抗体偶联药物的有关进展

化疗肿瘤治疗的常规手段之一,但由于细胞毒药物没有明显的靶向性,导致其副作用十分显著。因此免疫偶联药物由于其良好的靶向性及抗癌活性就成为了研究的热点。文章综述了细胞毒药物与单克隆抗体偶联的各种常用方法,包括使用偶联剂进行偶联、利用肽链进行偶联、利用二硫键进行偶联和利用大分子技术进行偶联,以及抗体偶联药物的研究现状。抗体偶联药物有细胞毒药物、抗体和偶联剂组成,利用各种偶联手段将单克隆抗体与细胞毒药物偶联,不仅可以将细胞毒药物特异性地靶向于肿瘤细胞,而且可以降低细胞毒药物对于正常细胞的杀伤,同时还可以具备缓释、提高药物抗肿瘤活性等效果,是未来肿瘤靶向治疗的发展方向之一。同时文章还结合作者的自身工作,对抗体偶联药物的未来发展方向提出了建议。     

抗体偶联药物的研发进展和挑战

抗体偶联药物（ADC）由单克隆抗体与不同数目的小分子毒素通过连接子偶联组成,是近年来肿瘤学发展较快的药物类别之一。由于兼具单抗药物的高靶向性以及细胞毒素在肿瘤组织中高活性的双重优点,ADC药物可高效杀伤肿瘤细胞,较化疗药物不良反应更低,较传统抗体类肿瘤药物具有更好的疗效,是近年来肿瘤创新药研发的热点。随着新一代工程抗体展现出良好的治疗前景以及新药研发技术的不断突破,抗体偶联药物经历了三个发展阶段,技术日臻成熟,但ADC药物还存在诸多问题和挑战。本文主要从抗体偶联药物的研发历程、抗体、连接子、偶联技术及细胞毒素的类型等方面进行综述,为ADC创新药物研发提供参考。     

肿瘤靶向抗体偶联物的研究进展

肿瘤靶向制剂已成为当今肿瘤治疗研究的热点,针对特定的靶点(抗原)可以制备相应的单抗。特异性单抗和蛋白毒素、放射性同位素、化疗药物偶联制备成相应的靶向抗体药物,这种抗体偶联物能增强药物的有效性,减少对正常组织的毒害。本文就三类肿瘤靶向抗体偶联物的特点、作用机制、上市药物以及发展趋势进行综述。     

抗体偶联药物研究进展

抗体-药物偶联物(Antibody-drug conjugates,ADCs)由“弹头”药物(细胞毒药物)、抗体以及偶联抗体和药物的偶联链3部分组成,其作为一种新型药物,结合了抗体的靶向特异性和小分子药物的细胞毒作用,已成为当今肿瘤研究领域的热点。根据其细胞毒药物来源可分为陆地与海洋两大类,本文总结了近年来这两大类抗体偶联药物的研究进展,并从靶点的特异性、抗体的亲和力、高效的细胞毒分子及合适的偶联链等方面对ADCs的发展关键进行了简要评述。     

小型化抗体偶联药物及类似物的研究进展

在癌症治疗中,实体瘤的治疗效果一直是医药界关注的热点。临床上用于治疗实体瘤的靶向药物——抗体和抗体偶联药物存在其相对分子质量较大,导致穿透性有限的问题,在实体瘤治疗中无法发挥预期疗效,且由于其在体内的循环时间长,易对肝和其他组织产生脱靶毒性,限制治疗窗。使用小型化的偶联物或类似药物,如抗体片段偶联药物、支架抗体偶联物或多肽偶联物,将有利于药物快速穿透肿瘤组织,使毒素在肿瘤组织内迅速聚集,且相比于传统抗体偶联药物,小型化偶联物通过肾脏代谢比率增加,从而降低药物因长时间体循环导致的不良反应。但是其过短的半衰期会造成进入肿瘤的实际药量减少,因此也衍生出不同半衰期延长方法,以调节药物半衰期,增加药物进入肿瘤组织的总量,提高治疗效果。通过对不同的小片段技术和代表性药物的临床前或临床进展情况进行介绍,以及对其发展方向进行讨论,以期为小型化抗体偶联药物及类似物的研发提供参考。     

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。     

基于定点偶联技术的抗体药物偶联物的临床研究进展与挑战

抗体药物偶联物是一类能够有效提高治疗指数的新一代抗肿瘤药物.传统的抗体药物偶联物使用非定点偶联技术,得到偶联位置和数目高度不均一的异质体,产品结构不均一,给产品质量的批间一致性控制带来挑战.定点偶联技术可以将小分子药物定点、定量地连接到抗体上,具有更好的药代动力学特性.简要总结了抗体药物偶联物的关键组成部分,抗体药物偶...     

