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人源化抗体研究历程及发展趋势 总被引:7,自引:0,他引:7
单克隆抗体从问世到目前广泛应用于临床,经历了一段曲折的发展历程。其中人源化抗体是一个重要的里程碑,并伴随着一系列重大的技术革新,如PCR技术、抗体库技术、转基因动物等。人源化抗体的形式也从最初的嵌合抗体、改型抗体等逐步发展为今天的人抗体。抗体人源化已经成为治疗性抗体的发展趋势,同时各种抗体衍生物也不断涌现,它们从不同角度克服抗体本身的应用局限,也为治疗人类疾病提供了更多利器。对单克隆抗体进行改造使之应用于临床治疗,不仅需要对抗体效应机制进行更细致深入的研究,同时还有赖于对人类免疫系统调控机制的全面精确认识。 相似文献
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与常规治疗药物相比,抗体药物具有靶向性强、特异性好等优点,其作为一类重要的治疗性药物,近年来在临床中的应用逐渐增多,为疾病的治疗提供了新的选择,应用范围逐渐从肿瘤、自身免疫性疾病及慢性炎症扩展到心血管和感染性等疾病中。人源抗体的全部结构是由人类抗体基因所编码的,因此避免了异种蛋白长期应用引起的不良反应,加之人源抗体制备技术的不断发展完善,使其逐渐成为治疗性抗体研发的首要选择。综述了近年来治疗性人源抗体的主要制备技术及其在临床中应用的最新进展,同时探讨了人源抗体制备技术的不足之处,以期为人源抗体的发展提供借鉴和思路。 相似文献
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重组抗体药物研究进展及应用 总被引:6,自引:0,他引:6
重组抗体药物的发展经历了鼠源单克隆抗体(McAb)、人 鼠嵌合抗体、人源化抗体和全人抗体等阶段,目前初步应用于抗肿瘤、抗自身免疫病、抗感染等领域。保持和提高抗体的亲和力、降低抗体的免疫原性是抗体药物基因工程改造的两大原则。在嵌合抗体成功的基础上,通过CDR移植、表面修饰、抗体库以及转基因鼠技术,逐步提高人源化程度至100%。然而,实验室水平的研究结果与实际应用仍然存在一定差距。就重组抗体药物的基本概况、现存的问题与可能的解决办法以及在肿瘤、病毒性疾病和阿尔茨海默病治疗上的应用情况等进行了综述。 相似文献
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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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作为一种具有靶向性的生物大分子,单克隆抗体始终是人们关注的热点之一,被广泛用于治疗肿瘤、病毒感染和抗移植排斥等。但鼠源单克隆抗体的临床应用受限于诱导产生人抗鼠抗体、肿瘤渗入量低、亲和力低和半衰期短等。随着分子生物学技术的发展及其向各学科的渗透,通过基因操作技术对抗体进行改造,可使其适用于多种疾病的治疗。抗体人源化已经成为治疗性抗体的发展趋势,同时各种抗体衍生物也不断涌现,它们从不同角度克服了抗体本身的应用局限,也为治疗人类疾病提供了利器。本文简要介绍上述技术的基本原理、特点和治疗性抗体的研究进展。 相似文献
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Design of humanized antibodies: from anti-Tac to Zenapax 总被引:3,自引:0,他引:3
Since the introduction of hybridoma technology, monoclonal antibodies have become one of the most important tools in the biosciences, finding diverse applications including their use in the therapy of human disease. Initial attempts to use monoclonal antibodies as therapeutics were hampered, however, by the potent immunogenicity of mouse (and other rodent) antibodies in humans. Humanization technology has made it possible to remove the immunogenicity associated with the use of rodent antibodies, or at least to reduce it to an acceptable level for clinical use in humans, thus facilitating the application of monoclonal antibodies to the treatment of human disease. To date, nine humanized monoclonal antibodies have been approved for use as human therapeutics in the United States. In this paper, we describe procedures for antibody humanization with an emphasis on strategies for designing humanized antibodies with the aid of computer-guided modeling of antibody variable domains, using as an example the humanized anti-CD25 monoclonal antibody, Zenapax. 相似文献
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多年来研究人员一直在寻求单克隆抗体在病毒性疾病中的临床应用。鼠源单克隆抗体可能会引发患的免疫反应,降低其疗效,故研究人员相继开发了嵌合抗体、改型抗体、噬菌体抗体及利用基因工程方法改造植物和动物产生人源抗体以应用于临床治疗。抗体工程在控制多种病毒感染性疾病方面已经发挥了一定作用并将发挥重要作用。 相似文献
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To date only a few neutralizing antibodies against HIV-1 exist. Since these neutralizing antibodies are only rarely found in sera of HIV-1 infected individuals an active vaccine is required. We recently developed murine anti-idiotypic antibody Ab2/3H6 against monoclonal antibody (mAb) 2F5, which is one of the most prominent neutralizing antibodies. Anti-idiotypic antibody Ab2/3H6 has been partially humanized and expressed as whole immunoglobulin G in Chinese hamster ovary cells in order to minimize the human anti-mouse antibody response. Here we describe the expression, purification, and immunohistochemical characterization of the chimeric Ab2/3H6 Fab fragment, which was finally used beside the whole IgG1 as an antigen for immunization of guinea pigs. The crude sera were screened for specific antibodies against the epitope of mAb 2F5 ELDKWA as well as for reactivity against HIV-1 gp41. 相似文献
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We have constructed a humanized antibody with specificity for the pre-S2 surface antigen of hepatitis B virus (HBV) by grafting the complementarity determining regions (CDRs) of parental murine monoclonal antibody (mAb) into human anti-Sm antibody framework regions. The humanized antibody has a substitution at position 94 in a framework region of the heavy chain variable region, and exhibits the same antigen binding affinity as the parental murine monoclonal and chimeric antibodies. In order to assess the stability of these antibodies, thermal inactivation of the parental, chimeric and humanized antibodies was analyzed. Fifty percent inactivation of the chimeric and humanized antibodies was observed at 63.7 degrees C and 68.7 degrees C, respectively, compared to 55.0 degrees C for murine antibody. The humanized antibody also exhibited increased stability against denaturant. Guanidine-induced unfolding monitored by the changes in fluorescence intensity at 360 nm showed that midpoints of the transition of the chimeric and humanized antibodies were 2.47 M and 2.56 M, respectively, whereas that of the murine antibody was 1.36 M. 相似文献
