双特异性单克隆抗体在乳腺癌免疫治疗中的研究进展

免疫治疗作为乳腺癌的辅助治疗方法近年来已取得很大进展，作为免疫治疗新方法，双特异性单克隆抗体以其优势为治疗乳腺癌开辟了新领域。由于其含有两个能与不同抗原决定簇特异性结合的单克隆抗体片段，它可以同时结合肿瘤细胞相关抗原和血循环中免疫效应细胞的受体，因而能将循环血液中的免疫效应细胞引至肿瘤组织，并诱导免疫效应细胞产生抗肿瘤活性，杀伤肿瘤细胞。     

双特异性抗体在肿瘤免疫治疗中的应用

双特异性抗体能够同时识别肿瘤靶细胞和免疫效应细胞，因此兼有抗体特异性和介导效应细胞的细胞毒作用的双重功能。可以用化学偶联，二次杂交瘤技术和基因工程方法得到双特异性抗体。双特异性抗体能将效应细胞聚集于肿瘤部位并激活效应细胞发挥抗肿瘤作用，其杀伤肿瘤细胞的作用机理包括细胞增殖，细胞因子释放，细胞毒性多肽和酶的调控。     

肿瘤抗原特异性主动免疫治疗研究进展

近年来，肿瘤免疫治疗领域中有关细胞抗原的理论为肿瘤的特异性主动免疫治疗研究带来了新的活力。现已发现肿瘤细胞表面粘蛋白的糖发生了改变，暴露出蛋白质核心部位。在上皮来源的肿瘤中，粘蛋白往往呈过度表达状态，因而可能成为免疫治疗的靶分子。由Ｈｅｒ２／ｎｅｕ原癌基因编码的Ｈｅｒ－２／ｎｅｕ蛋白在许多人类肿瘤细胞中过度表达，这种过度表达与肿瘤的形成及浸润有关。哺乳动物肿瘤中ｒａｓ基因突米发生率较高，针对各种不     

双特异性单克隆抗体在肿瘤治疗中的应用

双特异性单克隆抗体(BsMAh)是含有两个不同配体结合位点的免疫球蛋白分子，在疾病的诊断治疗上具有较大临床应用潜力，特别在肿瘤治疗方面，有其不容忽视的优越性。现综述近年来BsMAh在肿瘤治疗中的研究及应用进展。同时，对其人源化进程也进行了概述。     

乳腺癌免疫治疗的研究进展

免疫治疗是继手术、放射治疗、化疗、内分泌治疗等之后的乳腺癌重要治疗手段。近年来,随着免疫学的不断发展,乳腺癌的免疫治疗取得了很大的进步,并日益受到临床医师的重视。笔者简述了针对乳腺癌治疗相关靶点的治疗性疫苗,如免疫检查点相关疫苗、特异性抗原疫苗、细胞疫苗、病毒载体疫苗和双特异性抗体疫苗等,同时,还介绍了近年来针对乳腺癌的预防性疫苗,这将有利于临床医师进一步了解乳腺癌免疫治疗的现状与进展。     

乳腺癌的免疫治疗—细胞特异性免疫治疗的回顾

自传染病疫苗首次问世后,人们便开始寻找防治恶性肿瘤的特异性疫苗。近几十年来研究的方法和取得的成果差异甚大,但共同追求的目标始终如一。本文回顾了乳腺癌免疫治疗的历史,对已从设想进入实际的细胞特异性疫苗加以概述,并简单地介绍一下当前的研究趋势、进行的项目以及存在的问题。历史回顾免疫学治疗的历史可追溯到19世纪末20世纪初Herieourt,Von Leydon,Contamin等人的早期工作。有关特异性自主免疫治疗病     

乳腺癌的免疫治疗

随着生活水平的提高和饮食习惯的西化,中国女性罹患乳腺癌的比例逐渐增加,病死率亦逐步上升.同时,随着生物科学技术的发展,乳腺癌的治疗除了规范的手术治疗、化疗、放射治疗及内分泌治疗外,也逐渐延伸到免疫治疗,并且有多项药物已进入临床实验阶段.研究表明,乳腺癌患者的机体免疫反应处于抑制状态,一方面是患者体内免疫共刺激因子、细胞毒性T细胞相关抗原及辅助T细胞不足,另一方面是肿瘤细胞产生的可溶性免疫抑制分子滴度相对提高,使得免疫治疗易于耐受.     

