Recent progress in cancer therapy with radiolabeled monoclonal antibodies

"Progress in the use of RAIT for cancer therapy has been slow but steady, involving the reengineerin1g of antibodies (reducing murine component, altering size and clearance properties), and pretargeting methods for improvving tumor:blood and tumor:organ ratios are continuing to evolve".     

治疗性抗体的基础研究

抗体的靶向性提供了一个改进治疗制剂选择性的方法 .由于大部分抗原均可诱生抗体 ,因此抗体应用的潜力是巨大的 .临床上正用于治疗肿瘤 ,病毒感染 ,自身免疫病 ,中毒性休克 ,再狭窄 ,Rh溶血症和抗移植排斥等 .但单克隆抗体的临床应用受一定限制 ,主要障碍是诱导产生人抗鼠抗体(HAMA反应 ) ,肿瘤参入量低 ,亲和力低和半衰期短等 .然而 ,利用分子生物学技术能克服这些障碍 ,改善临床效果     

Therapy with monoclonal antibodies

Monoclonal antibodies (MABs) are an exciting development in the field of clinical immunology. Secreted in large amounts from hybrid myeloma (hybridoma) cell lines, MABs are directed at a specific antigen, such as tumor cell antigens, providing a major advantage over conventional, heterogeneous antisera. MABs have shown promise in the treatment of cancer, producing remission in some patients with leukemia and lymphoma. The future uses of MABs are enormous, including passive immunization against infections and allergies, treatment of autoimmune disease, and specific antibody treatment of drug intoxications. The impact of MAB technology on clinical medicine will be felt in the years to come.     

Bone marrow stem cell therapy for myocardial angiogenesis

Despite the recent advances in medical therapy and coronary revascularization procedures, coronary artery disease (CAD) remains the major cause of morbidity and mortality in the developing countries. In patients with severe CAD, persistent myocardial ischemia in hibernated myocardium resulted in progressive loss of cardiomyocytes with development of heart failure. As a result, therapeutic approaches to enhance neovascularization are being underwent intensive investigation. Recent experimental studies have demonstrated adult bone marrow (BM) can induce neovascularization in ischemic myocardium can improve heart function. These findings have prompted the development of different cellular transplantation approaches for heart diseases refractory to conventional therapy after myocardial infarction. Although the initial pilot clinical trials have shown potential clinical benefit of BM therapy for therapeutic angiogenesis, the long-term safety, the optimal timing and treatment strategy remains unclear. Furthermore, in order to acquire more optimized quality and quantity of BM derived stem cell for myocardial regeneration, several issues remain to be addressed, such as the development of a more efficient method of stem cells identification, purification and expansion. Emerging, rationally designed, randomized clinical trials are required to assess the clinical implication of BM derived stem cells therapy in treatment of CAD.     

单克隆抗体在疾病治疗中的应用

单克隆抗体(单抗)技术与分子生物学技术的结合使重组嵌合抗体、人源化抗体和全人抗体的技术得到迅速发展.由于这些单抗带有人抗体的Fc片段,因此,这些抗体不仅能中和抗原,更重要的是能介导细胞毒作用和激活补体系统.这些抗体已被用于治疗某些疾病,如癌症、免疫性疾病、感染性疾病和器官移植排斥.随着大规模CHO细胞生产工艺的发展,越来越多的单抗将应用于临床.     

单克隆抗体在疾病治疗中的应用

单克隆抗体(单抗)技术与分子生物学技术的结合使重组嵌合抗体、人源化抗体和全人抗体的技术得到迅速发展.由于这些单抗带有人抗体的Fc片段,因此,这些抗体不仅能中和抗原,更重要的是能介导细胞毒作用和激活补体系统.这些抗体已被用于治疗某些疾病,如癌症、免疫性疾病、感染性疾病和器官移植排斥.随着大规模CHO细胞生产工艺的发展,越来越多的单抗将应用于临床.     

Application of monoclonal antibodies as cancer therapy in solid tumors

Monoclonal antibodies have become an important new class of therapeutic agents approved for use in solid tumors. They function through several different mechanisms including inhibition of tumor-related signal transduction, induction of apoptosis, inhibition of angiogenesis, enhancing host immune response against cancer and targeted delivery of cytotoxic agents to the tumor site. Several monoclonal antibodies have now received regulatory approval--trastuzumab, cetuximab, panitumumab, bevacizumab, catumaxomab, ipilimumab and denosumab--across multiple solid tumor types, including breast, colorectal, head and neck, non-small cell lung cancers and melanomas, amongst others. These agents are employed clinically in some neoadjuvant/adjuvant and radical treatment settings, as well as more extensively in the metastatic and palliative settings. Current research is focused on innovative compound design, novel targets, predictive biomarker discovery, enriched patient populations, and combination strategies in order to overcome resistance and prolong disease control. Here we provide an overview of monoclonal antibodies approved for use in clinical oncology and those currently in clinical development.     

Bone marrow transplantation

Since the 1970s major progress in bone marrow transplantation has resulted in long-term survival and even cure for many patients with serious hematologic disease. Many patients undergoing the procedure, however, experience serious complications, including graft rejection, graft-versus-host disease, and infection. Preventing or treating these complications with drugs or other forms of immunotherapy is effective in many, but not all, patients.     

