Development of SL-101, An Immunotoxin that Targets Cancer Stem Cells

描述（由申请人提供）：肿瘤干细胞（CSCs）领域是肿瘤学中一个迅速崛起和令人兴奋的新领域。csc是一种恶性干细胞，可以产生并生长肿瘤。这些细胞只占肿瘤的一小部分（约0.5%-2%），但却负责整个肿瘤的生长。重要的是，CSCs对标准和靶向化疗具有耐药性，并且被认为是导致治疗失败和复发的原因。人们普遍预计，针对CSCs设计的新化合物将成为下一代肿瘤药物，具有提供持久、无复发反应的潜力。为了强调干细胞的重要性，NCI最近表示，该研究所“已将癌症干细胞确定为癌症研究中最重要的新思想之一……”（《波士顿环球报》2004年12月26日）。每年有10500例AML新病例，70%的患者在接受一线治疗后复发。白血病CSCs对标准化疗的耐药性可能是导致这种治疗失败的主要原因。Stemline Therapeutics的主要药物名为“SL-101”，旨在靶向并根除白血病csc。重要的是，白血病CSCs表达的CD123 （IL3Ra链）水平比正常造血细胞高10倍以上，使CD123成为治疗的理想靶点。SL-101是一种嵌合免疫毒素，由连接假单胞菌外毒素的单克隆抗体的cd123结合域组成，目前正在与美国国家癌症研究所合作开发。SL-101旨在满足白血病治疗的迫切需求，提供持久的缓解。Stemline拥有保护SL-101的独家授权知识产权。这项I期STTR拨款将涵盖SL-101临床前开发的关键阶段。特别的是，本研究旨在与纪念斯隆-凯特琳癌症中心（New York， NY）的Malcolm Moore博士合作，通过体外试验和人类急性白血病的体内模型来开发SL-101。SL-101将在白血病细胞系、原发性人类白血病和白血病CSC样本以及人类急性白血病异种移植模型中测试其作为抗白血病药物的功效。SL-101开发计划旨在通过动物功效来推进SL-101，届时公司预计将申请II期STTR，以资助进一步的IND前工作，包括所需的毒理学、生产和扩大规模，以支持IND申请，为I/II期临床试验做准备。每年有10500例AML新病例，70%的患者在接受一线治疗后复发。白血病干细胞对标准化疗的耐药性是导致治疗失败和复发的主要原因。Stemline Therapeutics公司的主要药物名为“SL-101”，旨在靶向并根除白血病干细胞。SL-101旨在满足白血病治疗的迫切需求，提供持久的缓解。这项I期STTR拨款将涵盖SL-101临床前开发的关键阶段。

DESCRIPTION (provided by applicant): The field of cancer stem cells (CSCs) is a rapidly emerging and exciting new area of oncology. CSCs are malignant stem cells that originate and grow tumors. These cells comprise a small portion (about 0.5%-2%) of a tumor, yet are responsible for the growth of the entire tumor. Importantly, CSCs are resistant to standard and targeted chemotherapy, and are believed to contribute to treatment failure and relapse. It is widely anticipated that new compounds designed to target CSCs will become the next generation of oncology drugs, with the potential to provide durable, relapse-free responses. Emphasizing the importance of CSCs, the NCI recently stated that the Institute "has identified cancer stem cells as 1 of the most important new ideas in cancer research..." (Boston Globe, 12/26/2004). There are 10,500 new cases of AML annually, and 70% of patients experience relapse after first- line therapy. The resistance of leukemia CSCs to standard chemotherapy is likely a major contributor to this treatment failure. Stemline Therapeutics' lead drug, named "SL-101", is designed to target and eradicate leukemia CSCs. Importantly, leukemia CSCs express more than 10-fold higher levels of CD123 (IL3Ra chain) than normal hematopoietic cells, making CD123 an ideal target for therapy. SL-101 is a chimeric immunotoxin consisting of the CD123-binding domain of a monoclonal antibody connected to a Pseudomonas exotoxin, and is in development in collaboration with the National Cancer Institute. SL-101 is designed to address the urgent need for leukemia therapies that provide durable remissions. Stemline has exclusively licensed intellectual property that protects SL-101. This Phase I STTR grant will cover the development of SL-101 through key phases of pre-clinical development. In particular, this study aims to develop SL-101 through in vitro assays and in vivo models of human acute leukemia in collaboration with Dr. Malcolm Moore at the Memorial Sloan-Kettering Cancer Center (New York, NY). SL-101 will be tested against leukemia cell lines and primary human leukemia and leukemia CSC samples, and in xenograft models of human acute leukemia, for its efficacy as an anti- leukemia agent. The SL-101 development plan is designed to advance SL-101 through animal efficacy at which time the Company expects to apply for a Phase II STTR to fund further pre-IND work including the required toxicology, manufacturing, and scale-up to support IND filing in preparation for Phase I/II clinical trials. There are 10,500 new cases of AML annually, and 70% of patients experience relapse after first- line therapy. The resistance of leukemia cancer stem cells to standard chemotherapy is the major contributor to this treatment failure and relapse. Stemline Therapeutics' lead drug, named "SL-101", is designed to target and eradicate leukemia cancer stem cells. SL-101 is designed to address the urgent need for leukemia therapies that provide durable remissions. This Phase I STTR grant will cover the development of SL-101 through key phases of pre-clinical development.