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High Prevalence of aCL-IgA and aβ2GPI-IgA in Drug-Free Schizophrenia Patients: Evidence of a Potential Autoimmune Link. 无药精神分裂症患者中 aCL-IgA 和 aβ2GPI-IgA 的高患病率:潜在自身免疫关联的证据。
IF 3 Q3 IMMUNOLOGY Pub Date : 2024-11-15 DOI: 10.3390/antib13040092
Samar Samoud, Imen Zamali, Fatma Korbi, Ahlem Mtiraoui, Ahlem Ben Hmid, Neila Hannachi, Yousr Galai, Hechmi Louzir, Yousri El Kissi

Background/objectives: Schizophrenia (SZ) is a complex psychiatric disorder with increasing evidence pointing to an autoimmune component, including the presence of antiphospholipid antibodies (aPLs). This study aims to assess the prevalence of anticardiolipin (aCL) and anti-beta-2 glycoprotein I (aβ2GPI) antibodies, particularly the IgG, IgA, and IgM isotypes, in drug-free SZ patients compared to healthy controls, and explore their possible involvement in the disease's pathophysiology.

Methods: Eighty SZ patients meeting DSM-IV criteria were recruited, along with 80 matched healthy controls. Serum samples were analyzed using enzyme-linked immunosorbent assays (ELISA) to quantify IgG, IgA, and IgM isotypes of aCL and aβ2GPI.

Results: SZ patients exhibited significantly higher levels of aCL-IgM and aCL-IgA (p < 0.05), as well as elevated aβ2GPI-IgA (22.5%, p < 0.001), compared to controls. No significant differences were observed in the aCL-IgG isotype. Interestingly, 72% of aPL-positive SZ patients were positive for aβ2GPI-IgA, with some also co-expressing multiple isotypes, suggesting a potential link between SZ and antiphospholipid syndrome (APS).

Conclusions: This study is the first to report a high prevalence of aCL-IgA and aβ2GPI-IgA in SZ patients, highlighting a possible autoimmune involvement in the disease. The presence of multiple aPL isotypes, particularly IgA, suggests a need for further investigation into their role in SZ pathogenesis and their potential association with APS.

背景/目的:精神分裂症(SZ)是一种复杂的精神疾病,越来越多的证据表明其自身免疫因素,包括抗磷脂抗体(aPL)的存在。本研究旨在评估抗心磷脂(aCL)和抗β-2糖蛋白I(aβ2GPI)抗体,尤其是IgG、IgA和IgM同型抗体在无药SZ患者中的流行率,并与健康对照组进行比较,探讨它们在该病病理生理学中可能的参与作用:招募了 80 名符合 DSM-IV 标准的 SZ 患者和 80 名匹配的健康对照者。采用酶联免疫吸附测定法(ELISA)对血清样本进行分析,以量化 aCL 和 aβ2GPI 的 IgG、IgA 和 IgM 异型:与对照组相比,SZ 患者的 aCL-IgM 和 aCL-IgA 水平明显更高(p < 0.05),aβ2GPI-IgA 水平也有所升高(22.5%,p < 0.001)。在 aCL-IgG 同工型中未观察到明显差异。有趣的是,72%的aPL阳性SZ患者的aβ2GPI-IgA也呈阳性,其中一些患者还同时表达多种同型,这表明SZ与抗磷脂综合征(APS)之间存在潜在联系:本研究首次报告了SZ患者中aCL-IgA和aβ2GPI-IgA的高流行率,突出了该疾病可能与自身免疫有关。多种 aPL 异型(尤其是 IgA)的存在表明,有必要进一步研究它们在 SZ 发病机制中的作用及其与 APS 的潜在关联。
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引用次数: 0
Ocular Mucous Membrane Pemphigoid Demonstrates a Distinct Autoantibody Profile from Those of Other Autoimmune Blistering Diseases: A Preliminary Study. 眼粘膜丘疹病显示出与其他自身免疫性水疱病不同的自身抗体谱:一项初步研究
IF 3 Q3 IMMUNOLOGY Pub Date : 2024-11-14 DOI: 10.3390/antib13040091
Yingzi Liu, Lei Bao, Dharm Sodha, Jing Li, Adrian Mansini, Ali R Djalilian, Xiaoguang Li, Hua Qian, Norito Ishii, Takashi Hashimoto, Kyle T Amber

