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Peter J.K. van Meer Marlous Kooijman Vera Brinks Christine C. Gispen-de Wied Beatriz Silva-Lima Ellen H.M. Moors Huub Schellekens 《MABS-AUSTIN》2013,5(5):810-816
The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish the relative immunogenicity of mAbs in NHPs and humans. The incidence of formation of antidrug-antibodies in NHPs and patients was comparable in only 59% of the cases. In addition, the type of antidrug-antibody response was different in NHP and humans in 59% of the cases. Humanization did not necessarily reduce immunogenicity in humans. Immunogenicity interfered with the safety assessment during non-clinical drug development when clearing or neutralizing antibodies were formed. While important to interpret the study results, immunogenicity reduced the quality of NHP data in safety assessment. These findings confirm that the ability to compare relative immunogenicity of mAbs in NHPs and humans is low. Furthermore, immunogenicity limits the value of informative NHP studies. 相似文献
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During the development of monoclonal antibodies (mAbs) and other therapeutic proteins, immunogenicity, in particular the induction of anti-drug antibodies (ADAs), is an important concern, and thus immunogenicity assessment is a requirement for their approval. Establishment of appropriate methods for detecting and characterizing ADAs is necessary for immunogenicity assessment, but the lack of commonly available reference standards makes it difficult to compare and evaluate the methods. It is also difficult to compare the data with those obtained by other methods or facilities without reference standards. Here, we developed a panel of ADAs against anti-CD20 rituximab (Rituxan®, MabThera®); the panel consisted of eight clones of recombinant human-rat chimeric mAbs that target rituximab. The anti-rituximab mAbs showed different binding properties (specificity, epitope and affinity), and different neutralization potencies for CD20 binding, complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. The molecular size of the immune complex consisting of rituximab and the anti-rituximab mAb differed among the clones, and was well correlated with their level of Fcγ-receptor activation. These results suggest that the ADAs chosen for the newly developed panel are suitable surrogates for human ADAs, which exhibit different potential to affect the efficacy and safety of rituximab. Next, we used this panel to compare several ADA-detecting assays and revealed that the assays had different abilities to detect the ADAs with different binding characteristics. We conclude that our panel of ADAs against rituximab will be useful for the future development and characterization of assays for immunogenicity assessment. 相似文献
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《MABS-AUSTIN》2013,5(4):662-671
The potential for immunogenicity is an ever-present concern during the development of biopharmaceuticals. Therapeutic antibodies occasionally elicit an antibody response in patients, which can result in loss of response or adverse effects. However, antibodies that bind a drug are sometimes found in pre-treatment serum samples, with the amount depending on drug, assay, and patient population. This review summarizes published data on pre-existing antibodies to therapeutic antibodies, including rheumatoid factors, anti-allotype antibodies, anti-hinge antibodies, and anti-glycan antibodies. Unlike anti-idiotype antibodies elicited by the drug, pre-formed antibodies in general appear to have little consequences during treatment. In the few cases where (potential) clinical consequences were encountered, antibodies were characterized and found to bind a distinct, unusual epitope of the therapeutic. Immunogenicity testing strategies should therefore always include a proper level of antibody characterization, especially when pre-formed antibodies are present. This minimizes false-positives, particularly due to rheumatoid factors, and helps to judge the potential threat in case a genuine pre-dose antibody reactivity is identified. 相似文献
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羧端部分缺失的HCV核心蛋白的融合表达,免疫原性及其应用 总被引:1,自引:0,他引:1
