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1.
Antibodies and antibody-based drugs are currently the fastest-growing class of therapeutics. Over the last three decades, more than 30 therapeutic monoclonal antibodies and derivatives thereof have been approved for and successfully applied in diverse indication areas including cancer, organ transplants, autoimmune/inflammatory disorders, and cardiovascular disease. The isotype of choice for antibody therapeutics is human IgG, whose Fc region contains a ubiquitous asparagine residue (N297) that acts as an acceptor site for N-linked glycans. The nature of these glycans can decisively influence the therapeutic performance of a recombinant antibody, and their absence or modification can lead to the loss of Fc effector functions, greater immunogenicity, and unfavorable pharmacokinetic profiles. However, recent studies have shown that aglycosylated antibodies can be genetically engineered to display novel or enhanced effector functions and that favorable pharmacokinetic properties can be preserved. Furthermore, the ability to produce aglycosylated antibodies in lower eukaryotes and bacteria offers the potential to broaden and simplify the production platforms and avoid the problem of antibody heterogeneity, which occurs when mammalian cells are used for production. In this review, we discuss the importance of Fc glycosylation focusing on the use of aglycosylated and glyco-engineered antibodies as therapeutic proteins. 相似文献
2.
Carter PJ 《Experimental cell research》2011,(9):769-1269
Protein therapeutics and its enabling sister discipline, protein engineering, have emerged since the early 1980s. The first protein therapeutics were recombinant versions of natural proteins. Proteins purposefully modified to increase their clinical potential soon followed with enhancements derived from protein or glycoengineering, Fc fusion or conjugation to polyethylene glycol. Antibody-based drugs subsequently arose as the largest and fastest growing class of protein therapeutics. The rationale for developing better protein therapeutics with enhanced efficacy, greater safety, reduced immunogenicity or improved delivery comes from the convergence of clinical, scientific, technological and commercial drivers that have identified unmet needs and provided strategies to address them. Future protein drugs seem likely to be more extensively engineered to improve their performance, e.g., antibodies and Fc fusion proteins with enhanced effector functions or extended half-life. Two old concepts for improving antibodies, namely antibody-drug conjugates and bispecific antibodies, have advanced to the cusp of clinical success. As for newer protein therapeutic platform technologies, several engineered protein scaffolds are in early clinical development and offer differences and some potential advantages over antibodies. 相似文献
3.
T-cell lymphomas represent a subpopulation of non-Hodgkin lymphomas with poor outcomes when treated with conventional chemotherapy. A variety of novel agents have been introduced as new treatment strategies either as first-line treatment or in conjunction with chemotherapy. Immunotherapy has been demonstrated to be a promising area for new therapeutics, including monoclonal antibodies and adoptive cellular therapeutics. T-cell therapeutics have been shown to have significant success in the treatment of B-cell malignancies and are rapidly expanding as potential treatment options for other cancers including T-cell lymphomas. Although treating T-cell lymphomas with T-cell therapeutics has unique challenges, multiple targets are currently being studied both preclinically and in clinical trials. 相似文献
4.
Jefferis R 《Biotechnology progress》2005,21(1):11-16
The adaptive immune system has the capacity to produce antibodies with a virtually infinite repertoire of specificities. Recombinant antibodies specific for human targets are established in the clinic as therapeutics and represent a major new class of drug. Therapeutic efficacy depends on the formation of complexes with target molecules and subsequent activation of downstream biologic effector mechanisms that result in elimination of the target. The activation of effector mechanisms is dependent on structural characteristics of the antibody molecule that result from posttranslational modifications, in particular, glycosylation. The production of therapeutic antibody with a consistent human glycoform profile has been and remains a considerable challenge to the biopharmaceutical industry. Recent research has shown that individual glycoforms of antibody may provide optimal efficacy for selected outcomes. Thus a further challenge will be the production of a second generation of antibody therapeutics customized for their clinical indication. 相似文献
5.
