Growth Factor Imaging and Photoimmunotherapy

该项目涵盖了分子成像计划的许多部分。我们过去和 继续专注于开发膜受体靶向剂，以诊断， 对患者进行分期和选择治疗。一类成像剂是基于抗体的。我们 我已经开发了多种放射性标记抗体，并完成了几项临床试验 涉及他们。此外，我们还开发了一种新的疗法，称为光免疫疗法（PIT） 它将一种特殊的光子吸收染料IR700与抗体结合。这个抗体光子 然后注射吸收剂偶联物（APC）并与肿瘤细胞上的同源受体结合 面暴露于近红外光（NIR）产生快速和选择性的癌细胞 杀人PIT是我们团队在2010年发现的，并进行了多个动物模型。通过 2013年，该发明被授权给Aspyrian，现在是Rakuten。在过去几年中 在头颈癌中进行的I期和II期研究的目标是44% 复发性头颈癌的缓解率。已经看到了几个长期的幸存者。 PIT目前正在全球进行第三阶段测试，并于2020年底在日本获得批准。与此同时， 开发针对免疫抑制细胞的PIT，希望能促进更强的 免疫反应比由肿瘤的PIT诱发的更强。例如，当Treg PIT与 对于小鼠模型中的抗肿瘤PIT，在诱导 记忆T细胞阻止肿瘤的进一步植入。我们正在研究这一现象 在小鼠模型中，在微观水平上，以更好地了解如何去除T reg细胞， 肿瘤微环境特异性地引起T细胞介导的细胞杀伤。与此同时 我们继续作为一个项目，开发针对PET的小分子和抗体缀合物， 显像在一个项目中，我们正在放射性标记Elotuzumab，一种针对受体的抗体 SLAMF7在多个肌瘤细胞上上调。如果成功，该代理应该能够 以确定骨髓瘤在全身的部位，这是一个长期追求的目标。我们也 开发针对CXCR4的药物，CXCR4是造血细胞上常见的受体， 癌的我们还与多家公司合作，帮助开发抗体药物偶联物 基于PET生物分布曲线。我们正在CC NIH启动一项临床试验， PIT作为可手术头颈癌患者术前的新辅助治疗。 已经开发了用于杀死Treg细胞的CD25抗体，并且目前正在制造 用于人体试验当与肿瘤靶向PIT组合时，该药剂将引起肿瘤靶向PIT。 对PIT的免疫应答显著增加，导致更深入的治疗 方面的影响.

This project spans many parts of the molecular imaging program. We have been and continue to be focused on developing membrane receptor targeted agents in order to diagnose, stage and select patients for therapy. One class of imaging agents is based on antibodies. We have developed multiple radiolabeled antibodies and have completed several clinical trials involving them. In addition we have developed a novel therapy called photoimmunotherapy (PIT) that conjugates a specific photon absorbing dye, IR700 to an antibody. This antibody photon absorber conjugate (APC) is then injected and binds to the cognate receptor on the tumor cell surface. Exposure to near infrared light (NIR) produces a rapid and selective cancer cell killing. PIT was discovered by our team in 2010 and multiple animal models were undertaken. By 2013 the invention was licensed to Aspyrian which is now Rakuten. Over the past several years Phase 1 and Phase II studies in head and neck cancers have been performed with a 44% objective response rate in recurrent head and neck cancers. Several long term survivors have been seen. PIT is now in global Phase 3 testing and was approved in Japan in late 2020. Meanwhile we are developing PIT that targets immunosuppressive cells in the hopes of promoting an even stronger immune response than is evoked by PIT of the tumor. When, for instance, Treg PIT is combined with anti tumor PIT in mouse models strong immunogenic responses are seen with induction of memory T cells preventing further implantation of the tumor. We are studying this phenomenon in mouse models at the microscopic level to better understand how removing T reg cells from the tumor microenvironment specifically causes T cell mediated cell killing. At the same time we continue as a program to develop targeted small molecule and antibody conjugates for PET imaging. In one project we are radiolabeling Elotuzumab, an antibody against the receptor SLAMF7 which is upregulated on multiple myeoma cells. If successful this agent should be able to identify sites of myeloma throughout the body, a long sought-after goal. We are also developing agents against CXCR4, a commonly found receptor on hematopoetic cells and some cancers. We have also worked with various companies to help develop antibody drug conjugates based on PET biodistribution profiles. We are initiating a clinical trial in the CC NIH to use PIT as a neoadjuvant therapy prior to surgery in patients with operable head and neck cancers. A CD25 antibody for killing Treg cells has been developed and is currently being manufactured for use in human trials. This agent, when combined with a tumor targeted PIT will cause a substantial increase in the immune response to PIT leading to more profound treatment effects.