Background: Ocular predominant mucous membrane pemphigoid (oMMP) is a severe subtype of autoimmune blistering disease (AIBD), which can result in scarring and vision loss. The diagnosis of oMMP is challenging as patients often have undetectable levels of circulating autoantibodies by conventional assays. Likewise, the principal autoantigen in oMMP has been an area of debate. Methods: In this preliminary experiment, we performed Phage Immunoprecipitation Sequencing (PhIP-seq) on sera from patients with oMMP, as well as non-ocular MMP, bullous pemphigoid, and mucocutaneous-type pemphigus vulgaris. Results: We identified several autoantigens unique to oMMP relative to other AIBDs. We then cross-referenced these antigens against previously published single-nuclei datasets, as well as the International Mouse Phenotyping Consortium Database. Several protein hits identified in our study demonstrated enriched expression on the anterior surface epithelia, including TNKS1BP1, SEC16B, FNBP4, CASZ1, GOLGB1, DOT1L, PRDM 15, LARP4B, and RPL6. Likewise, a previous study of mouse knockout models of murine analogs CASZ1, HIP1, and ELOA2 reported that these mice showed abnormalities in terms of the ocular surface and development in the eyes. Notably, PhIP-seq failed to identify the canonical markers of AIBDs such as BP180, BP230, desmogleins 1 and 3, or integrin β4, indicating that the patient autoantibodies react with conformational epitopes rather than linear epitopes. Conclusions: oMMP patients demonstrate a unique autoantibody repertoire relative to the other AIBDs. Further validation of the identified autoantibodies will shed light on their potentially pathogenic role.

背景:眼主要粘膜丘疹病(oMMP)是自身免疫性水疱病(AIBD)的一种严重亚型,可导致瘢痕形成和视力丧失。oMMP 的诊断具有挑战性,因为患者的循环自身抗体水平通常无法通过常规检测方法检测出来。同样,oMMP 的主要自身抗原也一直存在争议。方法:在这项初步实验中,我们对 oMMP 患者、非眼 MMP 患者、大疱性类天疱疮患者和寻常型粘液痤疮患者的血清进行了噬菌体免疫沉淀测序(PhIP-seq)。结果:我们发现了相对于其他AIBD而言,oMMP所特有的几种自身抗原。然后,我们将这些抗原与之前发表的单核数据集以及国际小鼠表型协会数据库进行了交叉比对。在我们的研究中发现的几种蛋白在前表面上皮细胞中富集表达,包括 TNKS1BP1、SEC16B、FNBP4、CASZ1、GOLGB1、DOT1L、PRDM 15、LARP4B 和 RPL6。同样,之前一项关于小鼠类似物 CASZ1、HIP1 和 ELOA2 基因敲除模型的研究报告称,这些小鼠在眼表和眼部发育方面表现出异常。值得注意的是,PhIP-seq未能鉴定出AIBDs的典型标记物,如BP180、BP230、desmogleins 1和3或整合素β4,这表明患者的自身抗体与构象表位而非线性表位发生反应。结论:与其他AIBD相比,oMMP患者表现出独特的自身抗体群。对已确定的自身抗体的进一步验证将揭示其潜在的致病作用。
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引用次数: 0
A Brief Chronicle of Antibody Research and Technological Advances. 抗体研究与技术进步简史》。
IF 3 Q3 IMMUNOLOGY Pub Date : 2024-11-11 DOI: 10.3390/antib13040090
Kazutaka Araki, Ryota Maeda

This review briefly traces the historical development of antibody research and related technologies. The path from early perceptions of immunity to the emergence of modern immunotherapy has been marked by pivotal discoveries and technological advances. Early insights into immunity led to the development of vaccination and serotherapy. The elucidation of antibody structure and function paved the way for monoclonal antibody technology and its application in diagnosis and therapy. Breakthroughs in genetic engineering have enabled the production of humanized antibodies and the advances in Fc engineering, thereby increasing therapeutic efficacy. The discovery of immune checkpoints and cytokines revolutionized the treatment of cancer and autoimmune diseases. The field continues to evolve rapidly with the advent of antibody-drug conjugates, bispecific antibodies, and CAR T-cell therapies. As we face global health challenges, antibody research remains at the forefront of medical innovation and offers promising solutions for the future.

