双-多特异性纳米抗体的构建形式

双特异性抗体（双抗）可以同时特异性结合2种不同抗原,已成为抗体工程领域研究的热点。这些研究主要集中在癌症治疗方面,虽疗效显著但还未达到临床最佳状态。由于双抗有2条重链和2条轻链,因而极易出现错配。为解决这一问题,研究者设计出许多不同的双抗形式,例如串联单链抗体、双可变结构域抗体或使用“knobs-into-holes”方式构建的抗体,但仍不能得到最优的双抗。纳米抗体是目前已知最小的全功能抗体,具有许多优异的理化特性,为构建双-多特异性抗体提供了一种全新的途径。     

多重特异性单克隆抗体研究进展

疾病的形成通常是涉及多个关键介质的复杂过程,因此针对单一成分的抗体药物有时并不能获得较好的临床疗效。多抗原靶向性治疗策略有望提高对一些复杂疾病的治疗效果,它们包括抗体的联合使用、多克隆抗体或混合抗体以及双特异性抗体等。近年来,双重或多重特异性单克隆抗体的出现为多抗原靶向性治疗提供了新策略和方法,此文对多重特异性单克隆抗体的研究进展做一综述。     

重组多克隆抗体：下一代抗体治疗药

抗体各种剂型用作治疗药已有一个世纪。传统的免疫球蛋白治疗具有反映自然免疫反应多样性的长处,但其临床应用很有限。然而,过去10年中已有30多个单克隆抗体成功进入药物市场。单克隆途径的长处是具特异性,但对复杂抗原引起的疾病无效。重组多克隆抗体是第3代抗体治疗药,能够处理复杂的和高突变性靶标,无疑为未来的商机提供了希望。     

重组双特异性抗体的研究进展（续）

单克隆抗体由于其靶向性强、副作用小等特点,在肿瘤、免疫系统疾病等多个领域取得了良好的疗效,但是由于只能针对单一明确的靶点,在临床上仍存在一定的局限性。因此,可以同时结合两个相同或者不同抗原上的不同表位的双特异性抗体在治疗肿瘤及自身免疫病等领域具有潜在优势。近年来,越来越多不同结构形式的双特异性抗体进入临床并取得了良好的疗效。此文对国内外多种适用于大规模生产的重组双特异性抗体结构及其在临床中的应用进行综述。     

重组双特异性抗体的研究进展（待续）

单克隆抗体由于其靶向性强、副作用小等特点,在肿瘤、免疫系统疾病等多个领域取得了良好的疗效,但是由于只能针对单一明确的靶点,在临床上仍存在一定的局限性。因此,可以同时结合两个相同或者不同抗原上不同表位的双特异性抗体在治疗肿瘤及自身免疫病等领域具有潜在优势。近年来,越来越多不同结构形式的双特异性抗体进入临床试验并取得了良好的疗效。此文对国内外多种适用于大规模生产的重组双特异性抗体结构及其在临床中的应用进行综述。     

抗体药物的药物代谢动力学特点及研究进展

抗体药物是一种可与相应抗原发生特异性结合的免疫球蛋白。该研究从抗体药物的结构入手，对抗体药物的药物代谢动力学基本特点进行综述，并着重介绍了其不同于小分子药物的独特代谢特征，主要包括与靶点介导的药物处置、新生儿 Fc受体介导的循环再利用、糖基化修饰和电荷异质性对清除速率的影响以及与抗药物抗体相结合导致清除加快。最后总结了纳米抗体、双特异性抗体、抗体药物偶联物等新型抗体药物的药物代谢动力学研究进展。     

抗体药物在肿瘤治疗中的应用与进展

单克隆抗体药物以其特异性高、亲和力强、血清半衰期长等优点在肿瘤治疗领域得到广泛应用。基于母体单克隆抗体而设计的双特异性抗体、抗体片段、抗体药物偶联物等将抗体类药物的开发推至新的高潮。通过对抗体药物在肿瘤治疗领域的应用和最新进展、抗体药物的结构和作用机制进行介绍,并对肿瘤治疗抗体药物上市与临床开发现状进行总结,以期为抗体药物在肿瘤治疗领域的未来发展提供参考。     

双特异性抗体在抗人类免疫缺陷病毒方面的研究进展

双特异性抗体（bispecific antibody,BsAb）是一种工程化的非自然抗体。由于大多数单克隆抗体（monoclonal antibody,mAb）的抗病毒活性有限,而双特异性抗体通过结构的修饰,可以同时作用于病毒和宿主细胞不同的抗原表位,在免疫治疗中具有更高的特异性以及更大广度及效力,在抗人类免疫缺陷病毒（HIV）研究领域中双特异性抗体的研究已成为一大热点,现就抗HIV双特异性抗体的研究作一综述。     