构建了丙型肝炎病毒核心蛋白的全长及N端和N端与谷胱甘肽巯基转移酶(GST)的融合表达克隆,比较了在不同大肠杆菌中的表达。表达蛋白为水溶性,经ELISA和蛋白质印迹分析,GSTC191的表达和稳定性都较差,GSTC69和GSTC40具有良好的稳定性,用GST亲和柱一步纯化,纯度可达90%,免疫小鼠可产生高滴度的抗体。应用表达的GSTC69和GSTC40抗原,检测人血清中的HCV核心蛋白抗体,初步结果 相似文献
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《MABS-AUSTIN》2013,5(5):861-869
ABSTRACTDespite recent advances in the development of tools to predict immunogenicity risk of biotherapeutic molecules, the ability of a protein to elicit the formation of anti-drug antibodies (ADA) remains one of the most common causes for termination of clinical development programs. In this study, we use ADA assays to detect and measure pre-existing reactivity or the ability of a molecule to produce an ADA-like response in serum from treatment-naïve, healthy donors. We report herein that the magnitude of pre-existing reactivity evaluated pre-clinically and expressed as the 90th percentile of Tier 2 inhibition correlates with the subsequent rate of ADA emergence in the clinic. Furthermore, a multi-domain biotherapeutic (IgG-scFv bispecific antibody) showed the highest pre-existing reactivity and incidence of treatment-emergent ADA (TE-ADA) (57% and 93%, respectively). Using the components of the multidomain molecule in the Tier 2 step of the ADA assay, we were able to identify the scFv as the target of the serum pre-existing reactivity. Most importantly, the domain specificity of pre-existing ADA was the same as that of the TE-ADA from patients treated with the molecule. Based on these data, we propose the evaluation of the magnitude and of the domain specificity of pre-existing reactivity as a powerful tool to understand the immunogenic potential of novel biotherapeutics. 相似文献
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Immune response and protective efficacy for the combination of four tuberculosis DNA vaccines were evaluated in this study. We obtained 1:200 antibody titers against Ag85B 21d after mice were vaccinated for the first time by four recombinant eukaryotic expression vectors containing coding sequences for Ag85B, MPT-64, MPT-63 and ESAT-6. The titers of Ag85B were elevated to 1:102400 after the second injection and decreased to 1:12800 after the third injection. Antibody titers for MPT-64 and MPT-63 reached 1:25600 21 d after the first vaccination, and were then decreased following the second and third injections. No antigen-specific antibody titer against ESAT-6 was detected in sera harvested from immunized mice at any time. These DNA vaccines evoked specific IFN-λ responses in the spleens of vaccinated mice as well. When challenged with M. tuberculosis H37Rv, we found that the lungs of the vaccinated mice produced 99.8% less bacterial counts than that of the empty-vector control group and the bacterial counts were also significantly less than that of the BCG group. Histopathological analyses showed that the lungs of vaccinated mice produced no obvious caseation while over 50%-70% of the pulmonary parenchyma tissue produced central caseation in the vector control group. Our results indicated that the combination of four tuberculosis DNA vaccines may generate high levels of immune responses and result in better animal protection. 相似文献
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Industrial production of monoclonal antibodies and therapeutic proteins by dialysis fermentation 总被引:2,自引:0,他引:2
Michael J. Comer Michael J. Kearns Jürgen Wahl Michael Munster Thomas Lorenz Berthold Szperalski Stefan Koch Ulrich Behrendt Herwig Brunner 《Cytotechnology》1990,3(3):295-299
A novel and powerful fermentation method is reported for the large-scale growth of mammalian cells and their secreted products. The system described illustrates many of the advantages of conventional batch fermentation processes but in addition has been shown to yield cell densities in excess of 1×107 cells/ml with concomitant increase in product concentration.Abbreviations MAb
Monoclonal Antibody
- STR
Stirred Tank Reactor
- FBS
Foetal Bovine Serum 相似文献
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单克隆抗体药物风雨飘摇20年 总被引:1,自引:1,他引:0
