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

描述（由申请人提供）：癌症干细胞（CSC）领域是肿瘤学的一个迅速崛起和令人兴奋的新领域。CSC是起源和生长肿瘤的恶性干细胞。这些细胞占肿瘤的一小部分（约0.5%-2%），但负责整个肿瘤的生长。重要的是，CSC对标准和靶向化疗具有抗性，并且被认为有助于治疗失败和复发。人们普遍预计，旨在靶向CSC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。NCI强调了CSCs的重要性，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想法之一。“（波士顿地球仪，2004年12月26日）。每年有10，500例AML新发病例，70%的患者在一线治疗后复发。白血病CSC对标准化疗的抗性可能是这种治疗失败的主要原因。Stemline Therapeutics的主要药物名为“SL-101”，旨在靶向和根除白血病CSC。重要的是，白血病CSC表达的CD 123（IL 3Ra链）水平比正常造血细胞高10倍以上，使CD 123成为治疗的理想靶点。SL-101是一种嵌合免疫毒素，由单克隆抗体的CD 123结合结构域与假单胞菌外毒素连接组成，目前正在与美国国家癌症研究所合作开发。SL-101旨在满足对提供持久缓解的白血病疗法的迫切需求。Stemline拥有保护SL-101的独家许可知识产权。该第一阶段STTR赠款将涵盖SL-101通过临床前开发的关键阶段的开发。特别是，本研究旨在与Memorial Sloan-Kettering Cancer Center（纽约，NY）的Malcolm摩尔博士合作，通过人急性白血病的体外测定和体内模型开发SL-101。SL-101将针对白血病细胞系和原代人白血病和白血病CSC样品以及在人急性白血病的异种移植模型中测试其作为抗白血病剂的功效。SL-101开发计划旨在通过动物疗效来推进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，制造和扩大规模，以支持IND申请，为I/II期临床试验做准备。每年有10，500例AML新发病例，70%的患者在一线治疗后复发。白血病干细胞对标准化疗的耐药性是治疗失败和复发的主要原因。Stemline Therapeutics的主要药物名为SL-101，旨在靶向和根除白血病干细胞。SL-101旨在满足对提供持久缓解的白血病疗法的迫切需求。该第一阶段STTR赠款将涵盖SL-101通过临床前开发的关键阶段的开发。

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.