CN1768266A - 纯化稳定的放射性碘偶联物的方法 - Google Patents
纯化稳定的放射性碘偶联物的方法 Download PDFInfo
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- CN1768266A CN1768266A CNA2004800091734A CN200480009173A CN1768266A CN 1768266 A CN1768266 A CN 1768266A CN A2004800091734 A CNA2004800091734 A CN A2004800091734A CN 200480009173 A CN200480009173 A CN 200480009173A CN 1768266 A CN1768266 A CN 1768266A
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Abstract
本发明涉及制备和纯化放射性碘标记的氨基多羧酸-附加的肽和导向剂的偶联物的方法。该方法包括(A)提供一种溶液,它含有(i)未结合的放射性碘(ii)没有与导向剂偶联的放射性碘标记的氨基多羧酸-附加的肽(iii)和与导向剂偶联的放射性碘标记的氨基多羧酸-附加的肽;(B)让所述溶液与阴离子交换树脂接触;和(C)让所述阴离子交换树脂和溶液一起通过能够截留阴离子交换树脂颗粒的过滤器。
Description
发明领域
本发明涉及用于放射性免疫检测和放射性免疫治疗的试剂的纯化,尤其涉及在体内具有增强了的稳定性并且在肿瘤部位具有增强了的保留能力的放射性碘标记的偶联物的纯化。
发明背景
放射性碘标记的单克隆抗体对于癌症的诊断和治疗来说是重要的,正如Goldenberg在Amer.J.Med.1993;94:297-312中所归纳的。在过去三十年中业已开发了多种方法,用于通过化学方法将放射性碘导入单克隆和多克隆抗体用于上述目的。在上述用途中,碘优选作为放射性标记使用,因为用于对蛋白进行放射性碘标记的化学方法是相对简单的,放射性碘具有有用的物理衰变特性,并且碘的同位素可以通过商业渠道获得。业已开发了各种化学方法,将碘连接在导向于癌细胞的抗体上。业已在以下文献中对上述化学方法进行了综述:Wilbur,Bioconjugate Chemistry 1992;3:433-70。最常见的连接方法是在原位制备亲电子的放射性碘物质,以便与抗体上的官能团反应。业已将诸如氯胺-T和iodogen的试剂用于制备亲电子的碘。蛋白上的酪氨酸基团通常是碘化位点。
Mabs的常规放射性碘标记需要用某些纯化方法除去所使用的氧化剂和未结合的放射性碘标记物。当使用诸如氯胺-T的缓冲液-可溶性氧化剂时,所述氧化剂和放射性碘标记物通常是通过大小排阻层析在大小排阻柱上除去的,如通过商业渠道获得的PD10柱。
使用直接放射性碘标记方案的主要缺陷是体内脱碘作用现象。抗体内化和体内溶酶体处理的结果是,标记过的蛋白被降解成小的肽,并且它的放射性碘以碘酪氨酸形式从细胞中释放或者作为连接于低分子肽片段的碘。上述发现业已披露在以下文献中:Geissler等,CancerResearch 1992;52:2907-2915和Shih等.,J.Nucl.Med.1994;35:899-908。所述从靶细胞去除放射性碘的方法降低了肿瘤与非肿瘤的区别,这对于放射性诊断来说是重要的,并且还减少了放射性碘在靶细胞中的停留时间,它能显著影响放射性治疗效果。
为了克服体内脱碘作用现象,业已设计了若干种方法,所述方法是通过在细胞内保留的碘放射性标记的设计。所述标记被称作“残余标记”。在一种方法中,放射性碘连接于不可代谢的碳水化合物,而后者被首先激活,然后与抗体偶联。该方法的例子是乳糖醇酪胺(LT)和二乳糖醇酪胺(Strobel等,Arch.Biochem.Biophys 1985;240:635-45)和酪氨酸纤维素二糖(Ali等,Cancer Research 1990;50:783s-88s)。在另一种方法中,使用了基于吡啶的部分″SIPC ″(Reist等,Cancer Research 1996;56:4970-4977)。业已探究了含有所有D氨基酸和多碱性氨基酸的五肽(Foulon等,Cancer Research2000;60:4453-4460)。在另一种方法中,含有DTPA-附加的,放射性碘标记的肽被成功地用作残余标记(Govindan等,BioconjugateChemistry 1999;10:231-240;Stein等,Cancer Research 2003;63:111-118)。
当放射性碘标记的小分子量材料与Mabs偶联时(以下称之为放射性碘标记的偶联物),正如在前面段落中的参考部分所披露的,还存在其他的要求,即同样需要除去未偶联的材料。这总是需要纯化的其他柱方法。所述碳水化合物方法导致了低的总体产量和比活性,并且涉及在处理结束时的纯化的柱方法。Reist等(同上)和Foulon等(同上)的方法涉及两个柱纯化步骤,一个是在放射性碘标记阶段,另一个是在抗体偶联阶段。Govindan等(同上;还披露于Stein等(同上))的方法涉及在处理结束时进行的一个柱纯化步骤,具有更高的总产量和比活性。
柱纯化方法通常是烦琐的,并且具有使人员接触辐射(特别是在处理用于临床规模的制剂时接触数百mCi的I-131)和严量的柱破坏的其他缺陷。在基于iodogen的放射性碘标记中,所述氧化剂是不溶于水的,并且是通过简单地注射或过滤掉放射性标记材料除去的。在所述情况下,需要除去的仅有的其他材料是未结合的放射性碘标记物。由于碘标记物与磷酸盐或氢氧化物离子结合强的阴离子交换树脂的相对高的亲和力,业已证实了通过使用阴离子交换树脂可以除去未结合的碘化物[Weadock等J Nuclear Medicine 1990;31:508-511];Behr TM等Nuklearmedizin 2002;41:71-79]。还可以使用固定化的氯胺-T氧化剂,如可通过商业渠道获得的″IODO-BEADS″与阴离子交换树脂的组合。尽管通过所述组合实现了直接放射性碘标记的抗体的纯化的某些简化,放射性碘标记的偶联物的使用仍然需要除去未偶联的小分子量部分。由于这种纯化通常是通过柱方法实现的,所述方法的现有缺陷造成了在纯化用于临床目的的几百毫居的放射性制剂时产生了实际问题。