1986年,美国FDA批准了第一个单克隆抗体药物上市.迄今,全世界共有21个治疗用抗体药物被批准上市,实现300亿美元的销售额,促进了国际、国内抗体药物的开发热潮.巨大的市场前景和亟待克服的技术问题及壁垒并存的现实不可避免地引发抗体药物的新一轮技术革命,而其结果又将毫无疑问地改变抗体药物的市场格局.抗体药物的研究和开发能否真正成为中国生物技术药物开启国际市场大门的新钥匙?何为我们首选的切入点?我们又该如何形成自己的特色和竞争优势?回顾国际抗体药物20年风雨飘摇的发展经历,总结其中的经验教训,无疑会给我们一些有益的启示. 相似文献
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Immunogenicity and protective efficacy study using combination of four tuberculosis DNA vaccines 总被引:4,自引:0,他引:4
Tuberculosis is an ancient scourge of mankind. According to statistics, there are more than 10 million new cases of tuberculosis each year and the annual death toll for tuberculosis exceeds three millions. The current available BCG is of questionable efficacy, and its protection ranges from 0 to 85%. Therefore, developing a safe and effective vaccine against this scourge is very important. Previous studies have shown that the secreted proteins of Mycobacterium tuberculosis (M. TB) can induc… 相似文献
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Vlasov G. P. Pankova G. A. Nikonova I. N. Antonov N. G. 《Russian Journal of Bioorganic Chemistry》2003,29(1):33-43
The synthesis of starburst polymer–protein conjugates on the basis of bovine serum albumin and horseradish peroxidase was performed with the aim to study the possibilities of regulation of the immune response against the components of the conjugates. These polymers had one-point binding between the protein and the modifying carbon-chain polymer that contained 1-vinyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (a salsolinol analogue) or bradykinin (peptide hormone) residues in its carbon chain. Changes in the chemical nature of the carbon-chain part of the polymer–protein conjugate were shown to increase or decrease the level of antibody production both against the low-molecular compounds attached to the polymeric fragments and against the protein carrier. 相似文献
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《Expert review of proteomics》2013,10(4):601-612
The Hedgehog pathway plays a crucial role in growth and patterning during embryonic development and is involved in stem cell maintenance and proliferation in adult tissues. Mutations that increase the overall activity of the pathway are often associated with a higher incidence of cancers. This article focuses on the mutations, misfoldings and deregulations of the Hedgehog pathway proteins that have been reported to be involved in different tumors, and on small molecules targeting these proteins shown to slow down the growth of certain tumors in various animal models. We propose that proteomics could be a powerful tool to identify new targets of the Hedgehog pathway, enabling the discovery of effective and novel treatments for cancers. 相似文献
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Abstract: A panel of monoclonal antibodies (MAbs) was produced against mouse brain proteins that bind to the tail domain of the neurofilament (NF) heavy (200-kDa) subunit (NF-H) in vitro. An in vivo association of the MAb ligands with NFs was confirmed by examining reactivity of the MAbs with immunoprecipitated NF-H complexes. Using this method we demonstrated association of the ligands of three of the MAbs with NFs. In contrast, glial fibrillary acidic protein and an unknown 97-kDa brain protein were not associated with NFs by this criterion. An 80-kDa doublet that coimmunoprecipitated with NF-H complexes, recognized by MAb 223, was shown by immunocytochemistry and immunoblotting to be synapsin Ia and Ib. Using a complementary approach, we confirmed an association of synapsin with NFs by demonstrating that immunoprecipitated synapsin I complexes contained NF-H and NF medium (160-kDa) subunits. MAbs 63 and 105 recognized a more complex set of proteins that had predominantly synaptic localizations. These data suggest that NFs may provide important support for attachment and/or transport of synaptic proteins in brain. 相似文献
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Heat shock proteins are ubiquitously expressed intracellular proteins and act as molecular chaperones in processes like protein
folding and protein trafficking between different intracellular compartments. They are induced during stress conditions like
oxidative stress, nutritional deficiencies and radiation. They are released into extracellular compartment during necrosis.
