CD38 Pretargeted Radioimmunotherapy for Myeloma

CD38 骨髓瘤预靶向放射免疫治疗

• 批准号: 8185529
• 负责人: Oliver W. Press
• 金额: $ 37.46万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8185529
• 关键词: 90Y; 90Y-DOTA-Biotin; American; Antigens; Attenuated; Biodistribution; Biological Models; Biotin; Blood Circulation; Bortezomib; Cells; Chimeric Proteins; Clinical; Combined Modality Therapy; DOTA-biotin; Diagnosis; Disease; Disease Progression; Disease remission; Dose; Drug Kinetics; Engineering; Human; Implant; Label; Liver; Lung; Malignant - descriptor; Malignant Neoplasms; Minor; Modeling; Molecular; Multiple Myeloma; Mus; New Agents; Nude Mice; One-Step dentin bonding system; Organ; Patients; Plasma Cells; Progression-Free Survivals; Radiation; Radio; Radioactivity; Radioimmunotherapy; Radiolabeled; Regimen; SCID-hu Mice; Safety; Streptavidin; Surface Antigens; Survival Rate; Testing; Thalidomide; Therapeutic; Therapeutic Effect; Toxic effect; Translations; Treatment Efficacy; Tretinoin; Up-Regulation; Xenograft Model; Xenograft procedure; bone; clinically relevant; dosimetry; improved; lenalidomide; leukemia/lymphoma; mouse model; neoplastic cell; novel; novel strategies; pre-clinical; programs; radiotracer; research study; response; subcutaneous; tumor; tumor xenograft

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. PUBLIC HEALTH RELEVANCE: Multiple myeloma 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 multiple myeloma has significantly improved response rates and survival for this disease. However, despite these exciting advances, virtually all Multiple Myeloma 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 in the treatment of leukemia and lymphoma is well established. In this application we will investigate the safety and efficacy of a new approach using "pretargeted" radioimmunotherapy directed at the CD38 cell surface antigen for treatment of multiple myeloma in two clinically relevant mouse models. We anticipate rapid translation of the results of these preclinical experiments into our clinical radioimmunotherapy program for multiple myeloma.

描述（由申请人提供）：多发性骨髓瘤（MM）是一种无法治愈的等离子体细胞恶性肿瘤，每年诊断出20,580例新病例。最近引入了硼替佐米，沙利度胺，勒纳替米德和其他用于治疗MM的新型药物，可显着提高反应率，无进展生存期以及该疾病的总体存活率。然而，尽管有这些令人兴奋的进步，但实际上所有MM患者最终在诊断仅5年的中位生存期后死于疾病进展，这强调了对这种疾病的持续改善方案的持续需求。放射免疫疗法（RIT）在白血病和淋巴瘤治疗方面的功效已得到很好的确定。在此应用中，我们将研究针对MM鼠模型中针对骨髓瘤相关的CD38抗原的预先靶向放射免疫疗法（PRIT）的安全性和功效。在目标1中，我们将比较使用直接标记的抗CD38 AB（OKT10）获得的放射性的生物分布与使用工程化的OKT10 SCFV4-Stretpavidin（SA）分子融合蛋白（SA）分子融合蛋白（随后是树状确定的“ Clearimeric of-Biot” 90y-laber's 90y-lab，使用了直接标记的抗CD38 AB（OKT10）与PRIT的生物分布。研究将在两个互补模型系统中进行，即带有皮下MM异种移植物的无胸腺小鼠和带有新鲜人类多发性骨髓瘤细胞的Scid-human小鼠，这些小鼠在含有人基质微环境的植入植入的人骨中。在AIM 2中，我们将比较常规90Y-DOTA-OKT10的毒性和治疗效率与使用OKT10 SCFV4-treptavidin（SA）融合蛋白在同一两种小鼠模型中用OKT10 SCFV4-treptavidin（SA）融合蛋白预先定位的90y-Dota-Biotin的毒性和治疗效率。在AIM 3中，我们将评估全反式六酸引起的CD38抗原上调对针对小鼠骨髓瘤异种移植物的放射性标记DOTA-生物素的生物分布和治疗功效的影响； SCID-HU小鼠骨髓瘤模型中的恶性血浆细胞。在AIM 4中，我们将使用抗CD38预先靶标RIT进行组合疗法的毒性和功效，其中有或没有Lenalidomide和/或Bortezomib，这是MM最有前途的两个新药物。我们假设该提案中定义的PRIT策略将扩大传递给MM细胞的辐射量，减少传递给肝脏，肺部和其他正常器官的辐射，提高缓解率和治愈率，延长生存率，并明显减轻与常规RIT相比的毒性。我们可以预测PRIT和Lenalidomide或Bortezomib的结合的协同抗肿瘤活性。我们预计，这些临床前实验的结果可以快速地转换为我们的MM临床RIT计划。 公共卫生相关性：多发性骨髓瘤是一种无法治愈的等离子体细胞恶性肿瘤，遭受66,000名美国人的困扰，每年诊断出20,580例新病例。最近引入了硼替佐米，沙利度胺，多纳程胺和其他用于治疗多发性骨髓瘤的新型药物，已显着提高了这种疾病的反应率和生存率。然而，尽管有这些令人兴奋的进步，但实际上所有多个骨髓瘤患者最终在诊断仅5年的中位生存期后死于疾病进展，这强调了对这种疾病的持续改善方案的持续需求。放射免疫疗法在白血病和淋巴瘤治疗方面的功效已经确定。在此应用中，我们将使用针对CD38细胞表面抗原的“有预定的”放射免疫疗法来研究一种新方法的安全性和功效，以治疗两种临床相关的小鼠模型。我们预计，这些临床前实验的结果可以快速转化为多发性骨髓瘤的临床放射免疫疗法计划。