IMMUNOTOXIN AND RECOMBINANT TOXIN THERAPY OF CANCER

为了治疗人类癌症，我们开发了一种免疫毒素， 命名为LMB-1，其中单抗B3偶联到LysPE38。LMB-1已被 已获FDA批准，准备进入临床试验。一秒钟 产生的重组免疫毒素LMB-7结合了可变区 B3抗体与PE38结合。这种制剂对携带人类的小鼠非常有效。 肿瘤异种移植，猴子耐受性良好。这些努力正在进行中。 为临床使用准备材料。PE的变异形式已经被创造出来 可以被聚乙二醇选择性地衍生化以还原 免疫原性，增加血液中的存活率。其中的几个 突变将被亚克隆到LMB-7中，看看这个重组 免疫毒素保持活性，免疫原性较低。此外，我们还有 开始确定LMB-7的主要免疫原性表位。一种螯合物 已经制备了B3抗体，当用111In标记时将 对小鼠的肿瘤进行成像。一种临床级放射结合物目前正在研制中 准备好了。针对IL2受体的单链免疫毒素已经被 制造并证明可导致荷瘤1L2的肿瘤完全消退 小鼠体内的受体。其中一种，抗Tac(FV)-PE38正在准备中 临床发展。一种与正常人的抗原发生反应的新抗体 前列腺癌和前列腺癌已经出现。该抗体是一种 免疫球蛋白和可变区已经被克隆并移植到人身上 IgG1恒定区。这种抗体在治疗中的可能用途 或者前列腺癌的诊断正在接受检查。其他免疫毒素 针对EGF受体，erbB2蛋白，IL6受体， 白介素4受体也在开发中。我们之前已经提出过 一个37kD的PE片段(aa280-613)转位到胞浆中 通过内质网中的小孔。使用无手机系统 含有微粒的，PE(280-)之间相互作用的直接证据 613)，获得了具有微体蛋白转运孔的蛋白质。

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.