本综述简要回顾了抗体研究和相关技术的历史发展。从早期对免疫的认识到现代免疫疗法的出现,其间充满了关键性的发现和技术进步。对免疫的早期认识促进了疫苗接种和血清疗法的发展。对抗体结构和功能的阐明为单克隆抗体技术及其在诊断和治疗中的应用铺平了道路。基因工程的突破使得人源化抗体的生产和 Fc 工程的进展成为可能,从而提高了疗效。免疫检查点和细胞因子的发现彻底改变了癌症和自身免疫性疾病的治疗。随着抗体药物共轭物、双特异性抗体和 CAR T 细胞疗法的出现,该领域继续快速发展。在我们面临全球健康挑战之际,抗体研究仍处于医学创新的前沿,并为未来提供了前景广阔的解决方案。
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引用次数: 0
Comparison of Conjugates Obtained Using DMSO and DMF as Solvents in the Production of Polyclonal Antibodies and ELISA Development: A Case Study on Bisphenol A. 使用 DMSO 和 DMF 作为溶剂生产多克隆抗体和开发 ELISA 时获得的共轭物的比较:关于双酚 A 的案例研究。
IF 3 Q3 IMMUNOLOGY Pub Date : 2024-10-29 DOI: 10.3390/antib13040089
Anna N Berlina, Nadezhda S Komova, Kseniya V Serebrennikova, Anatoly V Zherdev, Boris B Dzantiev

When developing immunochemical test systems, it is necessary to obtain specific antibodies. Their quality depends, among other things, on the immunogen used. When preparing hapten-protein conjugates to obtain antibodies for low-molecular-weight compounds, the key factors are the structure of the hapten itself, the presence of a spacer, the size of the carrier protein and the degree of its modification by hapten molecules. This work shows that one additional factor-the conditions for obtaining the hapten-protein conjugate-is overlooked. In this work, we have synthesized conjugates of bisphenol A derivative 4,4-bis(hydroxyphenyl)valeric acid (BVA), the protein carrier soybean trypsin inhibitor (STI), and bovine serum albumin (BSA) in reaction media combining water with two organic solvents: dimethylformamide (DMF) or dimethyl sulfoxide (DMSO). Namely, BSADMF-BVA, STIDMF-BVA, BSADMSO-BVA and STIDMSO-BVA conjugates were obtained. Rabbit polyclonal antibodies against the BSADMF-BVA conjugate demonstrated basically different interactions in the developed ELISA systems using either STIDMF-BVA or STIDMSO-BVA conjugates. The use of the STIDMF-BVA conjugate demonstrated the absence of competition in combination with antisera obtained from BSADMF-BVA in an ELISA. A competitive interaction was observed only with the use of the STIDMSO-BVA conjugate. Under the selected conditions, the detection limit of bisphenol A was 8.3 ng/mL, and the working range of determined concentrations was 18.5-290.3 ng/mL. The obtained data demonstrate the possibility of achieving sensitive immunoassays by simply varying the reaction media for the hapten-protein conjugation, which could provide an additional tool in the development of immunoassays for other low-molecular-weight compounds.

在开发免疫化学测试系统时,必须获得特异性抗体。抗体的质量主要取决于所使用的免疫原。在制备杂蛋白-蛋白质共轭物以获得低分子量化合物抗体时,关键因素是杂蛋白本身的结构、是否存在间隔物、载体蛋白的大小及其被杂蛋白分子修饰的程度。这项工作表明,还有一个因素被忽视了,即获得合体蛋白共轭物的条件。在这项工作中,我们在水与二甲基甲酰胺(DMF)或二甲基亚砜(DMSO)两种有机溶剂的反应介质中合成了双酚 A 衍生物 4,4-双(羟基苯基)戊酸(BVA)、蛋白质载体大豆胰蛋白酶抑制剂(STI)和牛血清白蛋白(BSA)的共轭物。即获得 BSADMF-BVA、STIDMF-BVA、BSADMSO-BVA 和 STIDMSO-BVA 结合物。在使用 STIDMF-BVA 或 STIDMSO-BVA 结合物开发的 ELISA 系统中,针对 BSADMF-BVA 结合物的兔多克隆抗体表现出基本不同的相互作用。在酶联免疫吸附试验中,使用 STIDMF-BVA 结合物与从 BSADMF-BVA 中获得的抗血清结合使用时不存在竞争。只有使用 STIDMSO-BVA 结合物时才会出现竞争性相互作用。在选定的条件下,双酚 A 的检测限为 8.3 纳克/毫升,测定浓度的工作范围为 18.5-290.3 纳克/毫升。所获得的数据表明,只需改变合蛋白共轭的反应介质,就能实现灵敏的免疫测定,这为开发其他低分子量化合物的免疫测定提供了新的工具。
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引用次数: 0
Anti-MET Antibody Therapies in Non-Small-Cell Lung Cancer: Current Progress and Future Directions. 非小细胞肺癌的抗-MET 抗体疗法:当前进展与未来方向》。
IF 3 Q3 IMMUNOLOGY Pub Date : 2024-10-18 DOI: 10.3390/antib13040088
Kinsley Wang, Robert Hsu