双特异性抗体治疗恶性肿瘤的研究进展

双特异性抗体(BsAb)，一方面结合免疫效应细胞上的激活分子或偶联毒素，另一方面利用抗体的特异性与肿瘤相关抗原(TAA)结合。通过双结合，激活效应细胞如细胞毒性T细胞和NK细胞，或通过免疫毒素发挥靶向抗肿瘤效应，是一种很有潜力的恶性肿瘤免疫治疗方式。本文对双特异性抗体的构建方法、作用机制及其相关研究加以概述。     

双特异性单克隆抗体在肿瘤治疗中的应用

双特异性单克隆抗体(BsMAb)是含有两个不同配体结合位点的免疫球蛋白分子,在疾病的诊断治疗上具有较大临床应用潜力,特别在肿瘤治疗方面,有其不容忽视的优越性.现综述近年来BsMAb在肿瘤治疗中的研究及应用进展.同时,对其人源化进程也进行了概述.     

肿瘤主动特异性免疫治疗的进展

免疫学、肿瘤免疫学理论的进展与生物技术的发展为肿瘤主动特异性免疫治疗(ASI)奠定了科学的基础,使之走出低谷,形成高潮,展示出良好的前景一、人类肿瘤抗原的确立及抗原提呈、免疫识别理论的突破肿瘤抗原:细胞癌变过程中出现的新抗原(neoantigen)物质的总称,肿瘤特异性抗原(TSA):久经争论的肿瘤免疫学的一个中心问题.TSTA的存在早在动物肿瘤中获得证实,TSTA诱发的特异性肿瘤排斥反应由T细胞介导,但TSTA的本质长期未能阐明,人类肿瘤抗原尤其是TSA是否存在过去也久悬未决.(一)人类肿瘤抗原的确立     

单克隆抗体Denosumab治疗乳腺癌的研究进展

目的:总结Denosumab在乳腺癌相关治疗领域的应用研究进展。方法:应用PUBMED和CNKI期刊全文数据库检索系统,以"Denosumab,RANKL,乳腺肿瘤,骨质疏松,骨转移癌"等为关键词,检索2004-2010的相关文献.共检索到英文文献117篇,中文文献2篇,通过查找全文,排除重复研究及与本研究无关的文献,符合条件的21篇文献纳入分析。结果:单克隆抗体Denosumab靶向细胞核因子κB受体活化因子配基(receptor activator of nuclear factor-κB ligand,RANKL),可以特异性地阻断破骨细胞生成及存活,在治疗骨质疏松症及代谢性骨病中表现良好。近年关于Denosumab在乳腺癌治疗领域中的初步研究显示,Denosumab对于改善骨密度及骨质代谢标志等方面,有快速、特异和持久的治疗作用;且未发生治疗相关的严重不良反应。结论:Denosumab对乳腺癌引发骨质破坏确有一定作用,但其长期随访结果以及与常规乳腺癌治疗手段的联合应用价值,仍有待进一步研究。     

Characterisation of a humanised bispecific monoclonal antibody for cancer therapy.

