共查询到18条相似文献,搜索用时 125 毫秒
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早期抗体药物是鼠源单克隆抗体,存在免疫原性强、半衰期短等问题。历经数十年的发展,抗体药物从最初的鼠源单抗,逐步发展为人鼠嵌合抗体、人源化抗体及全人源化抗体。通过片段重组、位点修饰、药物偶联等方法,科研人员研发了包括抗体融合蛋白、抗体偶联药物、双特异性抗体、小分子抗体片段等形式多样的抗体药物。抗体药物在恶性肿瘤、自身免疫病、感染性疾病的治疗上发挥重要作用。通过对抗体药物人源化历程,不同类型的抗体结构和特点,以及抗体药物在新型冠状病毒肺炎治疗中的应用进行综述,并对抗体药物的发展前景进行展望,以期为我国抗体药物的研发提供参考。 相似文献
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重组分子抗体是一类潜在的治疗用药物,约占目前进入临床试验的生物制品类药物的三分之一,FDA批准上市的抗体药物有近十种,其中多数为重组的完整人源抗体(包括人鼠嵌合抗体和人源化抗体),本对基因工程完整抗体的有关实验研究进行了综述。 相似文献
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嵌合抗体轻链基因在家蚕细胞中的重组与表达 总被引:2,自引:0,他引:2
用家蚕修饰型核多角体病毒为载体,在家蚕细胞获得人鼠嵌合的抗人小细胞肺癌抗体轻链基因的表达。PCR和Southern杂交证明了抗体轻链基因已组建家蚕病毒基因组中。Western blot和ELISA和分析都检测到在重组病毒感染的家蚕细胞中产生了人鼠嵌合的抗体轻链。 相似文献
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为降低人抗鼠抗体(HAMA)反应并在CHO细胞中高效表达抗人P185^erbB2人/鼠嵌合抗体,将抗人P185^erbB2单抗C25的轻、重链可变区基因分别克隆入具有人抗体恒定区基因组序列和弱化启动子驱地劝的选择标志基因的真核表达载体中,共转染CHO-dhfr^-细胞,经G418及氨甲喋呤(MTX)梯度加压筛选进行了嵌合抗体的高效表达,采用RT-PCR、ELISA、细胞ELISA、免疫荧光细胞化等实验证实了所表达的抗人P185^erbB2嵌合抗体的人源性及抗原特异性。培养上清中的抗体产量可达100mg/L,所表达的嵌合抗体具有抑制P185^erbB2高表达肿瘤细胞增殖的作用。 相似文献
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抗乙肝病毒表面抗原嵌合抗体基因在昆虫细胞中的表达 总被引:2,自引:1,他引:1
应用杆状病毒表达系统在昆虫细胞中表达了抗乙肝病毒表面抗原(HBsAg)人-鼠嵌合抗体重,轻链基因,鼠源单克隆抗体OH3重,轻链可变区(VH,VL)cDNA分别与人免疫球蛋白恒区γ3,k,cDNA拼接成人-鼠嵌合抗体基因,含嵌合抗体的转移载体与线性化病毒DNA共转染Sf9细胞,并通过点杂交PCR扩增和Southernblot分析获得重组病毒。Westernblot和竞争ELISA表明以重组病毒感染的 相似文献
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Alexander Bujotzek Florian Lipsmeier Seth F Harris Jörg Benz Andreas Kuglstatter 《MABS-AUSTIN》2016,8(2):288-305
Antibody humanization describes the procedure of grafting a non-human antibody's complementarity-determining regions, i.e., the variable loop regions that mediate specific interactions with the antigen, onto a β-sheet framework that is representative of the human variable region germline repertoire, thus reducing the number of potentially antigenic epitopes that might trigger an anti-antibody response. The selection criterion for the so-called acceptor frameworks (one for the heavy and one for the light chain variable region) is traditionally based on sequence similarity. Here, we propose a novel approach that selects acceptor frameworks such that the relative orientation of the 2 variable domains in 3D space, and thereby the geometry of the antigen-binding site, is conserved throughout the process of humanization. The methodology relies on a machine learning-based predictor of antibody variable domain orientation that has recently been shown to improve the quality of antibody homology models. Using data from 3 humanization campaigns, we demonstrate that preselecting humanization variants based on the predicted difference in variable domain orientation with regard to the original antibody leads to subsets of variants with a significant improvement in binding affinity. 相似文献
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单克隆抗体药物是一种新兴的治疗药物,具有高选择性,被用于多种疾病的治疗,如肿瘤、免疫疾病等,也可以用于中枢神经系统疾病,如阿尔茨海默病、帕金森病、中风和脑肿瘤等。然而,因为血脑屏障低通透性,限制了抗体药物在中枢神经系统疾病治疗中的应用,在很多神经系统疾病临床试验中,抗体药物并没有取得预期效果。如今,人们利用血脑屏障上内源性转运蛋白介导,设计了可以通过血脑屏障的抗体药物。对通过血脑屏障治疗性抗体药物研发进展及其应用前景进行了综述。 相似文献
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产生免疫原性的残基都是位于蛋白表面的暴露残基,为了消除鼠抗体对人的免疫原性,利用表面再塑方法对本室克隆的鼠抗人纤维蛋白抗体单链Fv片断进行了人源化分子设计。首先确定了鼠及人Fv表面残基,在此基础上分析了鼠与人Fv间表面残基的差异,将有差异的鼠表面残基换成人的。提出了残基最高频率人源化及最相似链人源化两种人源化方案。人源化后鼠抗人纤维蛋白抗体单链Fv的结构经Profile-3D验证是合理的,置换的表面残基溶液可及性未变,且未影响CDRs的结构,应不会影响与纤维蛋白的亲和力,为鼠抗体人源化实验研究奠定了基础。 相似文献
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《Bioscience, biotechnology, and biochemistry》2013,77(9):1903-1908
