ZW800-1: The 1st Zwitterionic NIR Fluorophore for Cancer Imaging & Ureter Mapping

7.项目摘要/摘要 使用不可见的近红外线(NIR)光的图像引导手术正在复兴之中。多重 商业成像系统，包括Curadel最先进的FLARE®系统，可用于 临床、兽医和人体外科。然而，该领域的最终成功将取决于创新 解决重要临床问题的近红外荧光团。 库拉德尔发明了一种名为“两性离子”的新型近红外荧光团。更准确地说，他们是 几何平衡，电中性，多离子聚亚甲基吲哚氰胺。两性离子近红外荧光团 单次静脉注射后在正常组织和器官中显示极低的非特异性结合和摄取 但具有极高的消光系数、量子产额和信号强度。正因为如此 特性，两性离子近红外荧光团创造了尽可能高的信号背景比(SBR)。 两性离子近红外荧光团有两个直接的临床用途，使它们变得如此有吸引力 在商业上。首先，它们可以通过N-羟基琥珀酰亚胺(NHS)在一个化学步骤中偶联 酯、四氟苯基(TFP)酯或马来酰亚胺对任何癌症靶向小分子、多肽模拟物， 抗体、蛋白质或纳米颗粒，从而产生用于癌症手术的靶向近红外荧光造影剂。 其次，当以最简单的羧酸形式注射时，两性离子近红外荧光团显示100%肾脏 排出并排出尿液。这会导致输尿管在接下来的几个小时内变成近红外荧光 一次静脉注射，从而使外科医生能够在癌症期间避开输尿管 腹部和骨盆的外科手术。输尿管损伤虽然不常见，但会导致极高的成本和 患者发病率。 由于其临床潜力，ZW800-1被NCI的实验中心视为高价值资产 治疗(NEXT)计划，并被接受进入首例人类肠道。在与FDA协商后， Next Program支付了完整的两种毒理学包、遗传毒性包和致突变性 包，所有的都是否定的(见附录)。因为ZW800-1和库拉德尔的药物组合超过 315个独特的化学实体，外科领域最重要的公司访问了我们，并且大多数 对投资和/或分销感兴趣。然而，我们收到的信息是一致的- 只有在ZW800-1的首个人体临床试验完成后，才会进行投资。 在这种直接到第二阶段(D2P2)SBIR应用中，我们解决当前困境的方法是 系统化的。ZW800-1无菌填充剂的ISO-7无菌冷冻干燥cGMP生产 5/4.8，然后在我们主要的学术合作网站莱顿大学进行1A/1B期临床研究 荷兰医学中心(LUMC)。AIMS的完成将使库拉德尔能够执行相当大的 分销/投资与外科领域的主要参与者达成协议，从而跨过“死亡之谷”。

7. PROJECT SUMMARY/ABSTRACT Image-guided surgery using invisible near-infrared (NIR) light is in the midst of a renaissance. Multiple commercial imaging systems, including Curadel's state-of-the-art FLARE® system, are available for pre- clinical, veterinary, and human surgery. However, the ultimate success of the field will depend on innovative NIR fluorophores that solve important clinical problems. Curadel has invented a novel family of NIR fluorophores termed “zwitterionic.” More precisely, they are geometrically balanced, electrically-neutral, polyionic polymethine indocyanines. Zwitterionic NIR fluorophores exhibit extremely low non-specific binding and uptake in normal tissues and organs after a single intravenous injection, yet have extremely high extinction coefficient, quantum yield, and signal strength. Because of these properties, zwitterionic NIR fluorophores create the highest possible signal-to-background ratio (SBR). There are two immediate clinical uses for zwitterionic NIR fluorophores that make them so attractive commercially. First, they can be conjugated in one chemical step, through either N-hydroxysuccinimide (NHS) esters, tetrafluorophenyl (TFP) esters, or maleimide to any cancer-targeted small molecule, peptidomimetic, antibody, protein, or nanoparticle thus creating a targeted NIR fluorescent contrast agent for cancer surgery. Second, when injected in their simplest carboxylic acid form, zwitterionic NIR fluorophores exhibit 100% renal clearance and elimination into urine. This causes the ureters to become NIR fluorescent for several hours after a single intravenous injection, thus providing surgeons with the ability to avoid the ureters during cancer surgeries of the abdomen and pelvis. Ureter damage, while uncommon, leads to extraordinarily high cost and patient morbidity. Because of its clinical potential, ZW800-1 was deemed a high value asset by the NCI's Experimental Therapeutics (NExT) Program and was accepted into the first-in-human tract. In consultation with the FDA, the NExT Program paid for a complete two-species toxicology package, a genotoxicity package, and mutagenicity package, all of which were negative (see Appendix). Because of ZW800-1, and Curadel's drug portfolio of over 315 unique chemical entities, the most important companies in the field of surgery have visited us, and most are interested in investment and/or distribution. The message we have received, though, is consistent – investment will only come after first-in-human clinical trials of ZW800-1 are completed. In this direct-to-Phase 2 (D2P2) SBIR application, our approach to solve our current dilemma is systematic. cGMP manufacturing of ZW800-1 under ISO-7, aseptic fill-finish including lyophilization under ISO 5/4.8, then a Phase 1A/1B clinical study at our major academic collaboration site, the Leiden University Medical Center (LUMC) in the Netherlands. Completion of the aims will position Curadel to execute a sizeable distribution/investment deal with a major player in the surgical space, and thus cross the “valley of death.”