Li等业已披露了柱方法(Bioconjugate Chemistry 1994;5:101-104),用于从未标记的DOTA-肽中纯化放射性金属-螯合的DOTA-肽,这是通过二乙基氨基乙基纤维素阴离子交换柱,并且用若干部分的水洗脱而进行的。在这种情况下,放射性金属-螯合的DOTA-肽具有中性电荷,并因此从柱中洗脱,同时,在螯合部分上带有负电荷的未标记的材料被阴离子交换柱保留。这是纯化放射性金属-螯合的双功能材料所必须的,所述材料随后偶联在抗体上,并且通过大小排阻柱方法纯化所述产物。因此,Li等的方法(同上)涉及多个步骤的方法和两个基于柱的纯化步骤。同样,所述基于柱的方法在用于小分子量部分的大规模放射性碘标记随后并且导向剂偶联时是不实用的。在后一种情况下,涉及数百毫居的放射性碘,因此需要更简单的纯化方法。
发明概述
本发明通过提供放射性碘标记的偶联物的纯化方法解决了上述问题,所述偶联物是通过放射性碘标记的氨基多羧酸-附加的肽与导向剂的共价连接而制备的。
本发明解决了对放射性碘标记的偶联物的纯化***的需要,所述偶联物来自多种放射性碘标记的,氨基多羧酸-附加的部分和导向剂。与本领域以前公知的方法相反,由于诸如抗体的导向剂的直接放射性碘标记,本发明涉及包括低分子量实体,如含有酪氨酸的双功能肽的放射性碘标记,和使放射性碘标记的部分与抗体偶联的方法。因此,本发明解决了通过纯化除去未结合的放射性碘标记物和未偶联的放射性碘标记的部分的需要。
本发明的方法提供了用残余的碘标记物进行抗体标记的更高的效率。所述方法还提供了具有低的聚集物含量的更高质量的稳定的放射性碘偶联物制剂。通过以下详细说明可以理解其他优点,如在一体化制备和纯化方法所赋予的简化和安全操作。
附图简述
图1表示粗制(未纯化的)产物(I-131-IMP-R4-hMN-14)的大小排阻(SEC)HPLC。主峰大约10分钟的保留是由于标记的hMN-14产生的,而靠近14分钟和18分钟的峰分别表示未偶联的I-131-IMPR4和I-131。
图2表示纯化的I-131-IMPR4-hMN14的SEC HPLC,并且证实了未偶联的I-131-IMPR4和I-131是通过阴离子交换完全除去的。
图-3表示纯化的产物和癌胚抗原(CEA)复合的混合物的SECHPLC,并且该HPLC证实了所述产物的免疫反应性被完全保留,正如通过所述峰的完全偏移所证实的,所述峰的完全偏移是由于抗体-抗原复合物的更高分子量材料的标记过的抗体。
定义
在以下说明中,广泛采用了多种术语。为了有助于理解本发明,本文提供了定义。
导向剂。″导向剂″是能够选择性地结合靶细胞的分子部分。导向剂的例子包括蛋白分子,它能够导向于抗原或由肿瘤或感染病变表达的受体,或能够导向于肿瘤或病变上的特殊受体的低分子量部分,或导向于肿瘤细胞或病变的合成核苷酸。优选的导向剂包括抗体和肽。
抗体。术语″抗体″包括单克隆抗体,如鼠类,嵌合的,人源化的或人类抗体,以及抗原结合片段。所述片段包括Fab,Fab′,F(ab)2,和F(ab′)2,它缺少完整抗体的Fc片段。所述片段还包括轻链可变区的分离的片段,重链和轻链可变区的″Fv″片段,(sFv)2片段(例如,参见:Tai等,Cancer Research Supplement,55:5983-5989,1995),和重组的单链多肽分子,其中,轻链和重链可变区是通过肽接头连接的。所说的″多价″抗体表示所述抗体能够与一个以上的抗原结合,所述抗原可能同时具有相同或不同的结构。″多特异性″抗体表示所述的抗体能够同时与具有不同结构的至少两种抗原结合。
偶联物。在本文中,偶联物是包括来标记过的或放射性标记的氨基多羧酸-附加的肽的分子(又被称作″低分子量部分″),它是与诸如单克隆抗体的导向剂共价连接的。所述偶联物保留了所述导向剂的生物特异性。例如,与和低分子量部分偶联之前相比,所述抗体导向剂的免疫反应性(结合抗原的能力)在偶联之后是大致相同的,或者仅略有减弱。
氨基多羧酸-附加的肽。术语″氨基多羧酸-附加的肽″表示通过氨基多羧酸与肽的共价连接形成的化学部分。所述连接优选是通过肽的氨基实现的。任何合适的氨基多羧酸都适合用于本发明。典型的氨基多羧酸包括亚氨基二乙酸,次氮基三乙酸,EDTA(乙二胺四乙酸),DTPA(二乙三胺四乙酸),TTHA(三乙四胺六乙酸),DOTA(1,4,7,10-四氮杂环十二烷N,N′,N″,N-四乙酸),或它们的各种主链取代形式,例如,异硫氰基苄根-EDTA/DTPA/TTHA/DOTA,以及多种其他的氨基多羧酸和可以容易推断的它们的衍生物。术语肽如下文所定义。
肽.在短语氨基多羧酸-附加的肽中所使用的术语″肽″表示由L或D-氨基酸组装的任何肽,或L和D-氨基酸的组合。所述肽优选是由2-40个氨基酸组装的,更优选由2-5个氨基酸组装,并且最优选由3-4个氨基酸组装。所述肽任选具有至少一个D-酪氨酸,它们是与诸如L或D-赖氨酸的碱性氨基酸连接的,后者构成了所述肽的羧基末端。该碱性氨基酸可以与氨基多羧酸结合。
溶液。在本文中,溶液表示含有抗体和放射性碘标记的氨基多羧酸,未结合的放射性碘标记物和未结合的放射性碘标记的氨基多羧酸的偶联物。优选的溶液是缓冲的水溶液。
未结合的放射性碘。在本文中,未结合的放射性碘表示没有氧化成活性碘物质的放射性碘物质,并且包括未氧化的放射性碘标记物,它不能与所述肽结合。
阴离子交换树脂。在本文中,″阴离子交换树脂″表示通过商业渠道获得的不溶性合成或天然的聚合物基质,它含有质子化的叔胺或四烷基铵官能团,其中,抗衡离子(阴离子)可以与测试底物的阴离子交换。
过滤器。在本文中,″过滤器″表示可以保留颗粒状物质的任何装置,如大小为0.10μm-0.30μm的过滤器,更优选大约0.22μm孔直径大小的过滤器。
氧化剂。在本文中,″氧化剂″表示用于将放射性碘氧化成有活性的放射性碘一氯化物分子的任何氧化剂,所述分子在放射性碘标记反应中是放射性碘标记物质,正如所披露的(同上)。
Iodogen方法。该术语表示涉及使用iodogen作氧化剂的放射性碘标记程序。Iodogen(1,3,4,6-四氯-3□,6□-二苯基甘脲)是水不溶性材料,它在接触放射性碘标记物的溶液时能产生有活性的放射性碘标记物质,正如所披露的(同上)。
氯胺-T方法。该术语表示将氯胺-T(N-氯甲苯磺胺钠)用作不溶于水的氧化剂,它在与放射性碘标记物溶液混合时能产生有活性的放射性碘标记物质,正如Wilbur所披露的(同上)。
连接部分。连接部分是能够与导向剂形成共价键的官能团,选自下组:马来酰亚胺,氯乙酰胺,溴乙酰胺,碘乙酰胺,乙烯砜,N-羟基琥珀酰亚胺酯,N-羟基磺基琥珀酰亚胺酯,酰胺化酯,异氰酸酯,或异硫氰酸酯。采用均双官能或杂双官能交联分子将所述连接部分导入氨基多羧酸-附加的肽。将纯双官能和杂双官能剂用作交联剂为本领域所公知(Wong,S.S.,1991;Chemistry of protein conjugation andcross-linking;CRC Press,Boca Raton,FL;pp 1-48)。
本发明的详细说明
