
Leu Gly Thr Thr Thr Asp Lys Thr Leu Ala Thr Asp Lys Glu Glu Thr
725 730 735
Tyr Lys Val Asp Phe Phe Ser Pro Ala Asp Lys Thr Lys Ala Val His
740 745 750
Thr Ala Lys Val Ile Val Gly Asp Glu Lys Thr Met Met Val Asn Leu
755 760 765
Ala Glu Gly Ala Thr Val Ile Gly Gly Ser Ala Asp Pro Val Asn Ala
770 775 780
Arg Lys Val Phe Asp Gly Gln Leu Gly Ser Glu Thr Asp Asn Ile Ser
785 790 795 800
Leu Gly Trp Asp Ser Lys Gln Ser Ile Ile Phe Lys Leu Lys Glu Asp
805 810 815
Gly Leu Ile Lys His Trp Arg Phe Phe Asn Asp Ser Ala Arg Asn Pro
820 825 830
Glu Thr Thr Asn Lys Pro Ile Gln Glu Ala Ser Leu Gln Ile Phe Asn
835 840 845
Ile Lys Asp Tyr Asn Leu Asp Asn Leu Leu Glu Asn Pro Asn Lys Phe
850 855 860
Asp Asp Glu Lys Tyr Trp Ile Thr Val Asp Thr Tyr Ser Ala Gln Gly
865 870 875 880
Glu Arg Ala Thr Ala Phe Ser Asn Thr Leu Asn Asn Ile Thr Ser Lys
885 890 895
Tyr Trp Arg Val Val Phe Asp Thr Lys Gly Asp Arg Tyr Ser Ser Pro
900 905 910
Val Val Pro Glu Leu Gln Ile Leu Gly Tyr Pro Leu Pro Asn Ala Asp
915 920 925
Thr Ile Met Lys Thr Val Thr Thr Ala Lys Glu Leu Ser Gln Gln Lys
930 935 940
Asp Lys Phe Ser Gln Lys Met Leu Asp Glu Leu Lys Ile Lys Glu Met
945 950 955 960
Ala Leu Glu Thr Ser Leu Asn Ser Lys Ile Phe Asp Val Thr Ala Ile
965 970 975
Asn Ala Asn Ala Gly Val Leu Lys Asp Cys Ile Glu Lys Arg Gln Leu
980 985 990
Leu Lys Lys
995
<210> 4
<211> 397
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体(synthetic construct)
<400> 4
His His His His His His Trp Ser His Pro Gln Phe Glu Lys Gly Gly
1 5 10 15
Gly Ser Gly Gly Gly Ser Gly Gly Ser Ser Ala Trp Ser His Pro Gln
20 25 30
Phe Glu Lys Phe Gln Val Leu Lys Ser Leu Gly Lys Leu Ala Met Gly
35 40 45
Ser Asp Ser Gln Ser Val Ser Ser Ser Ser Thr Gln Asp Pro His Arg
50 55 60
Gly Arg Gln Thr Leu Gly Ser Leu Arg Gly Leu Ala Lys Ala Lys Pro
65 70 75 80
Glu Ala Ser Phe Gln Val Trp Asn Lys Asp Ser Ser Ser Lys Asn Leu
85 90 95
Ile Pro Arg Leu Gln Lys Ile Trp Lys Asn Tyr Leu Ser Met Asn Lys
100 105 110
Tyr Lys Val Ser Tyr Lys Gly Pro Gly Pro Gly Ile Lys Phe Ser Ala
115 120 125
Glu Ala Leu Arg Cys His Leu Arg Asp His Val Asn Val Ser Met Val
130 135 140
Glu Val Thr Asp Phe Pro Phe Asn Thr Ser Glu Trp Glu Gly Tyr Leu
145 150 155 160
Pro Lys Glu Ser Ile Arg Thr Lys Ala Gly Pro Trp Gly Arg Cys Ala
165 170 175
Val Val Ser Ser Ala Gly Ser Leu Lys Ser Ser Gln Leu Gly Arg Glu
180 185 190
Ile Asp Asp His Asp Ala Val Leu Arg Phe Asn Gly Ala Pro Thr Ala
195 200 205
Asn Phe Gln Gln Asp Val Gly Thr Lys Thr Thr Ile Arg Leu Met Asn
210 215 220
Ser Gln Leu Val Thr Thr Glu Lys Arg Phe Leu Lys Asp Ser Leu Tyr
225 230 235 240
Asn Glu Gly Ile Leu Ile Val Trp Asp Pro Ser Val Tyr His Ser Asp
245 250 255
Ile Pro Lys Trp Tyr Gln Asn Pro Asp Tyr Asn Phe Phe Asn Asn Tyr
260 265 270
Lys Thr Tyr Arg Lys Leu His Pro Asn Gln Pro Phe Tyr Ile Leu Lys
275 280 285
Pro Gln Met Pro Trp Glu Leu Trp Asp Ile Leu Gln Glu Ile Ser Pro
290 295 300
Glu Glu Ile Gln Pro Asn Pro Pro Ser Ser Gly Met Leu Gly Ile Ile
305 310 315 320