Background/Objectives: Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer mortality globally, though advances in targeted therapies have improved treatment outcomes. The mesenchymal-epithelial transition (MET) gene plays a significant role in NSCLC, often through protein overexpression, exon 14 skipping mutations, and gene amplification, many of which arise as resistance mechanisms to other oncogenic drivers like epidermal growth factor receptor (EGFR) mutations. This review examines the development and clinical efficacy of anti-MET antibody therapies. Methods: A comprehensive literature search was conducted using major medical databases looking at key relevant studies on anti-MET antibody studies. Both authors reviewed the literature, assessed study quality, and interpreted the results from each study. Results: Amivantamab, a bispecific EGFR/MET antibody was approved to treat EGFR exon 20 insertion and now has recently been extended to target classical EGFR mutations with progression on osimertinib. Other important anti-MET targeted therapies in development include antibody drug conjugates such as telisotuzumab vedotin, REGN5093-M114, and AZD9592 and emibetuzumab, which is a humanized immunoglobulin G4 monoclonal bivalent MET antibody. Conclusions: MET plays a significant role in NSCLC and amivantamab along with other anti-MET targeted therapies play a role in directly targeting MET and addressing acquired resistance to oncogenic drivers. Future research should focus on developing novel MET antibody drugs and exploring new therapeutic combinations to enhance treatment efficacy and overcome resistance in NSCLC. Refining biomarker-driven approaches to ensure precise patient selection is also critical to optimizing treatment outcomes.

背景/目标:非小细胞肺癌(NSCLC)仍然是全球癌症死亡的主要原因,尽管靶向疗法的进步改善了治疗效果。间质-上皮转化(MET)基因在 NSCLC 中发挥着重要作用,通常是通过蛋白过表达、第 14 号外显子跳越突变和基因扩增等方式实现的,其中许多是作为表皮生长因子受体(EGFR)突变等其他致癌驱动因素的耐药机制而出现的。本综述探讨了抗MET抗体疗法的发展和临床疗效。方法:利用主要医学数据库对抗MET抗体研究的主要相关研究进行了全面的文献检索。两位作者审阅了文献,评估了研究质量,并解释了每项研究的结果。研究结果Amivantamab是一种双特异性表皮生长因子受体/MET抗体,已被批准用于治疗表皮生长因子受体外显子20插入,最近又扩展到针对奥希替尼治疗进展的表皮生长因子受体经典突变。其他正在开发的重要抗MET靶向疗法包括抗体药物共轭物,如telisotuzumab vedotin、REGN5093-M114、AZD9592和emibetuzumab,后者是一种人源化免疫球蛋白G4单克隆双价MET抗体。结论MET在NSCLC中发挥着重要作用,阿米万他单抗和其他抗MET靶向疗法在直接靶向MET和解决对致癌驱动因素的获得性耐药性方面发挥着作用。未来的研究应侧重于开发新型 MET 抗体药物和探索新的治疗组合,以提高疗效并克服 NSCLC 的耐药性。完善生物标志物驱动的方法以确保精确选择患者也是优化治疗效果的关键。
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引用次数: 0
Limited Biomarker Potential for IgG Autoantibodies Reactive to Linear Epitopes in Systemic Lupus Erythematosus or Spondyloarthropathy. 与系统性红斑狼疮或脊柱关节病中的线性表位发生反应的IgG自身抗体的生物标记潜力有限。
IF 3 Q3 IMMUNOLOGY Pub Date : 2024-10-12 DOI: 10.3390/antib13040087
S Janna Bashar, Zihao Zheng, Aisha M Mergaert, Ryan R Adyniec, Srishti Gupta, Maya F Amjadi, Sara S McCoy, Michael A Newton, Miriam A Shelef