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。     

抗 EGFR 单克隆抗体偶联载紫杉醇纳米粒对胃癌肿瘤靶向性能力研究

目的：为了增强载药纳米粒靶向肿瘤的能力,将载药纳米粒与抗上皮生长因子细胞增殖和信号传导受体（EGFR）单克隆抗体偶联,探究该偶联是否会增加胃癌肿瘤靶向性。方法将制备好的载药纳米粒在羟基胶乳微球偶联抗体（EDC）的作用下通过酰胺反应与抗 EGFR 单克隆抗体进行偶联,制备成载药免疫纳米粒。通过透析袋法测定纳米粒体外缓释效果,用 ELISA 法测定抗体与载药纳米粒偶联率,最后采用荧光标记法对胃癌模型鼠进行活体成像结果纳米粒表面光滑,分布均匀,粒径在200～300 nm 间,载药量为61．02％,并且具有缓慢释药的效果,抗体与载药纳米粒的偶联率达到了70％,最终荧光活体成像的结果显示,此免疫载药抗体具有靶向胃肿瘤的效果。结论我们制备的免疫纳米粒既可以缓释药物也存在一定肿瘤靶向性,所以将抗体与载药纳米粒偶联,可以增加肿瘤病灶处局部的药物浓度,以此来缓解抗肿瘤药物对人体其他正常组织毒副作用。     

肿瘤靶向药物抗体-药物偶联物的研究进展

抗体-药物偶联物(Antibody-drug conjugates,ADC)具有单克隆抗体的靶向特异性和细胞毒素的抗肿瘤能力,其利用化学接头将细胞毒性药物与单克隆抗体偶联,与肿瘤部位的靶抗原结合后释放毒素.尽管概念简单,但是结构设计复杂、药物副作用明显和疗效欠佳等问题为其进一步研究应用带来了挑战.随着新技术的出现,AD...     

Chemical warfare agents

Chemical warfare agents (CWA's) are defined as any chemical substance whose toxic properties are utilised to kill, injure or incapacitate an enemy in warfare and associated military operations. Chemical agents have been used in war since times immemorial, but their use reached a peak during World War I. During World War II only the Germans used them in the infamous gas chambers. Since then these have been intermittently used both in war and acts of terrorisms. Many countries have stockpiles of these agents. There has been a legislative effort worldwide to ban the use of CWA's under the chemical weapons convention which came into force in 1997. However the manufacture of these agents cannot be completely prohibited as some of them have potential industrial uses. Moreover despite the remedial measures taken so far and worldwide condemnation, the ease of manufacturing these agents and effectiveness during combat or small scale terrorist operations still make them a powerful weapon to reckon with. These agents are classified according to mechanism of toxicity in humans into blister agents, nerve agents, asphyxiants, choking agents and incapacitating/behavior altering agents. Some of these agents can be as devastating as a nuclear bomb. In addition to immediate injuries caused by chemical agents, some of them are associated with long term morbidities and psychological problems. In this review we will discuss briefly about the historical background, properties, manufacture techniques and industrial uses, mechanism of toxicity, clinical features of exposure and pharmacological management of casualties caused by chemical agents.     