Ile Met Met Thr Leu Cys Asp Gln Val Asp Ile Tyr Glu Phe Leu Pro
325 330 335
Ser Lys Arg Lys Thr Asp Val Cys Tyr Tyr Tyr Gln Lys Phe Phe Asp
340 345 350
Ser Ala Cys Thr Met Gly Ala Tyr His Pro Leu Leu Tyr Glu Lys Asn
355 360 365
Leu Val Lys His Leu Asn Gln Gly Thr Asp Glu Asp Ile Tyr Leu Leu
370 375 380
Gly Lys Ala Thr Leu Pro Gly Phe Arg Thr Ile His Cys
385 390 395
<210> 5
<211> 364
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体(synthetic construct)
<400> 5
His His His His His His His His His His Arg Asp Leu Ser Arg Leu
1 5 10 15
Pro Gln Leu Val Gly Val Ser Thr Pro Leu Gln Gly Gly Ser Asn Ser
20 25 30
Ala Ala Ala Ile Gly Gln Ser Ser Gly Glu Leu Arg Thr Gly Gly Ala
35 40 45
Arg Pro Pro Pro Pro Leu Gly Ala Ser Ser Gln Pro Arg Pro Gly Gly
50 55 60
Asp Ser Ser Pro Val Val Asp Ser Gly Pro Gly Pro Ala Ser Asn Leu
65 70 75 80
Thr Ser Val Pro Val Pro His Thr Thr Ala Leu Ser Leu Pro Ala Cys
85 90 95
Pro Glu Glu Ser Pro Leu Leu Val Gly Pro Met Leu Ile Glu Phe Asn
100 105 110
Met Pro Val Asp Leu Glu Leu Val Ala Lys Gln Asn Pro Asn Val Lys
115 120 125
Met Gly Gly Arg Tyr Ala Pro Arg Asp Cys Val Ser Pro His Lys Val
130 135 140
Ala Ile Ile Ile Pro Phe Arg Asn Arg Gln Glu His Leu Lys Tyr Trp
145 150 155 160
Leu Tyr Tyr Leu His Pro Val Leu Gln Arg Gln Gln Leu Asp Tyr Gly
165 170 175
Ile Tyr Val Ile Asn Gln Ala Gly Asp Thr Ile Phe Asn Arg Ala Lys
180 185 190
Leu Leu Asn Val Gly Phe Gln Glu Ala Leu Lys Asp Tyr Asp Tyr Thr
195 200 205
Cys Phe Val Phe Ser Asp Val Asp Leu Ile Pro Met Asn Asp His Asn
210 215 220
Ala Tyr Arg Cys Phe Ser Gln Pro Arg His Ile Ser Val Ala Met Asp
225 230 235 240
Lys Phe Gly Phe Ser Leu Pro Tyr Val Gln Tyr Phe Gly Gly Val Ser
245 250 255
Ala Leu Ser Lys Gln Gln Phe Leu Thr Ile Asn Gly Phe Pro Asn Asn
260 265 270
Tyr Trp Gly Trp Gly Gly Glu Asp Asp Asp Ile Phe Asn Arg Leu Val
275 280 285
Phe Arg Gly Met Ser Ile Ser Arg Pro Asn Ala Val Val Gly Arg Cys
290 295 300
Arg Met Ile Arg His Ser Arg Asp Lys Lys Asn Glu Pro Asn Pro Gln
305 310 315 320
Arg Phe Asp Arg Ile Ala His Thr Lys Glu Thr Met Leu Ser Asp Gly
325 330 335
Leu Asn Ser Leu Thr Tyr Gln Val Leu Asp Val Gln Arg Tyr Pro Leu
340 345 350
Tyr Thr Gln Ile Thr Val Asp Ile Gly Thr Pro Ser
355 360
<210> 6
<211> 969
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体(synthetic construct)
<400> 6
Glu Glu Lys Thr Val Gln Val Gln Lys Gly Leu Pro Ser Ile Asp Ser
1 5 10 15
Leu His Tyr Leu Ser Glu Asn Ser Lys Lys Glu Phe Lys Glu Glu Leu
20 25 30
Ser Lys Ala Gly Gln Glu Ser Gln Lys Val Lys Glu Ile Leu Ala Lys
35 40 45
Ala Gln Gln Ala Asp Lys Gln Ala Gln Glu Leu Ala Lys Met Lys Ile
50 55 60
Pro Glu Lys Ile Pro Met Lys Pro Leu His Gly Pro Leu Tyr Gly Gly
65 70 75 80
Tyr Phe Arg Thr Trp His Asp Lys Thr Ser Asp Pro Thr Glu Lys Asp
85 90 95
Lys Val Asn Ser Met Gly Glu Leu Pro Lys Glu Val Asp Leu Ala Phe
100 105 110
Ile Phe His Asp Trp Thr Lys Asp Tyr Ser Leu Phe Trp Lys Glu Leu
115 120 125
Ala Thr Lys His Val Pro Lys Leu Asn Lys Gln Gly Thr Arg Val Ile
130 135 140