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Soomin Yoon Yong-Sung Kim Hyunbo Shim Junho Chung 《Biotechnology and Bioprocess Engineering》2010,15(5):709-715
Since the first monoclonal antibody, muromonab-CD3, was approved for therapeutic use in 1986, numerous molecules have been
targeted using therapeutic antibody technology, resulting in 26 therapeutic antibodies being approved by the US FDA as of
November, 2009. Initial concerns regarding antibody drugs focused on immunogenicity, short serum half-life, and weak efficacy.
As the types of antibodies progressed from murine to chimeric, humanized, and fully human antibodies, great progress has been
made in immunogenicity and in vivo instability issues. For example, humanized antibodies, such as bevacizumab, exhibit less than 0.2% immunogenicity and a 20
day serum half-life, which is comparable to native immunoglobulin. Some recently developed antibodies are exceedingly efficacious
and have become first-line therapy for their target diseases. Here, we address and analyze all clinically approved therapeutic
antibodies to date by discussing immunogenicity, half-life, and efficacy. 相似文献
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Pharmacokinetics and biodistribution of a light-chain-shuffled CC49 single-chain Fv antibody construct 总被引:5,自引:0,他引:5
Pavlinkova G Colcher D Booth BJ Goel A Batra SK 《Cancer immunology, immunotherapy : CII》2000,49(4-5):267-275
Murine monoclonal antibodies to tumor-associated glycoprotein 72 (anti-TAG-72 mAb B72.3 and CC49) are among the most extensively
studied mAb for immunotherapy of adenocarcinomas. They have been used clinically to localize primary and metastatic tumor
sites; however, murine mAb generally induce potent human anti-(mouse antibody) responses. The immunogenicity of murine mAb
can be minimized by genetic humanization of these antibodies, where non-human regions are replaced by the corresponding human
sequences or complementary determining regions are grafted into the human framework regions. We have developed a humanized
CC49 single-chain antibody construct (hu/muCC49 scFv) by replacing the murine CC49 variable light chain with the human subgroup
IV germline variable light chain (Hum4 VL). The major advantages of scFv molecules are their excellent penetration into the tumor tissue, rapid clearance rate, and
much lower exposure to normal organs, especially bone marrow, than occur with intact antibody. The biochemical properties
of hu/muCC49 scFv were compared to those of the murine CC49 scFv (muCC49 scFv). The association constants (K
a) for hu/muCC49 and muCC49 constructs were 1.1 × 106 M−1 and 1.4 × 106 M−1 respectively. Pharmacokinetic studies in mice showed similar rapid blood and whole-body clearance with a half-life of 6 min
for both scFv. The biodistribution studies demonstrated equivalent tumor targeting to human colon carcinoma xenografts for
muCC49 and hu/muCC49 scFv. These results indicate that the human variable light-chain subgroup IV can be used for the development
of humanized or human immunoglobulin molecules potentially useful in both diagnostic and therapeutic applications with TAG-72-positive
tumors.
Received: 29 December 1999 / Accepted: 4 February 2000 相似文献
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No universal strategy exists for humanizing mouse antibodies, and most approaches are based on primary sequence alignment and
grafting. Although this strategy theoretically decreases the immunogenicity of mouse antibodies, it neither addresses
conformational changes nor steric clashes that arise due to grafting of human germline frameworks to accommodate mouse CDR
regions. To address these issues, we created and tested a structure-based biologic design approach using a de novo homology
model to aid in the humanization of 17 unique mouse antibodies. Our approach included building a structure-based de novo
homology model from the primary mouse antibody sequence, mutation of the mouse framework residues to the closest human
germline sequence and energy minimization by simulated annealing on the humanized homology model. Certain residues
displayed force field errors and revealed steric clashes upon closer examination. Therefore, further mutations were introduced to
rationally correct these errors. In conclusion, use of de novo antibody homology modeling together with simulated annealing
improved the ability to predict conformational and steric clashes that may arise due to conversion of a mouse antibody into the
humanized form and would prevent its neutralization when administered in vivo. This design provides a robust path towards the
development of a universal strategy for humanization of mouse antibodies using computationally derived antibody homologous
structures. 相似文献