Small molecules with EGFR-TK inhibitor activity

Specific and reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib are clinically active in advanced or metastatic NSCLC and both are approved in various countries for the treatment of patients that failed prior chemotherapy. Erlotinib has also prolonged survival in pancreatic cancer patients when added to gemcitabine and regulatory approval in this disease is being sought. Additional promising activity has been seen in other tumor types, such as ovarian cancer or head and neck malignancies, and phase III trials in these malignancies are ongoing or planned. Despite these successes, these agents have exhibited anecdotal or modest activity when used as single agents in unselected patients with various other tumor types. We have learned that the clinical development of these agents is far from simple and we need to better understand biological and clinical criteria for patient selection and how to best use the different available agents. The recent discovery of EGFR mutations and the potential identification of other markers that might predict patient response could help to optimize the use of these agents in the future. Irreversible EGFR inhibitors, dual EGF/HER2 and pan-ErbB receptor inhibitors may have greater antitumor activity although the tolerance of these compounds compared to specific EGFR TKIs needs further characterization. HER2 specific TKIs are also in development. Lapatinib, a dual EGFR/HER2 TK inhibitors, is particularly promising in breast cancer. Newer agents, such as BMS-599626, have recently entered into the clinic. In addition to the use of these agents as single agents, many clinical studies are addressing the role of combining them with hormonal agents, biological agents or chemotherapy.     

The Anti-inflammatory Activity of N-Substituted Indazolones in Mice

N-Substituted indazolones were shown to be potent anti-inflammatory and analgesic agents in mice at 8 mg/kg. In addition, the agents were able to protect against death caused by endotoxins similar to those found in chronic infections. In part, the ability of these agents to suppress the inflammatory process is due to their blockage of cytokine release, e.g. TNFα and IL-1, as well as their inhibition of high affinity binding to receptors on target cells of inflammation. Suppressing these receptors can be linked to the inhibition by the agents of lysosomal hydrolytic enzymes, prostaglandin cyclooxygenase and 5°-lipoxygenase activities. Free radical generation involved in inflammation was also stabilized in the presence of most of these agents.     

Dopaminergic activity of the antimuscarinic antiparkinsonian agents

The antimuscarinic antiparkinsonian agents are widely used in psychiatric practice to reduce the extrapyramidal motor symptoms caused by the neuroleptic antipsychotic medications. Although the antimuscarinic antiparkinsonian agents are effective in reducing extrapyramidal symptoms, their use in conjunction with neuroleptic treatment of psychosis has been reported to antagonize the therapeutic effects of the neuroleptic; there are also several reports of the antimuscarinic antiparkinsonian agents variously causing psychotic syndromes, mood elevating and stimulant effects, stereotypy, dyskinesia, behavioral agitation, and drug dependence in both psychiatric and normal populations. These drug-related phenomena are generally attributed to the antimuscarinic properties of these agents. A large body of data, however, has shown that the antimuscarinic antiparkinsonian agents also function as potent, indirect dopamine-agonists. Benztropine, the most widely prescribed of these medications, is one of the most potent known inhibitors of presynaptic dopamine reuptake. These antiparkinsonian agents also have potent agonist activity at the noradrenergic synapse, as well as minor activity at the serotonergic synapse. This paper reviews neuropharmacologic evidence suggesting that significant neurophysiologic effects can result from the dopaminergic--and possibly noradrenergic--activity of the antimuscarinic antiparkinsonian agents, similar in some cases to those observed with amphetamine. Greater attention to these properties may aid in interpretation of clinical and research observations involving these so-called "antimuscarinic" agents.     

Absorbable hemostatic agents.

PURPOSE: The pharmacology, clinical efficacy, adverse effects and toxicities, drug interactions, dosage and administration, and safety issues related to the use of absorbable hemostatic agents are reviewed. SUMMARY: Absorbable hemostatic agents exert their pharmacologic effects at various points within the coagulation cascade. These agents are indicated for use during surgical procedures as adjunctive therapy when bleeding is not controlled by conventional methods. Early clinical data on absorbable hemostatic agents revealed a beneficial effect with regard to controlling capillary bleeding, achieving hemostasis during vascular surgery, and controlling bleeding from fistula-puncture sites. Few randomized controlled clinical trials have directly compared available agents, but case reports describing the efficacy of absorbable hemostatic agents in specific situations, especially unlabeled uses of thrombin, abound. Existing trials have compared the efficacy of established agents with newer agents, including fibrin sealants, with varying results. A variety of rarely occurring adverse effects have been reported with the administration of absorbable hemostatic agents; some of these rare effects, such as paralysis, are quite severe. No standardized dosing regimens are available for these agents, although surgeons may have a preference for a particular regimen based on their own clinical experience. No drug interactions involving absorbable hemostatic agents have been published; however, the use of these agents with other medications that affect hemostasis may disrupt clot formation. CONCLUSION: Absorbable hemostatic agents are useful as adjunctive therapy during surgical procedures when conventional methods do not control bleeding. Although rare adverse effects have occurred with these agents, their careful administration will prevent serious adverse outcomes.     