Background: Autoantibodies are commonly used as biomarkers in autoimmune diseases, but there are limitations. For example, autoantibody biomarkers have poor sensitivity or specificity in systemic lupus erythematosus and do not exist in the spondyloarthropathies, impairing diagnosis and treatment. While autoantibodies suitable for strong biomarkers may not exist in these conditions, another possibility is that technology has limited their discovery. The purpose of this study was to use a novel high-density peptide array that enables the evaluation of IgG binding to every possible linear antigen in the entire human peptidome, as well as a novel machine learning approach that incorporates ELISA validation predictability in order to discover autoantibodies that could be developed into sensitive and specific markers of lupus or spondyloarthropathy.

Methods: We used a peptide array containing the human peptidome, several viral peptidomes, and key post-translational modifications (6 million peptides) to quantify IgG binding in lupus, spondyloarthropathy, rheumatoid arthritis, Sjögren's disease, and control sera. Using ELISA data for 70 peptides, we performed a random forest analysis that evaluated multiple array features to predict which peptides might be good biomarkers, as confirmed by ELISA. We validated the peptide prediction methodology in rheumatoid arthritis and COVID-19, conditions for which the antibody repertoire is well-understood, and then evaluated IgG binding by ELISA to peptides that we predicted would be highly bound specifically in lupus or spondyloarthropathy.

Results: Our methodology performed well in validation studies, but peptides predicted to be highly and specifically bound in lupus or spondyloarthropathy could not be confirmed by ELISA.

Conclusions: In a comprehensive evaluation of the entire human peptidome, highly sensitive and specific IgG autoantibodies were not identified in lupus or spondyloarthropathy. Thus, the pathogenesis of lupus and spondyloarthropathy may not depend upon unique autoantigens, and other types of molecules should be sought as optimal biomarkers in these conditions.

背景:自身抗体通常被用作自身免疫性疾病的生物标志物,但也存在局限性。例如,自身抗体生物标志物在系统性红斑狼疮中的敏感性或特异性较差,在脊柱关节病中也不存在,从而影响了诊断和治疗。虽然在这些疾病中可能不存在适合作为强生物标志物的自身抗体,但另一种可能是技术限制了它们的发现。本研究的目的是使用一种新型高密度肽阵列(可评估IgG与整个人类肽组中每一种可能的线性抗原的结合情况)以及一种新型机器学习方法(结合了ELISA验证的可预测性)来发现可开发为狼疮或脊柱关节病的灵敏特异标记物的自身抗体:我们使用包含人类肽体、几种病毒肽体和关键翻译后修饰(600 万肽)的肽阵列来量化狼疮、脊柱关节病、类风湿性关节炎、斯约格伦病和对照血清中的 IgG 结合。利用 70 种肽的 ELISA 数据,我们进行了随机森林分析,评估了多个阵列特征,以预测哪些肽可能是经 ELISA 证实的良好生物标记物。我们在类风湿性关节炎和 COVID-19 中验证了肽预测方法,这些病症的抗体复合物已被充分了解,然后我们通过 ELISA 评估了 IgG 与肽的结合情况,我们预测这些肽在红斑狼疮或脊柱关节病中具有高度特异性结合:我们的方法在验证研究中表现良好,但预测与狼疮或脊柱关节病高度特异性结合的肽却无法通过 ELISA 证实:结论:在对整个人类肽组的全面评估中,红斑狼疮或脊柱关节病未发现高度敏感和特异的IgG自身抗体。因此,红斑狼疮和脊柱关节病的发病机制可能并不依赖于独特的自身抗原,应该寻找其他类型的分子作为这些疾病的最佳生物标志物。
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引用次数: 0
Ophthalmic Use of Targeted Biologics in the Management of Intraocular Diseases: Current and Emerging Therapies. 眼科使用靶向生物制剂治疗眼内疾病:当前和新兴疗法。
IF 3 Q3 IMMUNOLOGY Pub Date : 2024-10-11 DOI: 10.3390/antib13040086
Yuan Zong, Miki Miyagaki, Mingming Yang, Jing Zhang, Yaru Zou, Kyoko Ohno-Matsui, Koju Kamoi

Background: Monoclonal antibodies (mAbs) have demonstrated substantial potential in the treatment of intraocular diseases. This review aimed to comprehensively evaluate the applications, efficacy, and safety of mAbs in the management of intraocular conditions.

