PRETARGETING RADIOIMMUNOTHERAPY OF CD20+ LYMPHOMAS

CD20 淋巴瘤的预靶向放射免疫治疗

• 批准号: 6546492
• 负责人: Oliver W. Press
• 金额: $ 35.95万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6546492
• 关键词: B lymphocyte; CD antigens; antibody; athymic mouse; avidin; biotin; chimeric proteins; disease /disorder model; immunoconjugates; lymphoma; neoplasm /cancer radioimmunotherapy; nonhuman therapy evaluation; pharmacokinetics

DESCRIPTION (provided by the applicant): Preliminary clinical trials have demonstrated that radiolabeled anti-CD2O monoclonal antibodies can achieve remissions in 65-90 percent of lymphoma patients failing chemotherapy. However, most patients treated with conventional radiolabeled antibodies (RAb) subsequently relapse and die of recurrent lymphoma. The objective of this research proposal is to optimize radioimmunotherapy (RIT) of B cell lymphomas utilizing two-step pretargeting amplification strategies to improve the efficacy and decrease the toxicity of conventional RIT. Two separate pretargeting approaches will be investigated, one using streptavidin (SA) and radioactive biotin and the second employing molecularly engineered bispecific anti-CD20 x anti-ligand antibodies which bind covalently to radiolabeled ligands. First, we will compare the biodistributions, toxicities and efficacies of anti-CD2O, anti-CD22, and anti-DR antibody-SA conjugates pretargeted to lymphoma xenografts in an athymic mouse model, followed by radiobiotin administration. Second, we will investigate the pharmacokinetics, biodistributions, toxicities, and efficacies of 2 molecularly engineered recombinant tetravalent single chain antibody-SA fusion proteins ([scFv]4-SA) and compare them to standard synthetic antibody-SA chemical conjugates. Third, we will compare the relative merits of 4 genetically engineered SA mutant molecules with native SA for pretargeting protocols in combination with either biotin or a synthetic divalent bis-biotin targeting molecule. These streptavidin mutants will afford a unique opportunity to test the effect of SA avidity on tumor penetration as delineated in the "binding site barrier" hypothesis. Fourth, we will evaluate the pharmacokinetics, biodistributions, toxicities, and efficacies of novel molecularly designed bispecific anti-CD2O x anti-ligand Abs which possesses a molecularly engineered binding pocket capable of binding covalently to synthetic radiolabeled electrophilic ligands. These bispecific anti-CD2O x anti-ligand Abs will be compared directly to the SA-biotin pretargeting approach in lymphoma xenograft models. We hypothesize that the pretargeting strategies defined in this proposal will improve the tumor-to-normal organ ratios of absorbed radiation compared with conventional RIT, allowing improvement in response rates and response durations with less toxicity than is currently feasible. We hypothesize that pretargeting will eliminate the necessity of administering myeloablative doses of 131I-anti-CD20 Ab with hematopoietic stem cell rescue to achieve maximal response rates and survival rates. We anticipate rapid translation of the results of these preclinical experiments into our clinical RIT program for human Non-Hodgkin's lymphomas.

描述（由申请人提供）：初步临床试验表明，放射性标记的抗CD 2 O单克隆抗体可以在65- 90%的化疗失败的淋巴瘤患者中实现缓解。然而，大多数接受常规放射性标记抗体（RAb）治疗的患者随后复发并死于复发性淋巴瘤。本研究的目的是优化B细胞淋巴瘤的放射免疫治疗（RIT），利用两步预靶向扩增策略，以提高疗效，降低常规RIT的毒性。将研究两种单独的预靶向方法，一种使用链霉亲和素（SA）和放射性生物素，第二种采用分子工程双特异性抗CD 20 x抗配体抗体，其共价结合放射性标记的配体。首先，我们将在无胸腺小鼠模型中比较预靶向淋巴瘤异种移植物的抗CD 2 O、抗CD 22和抗DR抗体-SA缀合物的生物分布、毒性和功效，随后给予放射性生物素。 其次，我们将研究2种分子工程重组四价单链抗体-SA融合蛋白（[scFv]4-SA）的药代动力学、生物分布、毒性和功效，并将其与标准合成抗体-SA化学缀合物进行比较。第三，我们将比较4个基因工程SA突变体分子与天然SA的相对优点，用于与生物素或合成的二价双生物素靶向分子组合的预靶向方案。这些链霉亲和素突变体将提供一个独特的机会来测试SA亲合力对肿瘤渗透的影响，如“结合位点屏障”假说所描述的。 第四，我们将评估新型分子设计的双特异性抗CD 2 O x抗配体抗体的药代动力学、生物分布、毒性和疗效，该抗体具有能够共价结合合成放射性标记亲电子配体的分子工程结合口袋。这些双特异性抗CD 2 O x抗配体Ab将在淋巴瘤异种移植模型中直接与SA-生物素预靶向方法进行比较。我们假设，在本提案中定义的预靶向策略将改善肿瘤与正常器官的吸收辐射比与传统的RIT相比，允许改善反应率和反应持续时间，毒性比目前可行的。我们假设，预靶向将消除给予清髓性剂量的131 I-抗-CD 20 Ab与造血干细胞拯救以实现最大应答率和生存率的必要性。我们期望这些临床前实验的结果能够快速转化为我们针对人类非霍奇金淋巴瘤的临床RIT计划。