Chlorotoxin as a Targeting Agent for Cancer Therapies

描述（由申请人提供）：与正常组织相比，抗体药物偶联物（adc）优先向癌细胞提供治疗分子。不幸的是，adc很难穿透大多数实体肿瘤，不能穿过血脑屏障，限制了其在肿瘤学迫切需要中的应用。我们的实验室发明了肿瘤涂料，一种肽药物偶联物（PDC），可以穿过血脑屏障，穿透脑肿瘤和其他实体肿瘤。Tumor Paint将于2013年底进入临床试验阶段，它使用CTX的一种变体（一种蝎子衍生的结状肽）作为靶向剂，优先向癌细胞递送吲哚菁绿（ICG）。在与癌细胞表面的膜联蛋白II（膜联蛋白A2）结合后，CTX偶联物被迅速内化，这是理想的成像和治疗递送的理想选择。为了实现使用打结肽（knottins）向癌细胞输送治疗药物的目标，我们的团队开发了一个平台，可以在3周内生产10,000种候选肽药物。我们确定并克服了开发打结肽作为癌症靶向剂的其他主要障碍。我们假设，结蛋白肽可以被设计为特异性和有效地提供治疗实体肿瘤。我们的目标是：(1)开发一种临床先导肽-药物偶联物，优先为脑肿瘤提供放射增敏剂；(2)鉴定一种优先诱导脑肿瘤细胞死亡的肽-药物偶联物。这项工作的意义在于，它创造了一种潜在的更好的替代adc的方法，可以有效和安全地直接向脑肿瘤输送治疗药物。

DESCRIPTION (provided by applicant): Antibody drug conjugates (ADCs) deliver therapeutic molecules preferentially to cancer cells compared to normal tissue. Unfortunately, ADCs penetrate poorly into most solid tumors and fail to cross the blood brain barrier, limiting utilityfor pressing needs in oncology. Our lab invented Tumor Paint, a peptide drug conjugate (PDC) that crosses the blood brain barrier and penetrates throughout brain tumors and other solid tumors. Tumor Paint, which is on track to enter clinical trials in late 2013, preferentially delivers indocyanine green (ICG) to cancer cells using a variant of CTX, a scorpion-derived knotted peptide as the targeting agent. Upon binding to cell surface Annexin II (Annexin A2) on cancer cells, CTX conjugates are rapidly internalized, which is ideal for imaging and also ideal for therapeutic delivery. Toward the goal of using knotted peptides (knottins) to deliver therapeutics to cancer cells, our team developed a platform that enables production of 10,000 peptide drug candidates in 3 weeks. We identified and overcame other major barriers to developing knotted peptides as targeting agents for cancer. We hypothesize that knottin peptides can be engineered to specifically and effectively deliver therapeutics to solid tumors. Our Aims are to (1) Develop a clinical lead peptide-drug conjugate that preferentially delivers a radiosensitizer t brain tumors and (2) Identify a peptide drug conjugate that preferentially induces cell death in brain tumors. The significance of this work is that it creates a potentially superior alternative t ADCs for effective and safe delivery of therapeutics directly to brain tumors.