ANTITUMOR CATALYTIC ANTIBODIES

化疗是临床治疗肺癌的有力武器 癌症。不幸的是，大多数抗肿瘤药物都与 严重的副作用，如严重的胃肠道和骨骼 骨髓毒性。这一特点在很大程度上是由于 这些剧毒药物对靶标缺乏选择性 肿瘤细胞高于正常细胞。因此，这两款车的设计 靶向药物或有效的药物输送载体对于 推进癌症化疗。这项提案旨在开发一种 新的通用战略，用于现场特定的交付 抗肿瘤疗法将依赖于设计和 靶向催化抗体(CAB)的优化 抗肿瘤药物氨基甲酸酯前药的特异性释放。首字母 模型研究将集中在油井的交付上 表征的抗肿瘤药物5-氟尿嘧啶(FUDR)和 阿糖胞苷(Ara-C)。在这些过程中开发的方法 调查将适用于未来的交付 现有的和未来的化疗药物。这样做的目的是 建议包括： L。设计合成：a)芳香族氨基酸氨基甲酸酯 Fudr和Ara-C的前药物，以及b)磷孢酰胺半抗原 产生的驾驶室将激活芳香族氨基酸氨基甲酸酯 Fudr和Ara-C的前体药物 2.制备噬菌体融合蛋白：a)小鼠抗体 来自用磷酰胺半抗原免疫的小鼠的文库，和b) 来自幼稚外周B淋巴细胞的人抗体库。 3.通过以下步骤从抗体噬菌体文库中产生抗体抗体：a) 用显色琼脂平板法鉴定活性催化剂， B)CAB的细菌表达，以及c)动力学 鉴定纯化后的出租车的功效。 4.构建可结合的双特异性催化抗体 人癌组织转铁蛋白受体的表面展示 体外培养。 5.评价双特异性催化抗体在小鼠体内的表达能力 与氨基甲酸酯类前体药物FUDR或Ara-C联合抑制 人癌细胞在体外生长的表面表现出 转铁蛋白受体。

Chemotherapy is a potent weapon in the clinical treatment of cancer. Unfortunately, most antitumor agents are associated with serious side effects such as severe gastrointestinal and bone marrow toxicity. This characteristic is due in large part to the lack of selectivity of these highly toxic drugs for the target tumor cells over normal cells. Therefore, the design of either targeted drugs or effective drug delivery vehicles is crucial to advancing cancer chemotherapy. This proposal seeks to develop a novel and general strategy for the site-specific delivery of antineoplastic therapeutics that will rely on the design and optimization of targeted catalytic antibodies (CAbs) for the site- specific release of carbamate prodrugs of antitumor agents. Initial model studies will concentrate on the delivery of the well characterized antineoplastic agents 5-fluorouridine (FUDR) and cytosine arabanoside (ara-C). Methods developed during these investigations will be applicable for the future delivery of existing and future chemotherapeutics. The objectives of this proposal are: l. To design and synthesize: a) aromatic amino acid carbamate prodrugs of FUDR and ara-C, and b) phosporamidate haptens capable of generating CAbs that will activate aromatic amino acid carbamate prodrugs of FUDR and ara-C. 2. To generate as bacteriophage fusion proteins: a) murine antibody libraries from mice immunized with phosphoramidate haptens, and b) human antibody libraries from naive peripheral B-lymphocytes. 3. To generate CAbs from an antibody bacteriophage library by: a) identifying active catalysts with a chromogenic agar plate assay, b) the bacterial expression of CAbs, and c) kinetically characterizing the efficacy of the purified CAbs. 4. To construct bispecific catalytic antibodies capable of binding the surface displayed transferrin receptor of human carcinomas in vitro. 5. To evaluate the ability of bispecific catalytic antibodies in combination with carbamate prodrugs of FUDR or ara-C to inhibit the growth of human carcinomas in vitro that surface display the transferrin receptor.