However, recent research findings highlights that, they are not solely present in cytoplasm, but also released into extracellular
compartment during normal conditions and even in the absence of necrosis. When present in extracellular compartment, they
have been shown to perform various functions like antigen presentation, intercellular signaling and induction of pro-inflammatory
cytokines. Heat shock proteins represents as dominant microbial antigens during infection. The phylogenetic similarity between
prokaryotic and eukaryotic heat shock proteins has led to proposition that, microbial heat shock proteins can induce self
reactivity to host heat shock proteins and result in autoimmune diseases. The self-reactivity of heat shock proteins protects
host against disease by controlling induction and release of pro-inflammatory cytokines. However, antibodies to self heat
shock proteins haven been implicated in pathogenesis of autoimmune diseases like arthritis and atherosclerosis. Some heat
shock proteins are potent inducers of innate and adaptive immunity. They activate dendritic cells and natural killer cells
through toll-like receptors, CD14 and CD91. They play an important role in MHC-antigen processing and presentation. These
immune effector functions of heat shock proteins are being exploited them as therapeutic agents as well as therapeutic targets
for various infectious diseases and cancers. 相似文献
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Matthew F. Higgins Nicholas Abu-Absi Elena Gontarz Ingo H. Gorr Klaus Kaiser Pramthesh Patel Frank Ritacco Patrick Sheehy Balakumar Thangaraj Tony Gill 《Biotechnology progress》2023,39(2):e3321
The COVID-19 pandemic has placed unprecedented pressure on biopharmaceutical companies to develop efficacious preventative and therapeutic treatments, which is unlikely to abate in the coming years. The importance of fast progress to clinical evaluation for treatments, which tackle unmet medical needs puts strain on traditional product development timelines, which can take years from start to finish. Although previous work has been successful in reducing phase 1 timelines for recombinant antibodies, through utilization of the latest technological advances and acceptance of greater business risk or costs, substantially faster development is likely achievable without increased risk to patients during initial clinical evaluation. To optimize lessons learned from the pandemic and maximize multi-stakeholder (i.e., patients, clinicians, companies, regulatory agencies) benefit, we conducted an industry wide benchmarking survey in September/October 2021. The aims of this survey were to: (i) benchmark current technical practices of key process and product development activities related to manufacturing of therapeutic proteins, (ii) understand the impact of changes implemented in COVID-19 accelerated Ab programs, and whether any such changes can be retained as part of sustainable long-term business practices and (iii) understand whether any accelerative action(s) taken have (negatively) impacted the wider development process. This article provides an in-depth analysis of this data, ultimately highlighting an industry perspective of how biopharmaceutical companies can sustainably adopt new approaches to therapeutic protein development and production. 相似文献
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Immunological Characterization of Trichocyst Proteins In the Ciliate Pseudomicrothorax Dubius 总被引:1,自引:0,他引:1
SIMONE EPERON BERNARD VIGUÈS ROBERT K. PECK 《The Journal of eukaryotic microbiology》1993,40(1):81-91
ABSTRACT. Ejectable trichocysts were isolated from the ciliate Pseudomicrothorax dubius. Polyclonal antibodies were raised against three groups of trichocyst proteins: G1 (30-31 kDa), G2 (26-27 kDa) and G3 (15-20 kDa). By indirect immunofluorescence, the three antisera strongly label the shafts of ejected trichocysts and the proximal ends of condensed trichocysts within the cells. By immunogold labeling for electron microscopy, the three sera specifically recognize the shafts of both extended and condensed trichocysts and shaft precursors in pretrichocysts as well. On one-dimensional immunoblots of isolated trichocysts, anti-G1 serum recognizes the G1 proteins, anti-G2 serum detects G2 proteins and some G1 proteins, and anti-G3 serum reacts with 15 bands, mainly the G3 and (30-41)-kDa proteins. In cells with and without trichocysts, the sera recognize non-ejectable trichocyst proteins at 41-42 kDa and 47 kDa. On two-dimensional immunoblots of isolated trichocysts, anti-G1 serum labels proteins with a pI of 4.75-5.7, anti-G2 serum labels proteins with a pI of 4.75-6.25 and anti-G3 serum labels proteins with a pI of 4.7-6.6. Analyses of cells with and without trichocysts allow identification of possible precursors between 41 and 47 kDa. Some are in the same pI range as their putative products, but others, labeled by anti-G3 serum, are less acidic than most of their mature products. 相似文献