TUMOR-ACTIVATED ENZYME PRODRUG THERAPY (TACEPT)

肿瘤激活酶前药疗法 (TACEPT)

• 批准号: 6074946
• 负责人: ROBERT F BALINT
• 金额: $ 11.45万
• 依托单位: PANORAMA RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-14 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6074946
• 关键词: antigens; antineoplastics; beta lactamase; biomarker; breast neoplasms; cephalosporins; chimeric proteins; drug design /synthesis /production; enzyme activity; neoplastic cell; ovary neoplasms; prodrugs; protein binding; protein engineering; protein purification; protooncogene; tissue /cell culture

Antibody-directed enzyme prodrug therapy (ADEPT) is a promising anti- cancer chemotherapeutic strategy in which enzymes are concentrated at the tumor site when administered as conjugates of tumor-specific antibodies. After unbound conjugate has cleared from the circulation, prodrugs may be administered which are non-toxic until activated by the tumor-bound enzyme. Beta-lactamase has been used with cephalosporin prodrugs of aniline mustards and anthracyclines to achieve promising anti-tumor effects in animals. The efficacy of ADEPT is limited, however, by the need for unbound conjugate to clear the circulation before the prodrug can be administered, by which time so much of the conjugate has been lost from the tumor that efficacy is compromised. To address this problem we have developed an interaction-dependent fragment complementation system for beta-lactamase. From a library of all possible combinations beta-lactamase fragments, we have isolated fragment pairs which complement to form the active enzyme only when the fragments are fused to proteins which interact with one another directly or via a third molecule. When fused to antibody fragments which recognize non-overlapping epitopes on tumor markers, these fragments should be able to reconstitute sufficient beta- lactamase activity on the tumor cell surface to produce unprecedented levels of tumor-localized cytotoxicity from beta-lactam prodrugs. PROPOSED COMMERCIAL APPLICATIONS: The primary goal of this work is to develop a new and effective strategy for the chemotherapeutic treatment of human cancer.

抗体导向的酶前药疗法(ADEPT)是一种很有前景的抗癌化疗策略，当酶作为肿瘤特异性抗体的偶联物给予肿瘤部位时，酶被集中在肿瘤部位。在游离结合物从循环中清除后，可以使用无毒的前药，直到被肿瘤结合酶激活。β-内酰胺酶已与头孢菌素前体药物、苯胺类芥菜类和蒽环类药物联合使用，在动物身上取得了良好的抗肿瘤效果。然而，ADEPT的疗效受到限制，因为在给药前需要无结合的结合物来清除循环，到那时，肿瘤中已经失去了太多的结合物，以至于疗效受到了影响。为了解决这个问题，我们开发了一种依赖相互作用的β-内酰胺酶片段互补系统。从所有可能的β-内酰胺酶组合片段库中，我们分离出只有当片段与相互直接或通过第三个分子相互作用的蛋白质融合时才能互补形成活性酶的片段对。当与识别肿瘤标记物上非重叠表位的抗体片段融合时，这些片段应该能够在肿瘤细胞表面重建足够的β-内酰胺酶活性，从而从β-内酰胺前药产生前所未有的肿瘤局部细胞毒性。拟议的商业应用：这项工作的主要目标是为人类癌症的化疗开发一种新的有效策略。