Pretargeted Radioimmunotherapy of CD20+ 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 20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，我们将在小鼠异种移植模型中比较预靶向α发射体（213 Bi，211 At）和常规RIT的体内生物分布、辐射剂量测定和治疗效果。第二，我们将采用新型数字放射自显影方法对沉积在肿瘤微簇和异种移植物中的α-发射体进行小规模微剂量测定，采用常规RIT或预靶向RIT（PRIT），并将这些发现与观察到的肿瘤根除率相关联。第三，我们将评估新型分子设计的双特异性抗CD 20 x抗配体Ab的药代动力学、生物分布、毒性和疗效，该抗体具有能够与合成的放射性标记的亲电子配体共价结合的分子工程结合口袋。这些双特异性抗CD 20 x抗配体Ab将直接与淋巴瘤模型中的SA-生物素预靶向方法进行比较。最后，我们将研究新型小分子布鲁顿酪氨酸激酶抑制剂（伊曲替尼）、PI 3 激酶-δ（idelalisib）和BH 3-模拟物（ABT-199）与使用α和β发射体的PRIT。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或90 Y标记的抗CD 20 Ab与造血干细胞拯救以实现最大应答率和存活率的必要性。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。

DESCRIPTION (provided by applicant): Preliminary clinical trials have demonstrated that radiolabeled anti-CD20 monoclonal antibodies can achieve remissions in 65-90% 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 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 in vivo biodistribution, radiation dosimetry, and therapeutic efficacy of pretargeted ß-emitting radionuclides (90Y, 177Lu) with pretargeted α-emitters (213Bi, 211At) and with conventional RIT in murine xenograft models. Second, we will employ novel new digital autoradiographic methods to perform small scale microdosimetry of alpha-emitters deposited in tumor micro- clusters and xenografts with either conventional RIT or pretargeted RIT (PRIT) and correlate these findings with observed tumor eradication rates. Third, we will evaluate the pharmacokinetics, biodistributions, toxicities and efficacies of novel, molecularly designed bispecific anti-CD20 x anti-ligand Abs which possesses a molecularly engineered binding pocket capable of binding covalently to synthetic radiolabeled electrophilic ligands. These bispecific anti-CD20 x anti-ligand Abs will be compared directly to the SA-biotin pretargeting approach in lymphoma models. Finally, we will investigate potential synergy of novel new small molecule inhibitors of Bruton tyrosine kinase (ibrutinib), PI3 kinase-delta (idelalisib), and BH3-mimetics (ABT-199) with PRIT using both α and ß emitters. 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- or 90Y- labeled 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.