出乎意料地,本发明人业已发现,与阴离子-交换树脂的短暂接触能有效除去未偶联的低分子量部分。通过从阴离子交换树脂中过滤而分离纯化的产物。为了从偶联物中过滤树脂,以及通过所述树脂除去的未反应的碘化物和碘化氨基多羧酸-附加的肽,任何能够截留颗粒状物质的过滤装置都可以使用。优选0.22μm的过滤装置。通过用阴离子交换树脂搅拌除去未偶联的低分子量材料的方法特别适合本发明的氨基多羧酸部分,如DTPA。
业已意外地发现了通过简单的一锅纯化方法能有效除去未偶联的多羧酸部分,该方法避免了纯化的烦琐的柱方法。根据阴离子交换树脂的抗衡离子的选择性,人们无法预测与阴离子交换树脂的短时间接触能够有效除去未偶联的低分子量部分,如多羧酸。例如,氢氧化物被认为对阴离子交换树脂具有弱结合能力,并且,乙酸基团的结合仅仅略微好于氢氧化物。乙酸基团与本发明的氨基多羧酸的相关性在于,氨基多羧酸包括位于氮原子上的乙酸残基,并且这些乙酸残基在pH>6的缓冲液中是作为乙酸完全离子化的。例如,根据生产商的产物文献(AG1andAG 2 Strong anion-exchange resin Instruction Manual,BioRadCorporation),碘化物在AG 1阴离子交换树脂上的选择性是氢氧化物(可任意设定为1)的175倍,而乙酸只比氢氧化物高3.2倍。另外,树脂是以磷酸酯形式使用的,它具有的相对选择性为5(与氢氧化物的1相比),这种选择性略好于乙酸。碘化物结合阴离子交换树脂的较高的选择性,仅仅预示了通过离子交换方法成功地除去了碘化物。不过,尽管乙酸与磷酸离子相比结合阴离子交换树脂具有较低的选择性,本发明人业已发现了离子交换方法能有效除去含有氨基多羧酸的小分子材料,它不能够根据阴离子交换树脂结合选择性而预测。尽管不希望受任何理论的约束,本发明人认为,这种改进的选择性是由于多个乙酸基团在相同分子上的存在,正如通过小分子量部分的氨基多羧酸亚结构所推测的。因此,业已发现,通过将氨基多羧酸部分掺入小分子量材料,未偶联的放射性碘标记的材料能够通过用阴离子交换树脂的悬浮液简单地搅拌几分钟并且过滤掉产物而有效地除去。本发明的简化方法在操作上是独特的,并且比Li等的方法(同上)更好,其优点在于,完全避免了纯化的柱方法。
阴离子交换树脂
对所述实验来说,使用了通过商业渠道获得的强碱性阴离子交换树脂,它包括与苯乙烯二乙烯基苯共聚物晶格连接的季铵基团。该树脂具有8%的交联,相当于分子量排阻极限为1000Da的孔径,以及100-200的中等目大小(150-75μm颗粒直径)。
不过,本发明不局限于上述特殊的阴离子交换树脂特征,但是包括上述强碱性阴离子交换树脂和弱碱性阴离子交换树脂,如通过商业渠道获得的二乙基氨基乙基纤维素。另外,在所述树脂上使用的交联程度是没有限制的。在强碱性阴离子交换树脂的特殊例子中,所述交联可以为2%(孔径的分子量排阻极限为2700Da)-12%(孔径的分子量排阻极限为400Da),并且树脂的粒度可以为20目-400目,相当于850μm-38μm颗粒直径范围。
偶联物
本发明涉及不可代谢的和放射性碘标记的肽的用途,它被用于标记抗体,以便所述放射性活性残留在体内。所述专门设计的肽包括2-40个氨基酸,优选2-5个氨基酸,优选包括D-氨基酸。D-氨基酸优选使用在肽与抗体的连接位点和与酪氨酸或酪胺结合的放射性碘之间的肽上。最优选的是,在该区域内,没有两个相邻的氨基酸是L-氨基酸。在这种场合下的甘氨酸是L-氨基酸。通过以这种方式使用D-氨基酸,将放射性碘连接于抗体的肽键不能在溶菌体中水解。另外,附加在所述肽上的一个或多个氨基多羧酸部分,以及N-末端和/或侧链氨基与具有用于与抗体共价结合的官能团的交联剂连接。所述共价抗体结合基团可以是氨基残基(用于与Mabs的氧化的Fc部分碳水化合物进行位点特异性结合),imidate或异硫氰酸酯(可以与蛋白的赖氨酸基团连接),马来酰亚胺,溴-或碘乙酰胺残基(对Mabs上的硫醇具有特异性)等。仅随最后一个D-酪氨酸单位并且被用于导入抗体-结合交联剂量的氨基酸可以是天然L-氨基酸。所述氨基多羧酸单位可以是亚氨基二乙酸,次氮基三乙酸,EDTA(乙二胺四乙酸),DTPA(二乙三胺四乙酸),TTHA(三乙四胺六乙酸),DOTA(1,4,7,10-四氮杂环十二烷N,N′,N″,N-四乙酸),NOTA(1,4,7-三氮杂环壬烷-N,N′,N″-三乙酸)或它的各种主链取代形式,例如,1-[(p-异硫氰基)苄基]-EDTA(苄基-EDTA),1-[(p-异硫氰基)苄基]-DTPA(苄基-DTPA),1-[(p-异硫氰基)苄基]-TTHA(苄基TTHA),1-[(p-异硫氰基)苄基]-DOTA(苄基-DOTA),1-[(p-异硫氰基)苄基]-NOTA(苄基-NOTA),还包括多种其他氨基多羧酸,并且可以方便地推断它们的衍生物。
在其他实施方案中,所述双功能可碘化的氨基多羧酸是通过将酪胺基和抗体结合基团连接于氨基多羧酸而衍生的。在所述结构中不包括易受蛋白酶水解的键。另外,氨基多羧酸,即用抗体结合单位取代的主链被转化成相应的双酸酐,它然后与D-酪氨酸反应,以便获得包括两个D-酪氨酸残基的实体。由于双功能氨基多羧酸和D-酪氨酸之间的酰胺键不能被蛋白酶识别,它们构成了不同形式的残留的碘标记。
碘化D-酪氨酸部分耐受脱碘酶这一事实是可用于本发明的有利特性。这种可能性披露于以下文献中:Dumas等,Biochem.Biophys.Acta 1973;293:36-47。
用于对抗体进行放射性碘标记的氨基多羧酸-附加的肽的例子选自下组:X-Gly-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH;X-D-Ala-D-Tyr-D-Tyr-D-Lys(DTPA);[X-D-Ala-D-Tyr-D-Tyr-D-Lys(1/2DTPA)]2;X-Lys(X)-Lys((1-(p-CSNH)苄基)DTPA)-D-Tyr-D-Tyr-D-Lys((1-(p-NH)苄基)DTPA)-OH;X-Lys(X)-Lys((1-(p-CSNH)苄基)DTPA)-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH;X-Asp-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH;X-Lys(X)-Asp-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH;X-Asp-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH;和X-Lys(X)-Asp-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH;其中X是交联剂,它包括用于与导向载体共价连接的官能团,包括诸如单克隆抗体,它的片段和构建体的蛋白。
在本发明范围内合适的放射性碘的例子有I-123,I-124,I-125或I-131。
