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。最近推出的硼替佐米、沙利度胺、来那度胺和其他治疗多发性骨髓瘤的新药显着提高了该疾病的缓解率、无进展生存率和总生存率。然而，尽管取得了这些令人兴奋的进展，但几乎所有 MM 患者在诊断后中位生存期仅为 5 年后最终都会死于疾病进展，这强调了对该疾病的改进治疗方案的持续需求。放射免疫疗法（RIT）治疗白血病和淋巴瘤的疗效已得到充分证实。在此应用中，我们将在 MM 小鼠模型中研究针对骨髓瘤相关 CD38 抗原的预靶向放射免疫疗法 (PRIT) 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 Ab (OKT10) 获得的放射性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、随后使用树枝状“清除剂”和 90Y 标记的 DOTA 生物素获得的 PRIT 生物分布。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。在目标 2 中，我们将在相同的两个小鼠模型中比较传统 90Y-DOTA-OKT10 与用 OKT10 scFv4-链霉亲和素 (SA) 融合蛋白预靶向的 90Y-DOTA-生物素的毒性和治疗效果。在目标3中，我们将评估全反式视黄酸诱导的CD38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。在目标 4 中，我们将研究使用抗 CD38 预靶向 RIT 联合治疗的毒性和功效，联合或不联合来那度胺和/或硼替佐米（两种最有前途的 MM 新药）。我们假设，与传统 RIT 相比，本提案中定义的 PRIT 策略将放大输送到 MM 细胞的辐射量，减少输送到肝脏、肺和其他正常器官的辐射，提高缓解和治愈率，延长生存期，并显着减弱毒性。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。我们预计这些临床前实验的结果将快速转化为我们的 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.