A humanised bispecific monoclonal antibody (bsMAb) with binding specificity for carcinoembryonic antigen (CEA) on one arm and a radiolabelled chelate (DTPA-90Y) on the other arm was generated by consecutively transfecting the humanised genes of an anti-CEA MAb and the chimerised genes of an anti-chelate MAb into eucaryotic BHK cells using the calcium-phosphate coprecipitation technique. The antibodies secreted were of IgG3 isotype with a shortened hinge region (delta gamma 3) and light chains. Double transfectomas were screened for the secretion of bsMAbs using a double determinant enzyme-linked immunosorbent assay (ELISA) based on solid phase attached HSA-benzyl-DTPA and an anti-idiotypic MAb selective for the CEA-specific arm. After purification on two immunoaffinity chromatography columns, the humanised bsMAbs were characterised by SDS-PAGE and a quantitative binding assay in antigen excess. The purification procedure resulted in 95% reactive bispecific MAb. This humanised bsMAb may be employed in two phase radioimmunotherapy, binding to the tumour via the anti-CEA arm and localising a radiolabelled chelate with the other arm, without inducing a strong immune response observed sometimes with murine MAbs.     

Phagocytosis of breast cancer cells mediated by anti-MUC-1 monoclonal antibody, DF3, and its bispecific antibody

Human epithelial mucin, MUC-1, is commonly expressed in adenocarcinoma including 80% of breast cancers. erbB-2 is overexpressed in approximately 30% of breast cancers. Expression of MUC-1 and erbB-2 may be partially overlapping but discoordinate. Therefore, combined use of antibodies directed against these two antigens might increase the number of patients who benefit from immunotherapy. Monoclonal antibody (MAb) DF3 recognizes the MUC-1 tandem repeat. We investigated phagocytosis and cytolysis of cultured human breast cancer cells by monocyte-derived macrophages mediated by MAb DF3 and its bispecific antibody (BsAb) DF3xH22 with the second epitope directed against the Fc component of phagocytic cells. Purified monocytes from healthy donors were cultured with granulocyte macrophage colony-stimulating factor with or without IFN-gamma. antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) assays were performed with these macrophages and MUC-1-expressing target cells (ZR75-1) in the presence of MAb DF3 and BsAb DF3xH22. ADCP was measured by two-color fluorescence flow cytometry using PKH2 (green fluorescent dye) and R-phytoerythrin (RPE) (red)-conjugated MAb against human CD14 and CD11b and was confirmed by confocal microscopy. ADCC was measured by (51)Cr release assay. Immunohistochemical staining studies of MUC-1 and erbB-2 were performed on 67 primary breast cancer tissues. Expression of MUC-1 and erbB-2 was partially overlapping but discoordinate in 67 consecutive breast cancers. Both MAb DF3 and BsAb DF3xH22 mediated ADCP. However, ADCP mediated by MAb DF3 was greater than that mediated by BsAb DF3xH22. ADCC as detected by (51)Cr release was not seen with either antibody. The addition of IFN-gamma to monocyte-derived macrophage cultures inhibited ADCP compared to granulocyte macrophage colony-stimulating factor alone. Given the partially overlapping but discoordinate expression of MUC-1 and erbB-2 in breast cancer, therapy directed toward both antigens should be considered. MAb DF3 and the BsAb DF3xH22, can effectively mediate phagocytosis of MUC-1-expressing target cells. Further investigations are needed to determine whether this antibody-induced phagocytosis results in long-term specific T-cell activation against MUC-1.     

中国乳腺癌免疫治疗转化研究进展

乳腺癌作为全球女性发病率最高的癌症,虽然辅助化疗、放疗、靶向治疗、内分泌治疗的使用已显著降低了患者的死亡风险,但仍有部分患者尤其是晚期患者无法从现有的治疗手段中获益。随着免疫治疗的不断发展,近年来中国的乳腺癌免疫治疗转化研究从基础到临床,从分子靶点、药物研发到临床试验,均取得了突破性的进展。本文将就中国乳腺癌免疫治疗转化研究中的治疗靶点、预测标志物、治疗手段等进行综述。      