Arg Thr Ile Pro Trp Arg Phe Leu Ala Gly Gly Asp Asn Ser Gly Ile
145 150 155 160
Ala Glu Asp Thr Ser Lys Tyr Pro Asn Thr Pro Glu Gly Asn Lys Ala
165 170 175
Leu Ala Lys Ala Ile Val Asp Glu Tyr Val Tyr Lys Tyr Asn Leu Asp
180 185 190
Gly Leu Asp Val Asp Val Glu His Asp Ser Ile Pro Lys Val Asp Lys
195 200 205
Lys Glu Asp Thr Ala Gly Val Glu Arg Ser Ile Gln Val Phe Glu Glu
210 215 220
Ile Gly Lys Leu Ile Gly Pro Lys Gly Val Asp Lys Ser Arg Leu Phe
225 230 235 240
Ile Met Asp Ser Thr Tyr Met Ala Asp Lys Asn Pro Leu Ile Glu Arg
245 250 255
Gly Ala Pro Tyr Ile Asn Leu Leu Leu Val Gln Val Tyr Gly Ser Gln
260 265 270
Gly Glu Lys Gly Gly Trp Glu Pro Val Ser Asn Arg Pro Glu Lys Thr
275 280 285
Met Glu Glu Arg Trp Gln Gly Tyr Ser Lys Tyr Ile Arg Pro Glu Gln
290 295 300
Tyr Met Ile Gly Phe Ser Phe Tyr Glu Glu Asn Ala Gln Glu Gly Asn
305 310 315 320
Leu Trp Tyr Asp Ile Asn Ser Arg Lys Asp Glu Asp Lys Ala Asn Gly
325 330 335
Ile Asn Thr Asp Ile Thr Gly Thr Arg Ala Glu Arg Tyr Ala Arg Trp
340 345 350
Gln Pro Lys Thr Gly Gly Val Lys Gly Gly Ile Phe Ser Tyr Ala Ile
355 360 365
Asp Arg Asp Gly Val Ala His Gln Pro Lys Lys Tyr Ala Lys Gln Lys
370 375 380
Glu Phe Lys Asp Ala Thr Asp Asn Ile Phe His Ser Asp Tyr Ser Val
385 390 395 400
Ser Lys Ala Leu Lys Thr Val Met Leu Lys Asp Lys Ser Tyr Asp Leu
405 410 415
Ile Asp Glu Lys Asp Phe Pro Asp Lys Ala Leu Arg Glu Ala Val Met
420 425 430
Ala Gln Val Gly Thr Arg Lys Gly Asp Leu Glu Arg Phe Asn Gly Thr
435 440 445
Leu Arg Leu Asp Asn Pro Ala Ile Gln Ser Leu Glu Gly Leu Asn Lys
450 455 460
Phe Lys Lys Leu Ala Gln Leu Asp Leu Ile Gly Leu Ser Arg Ile Thr
465 470 475 480
Lys Leu Asp Arg Ser Val Leu Pro Ala Asn Met Lys Pro Gly Lys Asp
485 490 495
Thr Leu Glu Thr Val Leu Glu Thr Tyr Lys Lys Asp Asn Lys Glu Glu
500 505 510
Pro Ala Thr Ile Pro Pro Val Ser Leu Lys Val Ser Gly Leu Thr Gly
515 520 525
Leu Lys Glu Leu Asp Leu Ser Gly Phe Asp Arg Glu Thr Leu Ala Gly
530 535 540
Leu Asp Ala Ala Thr Leu Thr Ser Leu Glu Lys Val Asp Ile Ser Gly
545 550 555 560
Asn Lys Leu Asp Leu Ala Pro Gly Thr Glu Asn Arg Gln Ile Phe Asp
565 570 575
Thr Met Leu Ser Thr Ile Ser Asn His Val Gly Ser Asn Glu Gln Thr
580 585 590
Val Lys Phe Asp Lys Gln Lys Pro Thr Gly His Tyr Pro Asp Thr Tyr
595 600 605
Gly Lys Thr Ser Leu Arg Leu Pro Val Ala Asn Glu Lys Val Asp Leu
610 615 620
Gln Ser Gln Leu Leu Phe Gly Thr Val Thr Asn Gln Gly Thr Leu Ile
625 630 635 640
Asn Ser Glu Ala Asp Tyr Lys Ala Tyr Gln Asn His Lys Ile Ala Gly
645 650 655
Arg Ser Phe Val Asp Ser Asn Tyr His Tyr Asn Asn Phe Lys Val Ser
660 665 670
Tyr Glu Asn Tyr Thr Val Lys Val Thr Asp Ser Thr Leu Gly Thr Thr
675 680 685
Thr Asp Lys Thr Leu Ala Thr Asp Lys Glu Glu Thr Tyr Lys Val Asp
690 695 700
Phe Phe Ser Pro Ala Asp Lys Thr Lys Ala Val His Thr Ala Lys Val
705 710 715 720
Ile Val Gly Asp Glu Lys Thr Met Met Val Asn Leu Ala Glu Gly Ala
725 730 735
Thr Val Ile Gly Gly Ser Ala Asp Pro Val Asn Ala Arg Lys Val Phe
740 745 750
Asp Gly Gln Leu Gly Ser Glu Thr Asp Asn Ile Ser Leu Gly Trp Asp
