CD38 Pretargeted Radioimmunotherapy for Myeloma

描述（由申请人提供）：多发性骨髓瘤（MM）是一种无法治愈的浆细胞恶性肿瘤，折磨着66,000名美国人，每年有20,580例新诊断病例。最近引入硼替佐米、沙利度胺、来那度胺和其他新型药物治疗MM，显著提高了该疾病的缓解率、无进展生存期和总生存期。然而，尽管有这些令人兴奋的进展，几乎所有MM患者最终在诊断后的中位生存期仅为5年后死于疾病进展，这强调了对该疾病改进方案的持续需求。放射免疫疗法（RIT）治疗白血病和淋巴瘤的疗效是公认的。在本应用中，我们将研究针对骨髓瘤相关CD38抗原的预先靶向放射免疫治疗（PRIT）在MM小鼠模型中的安全性和有效性。在Aim 1中，我们将比较使用直接放射性标记的抗CD38抗体（OKT10）获得的放射性生物分布与使用工程四价OKT10 scfv1 -链亲和素（SA）分子融合蛋白获得的PRIT的生物分布。然后是树突“清除剂”，然后是90y标记的dota生物素。研究将在两个互补的模型系统中进行，即携带皮下MM异种移植物的胸腺小鼠和携带新鲜人多发性骨髓瘤细胞的scid -人小鼠，这些细胞生长在植入的含有人基质微环境的人骨中。在Aim 2中，我们将在相同的两种小鼠模型中比较传统90Y-DOTA-OKT10与OKT10 scFv4-链亲和素（SA）融合蛋白预先靶向的90y - dota -生物素的毒性和治疗效果。在Aim 3中，我们将评估全反式维甲酸诱导CD38抗原上调对靶向小鼠骨髓瘤移植的放射标记dota生物素的生物分布和治疗效果的影响；SCID-hu小鼠骨髓瘤模型中的恶性浆细胞。在Aim 4中，我们将研究抗CD38预靶向RIT联合治疗的毒性和疗效，用或不用来那度胺和/或波特佐米这两种最有希望的MM新药。我们假设，本提案中定义的PRIT策略将增加MM细胞的辐射量，减少肝脏、肺和其他正常器官的辐射量，提高缓解率和治愈率，延长生存期。与常规RIT相比，毒性明显减弱。我们预测PRIT与来那度胺或硼替佐米联合使用的协同抗肿瘤活性。我们期望将这些临床前实验的结果快速转化为我们的MM临床RIT计划。

DESCRIPTION (provided by applicant): Multiple Myeloma (MM) is an incurable plasma cell malignancy that afflicts 66,000 Americans, with 20,580 new cases diagnosed each year. The recent introduction of bortezomib, thalidomide, lenalidomide, and other novel agents for treatment of MM has significantly improved response rates, progression-free survival, and overall survival for this disease. However, despite these exciting advances, virtually all MM patients eventually die of disease progression after a median survival of only 5 years from diagnosis, emphasizing the continuing need for improved regimens for this disease. The efficacy of radioimmunotherapy (RIT) in the treatment of leukemia and lymphoma is well established. In this application we will investigate the safety and efficacy of pretargeted radioimmunotherapy (PRIT) directed against the myeloma-associated CD38 antigen in murine models of MM. In Aim 1, we will compare the biodistribution of radioactivity obtained using a directly radiolabeled anti-CD38 Ab (OKT10) with the biodistribution of PRIT using an engineered tetravalent OKT10 scFv4-streptavidin (SA) molecular fusion protein, followed by a dendrimeric "clearing agent" and then 90Y-labeled DOTA-biotin. Studies will be done in two complementary model systems, namely, athymic mice bearing subcutaneous MM xenografts and SCID-human mice bearing fresh human multiple myeloma cells growing in implanted human bone containing human stromal microenvironment. In Aim 2, we will compare the toxicities and therapeutic efficacies of conventional 90Y-DOTA-OKT10 with those of 90Y-DOTA-biotin pretargeted with the OKT10 scFv4- streptavidin (SA) fusion protein in the same two mouse models. In Aim 3, we will assess the impact of CD38 antigen upregulation induced by all-trans-retinoic acid on the biodistribution and therapeutic efficacy of radiolabeled DOTA-biotin targeted to mouse myeloma xenografts; and malignant plasma cells in the SCID-hu mouse myeloma model. In Aim 4, we will investigate the toxicity and efficacy of combination therapy using anti- CD38 pretargeted RIT, with and without lenalidomide and/or bortezomib, two of the most promising new agents for MM. We hypothesize that the PRIT strategies defined in this proposal will amplify the amount of radiation delivered to MM cells, decrease the radiation delivered to the liver, lungs, and other normal organs, improve remission and cure rates, prolong survival, and markedly attenuate toxicities compared to conventional RIT. We predict synergistic anti-tumor activity with combinations of PRIT and lenalidomide or bortezomib. We anticipate rapid translation of the results of these preclinical experiments into our clinical RIT program for MM.