Novel Therapy for Hepatocellular Carcinoma

描述（由申请人提供）： 肝细胞癌（HCC）是世界上最常见和最致命的恶性肿瘤之一，目前尚无有效的治疗方法。由于肝脏的正常功能是解毒外源性物质，这种组织的癌症对化疗有着众所周知的抵抗力。此外，大多数患者不耐受由于基础肝病（即肝硬化、HBV、HCV感染等）而可能有效的治疗。为了克服这些局限性，我们建议开发一种针对临床验证的HCC靶点的基于抗体的生物药物。与常规方法相比，该疗法是a）肿瘤特异性的（正常组织的有限损伤），和B）对肝细胞解毒机制不敏感。 该项目的总体目标是开发一种新的治疗肝细胞癌（HCC）的方法。来自中国的令人信服的数据支持HEPAMA-1（一种131 I标记的鼠HCC特异性单克隆抗体）的开发。由我们上海生物化学与细胞生物学研究所的合作者进行的II期研究（>100例患者）表明，与传统化疗药物相比，这种治疗的接受者具有显著的生存优势，副作用最小。PRI独家授权了这项技术，并打算在中国境外开发一个改进的版本。这项资助的目的是支持这种新型和重要疗法的优化形式的临床前开发。为此，在第一阶段，我们将人源化抗体并鉴定靶抗原，然后确认高亲和力HCC特异性结合。接下来，我们将生产重组人源化抗体，优化碘化，并进行QC和稳定性研究。在第二阶段，我们将研究131-L标记的抗体在肝癌异种移植模型中的抗肿瘤活性。II期的最终目标将是提交IND并启动改进的、经验证的抗HCC抗体的I/II期人类临床研究。根据以前的人类研究， 抗体似乎是一个有前途的新的治疗肝癌。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is among the world's most common and lethal malignancies with no effective therapy. Because of the normal function of the liver to detoxify xenobiotics, cancers of this tissue are notoriously resistant to chemotherapy. Furthermore, most patients do not tolerate therapies that might otherwise be effective due to underlying liver disease (i.e. cirrhosis, HBV, HCV infections etc.) To overcome these limitations, we propose to develop an antibody-based biopharmaceutical against a clinically validated HCC target. In contrast to conventional approaches, this therapy is a) tumor-specific (limited damage of normal tissue), and b) not susceptible to mechanisms of hepatocyte detoxification. The overall goal of this project is to develop a novel therapy for hepatocellular carcinoma (HCC). Compelling data from China support the development of HEPAMA-1, a 131I-labeled murine HCC-specific monoclonal antibody. Phase II studies (>100 patients) carried out by our collaborators from the Shanghai Institute of Biochemistry and Cell Biology indicate significant survival advantage among recipients of this therapy with minimal adverse effects, in contrast to conventional chemotherapeutic drugs. PRI exclusively licensed this technology with the intention to develop an improved version outside of China. The purpose of this grant is to support the preclinical development of an optimized form of this novel and important therapy. To this end, in Phase I we will humanize the antibody and identify the target antigen, then confirm high affinity HCC specific binding. Next we will produce a recombinant humanized antibody, optimize iodination, and carry out QC and stability studies. In phase II, we will study the anti-tumor activity of the 131-l-labeled antibody in xenograft models of HCC. The final goal of phase II will be to submit an IND and initiate phase l/ll human clinical studies of the improved, validated anti-HCC antibody. Based on the previous human studies, this antibody appears to be a promising novel therapy for HCC.