抗体
在本发明的优选实施方案中,使用了诸如MAbs,多价抗体和多特异性抗体的抗体,这些抗体能够识别或结合标记物或肿瘤相关的抗原,这些抗原是以高水平在靶细胞上表达的,并且主要或者只能在相对正常组织为病变的细胞上表达,以及与某些正常细胞和需要消除的组织,如骨髓细胞和异位组织,如甲状旁腺,脾和子宫内膜相关的抗原,并且使用了能够迅速内化的抗体。所说的″多价″抗体表示能够结合一个以上抗原的抗体,所述抗原可以同时具有相同或不同的结构。所说的″多特异性″抗体表示所述抗体能够同时结合至少两个具有不同结构的抗原。例如,具有两种不同特异性的抗体被视为多价和多特异性的,因为它能够同时结合两种结构上不同的靶。另一方面,具有两种或两种以上特异性的抗体能结合相同的靶,但没有其他特异性,它就是多价而不是多特异性。多种多特异性和/或多价抗体可以通过分子工程生产。例如,双特异性融合蛋白可以是一价的,例如,由scFv组成,它具有结合单个抗原的结合位点,和Fab片段,它具有结合第二个抗原的单个结合位点。双特异性抗体还可以是二价的,例如,由IgG组成,它具有结合一种抗原的两个结合位点,和具有结合第二种抗原的两个结合位点的两个scFv。
可用于本发明范围内的抗体包括具有上述特性的mAbs,并且涉及但不局限于以下mAbs的用途:LL1(抗-CD74),LL2(抗-CD22),RS7(抗-上皮糖蛋白-1(EGP-1)),PAM-4(抗-MUCl),MN-14(抗-癌胚抗原),Mu-9(抗-结肠-特异性抗原-p),AFP(抗甲胎蛋白),抗***特异性膜抗原(PSMA),如J591,和G250(抗-碳酸酐酶IX)。可以用所述偶联物导向的其他有用的抗原包括HER-2/neu,CD19,CD20,VEGF,EGF受体,碱性磷酸酶,***酸磷酸酶,腱生蛋白,胎盘生长因子(P1GF),***(ILGF),和神经节苷脂。
在本发明的另一种优选实施方案中,所使用的抗体能迅速内化,然后重新表达,加工并且呈递到细胞表面上,使得细胞能够连续摄入并且增加循环免疫偶联物。最优选的抗体/抗原对的例子是LL1,即一种抗-CD74mAb(恒定链,II类特异性侣伴蛋白,Ii)。CD74抗原是在B细胞淋巴瘤,某些T细胞淋巴瘤,黑素瘤和某些其他癌上高水平表达的(Ong等,Immunology 1999;98:296-302)。
例如,用抗-CD74抗体治疗的疾病包括,但不局限于非何杰金氏淋巴瘤,黑素瘤和多发性骨髓瘤。CD74抗原在靶细胞表面上短时间连续表达,然后进行抗原的内化,并且再次表达所述抗原,使得导向性LL1抗体与它作为″有效负载″所携带的任何治疗部分一起内化。这使得可以在所述细胞内积累高的治疗浓度的LL1-治疗性免疫偶联物。内化的LL1免疫偶联物是通过溶酶体和核内体循环的,并且残余的放射性部分因此保留在靶细胞内。
在优选实施方案中,用于治疗人类疾病的抗体是人类的或人源化(cdr-嫁接的)形式的抗体;不过,可以使用鼠类和嵌合形式的抗体。对于兽医用途来说,相同物种的IgG可能是最有效的载体,不过跨物种的IgGs也保持可以使用。相同物种的IgG分子作为输送剂,对于减弱免疫反应来说是最优选的。在考虑重复治疗时,这是特别重要的。对于人类来说,人或人源化的IgG抗体不太可能由患者产生抗-IgG免疫反应。导向于内化抗原,诸如hLL1和hLL2的抗体在与靶细胞结合之后能够迅速内化,这意味着,被携带的放射性碘标记的抗体偶联物被迅速内化到细胞中。
所述Mab是鼠类抗体,嵌合抗体,人源化抗体,或人类抗体,并且可以是完整的,它的片段或各种工程改造的形式。在特别优选的实施方案中,MAb是衍生化的或二硫化物-还原成具有硫醇基。
抗体靶
抗体可用于治疗各种病变组织,细胞和器官,如心血管病变(例如,血凝块,栓塞物,动脉粥样硬化斑),淀粉样沉积物(例如,淀粉样变性病和阿尔茨海默病),传染性生物(例如,细菌,真菌,立克次体,病毒,寄生虫),炎症(例如,III类自身免疫病,如免疫介导的血小板减少,如急性特发性血小板减少性紫癜和慢性特发性性血小板减少性紫癜,皮肌炎,干燥综合征,多发性硬化,西登哈姆舞蹈病,重症肌无力,***性红斑狼疮,狼疮肾炎,风湿热,多腺体综合征,大疱性类天疱疮,糖尿病,过敏性紫癜,链球菌感染后肾炎,结节性红斑,高安动脉炎,阿狄森氏病,类风湿性关节炎,结节病,溃病性结肠炎,多形性红斑,IgA肾病,结节性多动脉炎,强直性脊柱炎,肺出血肾炎综合征,thromboangitis ubiterans,干燥综合征,原发性胆汁性肝硬化,桥本甲状腺炎,甲状腺毒症,硬皮病,慢性活动性肝炎,多肌炎/皮肌炎,多软骨炎,寻常天疤疮,韦格纳氏肉芽肿,膜性肾病,肌萎缩性侧索硬化,脊髓痨,巨细胞动脉炎/多肌痛,恶性贫血,急进性肾小球肾炎和纤维化肺泡炎等),移位或异位正常组织(例如,甲状旁腺,子宫内膜,脾,胸腺),和癌(液体(例如,白血病和淋巴瘤)和实体(例如,癌,肉瘤,神经胶质瘤,黑素瘤)。
下面将结合实施例说明本发明,这些实施例并不限定本发明的范围。
实施例
实施例1:用于用放射性碘标记的IMP-R4标记二硫化物还原的抗
-CEA MAb,hMN-14的简化的一锅制备和纯化方法
下面用IMP-R4作为小分子量材料说明该方法,它是放射性碘标记的,并且与二硫化物-还原的抗-CEA MAb,hMN-14偶联。IMP-R4具有以下结构:MCC-Lys(MCC)-Lys((1-(p-CSNH)苄基)DTPA)-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH,其中,MCC是4-(N-马来酰亚氨基甲基)-环己烷-1-羰基。IMP-R4是申请日为2000年10月26日的美国专利申请号09/696,740的主题的一部分。
将从供应商处购买的I-131碘化钠用7倍体积的pH 7.4的0.5M的磷酸钠缓冲,并且,利用另外的1.4mL的40mM pH7.4的磷酸钠转移到iodogen包被的管形瓶中,该管形瓶中放有搅棒,并且装有IMP-R4(0.13μmol/100mCi的I-131)。搅拌该溶液8-15分钟,并且用过量的4-羟基苯乙酸对未结合的放射性碘进行淬火。放射性碘标记的IMP-R4与二硫化物-还原的hMN-14偶联(在一种实验中IgG-SH-与IMP-R4的比例为0.6)30分钟,并且用连四硫酸钠对未使用的硫醇基封端。最后,添加磷酸盐形式的2-3mL的20%w/v阴离子交换树脂AGlX8(100-200目)的悬浮液,并且搅拌5分钟。然后将放射性标记材料过滤到无菌薄膜密封的容器中,使用Milli-FilDGS 0.22μm过滤单位(Millipore Corporation)。任选将人血清白蛋白添加到所述产物中,使最终浓度为l%-2.5%。
