Clinical translation of immunoliposomes for cancer therapy: recent perspectives

Introduction: Liposomes have been extensively investigated as drug delivery vehicles. Immunoliposomes (ILs) are antibody-conjugated liposomes designed to selectively target antigen-expressing cells. ILs can be used to deliver drugs to tumor cells for improving efficacy and reducing toxicity. In addition, ILs can be used in immunoassays, immunotherapy, and imaging. Although there has been extensive coverage on ILs in the literature, only a limited number of clinical trials have been reported and no IL drug has been approved by the FDA.

Areas covered: Factors to consider in developing ILs are discussed, including the choice of antibody or antibody fragment, the formulation of liposomes, and the conjugation chemistry. In addition, challenges and opportunities in clinical development of ILs are discussed. The purpose of this review is to provide an overview on the state of the art of ILs and to discuss potential future developments.

Expert opinion: IL research has had a lengthy history and numerous preclinical studies have yielded encouraging results. However, there are a number of obstacles to clinical translation of ILs. Given the unique capabilities of ILs, its potential for clinical application is underexplored. There is great potential for expanded role for ILs in the clinic and further efforts to this end are warranted.

Abbreviations: Ab: antibody; ADCs: antibody-drug conjugates; API: active pharmaceutical ingredient; ADCC: antibody-dependent cellular cytotoxicity; CR: complete remission; cGMP: current good manufacturing practice; DSPE: distearoyl phosphatidylethanolamine; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EPR: enhanced permeability and retention; Fc: fragment crystalline; Tf: transferrin; HACA: human-anti-chimeric antibody; HAHA: human-anti-human antibody; HAMA: human-anti-mouse antibody; HER2: human epidermal growth factor 2; IL: immunoliposome; LNPs: lipid nanoparticles; MRI: magnetic resonance imaging; MTD: maximum tolerated dose; PEG: polyethylene glycol; PET: positron emission tomography; PR: partial response; PSMA: prostate-specific membrane antigen; scFv: single-chain variable fragment; SPECT: single photon emission computed tomography; TTR: transthyretin     

Pharmacological treatment options for severe hypertriglyceridemia and familial chylomicronemia syndrome

Introduction: A spectrum of disorders, ranging from rare severe cases of homozygous null lipoprotein lipase deficiency (LPLD)–familial chylomicronemia syndrome (FCS) to heterozygous missense LPLD or polygenic causes, result in hypertriglyceridemia and pancreatitis. The effects of mutations are exacerbated by environmental factors such as diet, pregnancy, and insulin resistance.

Areas covered: In this review, authors discuss chronic treatment of FCS by ultra-low fat diets allied with the use of fibrates, omega-3 fatty acids, niacin, statins, and insulin-sensitizing therapies depending on the extent of residual lipoprotein lipase (LPL) activity; novel therapies in development target triglyceride (TG)-rich lipoprotein particle clearance. Previously, a gene therapy approach to LPL-alipogene tiparvovec showed that direct targeting of LPL function reduced pancreatitis events. An antisense oligonucleotide to apolipoprotein-C3, volanesorsen has been shown to decrease TGs by 70–80% and possibly to reduce rates of pancreatitis admissions. Studies are underway to validate its long-term efficacy and safety. Other approaches investigating the role of LPL modulating proteins such as angiopoietin-like petide-3 (ANGPTL3) are under consideration.

Expert opinion: Current therapeutic options are not sufficient for management of many cases of FCS. The availability of antisense anti-apoC3 therapies and, in the future, ANGPTL3 therapies may remedy this.     

注射用姜黄素脂质体过敏现象的初步研究

目的 比较3种不同粒径注射用姜黄素脂质体（CLI）引起的过敏反应,并判断可能的过敏反应类型。方法 将平均粒径约为70、100、130 nm的CLI （剂量为20 mg/kg,以姜黄素计）分别尾iv给予大鼠,分别于注射前,注射后10 min、7 d,眼眶采血,分离血清,ELISA法检测注射前后血清中过敏相关因子——补体C3a、C3b和C5a,组胺和抗体IgE、IgG、IgM的含量变化。将平均粒径约为100 nm的CLI和抗过敏药地塞米松（预处理2 h,2 mg/kg）联用给予大鼠,观察血清中补体C3a、C5a和组胺的含量变化。结果 给予3种粒径的CLI,血清中补体C3a、C3b、C5a和组胺含量均明显升高,与给药前比较差异具有统计学意义（P<0.01）;血清中抗体IgE、IgG、IgM的含量均无明显变化。预先给予地塞米松,在注射CLI前后C3a和C5a的含量无明显变化,组胺含量极低。结论 3种不同粒径CLI在体内引起的过敏反应一致,且可能是补体激活相关的假性过敏反应。     