抗肿瘤抗体药物研究进展

自1997年以来,抗体药物用于肿瘤治疗取得突破性的进展。据统计,国内外已有约17种抗体药物被批准用于临床肿瘤治疗。除了一直比较成功的裸抗体,抗体药物偶联物(ADC)成为抗肿瘤抗体药物研发的新热点。抗原靶标及作用机制特点决定了抗肿瘤抗体药物在临床的安全性和疗效。本文主要从肿瘤细胞杀伤机制、作为抗体靶标的肿瘤抗原、在临床的应用情况及ADC纳米粒研究方面对抗肿瘤抗体药物进行了综述。     

单克隆抗体类抗肿瘤药物的临床应用和进展

将化疗药物、放射性物质以及生物毒素等 与单克隆抗体偶联就得到单克隆类药物。由于抗原 抗体结合的特异性,这些偶联的药物被单克隆抗体 导向表达相应抗原的细胞并发挥抗肿瘤效应。单克 隆抗体类抗肿瘤药物有效地降低了传统肿瘤药物治 疗的不良反应,提高了治疗的精确性。     

Bispecific antibodies for dual-modality cancer therapy: killing two signaling cascades with one stone

The additive and synergistic therapeutic effects derived from combinations of chemotherapeutic drugs and radiation have established an indispensable paradigm: cancer must be attacked on multiple fronts. However, the increased antitumor efficacy of such combinational regimens is also associated with severe systemic toxicity, as these drugs cannot selectively target tumor cells. Monoclonal antibodies (mAbs), which have exquisite specificity for their antigens, are becoming an increasingly important class of antitumor agents, as they enhance the efficacy of various therapeutic regimens without significantly increasing systemic toxicity. Furthermore, preclinical and early clinical evidence indicate that combinations of antibody-based drugs provide even greater efficacy with minimal side effects. Unfortunately, the research, manufacturing and regulatory costs of mAb development pose a significant barrier to the use of antibody-based combination therapies. An emerging alternative is the use of dual-targeting bispecific antibodies (BsAbs). BsAbs are derived from the recombination of variable domains of two antibodies with different specificities; BsAbs are thus capable of binding both antigens of their parental antibodies. With the recent progress that has been made in antibody engineering technology, BsAbs that simultaneously target two tumor-associated molecules (eg, growth factor receptors) are being heralded for their potential to deliver two therapeutic moieties in a single molecule.     

Rationale and development of multispecific antibody drugs

Bispecific antibodies (bsAbs) have been on the scene for decades and represent the next generation of antibody-based therapeutics. Unlike monospecific, monoclonal antibodies (mAbs), bsAbs can target two or more disease mechanisms as a single agent and can offer certain unique therapeutic strategies that are difficult to acheive with mAbs. The lessons learned during the past 35 years of mAb development and 25 years of bsAbs experience are shaping development of the next generation of bsAbs and multispecific antibody-based drugs. Recent improvements in manufacturability and drug-like properties of certain BsAb formats, and clinical success for a few BsAbs, are reviving this area. In this article, we discuss the potential limitations of the first-generation mAbs and opportunities to improve upon existing mAb drugs, factors driving the multispecific antibody field and the strengths, weaknesses and development status of representative multispecific antibody concepts.     

Construction and stable gene expression of AGR2xPD1 bi-specific antibody that enhances attachment between T-Cells and lung tumor cells,suppress tumor cell migration and promoting CD8 expression in cytotoxic T-cells

There has been a substantial and consistent rise in the number of clinical trials to develop advanced and potent bispecific antibodies (BsAb) over the past two decades with multiple targets to improve the efficacy or tissue specificity of monoclonal antibodies (mAb) treatment for diseases with multiple determining factors or widely-expressed targets. In this study, we designed and synthesized BsAb AGR2xPD1 targeting extracellular AGR2, a paracrine signal, and PD1, an immune checkpoint protein. Our design is intended to use AGR2 binding to guide PD1 targeting for AGR2⁺cancer. We used this construction to produce AGR2xPD1 BsAb by generating clonally selected stable 293F cell line with high expression. Applying this BsAb in a T cell-Tumor cell co-culture system showed that targeting both PD1 and AGR2 with this BsAb induces the attachment of TALL-104 (CD8⁺ T-lymphocytes) cells onto co-cultured H460 AGR2⁺ Lung tumor cells and significantly reduces migration of H460 cells. T-cell expression of CD8 and IFNγ is also synergistically enhanced by the AGR2xPD1 BsAb treatment in the AGR2⁺H460 co-culture system. These effects are significantly reduced with AGR2 expression negative WI38 cells. Our results demonstrate that the AGR2xPD1 BsAb could be a potential therapeutic agent to provide better solid tumor targeting and synergetic efficacy for treating AGR2+ cancer by blocking AGR2 paracrine signaling to reduce tumor survival, and redirecting cytotoxic T-cells into AGR2+ cancer cells.     