755 760 765
Ser Lys Gln Ser Ile Ile Phe Lys Leu Lys Glu Asp Gly Leu Ile Lys
770 775 780
His Trp Arg Phe Phe Asn Asp Ser Ala Arg Asn Pro Glu Thr Thr Asn
785 790 795 800
Lys Pro Ile Gln Glu Ala Ser Leu Gln Ile Phe Asn Ile Lys Asp Tyr
805 810 815
Asn Leu Asp Asn Leu Leu Glu Asn Pro Asn Lys Phe Asp Asp Glu Lys
820 825 830
Tyr Trp Ile Thr Val Asp Thr Tyr Ser Ala Gln Gly Glu Arg Ala Thr
835 840 845
Ala Phe Ser Asn Thr Leu Asn Asn Ile Thr Ser Lys Tyr Trp Arg Val
850 855 860
Val Phe Asp Thr Lys Gly Asp Arg Tyr Ser Ser Pro Val Val Pro Glu
865 870 875 880
Leu Gln Ile Leu Gly Tyr Pro Leu Pro Asn Ala Asp Thr Ile Met Lys
885 890 895
Thr Val Thr Thr Ala Lys Glu Leu Ser Gln Gln Lys Asp Lys Phe Ser
900 905 910
Gln Lys Met Leu Asp Glu Leu Lys Ile Lys Glu Met Ala Leu Glu Thr
915 920 925
Ser Leu Asn Ser Lys Ile Phe Asp Val Thr Ala Ile Asn Ala Asn Ala
930 935 940
Gly Val Leu Lys Asp Cys Ile Glu Lys Arg Gln Leu Leu Lys Lys His
945 950 955 960
His His His His His His His His His
965
<210> 7
<211> 362
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体(synthetic construct)
<400> 7
Phe Gln Val Leu Lys Ser Leu Gly Lys Leu Ala Met Gly Ser Asp Ser
1 5 10 15
Gln Ser Val Ser Ser Ser Ser Thr Gln Asp Pro His Arg Gly Arg Gln
20 25 30
Thr Leu Gly Ser Leu Arg Gly Leu Ala Lys Ala Lys Pro Glu Ala Ser
35 40 45
Phe Gln Val Trp Asn Lys Asp Ser Ser Ser Lys Asn Leu Ile Pro Arg
50 55 60
Leu Gln Lys Ile Trp Lys Asn Tyr Leu Ser Met Asn Lys Tyr Lys Val
65 70 75 80
Ser Tyr Lys Gly Pro Gly Pro Gly Ile Lys Phe Ser Ala Glu Ala Leu
85 90 95
Arg Cys His Leu Arg Asp His Val Asn Val Ser Met Val Glu Val Thr
100 105 110
Asp Phe Pro Phe Asn Thr Ser Glu Trp Glu Gly Tyr Leu Pro Lys Glu
115 120 125
Ser Ile Arg Thr Lys Ala Gly Pro Trp Gly Arg Cys Ala Val Val Ser
130 135 140
Ser Ala Gly Ser Leu Lys Ser Ser Gln Leu Gly Arg Glu Ile Asp Asp
145 150 155 160
His Asp Ala Val Leu Arg Phe Asn Gly Ala Pro Thr Ala Asn Phe Gln
165 170 175
Gln Asp Val Gly Thr Lys Thr Thr Ile Arg Leu Met Asn Ser Gln Leu
180 185 190
Val Thr Thr Glu Lys Arg Phe Leu Lys Asp Ser Leu Tyr Asn Glu Gly
195 200 205
Ile Leu Ile Val Trp Asp Pro Ser Val Tyr His Ser Asp Ile Pro Lys
210 215 220
Trp Tyr Gln Asn Pro Asp Tyr Asn Phe Phe Asn Asn Tyr Lys Thr Tyr
225 230 235 240
Arg Lys Leu His Pro Asn Gln Pro Phe Tyr Ile Leu Lys Pro Gln Met
245 250 255
Pro Trp Glu Leu Trp Asp Ile Leu Gln Glu Ile Ser Pro Glu Glu Ile
260 265 270
Gln Pro Asn Pro Pro Ser Ser Gly Met Leu Gly Ile Ile Ile Met Met
275 280 285
Thr Leu Cys Asp Gln Val Asp Ile Tyr Glu Phe Leu Pro Ser Lys Arg
290 295 300
Lys Thr Asp Val Cys Tyr Tyr Tyr Gln Lys Phe Phe Asp Ser Ala Cys
305 310 315 320
Thr Met Gly Ala Tyr His Pro Leu Leu Tyr Glu Lys Asn Leu Val Lys
325 330 335
His Leu Asn Gln Gly Thr Asp Glu Asp Ile Tyr Leu Leu Gly Lys Ala
340 345 350
Thr Leu Pro Gly Phe Arg Thr Ile His Cys
355 360
<210> 8
<211> 354
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体(synthetic construct)
<400> 8
Arg Asp Leu Ser Arg Leu Pro Gln Leu Val Gly Val Ser Thr Pro Leu
