IMMUNOTOXIN AND RECOMBINANT TOXIN THERAPY OF CANCER

癌症的免疫毒素和重组毒素疗法

• 批准号: 3774342
• 负责人: I PASTAN
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3774342
• 关键词: cell free system; cytokine receptors; drug design /synthesis /production; epidermal growth factor; epitope mapping; exotoxins; growth factor receptors; human tissue; immunoconjugates; immunoglobulin G; immunoglobulin M; immunological substance; indium; interleukin 2; laboratory mouse; microsomes; mutant; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; protein transport; radiotracer; recombinant DNA; recombinant proteins; tumor antigens

For the treatment of human cancer, we have developed an immunotoxin, termed LMB-1, in which monoclonal B3 is coupled to LysPE38. LMB-1 has been approved by the FDA and is ready to enter clinical trials. A second generation recombinant immunotoxin, LMB-7, combines the variable region of the B3 antibody with PE38. This agent is very active in mice bearing human tumor xenografts, and is well tolerated by monkeys. Efforts are underway to prepare material for clinical use. Mutant forms of PE have been created which can be selectively derivatized by polyethylene glycol to reduce immunogenicity and increase survival in the blood. Several of these mutations will be subcloned into LMB-7 to see if this recombinant immunotoxin retains activity and is less immunogenic. In addition, we have begun to identify the principle immunogenic epitopes in LMB-7. A chelate of the B3 antibody has been prepared and when labeled with 111In will image tumors in mice. A clinical grade radioconjugate is currently being prepared. Single chain immunotoxins directed at the IL2 receptor have been made and shown to cause complete regression of tumors bearing 1L2 receptors in mice. One of these, anti-Tac(Fv)-PE38, is being prepared for clinical development. A new antibody that reacts with an antigen on normal prostate and prostate carcinomas has been developed. The antibody is an IgM and the variable regions have been cloned and grafted onto a human IgG1 constant region. The possible usefulness of this antibody for therapy or diagnosis of prostate cancer is being examined. Other immunotoxins directed against the EGF receptor, the erbB2 protein, the IL6 receptor, and the IL4 receptor are also being developed. We have previously proposed that a 37 kD fragment of PE (aa 280-613) translocates to the cytosol through pores in the endoplasmic reticulum. Using a cell-free system containing microsomes, direct evidence for an interaction between PE (280- 613) with microsomal protein transport pores has been obtained.

为了治疗人类癌症，我们开发了一种免疫毒素， 称为LMB-1，其中单克隆B3与LysPE 38偶联。LMB-1已经 已获得FDA批准，并准备进入临床试验。第二 第二代重组免疫毒素LMB-7结合了 B3抗体与PE38。该制剂在携带人类的小鼠中非常活跃。 肿瘤异种移植物，并且被猴子良好耐受。正在努力 准备临床使用的材料。PE的突变形式已经产生 其可以被聚乙二醇选择性地衍生化， 免疫原性并增加血液中的存活率。几个这样 突变将被亚克隆到LMB-7中，看看这个重组体是否 免疫毒素保留活性且免疫原性较低。另外我们有 开始鉴定LMB-7中的主要免疫原性表位。螯合物 的B3抗体已经制备，当用111 In标记时， 小鼠肿瘤成像。目前正在研制一种临床级放射性结合物， 制备针对IL 2受体的单链免疫毒素已经被发现， 制备并显示可导致携带1L2的肿瘤完全消退 小鼠的受体。其中之一，抗Tac（Fv）-PE38，正在制备用于 临床发展。一种新的抗体，与正常人的抗原反应， 已经发展出前列腺和前列腺癌。述抗体是 IgM和可变区已经被克隆并移植到人类 IgG1恒定区。这种抗体用于治疗的可能用途 或诊断为前列腺癌正在接受检查。其他免疫毒素 针对EGF受体、erbB2蛋白、IL 6受体， 和白细胞介素4受体也在开发中。我们之前提出 一个37kD的PE片段（aa 280 - 613）易位到胞质溶胶中 通过内质网中的小孔使用无细胞系统 含有微粒体，PE（280- 613)具有微粒体蛋白质转运孔。