Methods: A comprehensive literature search was conducted in major medical databases through July 2024. Relevant studies on monoclonal antibodies for intraocular diseases were included. Two independent researchers screened the literature, extracted data, and assessed study quality. Cost-effectiveness analyses were also reviewed.

Results: Anti-vascular endothelial growth factor (VEGF) antibodies, such as bevacizumab, ranibizumab, and aflibercept, showed significant therapeutic effects in neovascular age-related macular degeneration (NVAMD), diabetic macular edema (DME), and retinal vein occlusion (RVO). Tumor necrosis factor-alpha (TNF-α) inhibitors demonstrated promising results in treating noninfectious uveitis. Complement system-targeted therapies like pegcetacoplan offered new options for geographic atrophy. Anti-VEGF antibodies showed potential in managing retinopathy of prematurity (ROP). However, challenges persist, including high costs, potential drug resistance, and limited long-term safety data in certain scenarios.

Conclusions: Monoclonal antibodies are vital for treating intraocular diseases, but continuous innovation and rigorous clinical evaluation are essential. Future research should focus on developing novel delivery systems, exploring combination therapies, conducting long-term follow-up studies, and investigating personalized treatment strategies to provide safer, more effective, and cost-effective therapeutic solutions.

背景:单克隆抗体(mAbs)在治疗眼内疾病方面具有巨大潜力。本综述旨在全面评估 mAbs 在眼内疾病治疗中的应用、疗效和安全性:方法:在 2024 年 7 月之前的主要医学数据库中进行了全面的文献检索。方法:在截至 2024 年 7 月的主要医学数据库中进行了全面的文献检索,纳入了有关单克隆抗体治疗眼内疾病的相关研究。两名独立研究人员筛选文献、提取数据并评估研究质量。此外,还对成本效益分析进行了审查:抗血管内皮生长因子(VEGF)抗体,如贝伐单抗、雷尼珠单抗和阿夫利百普,对新生血管性老年黄斑变性(NVAMD)、糖尿病性黄斑水肿(DME)和视网膜静脉闭塞(RVO)有显著疗效。肿瘤坏死因子-α(TNF-α)抑制剂在治疗非感染性葡萄膜炎方面取得了可喜的成果。补体系统靶向疗法(如培西他克普兰)为治疗地理萎缩提供了新的选择。抗血管内皮生长因子抗体显示出治疗早产儿视网膜病变(ROP)的潜力。然而,挑战依然存在,包括高昂的成本、潜在的耐药性以及某些情况下有限的长期安全性数据:结论:单克隆抗体对治疗眼内疾病至关重要,但持续创新和严格的临床评估必不可少。未来的研究应侧重于开发新型给药系统、探索联合疗法、开展长期随访研究以及调查个性化治疗策略,以提供更安全、更有效、更经济的治疗方案。
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引用次数: 0
Preventative Cancer Vaccine-Elicited Human Anti-MUC1 Antibodies Have Multiple Effector Functions. 预防癌症疫苗诱导的人类抗 MUC1 抗体具有多种效应功能
IF 3 Q3 IMMUNOLOGY Pub Date : 2024-10-10 DOI: 10.3390/antib13040085
Michelle L McKeague, Jason Lohmueller, Matthew T Dracz, Najla Saadallah, Eric D Ricci, Donella M Beckwith, Ramya Ayyalasomayajula, Maré Cudic, Olivera J Finn

Background/objectives: Mucin-1 (MUC1) is a transmembrane glycoprotein that is overexpressed and hypoglycosylated in premalignant and malignant epithelial cells compared to normal cells, creating a target antigen for humoral and cellular immunity. Healthy individuals with a history of advanced colonic adenomas and at high risk for colon cancer were enrolled in a clinical trial to evaluate the feasibility of using a MUC1 peptide vaccine to prevent colon cancer. Anti-MUC1 antibodies elicited by this vaccine were cloned using peripheral blood B cells and sera collected two weeks after a one-year booster. Twelve of these fully human monoclonal antibodies (mAb) were tested for binding to MUC1+ target cells, and three with the highest binding were further evaluated for various effector functions important for tumor rejection.