典型的回收如下:从57.4mCi的I-131开始,最终产物包括40mCi(69.9%),而在一轮中涉及123mCi的I-131,最终的产物包括63mCi(51%)。在使用40mCu-123mCi的I-131进行放射性标记(n=9)时,通过HPLC分析测定的总体结合范围为61%-75%,而回收率在50%-70%范围内。通过与CEA复合并且通过HPLC分析判断的免疫反应性>95%。通过HPLC分析判断最终产物的纯度>95%,聚焦物<5%,比活性在5mCi/mg-6mCi/mg范围内。
实施例2:在缓冲液中和对血清侵袭的体外稳定性
浓度为0.9mCi/mL的纯化的实施例1产物(62.9mCi的总放射性)和浓度为0.2mg/mL的抗体存在于含有2.5%HAS的磷酸缓冲液中,在室温下放置20小时,并且通过大小排阻HPLC分析。典型的磷酸缓冲液是0.1M磷酸钠水溶液,将pH调整到6.0-7.5之间。这证实了所述产物实际上是没有变化的。与20倍摩尔过量的CEA抗原复合,揭示了免疫反应性的保留。
在第二种实施方案中,所述产物在人血清中稀释33.3倍,并且在37℃下温育20小时。在此时进行的分析证实了标记物的可以忽略的损失,并且所述材料仍然与CEA复合,表明了免疫反应性的保留。
实施例3:在较低pH下标记和纯化
根据实施例1的方法,改变如下:I-131碘化钠的缓冲是用7倍体积的pH 6的0.3M磷酸钠进行的,然后使用1.4mL pH6的0.03M磷酸钠将缓冲过的I-131转移到iodogen管形瓶中。在放射性碘标记之后,与二硫化物-还原的hMN-14偶联,并且通过与AG1X8阴离子交换树脂搅拌进行纯化,从56.5mCi的I-131碘化钠起始,获得了纯化I-131-IMP-R4-hMN-14的39mCi(69%)的回收率。在另一种实验中,使用相同的方法,从109.8mCi的I-131碘化钠获得了69.3mCi的纯化的产物(63.1%)。另外,在上述两种实验中,通过与CEA复合证明了免疫反应性的完全保留。
实施例4:使用固定化的氯胺-T作为氧化剂进行放射性碘标记,
然后进行偶联和阴离子交换纯化。
在本实验中,用通过商业渠道获得的固定化氯胺-T(IODO-BEADS)取代iodogen。将一个或多个珠用于放射性碘标记管形瓶中。另外,操作与实施例1所述相同。这样,在阴离子交换纯化,并且通过简单的过滤分离产物之后获得了纯化的I-131-IMP-R4-hMN-14。
在本申请中所提到的所有文献,包括专利,专利申请和期刊的内容被以整体形式收作本文参考。
Claims (50)
1.一种制备和纯化放射性碘标记的氨基多羧酸-附加的肽和导向剂的偶联物的方法,包括:
(A)提供一种溶液,它含有(i)未结合的放射性碘(ii)没有与导向剂偶联的放射性碘标记的氨基多羧酸-附加的肽(iii)和与导向剂偶联的放射性碘标记的氨基多羧酸-附加的肽;
(B)让所述溶液与阴离子交换树脂接触;和
(C)让所述阴离子交换树脂和溶液一起通过能够截留阴离子交换树脂颗粒的过滤器;
以便获得所述放射性碘标记的氨基多羧酸-附加的肽和导向剂的偶联物。
2.如权利要求1的方法,其中,溶液(A)是通过对氨基多羧酸-附加的肽进行放射性碘标记,以便形成放射性碘标记的肽而制备的;和
让所述放射性碘标记的氨基多羧酸-附加的肽与导向剂偶联,以便形成放射性碘标记的氨基多羧酸-附加的肽的偶联物。
3.如权利要求1的方法,其中,所述肽的放射性碘标记是用氧化剂进行的,以便由放射性碘化钠产生放射性碘,它能够结合所述肽。
4.如权利要求3的方法,其中,所述氧化剂是iodogen或氯胺-T。
5.如权利要求4的方法,其中,所述氧化剂是氯胺-T,并且所述放射性碘标记是在存在固定化的,不溶性的,球形的氯胺-T的条件下进行的。
6.如权利要求1的方法,其中,所述过滤器的孔的直径为0.1μm-0.3μm。
7.如权利要求1的方法,其中,所述阴离子交换树脂由聚合物晶格上的季铵官能团组成,并且,在所述聚合物上的交联程度大约为2%-12%。
8.如权利要求1的方法,其中,所述阴离子交换树脂由聚合物晶格上的叔胺官能团组成。
9.如权利要求7或8的方法,其中,所述树脂的粒度为20目-400目(颗粒直径为850μm-38μm)。
10.如权利要求1的方法,其中,所述偶联物的纯化的溶液包括低于10%的组合的未偶联的放射性碘和未偶联的放射性碘标记的肽,它们是在接触所述阴离子交换树脂之前最初存在于所述溶液中的。
11.如权利要求1的方法,还包括一起搅拌所述树脂和所述溶液。
12.如权利要求1的方法,还包括让所述溶液通过装有阴离子交换树脂的柱。
13.如权利要求1的方法,其中,权利要求1的氨基多羧酸-附加的肽选自下组:
X-Gly-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH;
X-D-Ala-D-Tyr-D-Tyr-D-Lys(DTPA);
[x-D-Ala-D-Tyr-D-Tyr-D-Lys(1/2DTPA)]2;
X-Lys(X)-Lys((1-(p-CSNH)苄基)DTPA)-D-Tyr-D-Tyr-D-Lys((1-(p-NH)苄基)DTPA)-OH;
X-Lys(X)-Lys((1-(p-CSNH)苄基)DTPA)-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH;
X-Asp-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH;
X-Lys(MCC)-Asp-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH;
X-Asp-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH;和
X-Lys(X)-Asp-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH;
其中,X是交联剂,它包括能够与所述导向剂形成共价连接的连接部分。
14.如权利要求1或13的方法,其中,所述导向剂是通过连接部分与所述氨基多羧酸-附加的肽偶联的,连接部分包括马来酰亚胺,氯乙酰胺,溴乙酰胺,碘乙酰胺,乙烯砜,N-羟基琥珀酰亚胺酯,N-羟基磺基琥珀酰亚胺酯,酰胺化酯,异氰酸酯,或异硫氰酸酯。
15.如权利要求14的方法,其中,所述马来酰亚胺连接部分是4-(N-马来酰亚氨基甲基)-环己烷-1-羰基部分。
16.如权利要求14的方法,其中,所述马来酰亚胺连接部分是2-(N-马来酰亚氨基)乙酰部分。
17.如权利要求1的方法,其中,所述氨基多羧酸是EDTA,DTPA,苄基-EDTA,苄基-DTPA,苄基-DOTA,TTHA(三乙四胺六乙酸),NOTA,或苄基-NOTA。