实体瘤的单克隆抗体治疗

单克隆抗体是以肿瘤的特异性蛋白为靶点，在肿瘤治疗中具有特异性、有效性、低毒性的特点。单克隆抗体治疗的靶点包括细胞表面抗原和生长因子受体等。单克隆抗体单一治疗和联合化疗、放疗在实体瘤治疗中显示出了很好的疗效，抗体与放射性核素结合的放射免疫性治疗也有明显的疗效。本文通过单抗治疗机制和临床治疗试验两方面介绍了几种单克隆抗体以及抗体的治疗战略。     

荧光蛋白标记的促红细胞生长素融合蛋白的设计和预测

目的：探讨pTRE顺式作用元件调控，EGFP标记hEPO(hEPO-EGFP)融合蛋白设计的合理性。方法：应用Gene Construction Kit2．5、www．expasy．com网站提供的分析方案，分析重组体的开放读框以及融合蛋白的柔性．并作蛋白质二级结构模拟。结果：重组体的转录受pTRE顺式作用元件调控，Linker所在部位柔性高，融合蛋白表达后，二级结构预测Linker不改变蛋白结构，完全符合作者设计EGFP标记hEPO融合蛋白的初衷。结论：重组蛋白设计合理，融合蛋白有很大可能保留了hEPO和EGFP的理化特性，为进一步的实践操作提供了可靠的理论基础。     

过氧化物酶-抗过氧化物酶复合物(PAP)检测血清抗核抗体

目的 探讨过氧化物酶－抗过氧化物酶复合物（PAP）检测血清抗核抗体（ANA）的实用性。方法 以小鼠肝细胞为基质,对PAP方法测定血清ANA的滴度、核型进行了方法学检测,并同时与间接免疫荧光法相比较,测定了203例正常人及46例风湿病患者的血清ANA。结果 PAP法敏感性高于IIF法,滴度是IIF法的10－640倍。PAP可提高血清ANA的阳性检出率,还可提高核型的清晰度。结论 PAP法适用于缺乏荧光显微镜的基层医院开展ANA的检测。     

空肠弯曲菌共同抗原的实验研究及初步应用

用甘氨酸制备空肠弯曲菌酸提取物，能和５２种空肠弯曲菌分型血清发生交叉反应，提示空肠弯曲菌各型间存在共同抗原。ＳＤＳ－ＰＡＧＥ分析，显示该菌共同抗原分子量为３１０００。用其包被建立ＥＬＩＳＡ法检测２０３例腹泻病人血清抗体，与培养法比较，总符合率达９３．６％。     

血清特异性抗体检测方法的探讨及临床意义

目的　探讨适合中国东北地区的特异性抗体的检测方法、阳性标准及临床意义。方法　应用酶联免疫吸附试验 (ELISA)方法检测抗原物质特异性抗体 ,摸索反应条件。按确定的最适条件对中国东北地区 5 8例哮喘病人及4 7例健康对照者血清中特异性抗体进行检测。结果　确定了ELISA方法的最适包被浓度 ,最适反应浓度 ,和反应时间及温度。以OD值≥健康对照组平均OD值的 1 5倍作为阳性标准 ,发现本地区哮喘病人血清中对蒿草花粉、春季花粉、淡水鱼、蒜这 4种抗原物质的特异性抗体阳性率高于正常对照组 (P <0 0 5 )。结论　可以将以上改良的ELISA方法和阳性标准应用于本地区的哮喘病人过敏原的检测。     

A review of antibody-based therapeutics targeting G protein-coupled receptors: an update

ABSTRACT

Introduction

G protein-coupled receptors (GPCRs) play key roles in many biological functions and are linked to many diseases across all therapeutic areas. As such, GPCRs represent a significant opportunity for antibody-based therapeutics.