1 5 10 15
Gln Gly Gly Ser Asn Ser Ala Ala Ala Ile Gly Gln Ser Ser Gly Glu
20 25 30
Leu Arg Thr Gly Gly Ala Arg Pro Pro Pro Pro Leu Gly Ala Ser Ser
35 40 45
Gln Pro Arg Pro Gly Gly Asp Ser Ser Pro Val Val Asp Ser Gly Pro
50 55 60
Gly Pro Ala Ser Asn Leu Thr Ser Val Pro Val Pro His Thr Thr Ala
65 70 75 80
Leu Ser Leu Pro Ala Cys Pro Glu Glu Ser Pro Leu Leu Val Gly Pro
85 90 95
Met Leu Ile Glu Phe Asn Met Pro Val Asp Leu Glu Leu Val Ala Lys
100 105 110
Gln Asn Pro Asn Val Lys Met Gly Gly Arg Tyr Ala Pro Arg Asp Cys
115 120 125
Val Ser Pro His Lys Val Ala Ile Ile Ile Pro Phe Arg Asn Arg Gln
130 135 140
Glu His Leu Lys Tyr Trp Leu Tyr Tyr Leu His Pro Val Leu Gln Arg
145 150 155 160
Gln Gln Leu Asp Tyr Gly Ile Tyr Val Ile Asn Gln Ala Gly Asp Thr
165 170 175
Ile Phe Asn Arg Ala Lys Leu Leu Asn Val Gly Phe Gln Glu Ala Leu
180 185 190
Lys Asp Tyr Asp Tyr Thr Cys Phe Val Phe Ser Asp Val Asp Leu Ile
195 200 205
Pro Met Asn Asp His Asn Ala Tyr Arg Cys Phe Ser Gln Pro Arg His
210 215 220
Ile Ser Val Ala Met Asp Lys Phe Gly Phe Ser Leu Pro Tyr Val Gln
225 230 235 240
Tyr Phe Gly Gly Val Ser Ala Leu Ser Lys Gln Gln Phe Leu Thr Ile
245 250 255
Asn Gly Phe Pro Asn Asn Tyr Trp Gly Trp Gly Gly Glu Asp Asp Asp
260 265 270
Ile Phe Asn Arg Leu Val Phe Arg Gly Met Ser Ile Ser Arg Pro Asn
275 280 285
Ala Val Val Gly Arg Cys Arg Met Ile Arg His Ser Arg Asp Lys Lys
290 295 300
Asn Glu Pro Asn Pro Gln Arg Phe Asp Arg Ile Ala His Thr Lys Glu
305 310 315 320
Thr Met Leu Ser Asp Gly Leu Asn Ser Leu Thr Tyr Gln Val Leu Asp
325 330 335
Val Gln Arg Tyr Pro Leu Tyr Thr Gln Ile Thr Val Asp Ile Gly Thr
340 345 350
Pro Ser
<210> 9
<211> 959
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体(synthetic construct)
<400> 9
Glu Glu Lys Thr Val Gln Val Gln Lys Gly Leu Pro Ser Ile Asp Ser
1 5 10 15
Leu His Tyr Leu Ser Glu Asn Ser Lys Lys Glu Phe Lys Glu Glu Leu
20 25 30
Ser Lys Ala Gly Gln Glu Ser Gln Lys Val Lys Glu Ile Leu Ala Lys
35 40 45
Ala Gln Gln Ala Asp Lys Gln Ala Gln Glu Leu Ala Lys Met Lys Ile
50 55 60
Pro Glu Lys Ile Pro Met Lys Pro Leu His Gly Pro Leu Tyr Gly Gly
65 70 75 80
Tyr Phe Arg Thr Trp His Asp Lys Thr Ser Asp Pro Thr Glu Lys Asp
85 90 95
Lys Val Asn Ser Met Gly Glu Leu Pro Lys Glu Val Asp Leu Ala Phe
100 105 110
Ile Phe His Asp Trp Thr Lys Asp Tyr Ser Leu Phe Trp Lys Glu Leu
115 120 125
Ala Thr Lys His Val Pro Lys Leu Asn Lys Gln Gly Thr Arg Val Ile
130 135 140
Arg Thr Ile Pro Trp Arg Phe Leu Ala Gly Gly Asp Asn Ser Gly Ile
145 150 155 160
Ala Glu Asp Thr Ser Lys Tyr Pro Asn Thr Pro Glu Gly Asn Lys Ala
165 170 175
Leu Ala Lys Ala Ile Val Asp Glu Tyr Val Tyr Lys Tyr Asn Leu Asp
180 185 190
Gly Leu Asp Val Asp Val Glu His Asp Ser Ile Pro Lys Val Asp Lys
195 200 205
Lys Glu Asp Thr Ala Gly Val Glu Arg Ser Ile Gln Val Phe Glu Glu
210 215 220
Ile Gly Lys Leu Ile Gly Pro Lys Gly Val Asp Lys Ser Arg Leu Phe
225 230 235 240
Ile Met Asp Ser Thr Tyr Met Ala Asp Lys Asn Pro Leu Ile Glu Arg
245 250 255
