Growth Factor Imaging and Photoimmunotherapy

这个项目跨越了分子成像计划的许多部分。我们一直并将继续致力于开发膜受体靶向药物，以便对患者进行诊断、分期和选择治疗。一类显像剂是基于抗体的。我们已经开发了多种放射性标记抗体，并完成了几项涉及它们的临床试验。此外，我们还开发了一种名为光免疫疗法(PIT)的新疗法，它将特定的光子吸收染料IR700连接到抗体上。然后注射这种抗体光子吸收结合物(APC)，并与肿瘤细胞表面的同源受体结合。暴露在近红外光(NIR)下会迅速选择性地杀死癌细胞。PIT是我们团队在2010年发现的，并进行了多种动物模型的制作。到2013年，这项发明被授权给阿斯皮里安，也就是现在的乐天。在过去的几年里，头颈部癌症的第一阶段和第二阶段研究在复发的头颈部癌症中进行了44%的客观应答率。已经看到了几名长期幸存者。PIT目前处于全球第三阶段测试，并于2020年底在日本获得批准。与此同时，我们正在开发针对免疫抑制细胞的PIT，希望能促进比肿瘤PIT更强的免疫反应。例如，当Treg Pit与抗肿瘤Pit在小鼠模型中联合使用时，可以看到强烈的免疫原性反应，诱导记忆T细胞阻止肿瘤的进一步种植。我们正在从微观水平上研究小鼠模型中的这种现象，以更好地理解从肿瘤微环境中移除T reg细胞是如何特异性地导致T细胞介导的细胞杀伤的。与此同时，我们继续作为一个计划，为PET成像开发有针对性的小分子和抗体结合物。在一个项目中，我们正在放射性标记elotuzumab，这是一种针对受体SLAMF7的抗体，它在多个骨髓瘤细胞上上调。如果成功，这种药物应该能够识别全身骨髓瘤的部位，这是一个长期追求的目标。我们还在开发针对CXCR4的药物，CXCR4是一种在造血细胞和一些癌症上常见的受体。我们还与多家公司合作，帮助开发基于PET生物分布特征的抗体药物结合物。我们正在美国国立卫生研究院启动一项临床试验，在可手术的头颈部癌症患者手术前使用PIT作为一种新的辅助治疗。一种用于杀死Treg细胞的CD25抗体已经开发出来，目前正在制造用于人体试验。本剂与肿瘤靶向PIT联合使用，将使PIT免疫应答大幅增加，治疗效果更加深刻。

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.