18.如权利要求1的方法,其中,所述肽是IMP-R4,它是:MCC-Lys(MCC)-Lys((1-(p-CSNH)苄基)DTPA)-D-Tyr-D-Lys((1-(p-CSNH)苄基)DTPA)-OH,并且其中MCC是4-(N-马来酰亚氨基甲基)-环己烷-1-羰基部分。
19.如权利要求1的方法,其中,所述导向剂是单克隆抗体(MAb)。
20.如权利要求19的方法,其中,所述单克隆抗体是与恶性疾病相关的。
21.如权利要求19的方法,其中,所述单克隆抗体是与心血管病相关的。
22.如权利要求19的方法,其中,所述单克隆抗体是与自身免疫病相关的。
23.如权利要求22的方法,其中,所述自身免疫病是III类自身免疫病。
24.如权利要求23的方法,其中,所述III类自身免疫病选自下组:免疫介导的血小板减少,皮肌炎,干燥综合征,多发性硬化,西登哈姆舞蹈病,重症肌无力,***性红斑狼疮,狼疮肾炎,风湿热,多腺体综合征,大疱性类天疱疮,糖尿病,过敏性紫瘢,链球菌感染后肾炎,结节性红斑,高安动脉炎,阿狄森氏病,类风湿性关节炎,结节病,溃疡性结肠炎,多形性红斑,IgA肾病,结节性多动脉炎,强直性脊柱炎,肺出血肾炎综合征,thromboangitis ubiterans,干燥综合征,原发性胆汁性肝硬化,桥本甲状腺炎,甲状腺毒症,硬皮病,慢性活动性肝炎,多肌炎/皮肌炎,多软骨炎,寻常天疱疮,韦格纳氏肉芽肿,膜性肾病,肌萎缩性侧索硬化,脊髓痨,巨细胞动脉炎/多肌痛,恶性贫血,急进性肾小球肾炎和纤维化肺泡炎。
25.如权利要求19的方法,其中,所述单克隆抗体与阿尔茨海默病相关。
26.如权利要求19的方法,其中,所述单克隆抗体与传染性生物相关。
27.如权利要求19的方法,其中,所述单克隆抗体是内化抗体。
28.如权利要求19的方法,其中,所述单克隆抗体是抗-CEA MAb,MN-14;抗-EGP-1MAb;抗-CD22MAb;抗-CD20MAb;抗-结肠-特异性抗原-p MAb;抗-CD74 MAb;抗-MUC1 MAb;抗-AFP MAb;抗***特异性膜抗原;或抗-碳酸酐酶IX Mab。
29.如权利要求19的方法,其中,所述单克隆抗体是鼠类抗体,嵌合抗体,人源化抗体,或人类抗体,并且可以是完整的,它们的片段或各种工程改造形式。
30.如权利要求19的方法,其中,所述单克隆抗体是衍生化的或二硫化物-还原成具有硫醇基。
31.如权利要求1的方法,其中,所述放射性碘是I-123,I-124,I-125或I-131。
32.如权利要求1的方法,其中,由导向载体导向的抗原包括HER-2/neu,CD19,CD20,VEGF,EGF受体,碱性磷酸酶,***酸磷酸酶,腱生蛋白,胎盘生长因子(P1GF),***(ILGF)和神经节苷脂。
33.如权利要求19的方法,其中,所述单克隆抗体能够导向于心血管病变,淀粉样沉积物,传染性生物,炎症,自身免疫病,移位或异位的正常组织,和流体癌或实体癌。
34.如权利要求19的方法,其中,所述单克隆抗体能够导向于血凝块,栓塞物,动脉粥样硬化斑,淀粉样变性,细菌,真菌,立克次体,病毒,寄生虫,类风湿性关节炎,***性红斑狼疮,多发性硬化,移位或异位的甲状旁腺组织,移位或异位的子宫内膜组织,移位或异位的脾组织,移位或异位的胸腺组织,白血病,淋巴瘤,癌,肉瘤,神经胶质瘤,或黑素瘤。
35.如权利要求1的方法,其中,所述导向剂是多价抗体或多价、多特异性抗体。
36.如权利要求35的方法,其中,所述多价抗体或多价、多特异性抗体与恶性疾病相关。
37.如权利要求35的方法,其中,所述多价抗体或多价、多特异性抗体与心血管病相关。
38.如权利要求35的方法,其中,所述多价抗体或多价、多特异性抗体与自身免疫病相关。
39.如权利要求38的方法,其中,所述自身免疫病是III类自身免疫病。
40.如权利要求39的方法,其中,所述III类自身免疫病选自下组:免疫介导的血小板减少,皮肌炎,干燥综合征,多发性硬化,西登哈姆舞蹈病,重症肌无力,***性红斑狼疮,狼疮肾炎,风湿热,多腺体综合征,大疱性类天疱疮,糖尿病,过敏性紫瘢,链球菌感染后肾炎,结节性红斑,高安动脉炎,阿狄森氏病,类风湿性关节炎,结节病,溃疡性结肠炎,多形性红斑,IgA肾病,结节性多动脉炎,强直性脊柱炎,肺出血肾炎综合征,thromboangitis ubiterans,干燥综合征,原发性胆汁性肝硬化,桥本甲状腺炎,甲状腺毒症,硬皮病,慢性活动性肝炎,多肌炎/皮肌炎,多软骨炎,寻常天疱疮,韦格纳氏肉芽肿,膜性肾病,肌萎缩性侧索硬化,脊髓痨,巨细胞动脉炎/多肌痛,恶性贫血,急进性肾小球肾炎和纤维化肺泡炎。
41.如权利要求35的方法,其中,所述多价抗体或多价、多特异性抗体与阿尔茨海默病相关。
42.如权利要求35的方法,其中,所述多价抗体或多价、多特异性抗体与传染性生物相关。
43.如权利要求35的方法,其中,所述多价抗体或多价、多特异性抗体是内化抗体。
44.如权利要求35的方法,其中,所述多价抗体或多价、多特异性抗体是衍生化的或二硫化物-还原成具有硫醇基。
45.如权利要求35的方法,其中,所述多价抗体或多价,多特异性抗体能够导向于心血管病变,淀粉样沉积物,传染性生物,炎症,自身免疫病,移位或异位的正常组织,和流体癌或实体癌。
46.如权利要求35的方法,其中,所述多价抗体或多价、多特异性抗体包括以下物质的结合位点:CD74,CD22,上皮糖蛋白-1,MUC1,癌胚抗原,结肠-特异性抗原-p,甲胎蛋白,***特异性膜抗原,碳酸酐酶IX,HER-2/neu,CD19,CD20,VEGF,EGF受体,碱性磷酸酶,***酸磷酸酶,腱生蛋白,胎盘生长因子(P1GF),***(ILGF),和神经节苷脂。
47.如权利要求35的方法,其中,所述多价抗体或多价、多特异性抗体能够导向于血凝块,栓塞物,动脉粥样硬化斑,淀粉样变性,细菌,真菌,立克次体,病毒,寄生虫,类风湿性关节炎,***性红斑狼疮,多发性硬化,移位或异位的甲状旁腺组织,移位或异位的子宫内膜组织,移位或异位的脾组织,移位或异位的胸腺组织,白血病,淋巴瘤,癌,肉瘤,神经胶质瘤,或黑素瘤。
48.如权利要求24的方法,其中,所述免疫介导的血小板减少是急性特发性血小板减少性紫瘢或慢性特发性性血小板减少性紫瘢。
49.如权利要求40的方法,其中,所述免疫介导的血小板减少是急性特发性血小板减少性紫瘢或慢性特发性性血小板减少性紫瘢。
50.如权利要求19的方法,其中,所述单克隆抗体选自下组:MN-14,RS7,LL2,1F5,A20,Mu9,LL1,PAM-4,Immu31,J591和G250。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105579434A (zh) * | 2013-03-08 | 2016-05-11 | 南加州大学 | 基于乙烯基砜的18f标记组合物和方法及其用途 |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7591994B2 (en) | 2002-12-13 | 2009-09-22 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
