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）优先向癌细胞递送治疗分子。不幸的是，ADC渗透到大多数实体肿瘤中的效果很差，并且无法穿过血脑屏障，限制了肿瘤学迫切需求的实用性。我们的实验室发明了Tumor Paint，这是一种肽药物缀合物（PDC），可以穿过血脑屏障并渗透到脑肿瘤和其他实体肿瘤中。肿瘤涂料，这是在轨道上进入临床试验在2013年底，优先提供吲哚菁绿色（ICG）的癌细胞使用的一种变体的CTX，蝎子衍生的打结肽作为靶向剂。在与癌细胞上的细胞表面膜联蛋白II（膜联蛋白A2）结合后，CTX缀合物迅速内化，这对于成像是理想的，并且对于治疗递送也是理想的。为了实现使用knotted peptides（knottins）向癌细胞提供治疗药物的目标，我们的团队开发了一个平台，可以在3周内生产10，000种肽候选药物。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工程化以特异性和有效地将治疗剂递送至实体瘤。我们的目标是（1）开发一种临床先导肽-药物偶联物，其优先向脑肿瘤递送放射增敏剂，和（2）鉴定一种肽药物偶联物，其优先诱导脑肿瘤中的细胞死亡。这项工作的意义在于，它创造了一种潜在的上级替代ADC，用于将治疗剂直接有效和安全地递送至脑肿瘤。

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.