《MABS-AUSTIN》2013,5(3):221-232
Drug development from early discovery to late stage commercialization is a long arduous process where a number of factors are taken into consideration when deciding on a particular immunoglobulin isotype for a therapeutic purpose. There are no general rules for which isotype is selected; however, prior experiences, effector function and the specific therapy targeted, as well as extensive testing early in development help in paring the number of candidates. Over 20 monoclonal antibodies are FDA-approved, and most are IgG1 isotype, although a number of non-IgG1 molecules have been approved recently and the number in development is on the rise. Analytical techniques that examine the physicochemical properties of a molecule provide vital information on the stability and efficacy of candidate antibody therapeutics, but most of these studies are conducted using standard buffers and under well defined storage conditions. It has recently become apparent that analysis of antibody therapeutics recovered after circulation in blood show altered physicochemical characteristics, and in many instances therapeutic molecules recovered from serum show lower potency. This review examines some of these studies, with a focus on the physicochemical changes observed in the molecules. Technologies that can facilitate rapid screening of candidate antibody therapeutics directly from blood are highlighted. The facts indicate that antibody therapeutic development programs must incorporate understanding of the basic biology of the isotype and its stability in serum, which is the intended environment of the therapeutic. 相似文献
6.
Pearline Zhaoying Teo Paul J. Utz Joseph A. Mollick 《Cancer immunology, immunotherapy : CII》2012,61(12):2295-2309
Monoclonal antibodies are widely used in the treatment of many B cell lymphomas and certain solid tumors. All currently approved therapeutic monoclonal antibodies are of the immunoglobulin G (IgG) isotype. We hypothesized that tumor-specific monoclonal antibodies of the IgE isotype may serve as effective cancer therapeutics. To test this hypothesis, we produced mouse?Chuman chimeric IgE antibodies specific for the human B cell antigen CD20 and the epithelial antigen MUC1. We demonstrate here that anti-hCD20 IgE antibodies have in vitro cytotoxic activity when used with purified allergic effector cells derived from umbilical cord blood. At an effector-tumor ratio of 2:1, mast cells and tumor-specific IgE induced a 2.5-fold increase in tumor cell death, as compared to control IgE. Similar results were observed when eosinophils were used as effector cells. In an in vivo murine model of breast carcinoma, administration of anti-hMUC1 IgE reduced the growth of MUC1+ tumors by 25?C30?% in hFc??RI transgenic mice. In contrast, local production of IgE and cytokines chemotactic for macrophages, eosinophils and mast cells led to complete tumor eradication. These results suggest that allergic effector cells activated by IgE and cell surface antigens have the capacity to induce tumor cell death in vitro and in vivo. The use of chimeric antibodies and hFc??RI transgenic mice will greatly enhance investigations in the nascent field of allergo-oncology. 相似文献
7.
Therapeutic monoclonal antibodies are the fastest growing class of biological therapeutics for the treatment of various cancers and inflammatory disorders. In cancer immunotherapy, some IgG1 antibodies rely on the Fc-mediated immune effector function, antibody-dependent cellular cytotoxicity (ADCC), as the major mode of action to deplete tumor cells. It is well-known that this effector function is modulated by the N-linked glycosylation in the Fc region of the antibody. In particular, absence of core fucose on the Fc N-glycan has been shown to increase IgG1 Fc binding affinity to the FcγRIIIa present on immune effector cells such as natural killer cells and lead to enhanced ADCC activity. As such, various strategies have focused on producing afucosylated antibodies to improve therapeutic efficacy. This review discusses the relevance of antibody core fucosylation to ADCC, different strategies to produce afucosylated antibodies, and an update of afucosylated antibody drugs currently undergoing clinical trials as well as those that have been approved. 相似文献
8.
Filpula D 《Biomolecular engineering》2007,24(2):201-215
Antibody engineering has become a well-developed discipline, encompassing discovery methods, production strategies, and modification techniques that have brought forth clinically investigated and marketed therapeutics. The realization of the long-standing goal of production of fully human monoclonal antibodies has focused intensive research on the clinical employment of this potent drug category. However, antibodies are large macromolecules that pose numerous challenges in formulation, optimal pharmacokinetics, manufacturing, stability, and process development. While further improvements in discovery technologies, such as phage display, ribosome display, and transgenic animals continue to advance our capacity to rapidly screen and refine optimal binding molecules, antibody engineers have recently focused more of their efforts on improving protein production and stability, as well as engineering improved biological properties in the effector domains of monoclonal antibodies. A second long-standing goal of antibody engineering, the development of targeted drugs, has not been wholly realized, but this obvious application for antibodies is currently undergoing increasing exploration. Minimal binding proteins, such as Fab, scFv, and single variable domains are the preferred targeting elements for some investigational drugs, whereas non-immunoglobulin scaffold proteins have been explored as binding proteins in other designs. The necessity to utilize non-protein components in targeted drugs, such as polymers, linkers, and cytotoxics, has brought a convergence of the fields of bioconjugate chemistry and protein engineering in experimental antibody therapeutics. 相似文献
9.