Cripto monoclonal antibodies

The success of molecular target-based cancer therapy exampled by Herceptin targeting Her2 indicates that cancer immunotherapy involves identifying and targeting key molecular drivers of cancer. Recently, the human Cripto, a founding member of the epidermal growth factor-Cripto-FRL1-Cryptic (EGF-CFC) protein family has been demonstrated to be a unique molecule and could be targeted by anti-Cripto monoclonal antibodies for the treatment of cancer. Cripto plays an important role in embryonic development, tumorigenesis, cancer cell proliferation and survival. Cripto is upregulated in most epithelial cancers but is absent or weakly expressed in normal cells. Cripto expression is associated with tumorigenesis and invasion. Cripto is also involved in tumor metastasis, which is strongly supported by the recent discovery that the phenotypic changes of increased motility and invasiveness of cancer cells are reminiscent of the epithelial mesenchymal transition (EMT) that occurs during embryonic development. In this review, we emphasize that the EGF-like region of Cripto plays a critical role in Cripto signaling-mediated tumor growth and EMT. Therefore the EGF-like region should be regarded as a therapeutic point for monoclonal antibody (MAb) intervention. The mechanisms of action of these MAbs to the EGF-like region of Cripto are most likely through intervention of c-Src signaling. The CFC region of Cripto is another region to be targeted for treatment of cancer, as the Cripto can bind to activin B through the CFC region to stimulate cell proliferation. The MAbs to the CFC region block the binding of Cripto and activin B and result in an inhibition of cell growth. Therefore the MAbs to Cripto may be of value in the treatment of various cancers.     

Understanding monoclonal antibodies

Elsewhere in this issue, we review new treatments for neovascular age-related macular degeneration, of which, bevacizumab and ranibizumab are monoclonal antibodies. These are two of a growing number of monoclonal antibodies currently available for therapeutic use in the UK. We have reviewed some of the others before: bevacizumab and cetuximab for colorectal cancer; infliximab for rheumatoid arthritis; omalizumab for severe asthma; and trastuzumab for breast cancer. The expanding range of these products and their clinical applications can make it difficult to keep abreast of developments in this field. With this in mind, we describe the key principles underlying the production, use and naming of monoclonal antibodies.     

Bone marrow granulomas possibly associated with amiodarone

Amiodarone is a class III antiarrhythmic agent that is effective in treating different types of cardiac dysrhythmias. It was approved only for treatment of life-threatening ventricular dysrhythmias refractory to other therapy; however, its use for atrial dysrhythmias such as atrial fibrillation is well accepted. Adverse effects associated with amiodarone include pulmonary, hepatic, thyroid, ocular, and neurologic toxicities. Our patient experienced intermittent fever, night sweats, and fatigue while taking the drug for treatment of atrial fibrillation. Bone marrow biopsy showed granuloma formation after 17 months of therapy with amiodarone. Amiodarone was discontinued due to significant hypotension and shortness of breath. To our knowledge, this is the third case report of granuloma formation in bone marrow possibly associated with this agent.     

Radiolabelled peptides and monoclonal antibodies for therapy decision making in inflammatory diseases

Radiolabelled peptides and monoclonal antibodies are an emerging class of radiopharmaceuticals for imaging inflammation with clinical implications for several chronic inflammatory disorders for diagnosis, therapy decision making and follow up. In the last decades, a number of novel monoclonal antibodies and peptides have been introduced for the treatment of different inflammatory disorders and also labelled with a variety of radionuclides depending upon the specific applications, diagnostic or therapeutic, by using direct or indirect methods. These radiopharmaceuticals bind to their targets with high affinity and specificity and therefore have an excellent diagnostic potential for the imaging of patients with chronic inflammatory diseases. In this review article we describe the characteristics of peptides, cytokines and monoclonal antibodies with a particular emphasis on their role in therapy decision making and follow up in different inflammatory diseases.     

抗伸展的乙酰胆碱酯酶的单克隆抗体

用还原并烷基化的伸展的电鳐电器官乙酰胆碱酯酶(RA·AChE)为抗原,免疫BALB/c小鼠,经2次基础免疫及3次加强免疫注射后,取脾脏细胞与SP2/0 Ag 14小鼠骨髓瘤细胞,在PEG 1000作用下融合,经克隆筛选,获5个分泌抗RA-AChE单克隆抗体的杂交癌细胞系,细胞培养上清液滴度可达1:10~3,细胞注射同系小鼠制备的腹水抗体,滴度达1:10~5～10~6,表位分析提示5个单克隆抗体分别作用于AChE上的3个抗原决定簇,ELISA测定表明它们与RA-AChE及天然AChE均有较强的抗原抗体反应,但对天然AChE的催化活性无明显抑制作用。     

Heterogeneity of monoclonal antibodies

Heterogeneity of monoclonal antibodies is common due to the various modifications introduced over the lifespan of the molecules from the point of synthesis to the point of complete clearance from the subjects. The vast number of modifications presents great challenge to the thorough characterization of the molecules. This article reviews the current knowledge of enzymatic and nonenzymatic modifications of monoclonal antibodies including the common ones such as incomplete disulfide bond formation, glycosylation, N-terminal pyroglutamine cyclization, C-terminal lysine processing, deamidation, isomerization, and oxidation, and less common ones such as modification of the N-terminal amino acids by maleuric acid and amidation of the C-terminal amino acid. In addition, noncovalent associations with other molecules, conformational diversity and aggregation of monoclonal antibodies are also discussed. Through a complete understanding of the heterogeneity of monoclonal antibodies, strategies can be employed to better identify the potential modifications and thoroughly characterize the molecules.