Methods: Immune cells were incubated together with target cells expressing variations in the number, distance, and membrane anchoring properties of the MUC1 epitope in the presence of each mAb.

Results: All three mAbs mediated antibody-dependent cytokine release (ADCR), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). Two also mediated antibody-dependent trogocytosis/trogoptosis (ADCT). None were capable of complement-dependent cytotoxicity (CDC).

Conclusions: ADCP and ADCT functions were more efficient when antibodies bound epitopes proximal to and anchored to the membrane, providing insight for future therapeutic antibody validation strategies.

背景/目的:粘蛋白-1(MUC1)是一种跨膜糖蛋白,与正常细胞相比,它在癌前病变和恶性上皮细胞中过度表达且糖基化过低,从而成为体液免疫和细胞免疫的靶抗原。有晚期结肠腺瘤病史和结肠癌高风险的健康人参加了一项临床试验,以评估使用 MUC1 肽疫苗预防结肠癌的可行性。使用外周血 B 细胞和一年强化治疗两周后收集的血清克隆了该疫苗激发的抗 MUC1 抗体。对其中 12 种全人源单克隆抗体(mAb)与 MUC1+ 靶细胞的结合力进行了测试,并对结合力最高的 3 种单克隆抗体进一步评估了其对肿瘤排斥的各种效应功能:方法:在每种 mAb 存在的情况下,将免疫细胞与表达不同数量、距离和膜锚定特性的 MUC1 表位的靶细胞一起孵育:结果:所有三种 mAb 都能介导抗体依赖性细胞因子释放(ADCR)、抗体依赖性细胞毒性(ADCC)和抗体依赖性细胞吞噬(ADCP)。其中两种还介导了抗体依赖性逆细胞吞噬/凋亡(ADCT)。结论:ADCP和ADCT功能在抗体结合近端表位并锚定在膜上时更有效,这为未来的治疗性抗体验证策略提供了启示。
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引用次数: 0
B Cell and Antibody Responses in Bovine Tuberculosis. 牛结核病的 B 细胞和抗体反应。
IF 3 Q3 IMMUNOLOGY Pub Date : 2024-10-09 DOI: 10.3390/antib13040084
Laura Inés Klepp, Federico Carlos Blanco, María Mercedes Bigi, Cristina Lourdes Vázquez, Elizabeth Andrea García, Julia Sabio Y García, Fabiana Bigi

The development of vaccines and effective diagnostic methods for bovine tuberculosis requires an understanding of the immune response against its causative agent, Mycobacterium bovis. Although this disease is primarily investigated and diagnosed through the assessment of cell-mediated immunity, the role of B cells and antibodies in bovine tuberculosis has been relatively undervalued and understudied. Current evidence indicates that circulating M. bovis-specific antibodies are not effective in controlling the disease. However, local humoral immune responses may contribute to either defence or pathology. Recent studies in animal models and cattle vaccine trials suggest a potential beneficial role of B cells in tuberculosis control. This review discusses the role of B cells and antibodies in bovine tuberculosis and explores antibody-based diagnostics for the disease, including traditional techniques, such as different ELISA, new platforms based on multiple antigens and point-of-care technologies. The high specificity and sensitivity values achieved by numerous antibody-based tests support their use as complementary tests for the diagnosis of bovine tuberculosis, especially for identifying infected animals that may be missed by the official tests.