Tomoyuki Igawa Hiroyuki Tsunoda Taichi Kuramochi Zenjiro Sampei Shinya Ishii Kunihiro Hattori 《MABS-AUSTIN》2011,3(3):243-252
Since the first generation of humanized IgG1 antibodies reached the market in the late 1990s, IgG antibody molecules have been extensively engineered. The success of antibody therapeutics has introduced severe competition in developing novel therapeutic monoclonal antibodies, especially for promising or clinically validated targets. Such competition has led researchers to generate so-called second or third generation antibodies with clinical differentiation utilizing various engineering and optimization technologies. Parent IgG antibodies can be engineered to have improved antigen binding properties, effector functions, pharmacokinetics, pharmaceutical properties and safety issues. Although the primary role of the antibody variable region is to bind to the antigen, it is also the main source of antibody diversity and its sequence affects various properties important for developing antibody therapeutics. Here we review recent research activity in variable region engineering to generate superior antibody therapeutics.Key words: antibody therapeutics, variable region, engineering, affinity, pharmacokinetics, stability, immunogenicity 相似文献
10.
Newcombe C Newcombe AR 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2007,848(1):2-7
Antibody based therapies using monoclonal or polyclonal antibodies are emerging as an important therapeutic approach for the treatment of a number of diseases. With increasing emphasis on new technologies associated with monoclonal antibody expression and purification, the clinical need of polyclonal therapeutics for treatment of a variety of specific illnesses and infections is often overlooked. Despite being largely abandoned in the early twentieth century due to the development of antibiotics, polyclonal antibody therapeutics are today widely used in medicine for viral and toxin neutralization and for replacement therapy in patients with immunoglobulin deficiencies. Over the past 20 years, intravenous immunoglobulins have shown beneficial immunomodulatory and anti-inflammatory effects in many illnesses. Hyperimmune antibody preparations have been used over the past century for the treatment of a variety of infectious agents and medical emergencies, including digoxin toxicity, snake envenomation and spider bites. Here, we examine the contemporary techniques and applications, and assess the future therapeutic potential, for polyclonal-derived antibody therapeutics. 相似文献
11.
Ivan R Correia 《MABS-AUSTIN》2010,2(3):221-232
Drug development from early discovery to late stage commercialization is a long arduous process where a number of factors are taken into consideration when deciding on a particular immunoglobulin isotype for a therapeutic purpose. There are no general rules for which isotype is selected; however, prior experiences, effector function and the specific therapy targeted, as well as extensive testing early in development help in paring the number of candidates. Over 20 monoclonal antibodies are FDA-approved, and most are IgG1 isotype, although a number of non-IgG1 molecules have been approved recently and the number in development is on the rise. Analytical techniques that examine the physicochemical properties of a molecule provide vital information on the stability and efficacy of candidate antibody therapeutics, but most of these studies are conducted using standard buffers and under well defined storage conditions.It has recently become apparent that analysis of antibody therapeutics recovered after circulation in blood show altered physicochemical characteristics, and in many instances therapeutic molecules recovered from serum show lower potency. This review examines some of these studies, with a focus on the physicochemical changes observed in the molecules. Technologies that can facilitate rapid screening of candidate antibody therapeutics directly from blood are highlighted. The facts indicate that antibody therapeutic development programs must incorporate understanding of the basic biology of the isotype and its stability in serum, which is the intended environment of the therapeutic.Key words: serum, IgG isotypes, IgG1, IgG2, IgG3, IgG4, stability, primary, secondary, tertiary, Fab exchange, disulfide 相似文献
12.