Agonistic anti-human Fas antibodies that can induce apoptosis are thought to have therapeutic effects for various diseases resulting from an abnormality of the Fas/FasL system. However, some anti-Fas antibodies show toxicity, and it is difficult to investigate their therapeutic and toxicological effect using animals because of their species specificity. We previously obtained a murine anti-human Fas mAb, HFE7A. HFE7A reacted with both human and murine Fas, and mitigated lymphadenopathy without any sign of hepatotoxicity in MRLgld/gld mice. It is suggested that humanized HFE7A would be a therapeutic treatment for various diseases resulting from an abnormality of the Fas/FasL system. Here we isolated the cDNAs that code for the heavy and light chains of HFE7A and identified the corresponding nucleotide sequences. The recombinant HFE7A was indistinguishable in binding and apoptosis-inducing activity to that from a hybridoma cell line. These data provide essential information for the humanization and clinical application of the humanized HFE7A. 相似文献
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产生免疫原性的残基主要是位于蛋白表面的暴露残基,为了消除鼠抗体对人的免疫原性,利用表面再塑的方法对本室克隆的鼠抗人纤维蛋白抗体单链Fv片段进行了人源化分子设计.首先确定了鼠及人Fv片段的表面残基,在此基础上分析了鼠与人抗体Fv片段表面残基的差异,将存在差异的鼠抗体的表面残基换成人的,从而实现鼠抗体的人源化.提出了残基最高频率人源化及最相似链人源化两种分子设计方案.人源化的鼠抗人纤维蛋白抗体单链Fv片段的结构经Profiles-3D检测证明合理,替换的表面残基的溶剂可及性未变,而且未对CDRs的空间构象产生明显影响,应不会影响与纤维蛋白的亲和力,为鼠抗体人源化实验研究奠定了基础. 相似文献
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Sherry L La Porte Charles Eigenbrot Mark Ultsch Wei-Hsien Ho Davide Foletti Alison Forgie Kevin C Lindquist David L Shelton Jaume Pons 《MABS-AUSTIN》2014,6(4):1059-1068
Nerve growth factor (NGF) is indispensable during normal embryonic development and critical for the amplification of pain signals in adults. Intervention in NGF signaling holds promise for the alleviation of pain resulting from human diseases such as osteoarthritis, cancer and chronic lower back disorders. We developed a fast, high-fidelity method to convert a hybridoma-derived NGF-targeted mouse antibody into a clinical candidate. This method, termed Library Scanning Mutagenesis (LSM), resulted in the ultra-high affinity antibody tanezumab, a first-in-class anti-hyperalgesic specific for an NGF epitope. Functional and structural comparisons between tanezumab and the mouse 911 precursor antibody using neurotrophin-specific cell survival assays and X-ray crystal structures of both Fab-antigen complexes illustrated high fidelity retention of the NGF epitope. These results suggest the potential for wide applicability of the LSM method for optimization of well-characterized antibodies during humanization. 相似文献
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《MABS-AUSTIN》2013,5(4):1059-1068
Nerve growth factor (NGF) is indispensable during normal embryonic development and critical for the amplification of pain signals in adults. Intervention in NGF signaling holds promise for the alleviation of pain resulting from human diseases such as osteoarthritis, cancer and chronic lower back disorders. We developed a fast, high-fidelity method to convert a hybridoma-derived NGF-targeted mouse antibody into a clinical candidate. This method, termed Library Scanning Mutagenesis (LSM), resulted in the ultra-high affinity antibody tanezumab, a first-in-class anti-hyperalgesic specific for an NGF epitope. Functional and structural comparisons between tanezumab and the mouse 911 precursor antibody using neurotrophin-specific cell survival assays and X-ray crystal structures of both Fab-antigen complexes illustrated high fidelity retention of the NGF epitope. These results suggest the potential for wide applicability of the LSM method for optimization of well-characterized antibodies during humanization. 相似文献