要开发牛结核病疫苗和有效的诊断方法,就必须了解牛结核病致病菌牛分枝杆菌的免疫反应。虽然这种疾病主要是通过评估细胞介导免疫进行调查和诊断的,但 B 细胞和抗体在牛结核病中的作用却相对被低估,研究也相对不足。目前的证据表明,循环中的牛结核杆菌特异性抗体不能有效控制疾病。然而,局部体液免疫反应可能有助于疾病的防御或病理变化。最近在动物模型和牛疫苗试验中进行的研究表明,B 细胞在结核病控制中可能起到有益的作用。本综述讨论了 B 细胞和抗体在牛结核病中的作用,并探讨了基于抗体的疾病诊断方法,包括传统技术(如不同的 ELISA)、基于多种抗原的新平台和护理点技术。许多基于抗体的检测方法都具有很高的特异性和灵敏度,支持将其作为诊断牛结核病的辅助检测方法,特别是用于识别官方检测方法可能漏检的受感染动物。
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引用次数: 0
Metabolic Engineering of Glycofusion Bispecific Antibodies for α-Dystroglycanopathies. 用于α-肌张力障碍性疾病的糖融合双特异性抗体的代谢工程。
IF 3 Q3 IMMUNOLOGY Pub Date : 2024-10-07 DOI: 10.3390/antib13040083
Xiaotian Zhong, Guoying Grace Yan, Apurva Chaturvedi, Xiuling Li, Yijie Gao, Mahasweta Girgenrath, Chris J Corcoran, Liz Diblasio-Smith, Edward R LaVallie, Teresse de Rham, Jing Zhou, Molica Abel, Logan Riegel, Sean K H Lim, Laird Bloom, Laura Lin, Aaron M D'Antona

Background: α-dystroglycanopathies are congenital muscular dystrophies in which genetic mutations cause the decrease or absence of a unique and complex O-linked glycan called matriglycan. This hypoglycosylation of O-linked matriglycan on the α-dystroglycan (α-DG) protein subunit abolishes or reduces the protein binding to extracellular ligands such as laminins in skeletal muscles, leading to compromised survival of muscle cells after contraction. Methods: Surrogate molecular linkers reconnecting laminin-211 and the dystroglycan β-subunit through bispecific antibodies can be engineered to improve muscle function in the α-dystroglycanopathies. This study reports the metabolic engineering of a novel glycofusion bispecific (GBi) antibody that fuses the mucin-like domain of the α-DG to the light chain of an anti-β-DG subunit antibody. Results: Transient HEK production with the co-transfection of LARGE1, the glycoenzyme responsible for the matriglycan modification, produced the GBi antibody only with a light matriglycan modification and a weak laminin-211 binding activity. However, when a sugar feed mixture of uridine, galactose, and manganese ion (Mn2+) was added to the culture medium, the GBi antibody produced exhibited a dramatically enhanced matriglycan modification and a much stronger laminin-binding activity. Conclusions: Further investigation has revealed that Mn2+ in the sugar feeds played a critical role in increasing the matriglycan modification of the GBi antibody, key for the function of the resulting bispecific antibody.

背景:α-肌营养不良症(α-dystroglycanopathies)是一种先天性肌肉营养不良症,在这种疾病中,基因突变会导致一种独特而复杂的 O 链糖基 matriglycan 减少或缺失。α-肌营养不良蛋白(α-DG)亚基上的O-连接聚糖糖基化减少,导致该蛋白与骨骼肌中的层粘连蛋白等细胞外配体的结合丧失或减少,从而影响肌肉细胞在收缩后的存活。方法:通过双特异性抗体重新连接层粘连蛋白-211和肌萎缩蛋白β亚基的替代分子连接体可被设计用于改善α-肌萎缩蛋白病的肌肉功能。本研究报告了一种新型糖融合双特异性(GBi)抗体的代谢工程,该抗体将α-DG的粘蛋白样结构域与抗β-DG亚基抗体的轻链融合在一起。结果:通过共转染 LARGE1(负责 matriglycan 修饰的糖酵解酶),瞬时 HEK 生产出的 GBi 抗体仅具有轻度 matriglycan 修饰和较弱的层粘连蛋白-211 结合活性。然而,当在培养基中加入尿苷、半乳糖和锰离子(Mn2+)的糖饲料混合物时,产生的 GBi 抗体显示出显著增强的 matriglycan 修饰和更强的层粘连蛋白结合活性。结论进一步的研究发现,糖料中的 Mn2+ 在增强 GBi 抗体的 matriglycan 修饰方面发挥了关键作用,这是所制备的双特异性抗体发挥功能的关键。
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引用次数: 0
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Antibodies
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