Gly Ala Pro Tyr Ile Asn Leu Leu Leu Val Gln Val Tyr Gly Ser Gln
260 265 270
Gly Glu Lys Gly Gly Trp Glu Pro Val Ser Asn Arg Pro Glu Lys Thr
275 280 285
Met Glu Glu Arg Trp Gln Gly Tyr Ser Lys Tyr Ile Arg Pro Glu Gln
290 295 300
Tyr Met Ile Gly Phe Ser Phe Tyr Glu Glu Asn Ala Gln Glu Gly Asn
305 310 315 320
Leu Trp Tyr Asp Ile Asn Ser Arg Lys Asp Glu Asp Lys Ala Asn Gly
325 330 335
Ile Asn Thr Asp Ile Thr Gly Thr Arg Ala Glu Arg Tyr Ala Arg Trp
340 345 350
Gln Pro Lys Thr Gly Gly Val Lys Gly Gly Ile Phe Ser Tyr Ala Ile
355 360 365
Asp Arg Asp Gly Val Ala His Gln Pro Lys Lys Tyr Ala Lys Gln Lys
370 375 380
Glu Phe Lys Asp Ala Thr Asp Asn Ile Phe His Ser Asp Tyr Ser Val
385 390 395 400
Ser Lys Ala Leu Lys Thr Val Met Leu Lys Asp Lys Ser Tyr Asp Leu
405 410 415
Ile Asp Glu Lys Asp Phe Pro Asp Lys Ala Leu Arg Glu Ala Val Met
420 425 430
Ala Gln Val Gly Thr Arg Lys Gly Asp Leu Glu Arg Phe Asn Gly Thr
435 440 445
Leu Arg Leu Asp Asn Pro Ala Ile Gln Ser Leu Glu Gly Leu Asn Lys
450 455 460
Phe Lys Lys Leu Ala Gln Leu Asp Leu Ile Gly Leu Ser Arg Ile Thr
465 470 475 480
Lys Leu Asp Arg Ser Val Leu Pro Ala Asn Met Lys Pro Gly Lys Asp
485 490 495
Thr Leu Glu Thr Val Leu Glu Thr Tyr Lys Lys Asp Asn Lys Glu Glu
500 505 510
Pro Ala Thr Ile Pro Pro Val Ser Leu Lys Val Ser Gly Leu Thr Gly
515 520 525
Leu Lys Glu Leu Asp Leu Ser Gly Phe Asp Arg Glu Thr Leu Ala Gly
530 535 540
Leu Asp Ala Ala Thr Leu Thr Ser Leu Glu Lys Val Asp Ile Ser Gly
545 550 555 560
Asn Lys Leu Asp Leu Ala Pro Gly Thr Glu Asn Arg Gln Ile Phe Asp
565 570 575
Thr Met Leu Ser Thr Ile Ser Asn His Val Gly Ser Asn Glu Gln Thr
580 585 590
Val Lys Phe Asp Lys Gln Lys Pro Thr Gly His Tyr Pro Asp Thr Tyr
595 600 605
Gly Lys Thr Ser Leu Arg Leu Pro Val Ala Asn Glu Lys Val Asp Leu
610 615 620
Gln Ser Gln Leu Leu Phe Gly Thr Val Thr Asn Gln Gly Thr Leu Ile
625 630 635 640
Asn Ser Glu Ala Asp Tyr Lys Ala Tyr Gln Asn His Lys Ile Ala Gly
645 650 655
Arg Ser Phe Val Asp Ser Asn Tyr His Tyr Asn Asn Phe Lys Val Ser
660 665 670
Tyr Glu Asn Tyr Thr Val Lys Val Thr Asp Ser Thr Leu Gly Thr Thr
675 680 685
Thr Asp Lys Thr Leu Ala Thr Asp Lys Glu Glu Thr Tyr Lys Val Asp
690 695 700
Phe Phe Ser Pro Ala Asp Lys Thr Lys Ala Val His Thr Ala Lys Val
705 710 715 720
Ile Val Gly Asp Glu Lys Thr Met Met Val Asn Leu Ala Glu Gly Ala
725 730 735
Thr Val Ile Gly Gly Ser Ala Asp Pro Val Asn Ala Arg Lys Val Phe
740 745 750
Asp Gly Gln Leu Gly Ser Glu Thr Asp Asn Ile Ser Leu Gly Trp Asp
755 760 765
Ser Lys Gln Ser Ile Ile Phe Lys Leu Lys Glu Asp Gly Leu Ile Lys
770 775 780
His Trp Arg Phe Phe Asn Asp Ser Ala Arg Asn Pro Glu Thr Thr Asn
785 790 795 800
Lys Pro Ile Gln Glu Ala Ser Leu Gln Ile Phe Asn Ile Lys Asp Tyr
805 810 815
Asn Leu Asp Asn Leu Leu Glu Asn Pro Asn Lys Phe Asp Asp Glu Lys
820 825 830
Tyr Trp Ile Thr Val Asp Thr Tyr Ser Ala Gln Gly Glu Arg Ala Thr
835 840 845
Ala Phe Ser Asn Thr Leu Asn Asn Ile Thr Ser Lys Tyr Trp Arg Val
850 855 860
Val Phe Asp Thr Lys Gly Asp Arg Tyr Ser Ser Pro Val Val Pro Glu
