CD38 Pretargeted Radioimmunotherapy for Myeloma

描述(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，困扰着66,000名美国人，每年有20,580例新诊断病例。最近推出的波特佐米、沙利度胺、来那度胺和其他治疗多发性骨髓瘤的新药显著提高了这种疾病的应答率、无进展生存率和总生存率。然而，尽管有这些令人兴奋的进展，几乎所有的MM患者在确诊后中位生存期仅5年后最终死于疾病进展，强调了对这种疾病改进治疗方案的持续需要。放射免疫治疗(RIT)在白血病和淋巴瘤的治疗中的疗效是确定的。在这项应用中，我们将研究针对骨髓瘤相关CD38抗原的预靶向放射免疫疗法(PIT)在MM小鼠模型中的安全性和有效性。在目标1中，我们将比较使用直接放射性标记的抗CD38抗体(OKT10)获得的放射性的生物分布与使用工程四价OKT10 scFv4-链霉亲和素(SA)分子融合蛋白获得的PRIT的生物分布，然后是树状大分子“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MM皮下移植的无瘤小鼠和携带新鲜人多发性骨髓瘤细胞的SCID-人小鼠，这些细胞生长在含有人类基质微环境的植入的人骨中。在目的2中，我们将比较常规90Y-DOTA-OKT10和90Y-DOTA-生物素与OKT10 scFv4-Streptavidin(SA)融合蛋白预靶向90Y-DOTA-生物素在相同的两种小鼠模型中的毒性和治疗效果。在目的3中，我们将评估全反式维甲酸诱导的CD38抗原上调对靶向小鼠骨髓瘤移植瘤的放射性标记DOTA-生物素的生物分布和治疗效果的影响；以及对SCID-Hu小鼠骨髓瘤模型中恶性浆细胞的影响。在目标4中，我们将研究抗CD38预靶向RIT与来那度胺和/或Bortezomib的联合治疗的毒性和有效性，来那度胺和/或Bortezomib是治疗MM的两种最有前景的新药物。我们假设，与传统的RIT相比，本建议中定义的PRIT策略将放大向MM细胞的辐射量，减少向肝脏、肺和其他正常器官的辐射，提高缓解率和治愈率，延长生存期，并显著减轻毒性。我们预测PRIT与来那度胺或硼替佐米联合应用具有协同抗肿瘤活性。我们期待将这些临床前实验的结果迅速转化为我们针对MM的临床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.