Fc receptors and immunoglobulin binding factors 总被引:5,自引:0,他引:5
W H Fridman 《FASEB journal》1991,5(12):2684-2690
Receptors for the Fc portion of Ig (Fc receptors, FcR) are found on all cell types of the immune system. Three types of FcR react with IgG: Fc gamma RI is a high-affinity receptor binding IgG monomers whereas Fc gamma RII and Fc gamma RIII are low-affinity receptors binding IgG immune complexes; the three types of Fc gamma R are members of the Ig superfamily. Two FcR react with IgE:Fc epsilon RI is a multichain receptor binding IgE with high affinity; it is composed of an IgE-binding alpha chain, homologous to Fc gamma RIII, and of gamma and beta chains that are necessary for receptor expression and signal transduction. The low-affinity Fc epsilon RII is the only FcR described so far that is not a member of the Ig superfamily but resembles animal lectins; it is composed of a transmembrane chain with an intracytoplasmic NH2 terminus. Fc alpha R has homology with Fc gamma R and is a member of the Ig superfamily. Receptors for IgM and IgD are not characterized yet. Finally, Ig transport is made by FcR-like molecules such as the poly-Ig receptor or an MHC-like receptor found on neonatal intestine. A remarkable property of most FcR is the fact that they are released in cell supernatants and circulate in biological fluids as immunoglobulin binding factors (IBF) generated either by cleavage at the cell membrane or by splicing of FcR transmembrane exon. Immunoglobulin binding factors may interfere with Ig-mediated functions and have direct immunoregulatory activities. Involvement of FcR or IBF has been postulated in several diseases, and monoclonal antibodies to FcR are beginning to be used in therapeutics, particularly to target cytotoxic effector lymphocytes and monocytes to tumor cells. 相似文献
13.
Artificial chromosome vectors and expression of complex proteins in transgenic animals 总被引:4,自引:0,他引:4
Artificial chromosome vectors are autonomous, replicating DNA sequences containing a centromere, two telomeres and origins of replication. Artificial chromosomes have been proposed as possible vectors for transferring very large sequences of DNA into animals. Our goal has been to insert the entire human heavy- and light-chain immunoglobulin loci into cattle as a step in developing a production system for large quantities of human therapeutic polyclonal antibodies. A mitotically stable fragment of chromosome 14, containing the human heavy-chain locus, was identified. A chromosome cloning system was used to transfer the human lambda locus from an unstable chromosome 22 fragment to the chromosome 14 fragment to create a human artificial chromosome (HAC) carrying both immunoglobulin loci. The HAC vector was introduced into bovine primary fibroblasts. Selected fibroblast clones were rejuvenated and expanded by producing cloned fetuses. Cloned fetal cells were selected and recloned to produce 21 healthy, transchromosomic (Tc) calves. Four were analyzed and shown to functionally rearrange both heavy- and light-chain human immunoglobulin loci and produce human polyclonal antibodies. These results demonstrate the feasibility of using HAC vectors for production of transgenic livestock. More importantly, Tc cattle containing human immunoglobulin genes may be used to produce novel human polyclonal therapeutics. 相似文献
14.
《MABS-AUSTIN》2013,5(3):243-252
Since the first generation of humanized IgG1 antibodies reached the market in the late 1990s, IgG antibody molecules have been extensively engineered. The success of antibody therapeutics has introduced severe competition in developing novel therapeutic monoclonal antibodies, especially for promising or clinically validated targets. Such competition has led researchers to generate so-called second or third generation antibodies with clinical differentiation utilizing various engineering and optimization technologies. Parent IgG antibodies can be engineered to have improved antigen binding properties, effector functions, pharmacokinetics, pharmaceutical properties and safety issues. Although the primary role of the antibody variable region is to bind to the antigen, it is also the main source of antibody diversity and its sequence affects various properties important for developing antibody therapeutics. Here we review recent research activity in variable region engineering to generate superior antibody therapeutics. 相似文献
15.
Alternative non-antibody scaffolds for molecular recognition 总被引:3,自引:0,他引:3
Skerra A 《Current opinion in biotechnology》2007,18(4):295-304
Originally proposed one decade ago, the idea of engineering proteins outside the immunoglobulin family for novel binding functions has evolved as a powerful technology. Several classes of protein scaffolds proved to yield reagents with specificities and affinities in a range that was previously considered unique to antibodies. Such engineered protein scaffolds are usually obtained by designing a random library with mutagenesis focused at a loop region or at an otherwise permissible surface area and by selection of variants against a given target via phage display or related techniques. Whereas a plethora of protein scaffolds has meanwhile been proposed, only few of them were actually demonstrated to yield specificities towards different kinds of targets and to offer practical benefits such as robustness, smaller size, and ease of expression that justify their use as a true alternative to conventional antibodies or their recombinant fragments. Currently, the most promising scaffolds with broader applicability are protein A, the lipocalins, a fibronectin domain, an ankyrin consensus repeat domain, and thioredoxin. Corresponding binding proteins are not only of interest as research reagents or for separation in biotechnology but also as potential biopharmaceuticals, especially in the areas of cancer, autoimmune and infectious diseases as well as for in vivo diagnostics. The medical prospects have boosted high commercial expectations, and many of the promising scaffolds are under development by biotech start-up companies. Although some issues still have to be addressed, for example immunogenicity, effector functions, and plasma half-life in the context of therapeutic use or low-cost high-throughput selection for applications in proteomics research, it has become clear that scaffold-derived binding proteins will play an increasing role in biotechnology and medicine. 相似文献
16.