US20160279239A1 (en) | 2011-05-02 | 2016-09-29 | Immunomedics, Inc. | Subcutaneous administration of anti-cd74 antibody for systemic lupus erythematosus and autoimmune disease |
ES2350477T5 (es) * | 2002-03-01 | 2020-05-06 | Immunomedics Inc | Internalización de anticuerpos anti-CD74 y métodos de uso |
DE10303974A1 (de) | 2003-01-31 | 2004-08-05 | Abbott Gmbh & Co. Kg | Amyloid-β(1-42)-Oligomere, Verfahren zu deren Herstellung und deren Verwendung |
WO2005021494A2 (en) * | 2003-06-13 | 2005-03-10 | Immunomedics, Inc. | D-amino acid peptides |
EP1964847A3 (en) * | 2003-06-25 | 2008-09-17 | Peregrine Pharmaceuticals, Inc. | Method and apparatus for continuous large-scale radiolabeling of proteins |
US7318925B2 (en) | 2003-08-08 | 2008-01-15 | Amgen Fremont, Inc. | Methods of use for antibodies against parathyroid hormone |
AU2003282780A1 (en) | 2003-08-08 | 2005-03-07 | Abgenix, Inc. | Antibodies directed to parathyroid hormone (pth) and uses thereof |
US20160355591A1 (en) | 2011-05-02 | 2016-12-08 | Immunomedics, Inc. | Subcutaneous anti-hla-dr monoclonal antibody for treatment of hematologic malignancies |
GB0520529D0 (en) | 2005-10-10 | 2005-11-16 | Ge Healthcare Ltd | Automated radiolabelling method |
IL297746A (en) | 2005-11-30 | 2022-12-01 | Abbvie Inc | Monoclonal antibodies against amyloid beta protein and uses thereof |
BRPI0619249A2 (pt) | 2005-11-30 | 2011-09-20 | Abbott Lab | anticorpos anti-globulÈmeros-aß, frações que se ligam a antìgeno destes, hibridomas correspondentes, ácidos nucléicos, vetores, células hospedeiras, métodos de produzir os ditos anticorpos, composições compreendendo os ditos anticorpos, usos dos ditos anticorpos e métodos de usar os ditos anticorpos |
US8455626B2 (en) | 2006-11-30 | 2013-06-04 | Abbott Laboratories | Aβ conformer selective anti-aβ globulomer monoclonal antibodies |
US20100311767A1 (en) | 2007-02-27 | 2010-12-09 | Abbott Gmbh & Co. Kg | Method for the treatment of amyloidoses |
CA2796339C (en) | 2010-04-15 | 2020-03-31 | Abbott Laboratories | Amyloid-beta binding proteins |
US8524239B2 (en) | 2010-07-09 | 2013-09-03 | The United States of America as represented by the Secrectary, Department of Health and Human Services | Photosensitizing antibody-fluorophore conjugates |
EP2603524A1 (en) | 2010-08-14 | 2013-06-19 | AbbVie Inc. | Amyloid-beta binding proteins |
EP2731626B1 (en) * | 2011-07-11 | 2018-12-19 | THE UNITED STATES OF AMERICA, represented by the S | Photosensitizing antibody-fluorophore conjugates |
US8927732B2 (en) | 2012-03-30 | 2015-01-06 | General Electric Company | Biotin stannane for HPLC-free radioiodination |
KR101426422B1 (ko) | 2012-05-10 | 2014-08-06 | 한국원자력연구원 | 안질환 또는 암 치료용 아이오딘 씨드의 제조방법 및 이에 의하여 제조되는 아이오딘 씨드 |