865 870 875 880
Leu Gln Ile Leu Gly Tyr Pro Leu Pro Asn Ala Asp Thr Ile Met Lys
885 890 895
Thr Val Thr Thr Ala Lys Glu Leu Ser Gln Gln Lys Asp Lys Phe Ser
900 905 910
Gln Lys Met Leu Asp Glu Leu Lys Ile Lys Glu Met Ala Leu Glu Thr
915 920 925
Ser Leu Asn Ser Lys Ile Phe Asp Val Thr Ala Ile Asn Ala Asn Ala
930 935 940
Gly Val Leu Lys Asp Cys Ile Glu Lys Arg Gln Leu Leu Lys Lys
945 950 955
Claims (36)
1.一种具有下式的糖缀合物:
[[有效载荷]x—唾液酸苷—Gal—GlcNAc]y—CBA,
其中CBA表示细胞结合剂;
GlcNAc表示N-乙酰葡糖胺,其任选地被岩藻糖取代;
Gal表示半乳糖;
唾液酸苷表示经修饰的唾液酸;
有效载荷,其在每种情况下可以相同或不同,表示药物或诊断标记;
其中所述有效载荷不包括吡咯并苯二氮
x是1-8的整数;并且
y是1-8的整数,优选地1或2。
2.根据任一前述权利要求所述的糖缀合物,其具有下式:
其中
Rfa是氢或岩藻糖部分;
QQ是氢或至少一个缀合的有效载荷;
ZZ是羟基或至少一个缀合的有效载荷;
YY是羟基或至少一个缀合的有效载荷;
XX是羟基或至少一个缀合的有效载荷;并且
其中QQ、ZZ、YY和XX中的至少一者是至少一个缀合的有效载荷。
3.根据任一前述权利要求所述的糖缀合物,其中Rfa为岩藻糖部分。
4.根据任一前述权利要求所述的糖缀合物,其中Rfa为具有以下结构的岩藻糖部分:
5.根据任一前述权利要求所述的糖缀合物,其中CBA为蛋白质。
6.根据任一前述权利要求所述的糖缀合物,其中CBA为抗体。
7.根据任一前述权利要求所述的糖缀合物,其中CBA为单克隆抗体。
8.根据任一前述权利要求所述的糖缀合物,其中CBA为蛋白质,并且所述糖缀合物具有以下结构:
9.根据任一前述权利要求所述的糖缀合物,其中CBA为抗体,并且所述GlcNAc经由天冬酰胺侧链缀合至所述抗体。
10.根据任一前述权利要求所述的糖缀合物,其中CBA为抗体,并且所述GlcNAc缀合至Fc结构域中的至少一个Asn297残基。
11.根据任一前述权利要求所述的糖缀合物,其中CBA为抗体,并且所述GlcNAc缀合至Fc结构域中的两个Asn297残基。
12.根据任一前述权利要求所述的糖缀合物,其中所述有效载荷包含至少一种细胞毒素、免疫调节剂、抗病毒剂、抗细菌剂、肽或寡核苷酸。
13.根据任一前述权利要求所述的糖缀合物,其中所述有效载荷包含在23℃下的水溶解度小于20mg/ml、小于10mg/ml、小于5mg/ml、小于2.5mg/ml、小于1mg/ml、小于0.5mg/ml、小于0.1mg/ml、小于0.05mg/ml或小于0.01mg/ml的至少一种药物。
14.根据任一前述权利要求所述的糖缀合物,其中所述有效载荷包含DNA损伤剂、微管蛋白聚合抑制剂、拓扑异构酶抑制剂、RNA剪接抑制剂、RNE聚合酶抑制剂或其组合。
15.根据任一前述权利要求所述的糖缀合物,其中所述有效载荷包含秋水仙碱、长春花生物碱、蒽环类药物、喜树碱、多柔比星、柔红霉素、紫杉烷、多拉司他汀、安丝霉素、吡啶并苯二氮艾日布林、念珠藻素、烯-二炔抗生素、微管溶素、依沙替康、伊立替康、抑制性肽、鹅膏蕈碱、脱三角梅蛋白、倍癌霉素、美坦辛、奥瑞斯他汀或其组合。
16.根据任一前述权利要求所述的糖缀合物,其中QQ、XX、YY和ZZ中的至少一者具有下式:
其中Het表示杂环系统,其在每种情况下可以相同或不同;
L1选自空或子接头,其在每种情况下可以相同或不同;
L2选自空或子接头,其在每种情况下可以相同或不同;
x1选自1、2、3、4、5、6、7或8;
x2选自1、2、3、4、5、6、7或8;并且
x3选自1、2、3、4、5、6、7或8。
17.根据任一前述权利要求所述的糖缀合物,其中:
a)XX、YY和ZZ各自是OH;
b)XX和YY都是OH,并且QQ是H;
c)XX和YY都是OH。
18.根据任一前述权利要求所述的糖缀合物,其中QQ具有下式:
19.根据任一前述权利要求所述的糖缀合物,其中ZZ具有下式:
20.根据任一前述权利要求所述的糖缀合物,其中Het具有下式:
其中H1表示杂环,并且A表示碳环或杂环。
21.根据任一前述权利要求所述的糖缀合物,其中A为8原子碳环或杂环。
22.根据任一前述权利要求所述的糖缀合物,其中H1是由(a)1,3偶极体或1,2,4,5四嗪两者之一与(b)应变环炔或应变环烯两者之一之间的环加成反应形成的杂环。
23.根据任一前述权利要求所述的糖缀合物,其中H1包括三唑、1,2哒嗪、噁唑、异噁唑、噁二唑及其饱和和部分不饱和的类似物。
24.根据任一前述权利要求所述的糖缀合物,其中A具有下式:
其中RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’独立地选自空、H、F、Cl、Br、I、C1-4烷基、C1-4烷氧基、芳基;并且其中RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’中的任一个可以是L1或L2,其中RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’中的任何两者或更多者可以一起形成环;
W可以是具有下式的基团:
其中L1/2表示H、L1或L2两者之一,
前提条件为当W、RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’中的一个包括L1时,W、RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’都不包括L2;并且L2键合到H1;并且
当W、RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’中的一个包括L2时,W、RA1、RA1’、RA2、RA2’、RA3、RA3’、RA4和RA4’都不包括L1,并且L1键合到H1。
25.根据任一前述权利要求所述的糖缀合物,其中A环具有下式:
26.根据任一前述权利要求所述的糖缀合物,其中L2具有下式:
—L21—L22—L23—L24—L25—L26—,
其中:
L21键合到杂环系统,并且选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR21、OC(=O)、OC(=O)NR21、NR21C(=O)、NR21C(=O)O、NR21C(=O)、NR21C(=O)NR21、OC(=O)O,其中R21在每种情况下选自H和C1-4烷基;