《MABS-AUSTIN》2013,5(7):1197-1205
ABSTRACTRecently it has become possible to query the great diversity of natural antibody repertoires using next-generation sequencing (NGS). These methods are capable of producing millions of sequences in a single experiment. Here we compare clinical-stage therapeutic antibodies to the ~1b sequences from 60 independent sequencing studies in the Observed Antibody Space database, which includes antibody sequences from NGS analysis of immunoglobulin gene repertoires. Of 242 post-Phase 1 antibodies, we found 16 with sequence identity matches of 95% or better for both heavy and light chains. There are also 54 perfect matches to therapeutic CDR-H3 regions in the NGS outputs, suggesting a nontrivial amount of convergence between naturally observed sequences and those developed artificially. This has potential implications for both the legal protection of commercial antibodies and the discovery of antibody therapeutics. 相似文献
17.
Antibody preparations have a long history of providing protection from infectious diseases. Although antibodies remain the only natural host-derived defense mechanism capable of completely preventing infection, as products, they compete against inexpensive therapeutics such as antibiotics, small molecule inhibitors and active vaccines. The continued discovery in the monoclonal antibody (mAb) field of leads with broadened cross neutralization of viruses and demonstrable synergy of antibody with antibiotics for bacterial diseases, clearly show that innovation remains. The commercial success of mAbs in chronic disease has not been paralleled in infectious diseases for several reasons. Infectious disease immunotherapeutics are limited in scope as endemic diseases necessitate active vaccine development. Also, the complexity of these small markets draws the interest of niche companies rather than big pharmaceutical corporations. Lastly, the cost of goods for mAb therapeutics is inherently high for infectious agents due to the need for antibody cocktails, which better mimic polyclonal immunoglobulin preparations and prevent antigenic escape. In cases where vaccine or convalescent populations are available, current polyclonal hyperimmune immunoglobulin preparations (pIgG), with modern and highly efficient purification technology and standardized assays for potency, can make economic sense. Recent innovations to broaden the potency of mAb therapies, while reducing cost of production, are discussed herein. On the basis of centuries of effective use of Ab treatments, and with growing immunocompromised populations, the question is not whether antibodies have a bright future for infectious agents, but rather what formats are cost effective and generate safe and efficacious treatments to satisfy regulatory approval. 相似文献
18.
《MABS-AUSTIN》2013,5(1):67-70
Monoclonal antibodies (mAbs) as a class of novel oncology therapeutics are demonstrating clinical efficacy as measured by tumor response (shrinkage in tumor size), and prolongations in progression-free survival (PFS) and overall survival (OS). However, clinical benefits are often limited to when antibodies are used in combination with chemotherapy or radiation modalities, with tumor responses only seen in a fraction of patients, and improvements in PFS and OS are incremental (1). The potential of mAbs and mAb constructs has yet to be fully exploited for maximal clinical benefits. New approaches to further improve the effectiveness of these mAb therapies include (a) selection of patients who may derive the most benefit based on the molecular characteristics of their tumors; (b) improvements in biodistribution to maximize delivery of mAbs to susceptible tumor cells; and (c) optimization of antibody immune effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC). 相似文献
19.
It is now well established that antibodies have numerous potential benefits when developed as therapeutics. Here, we evaluate the technical challenges of raising antibodies to membrane-spanning proteins together with enabling technologies that may facilitate the discovery of antibody therapeutics to ion channels. Additionally, we discuss the potential targeting opportunities in the anti-ion channel antibody landscape, along with a number of case studies where functional antibodies that target ion channels have been reported. Antibodies currently in development and progressing towards the clinic are highlighted. 相似文献
20.
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