Psychoactive agents, seizure production, and sudden death in epilepsy

Major tranquilizers as well as antidepressant agents have been associated with clinical seizures in patients administered these agents. The incidence of such seizures is generally low when these drugs are administered in therapeutic doses. However, administration of large doses of these agents has been associated with many cases of convulsion production. The effects that these drugs have on animal models of epilepsy have been examined. It appears that the phenothiazines act as convulsant agents at lower doses, whereas, at higher doses, they act as anticonvulsant drugs. Antidepressants, on the other hand, appear to exert an anticonvulsant effect at low doses and convulsant effects at high doses. The mechanism by which these agents alter the seizure threshold is not yet known. Clinically, drugs of lower seizure production potential should be substituted for those drugs with greater potential in treating epileptic patients for psychiatric ailments. The problem of sudden death in epileptic patients is one that must be confronted. Sudden death has most frequently been attributed to autonomic dysfunction and cardiac arrhythmia in these patients. The contribution of stress in sudden death production also must be taken into account. In addition, some psychoactive agents have been associated with sudden death as well as cardiac arrhythmia and seizure production. Thus, in light of the possible additivity of the factors involved in the production of sudden death, the administration of a psychoactive agent to an epileptic patient should be approached with caution. Those agents that do not alter cardiac rhythm or seizure threshold should be administered if a psychoactive agent is deemed necessary for the management of psychiatric illness in the epileptic patient.     

Susceptibility of spore-forming butyric acid bacteria to antimicrobial agents

Antimicrobial agents occasionally cause certain adverse effects, such as diarrhea and loose stool, by altering the composition of the intestinal flora. Antibiotic-resistant lactic acid bacteria are used to prevent these adverse effects. Although these bacteria are not resistant to several recently introduced antimicrobial agents, bacterial preparations are still sometimes prescribed concomitantly with these antimicrobial agents. In this study, we investigated whether the administration of the spore-forming butyric acid bacteria Clostridium butyricum improves the adverse clinical effects by preventing diarrhea. Inhibition of C. butyricum growth was observed with 17 of the 20 antimicrobial agents used. However, dilution of 11 of these 17 agents resulted in the regrowth of C. butyricum. These results suggest that C. butyricum may survive exposure to several antibiotic agents by forming spores. Further, a decrease in the antimicrobial agent concentration in the gastrointestinal tract permits the vegetative growth of C. butyricum, which functions as a probiotic.     

生物技术药物治疗系统性红斑狼疮的研究进展

系统性红斑狼疮是一种侵犯身体多脏器的典型的自体免疫疾病,对人体危害极大。严重肾脏受累的系统性红斑狼疮患者如果不给予适当治疗会进展到末期肾病,甚至死亡。系统性红斑狼疮的治疗是现今研究关注的热点。现有的激素治疗由于副作用以及对病程恶化无显著改善而限制了其临床应用。生物技术药物因其良好的靶向性为治疗系统性红斑狼疮提供了新的思路,其安全性和有效性已在临床试验中证明。本文对生物技术药物用于治疗系统性红斑狼疮的研究作一综述。     

Preventive and therapeutic approaches to viral agents of bioterrorism

Certain viruses, such as those that cause smallpox and hemorrhagic fevers, have been identified as possible bioterrorism agents by the Centers for Disease Control and Prevention. They have been designated as potential threats because large quantities can be propagated in cell culture, they are transmissible as aerosols and, for the most part, there are only limited vaccine and pharmaceutical strategies for either prevention or treatment of established infection. An additional concern is the potential to genetically modify these agents to enhance virulence or promote resistance to vaccines or identified antivirals. Although the major impact of these agents is human illness, the release of zoonotic agents, such as the Nipah virus, would have consequences for both humans and animals because infected and noninfected animals might need to be sacrificed to control the spread of infection. Continued research is necessary to develop effective strategies to limit the impact of these biological threats.