L22选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR22、OC(=O)、OC(=O)NR22、NR22C(=O)、NR22C(=O)、NR22C(=O)O、NR22C(=O)NR22、OC(=O)O,其中R22在每种情况下选自H和C1-4烷基;
L23选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、S、聚(乙烯)、聚(缩醛);聚(甘油)、O、NR23、OC(=O)、OC(=O)NR23、NR23C(=O)、NR23C(=O)、NR23C(=O)O、NR23C(=O)NR23、OC(=O)O,其中R23在每种情况下选自H和C1-4烷基;
L24选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR24、OC(=O)、OC(=O)NR24、NR24C(=O)、NR24C(=O)、NR24C(=O)O、NR24C(=O)NR24、OC(=O)O,其中R24在每种情况下选自H和C1-4烷基;
L25选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR25、OC(=O)、OC(=O)NR25、NR25C(=O)、NR25C(=O)、NR25C(=O)O、NR25C(=O)NR25、OC(=O)O,其中R25在每种情况下选自H和C1-4烷基;
L26键合到唾液酸苷,并且选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR26、OC(=O)、OC(=O)NR26、NR26C(=O)、NR26C(=O)、NR26C(=O)O、NR26C(=O)NR26、OC(=O)O,其中R26在每种情况下选自H和C1-4烷基。
27.根据任一前述权利要求所述的糖缀合物,其中
L21为空、OC(O)NH、C1-8亚烷基,优选地C1-3亚烷基或亚芳基,例如1,4-亚苯基;
L22为空或C1-8亚烷基,优选地C1-3亚烷基;
L23为为空、C(=O)NH、NHC(=O)、NHC(=O)O或OC(=O)NH;
L24为空或聚(乙烯),
L25为空或C1-8亚烷基,优选地C1-3亚烷基,并且
L26为空或杂环基或杂芳基,例如三唑、1,2哒嗪、噁唑、异噁唑、噁二唑及其饱和和部分不饱和的类似物。
28.根据任一前述权利要求所述的糖缀合物,其中L1为空或具有下式的基团:
—L11—L12—L13—(L14—L15—L16)x—,
其中:
x选自1、2、3、4、5、6、7或8;
L11键合到杂环系统,并且选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR11、OC(=O)、OC(=O)NR11、NR11C(=O)、NR11C(=O)、NR11C(=O)NR11、OC(=O)O,其中R11在每种情况下选自H和C1-4烷基;
L12选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR12、OC(=O)、OC(=O)NR12、NR12C(=O)、NR12C(=O)、NR12C(=O)NR12、OC(=O)O,其中R12在每种情况下选自H和C1-4烷基;
L13选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR13、OC(=O)、OC(=O)NR13、NR13C(=O)、NR13C(=O)、NR13C(=O)NR13、OC(=O)O,其中R13在每种情况下选自H和C1-4烷基;
L14选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR14、OC(=O)、OC(=O)NR14、NR14C(=O)、NR14C(=O)、NR14C(=O)NR14、OC(=O)O,其中R14在每种情况下选自H和C1-4烷基;
L15选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR15、OC(=O)、OC(=O)NR15、NR15C(=O)、NR15C(=O)、NR15C(=O)NR15、OC(=O)O,其中R15在每种情况下选自H和C1-4烷基;
L16键合到有效载荷,并且选自空、C1-8亚烷基、亚芳基、杂芳基、杂环基、聚(乙烯)、聚(缩醛);聚(甘油)、S、O、NR16、OC(=O)、OC(=O)NR16、NR16C(=O)、NR16C(=O)、NR16C(=O)NR16、OC(=O)O,其中R16在每种情况下选自H和C1-4烷基。
29.根据任一前述权利要求所述的糖缀合物,其中L1具有下式:
其中y1选自1、2、3、4和5;其中y为1-1,000;并且R456选自氢或式(456)的部分:
30.根据任一前述权利要求所述的糖缀合物,其中L1具有式
其中RSIP是一个或多个自分解间隔基,RCL是可裂解基团,并且RL1当存在时是附加接头,x1.5是选自1、2、3、4、5、6、7和8的整数;并且x1.6是选自1、2、3、4、5、6、7和8的整数。
31.根据任一前述权利要求所述的糖缀合物,其中RSIP具有下式:
其中Xz是O、NH或NC1-4烷基;
Rco键合到所述有效载荷中的杂原子上,并且选自C=O、SO2、P(=O)OH或具有下式的基团:
其中Rea1和Rea2独立地选自H和C1-4烷基;并且
以下两者之一:
a)Xz1是氢并且Xz2是RCL,其中RCL键合至RL1;或者
b)Xz1是RL1并且Xz2是RCL;
其中z是1或0,z1是1或0,Raa1、Raa2和Raa3独立地选自H、任选地被苯基取代的C1-6烷基、COOH、NH2、COHNH2、NHC(O)NH2;并且
以下两者之一:
a)RCC是H、肽基、C1-6烷基、环烷基、芳基、杂芳基或杂环基,并且RCC1是RSIP,其中所述RSIP进一步键合到RL1和所述有效载荷;或者
b)RCC是RL1并且RCC1是RSIP,其中所述RSIP键合到所述有效载荷。
32.根据任一前述权利要求所述的糖缀合物,其中RCL具有下式:
33.根据任一前述权利要求所述的糖缀合物,其中RCL具有下式:
其中RCC1是RSIP,其中所述RSIP进一步键合到RL1和所述有效载荷。
34.根据任一前述权利要求所述的糖缀合物,其中RCL具有下式:
其中RCC2是RSIP或所述有效载荷中的杂原子,并且RCC是L1。
35.根据任一前述权利要求所述的糖缀合物,其中RCL具有下式:
36.根据权利要求2至35中任一项所述的糖缀合物,其中QQ、XX、YY和ZZ中的至少一者是具有下式的至少一个缀合的有效载荷:
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