A humanized Anti-c-erbB-2 monoclonal antibody for the treatment of breast cancer

The c-erbB-2 product is thought to be a unique and useful target for antibody therapy of cancers that overexpress the c-erbB-2 gene. Its overexpression is also speculated to be correlated with chemoresistance to doxorubicin. The in vitro and in vivo anti-tumor effects of a humanized antibody directed against the extracellular domain of the c-erbB-2 gene product, rhu4D5, were examined. Rhu4D5 had direct antiproliferative activity against the SK-BR-3 cell line which overexpresses c-erbB-2. The in vivo treatment, using rhu4D5, of SCID mice carrying xenografts of 4-1ST human gastric carcinoma, which overexpresses c-erbB-2, revealed that the recombinant protein had potent anti-tumor activity. Furthermore, the cytotoxic action of human peripheral blood mononuclear cells against the SK-BR-3 cell line was significantly augmented with the administration of rhu4D5, but not with mu4D5. These results indicate that rhu4D5 might be a more efficacious treatment than previously predicted by preclinical studies.     

Perceptions of Herceptin: a monoclonal antibody for the treatment of breast cancer

In September 1998 Trastuzumab (Herceptin) became the second monoclonal antibody approved for the treatment of a malignant condition, and the first antibody approved for the treatment of a solid tumor. It is a mouse-human chimeric antibody that produces anti-tumor effects by blocking the HER2-neu receptor, and can also interact with human immune cells to effect antibody dependent cell-mediated cytotoxicity. Pivotal trials in breast cancer showed that it has activity as a single agent in a subset of patients whose tumors greatly over-express HER2, but results were even more impressive when it was used in combination with chemotherapy. It should also prove to be useful in the treatment of subsets of patients with other adenocarcinomas whose tumors over-express HER2.     

Application of anti-sialyl Lea monoclonal antibody, KM231, for immunotherapy of cancer.

A mouse monoclonal antibody (MoAb), KM231 raised against human gastric cancer was found to recognize sialyl Lea -epitope expressed on glycoprotein and glycolipid with high affinity. KM231 reacted with many human gastrointestinal cancer tissues and could detect the antigen shed in sera of cancer patients. The present study was designed to evaluate competence of KM231 for immunotherapy of cancer. We first confirmed that KM231 could probe the cancer cells in vivo by injecting biotinylated KM231 into nude mice bearing human colorectal carcinoma cell, SW1116. Light- and electron-microscopic examination showed that the MoAb was localized in the tumor tissues and bound to the plasma membrane and cytoplasmic endosomes. Imaging studies with 125I-labeled KM231 revealed specific localization of the antibody in SW1116 tumors transplanted into nude mice. From Scatchard analysis of KM231 binding, the number of KM231 molecules bound to per SW1116 cell was calculated approximately 1.9 x 10(6) and the association constant was 1.3 x 10(8) liter/mol. We made KM231-ricin A chain immunotoxin for evaluating the tumoricidal effect of KM231. The immunotoxin exerted strong cytotoxicity toward sialyl Lea-expressing tumor cells specifically in vitro, but not toward sialyl Lea non-expressing cells. The in vivo tumoricidal effect of the immunotoxin was examined on ascites and subcutaneous xenograft tumors in nude mice. Three intraperitoneal injections of the immunotoxin (1.6 x 10(-6) mol) into nude mice bearing SW1116 ascites tumor resulted in extension of survival by 204% compared with controls. Further, repeated intraperitoneal administration of the immunotoxin (1.4 - 2 x 10(-6) mol) significantly inhibited the growth of established subcutaneous tumor (ratio of tumor inhibition = 0.7 - 0.54). These results indicated that KM231 has the ability to probe sialyl Lea-expressing tumor cells in vivo with high efficiency and to become tumoricidal drug when it conjugated with cytotoxic reagents like ricin A chain.     

肿瘤免疫治疗

肿瘤免疫治疗主要是通过抗原提呈细胞、免疫效应细胞、免疫负性调节通路、肿瘤来源免疫抑制分子等途径发挥作用,对延长肿瘤患者生存时间、提高生活质量有一定疗效.目前已有预防性癌症疫苗问世,同时大量的基础研究取得了令人瞩目的进展,尤其是对免疫监视、黏膜免疫等方面的进一步认识为肿瘤的免疫治疗提供了新的路径.