CN106470705B (zh) | 2014-08-08 | 2020-03-31 | 美国政府(由卫生和人类服务部的部长所代表) | 在体内和在体外的靶标的光控移除 |
WO2017027247A1 (en) | 2015-08-07 | 2017-02-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Near infrared photoimmunotherapy (nir-pit) of suppressor cells to treat cancer |
EP3337514B8 (en) | 2015-08-18 | 2022-04-06 | Rakuten Medical, Inc. | Composition comprising a conjugate comprising a phthalocyanine dye linked to a targeting molecule for photoimmunotherapy |
CN114699525A (zh) | 2015-08-18 | 2022-07-05 | 乐天医药生技股份有限公司 | 酞菁染料偶联物的制造方法及稳定偶联物 |
EP3606964A4 (en) | 2017-04-03 | 2020-12-09 | Immunomedics, Inc. | SUBCUTANE ADMINISTRATION OF ANTIBODY DRUG CONJUGATES FOR CANCER THERAPY |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI82379C (fi) | 1981-10-27 | 1991-03-11 | Univ California | Radioaktivt maerkta monoklonala antikroppar samt en komposition innehaollande dessa och anvaendbar som diagnostiskt radiofarmaseutiskt medel. |
SE466403B (sv) * | 1988-03-24 | 1992-02-10 | Kurt G I Nilsson | Saett att syntetisera oligosackarider |
FR2652004B1 (fr) | 1989-09-21 | 1994-10-28 | Immunotech Partners | Nouveaux derives hydrophiles, application au diagnostic et a la therapeutique, kits diagnostiques ou therapeutiques et reactifs immunologiques. |
US5273738A (en) | 1990-03-03 | 1993-12-28 | Fred Hutchinson Cancer Research Center | Radiation delivery to lymphoid and marrow tissues |
EP0492478B1 (en) | 1990-12-21 | 1995-07-19 | Pliva Farmaceutska, Kemijska, Prehrambena I Kozmeticka Industrija S P.O. | Tert-butyloxycarbonyl-L-tyrosyl-peptidoglycan monomer and 125 I-labelled derivative thereof, their preparation and use |
US5554745A (en) | 1992-05-14 | 1996-09-10 | National Starch And Chemical Investment Holding Corporation | Aldehyde cationic derivatives of galactose containing polysaccharides used as paper strength additives |
EP0757559A4 (en) | 1994-04-29 | 1999-06-23 | Molecular Medicine Center | COMPOSITION FOR THE ADMINISTRATION OF TOXIC RADIOISOTOPES IN THE CELL CORE AND THEIR USE |
US5672335A (en) | 1994-11-30 | 1997-09-30 | Schering Aktiengesellschaft | Use of metal complexes as liver and gallbladder X-ray diagnostic agents |
US6663866B1 (en) | 1996-08-28 | 2003-12-16 | Immunomedics, Inc. | Stable radioiodine conjugates and methods for their synthesis |
ATE194143T1 (de) | 1996-08-28 | 2000-07-15 | Immunomedics Inc | Stabile radioiodium-konjugate und verfahren zu deren herstellung |
US6558669B1 (en) | 1996-08-28 | 2003-05-06 | Immunomedics, Inc. | Stable radioiodine conjugates and methods for their synthesis |
JP2005532343A (ja) * | 2002-05-29 | 2005-10-27 | イミューノメディクス、インコーポレイテッド | 脳およびcns腫瘍の放射免疫治療のための方法および組成物 |
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US10471161B2 (en) | 2013-03-08 | 2019-11-12 | University Of Southern California | Vinylsulfone-based 18F-labeling compositions and methods and uses thereof |
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