New anti-mitotic drugs with distinct anti-calmodulin activity

Bisindole Vinca alkaloids target microtubule system causing anti-mitotic activity. The problem of their clinical application is the lack of selectivity resulting in toxic side effects. In this paper we review the late history of new bisindole derivatives focusing on KARs recognized as potent anti-cancer drugs with low side effect. KARs, just as other bisindoles, impede microtubule assembly of mitotic spindle, however, they display no anti-calmodulin activity. This new drug family appears to be less potent than vinblastine in vitro systems, but it shows high antitumor efficacy with considerably higher doses being well tolerated in the animal tumor models. 3D data of calmodulin complexed with KAR-2 explain the specificity and unique pharmacology of KAR derivatives.     

Impact of Buffers on Colloidal Property and Aggregation Propensities of a Bispecific Antibody

Bispecific antibodies represent a promising avenue whereby 2 different binding specificities of a single-chain antibody can be grafted into a common Fc fragment to generate one antibody-like molecule. Despite the promising efficacy of such modalities, they may lack manufacturability because of stability and aggregation issues. Herein, we performed a systematic buffer screening for an aggregation-prone therapeutic bispecific antibody (BsAb) during early stage development. To this end, various buffers (histidine, glutamate, acetate, and arginine) and buffer combinations, including arginine and glutamate (Arg + Glu), were evaluated for their stabilizing effects on BsAb. Specifically, we identified an equimolar combination of histidine and glutamate (His + Glu at pH 5.0) buffer that showed enhanced colloidal stability as measured by dynamic light scattering interaction parameter (k_D). This implies a role of net protein-protein interaction in mediating aggregation propensity of the protein. Two-dimensional nuclear magnetic resonance and multiangle light scattering experiments suggest the formation of a reversible dimer as a potential precursor to overall aggregation process. Furthermore, 1D nuclear magnetic resonance studies suggest a unique mode of interaction of histidine with BsAb that can be modulated by other buffer components or ionic strength.     

双吲哚类生物碱的抗肿瘤活性研究进展

癌症是仅次于心脑血管疾病的第二大类致死性疾病,每年数百万人因此丧生。抗肿瘤药物对癌症的防治至关重要,然而目前的抗肿瘤药物特异性普遍较差,往往会导致各种副作用。不仅如此,日益严峻的耐药性问题使得现有药物的疗效呈逐年下降之势。因此,亟需开发新型抗肿瘤药物。双吲哚类生物碱具有结构特殊、类药性强、选择性高和毒副作用小等特点,在抗肿瘤方面的活性引起了药物研发人员的普遍关注。本文从结构特点和生物活性方面,总结了近年来双吲哚类生物碱的抗肿瘤领域的最新研究进展。     

Artemisinin-derived dimers as potential anticancer agents: Current developments,action mechanisms,and structure–activity relationships

Anticancer agents play a pivotal role in cancer treatment. However, most of the anticancer drugs currently used in the clinics have a severe anticancer scenario, as well as low specificity and fatal side effects. Thus, there is an urgent demand to develop novel drugs with great efficacy, high specificity, and low side effects. Artemisinin and its semisynthetic derivatives are mainstays of chemotherapy against malaria, and artemisinin-based compounds, especially artemisinin-derived dimers, also exhibit excellent in vitro and in vivo anticancer activity. The structure–activity relationship (SAR) demonstrated that the linker between the two artemisinin moieties influenced the anticancer activity significantly; so, the rational design of the linker may provide valuable therapeutic intervention for the treatment of cancer. This review outlines the potential anticancer activity of artemisinin-derived dimers tethered by different linkers. The SARs, as well as mechanisms of action, are discussed to provide insights for the rational design of more effective dimers.     

Metabolic Diseases Drug Discovery-Strategic Research Institute's Third International World Summit. Dipeptidyl peptidase-IV inhibitors 26-27 July 2004, San Diego, CA, USA

The majority of the presentations a the conference were on three highly sought-after targets for type 2 diabetes mellitus, namely PTP1B, PPARs and DPP-IV, reflecting the current focus and trend in the industry. A couple of novel targets were discussed, including the potential of myostatin as a type 2 diabetes mellitus target and a novel GPCR target. While small molecules were dominant, several biological-based approaches were covered: antibody therapeutics and oligonucleotide-based approaches (ASO and siRNA). In searching for small-molecule leads, structure-based rational design and focused combination chemistry appear to produce better results than a random high-throughput approach over the entire chemical library. The biggest challenges for diabetes and obesity drugs remain similar to those mentioned in previous meetings: increasing specificity to reduce side effects and maintaining long-term effect while maintaining or increasing efficacy. Due to the tremendous interest of the pharmaceutical industry in metabolic disease drug development, our knowledge of food intake and metabolism regulation has increased exponentially. Overall, the prospect of better drugs for, and better control of, type 2 diabetes mellitus and obesity is promising.     

前药设计在口服药物研发中的应用

前药是指在体外无活性,在体内经过化学或酶的作用转化成有活性的母体药物而发挥药理作用的化合物。应用前药技术能解决口服药物常见的缺点如水溶性和脂溶性不佳、首过效应强、药效持续时间短、毒副作用大以及口感差等。分别从提高生物利用度、提高靶向性及减小毒性等几个方面综述前药技术在口服药物研发中的应用情况。