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，困扰着66，000名美国人，每年诊断出20，580例新病例。最近引入硼替佐米、沙利度胺、来那度胺和其他用于治疗MM的新型药物显著改善了这种疾病的缓解率、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患者最终死于疾病进展后，中位生存期仅为5年，从诊断，强调持续需要改善这种疾病的方案。放射免疫疗法（RIT）在治疗白血病和淋巴瘤中的疗效已得到公认。在本申请中，我们将研究针对MM小鼠模型中骨髓瘤相关CD 38抗原的预靶向放射免疫治疗（PRIT）的安全性和有效性。在目的1中，我们将比较使用直接放射性标记的抗CD 38 Ab（OKT 10）获得的放射性的生物分布与使用工程化四价OKT 10 scFv 4-链霉亲和素（SA）分子融合蛋白的PRIT的生物分布，随后是树枝状聚合物“清除剂”，然后是90 Y-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异种移植物的无胸腺小鼠和携带在含有人基质微环境的植入人骨中生长的新鲜人多发性骨髓瘤细胞的SCID-人小鼠。在目的2中，我们将在相同的两种小鼠模型中比较常规90 Y-DOTA-OKT 10与用OKT 10 scFv 4-链霉亲和素（SA）融合蛋白预靶向的90 Y-DOTA-生物素的毒性和治疗功效。在目标3中，我们将评估由全反式视黄酸诱导的CD 38抗原上调对放射性标记的DOTA-生物素靶向小鼠骨髓瘤异种移植物和SCID-hu小鼠骨髓瘤模型中的恶性浆细胞的生物分布和治疗功效的影响。在目标4中，我们将研究使用抗-CD 38预靶向RIT的联合治疗的毒性和功效，有和没有来那度胺和/或硼替佐米，这两种最有希望的MM新药物。我们假设在该提议中定义的PRIT策略将放大递送至MM细胞的辐射量，减少递送至肝、肺和其他正常器官的辐射，与常规RIT相比，改善缓解率和治愈率，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的组合具有协同抗肿瘤活性。我们期望这些临床前实验的结果能够快速转化为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.