Radioimmunotherapy of CD20+ Lymphomas & CD45+Leukemias

放射免疫治疗（RIT）使用放射标记的抗cd20单克隆抗体（Ab）诱导50-90%的复发性淋巴瘤（NHL）患者缓解；然而，大多数患者最终死于复发性淋巴瘤。我们的研究小组已经记录了放射标记的抗cd45单克隆抗体在同种异体干细胞移植（SCT）治疗急性髓性白血病（AML）的应用，但毒性仍然很高，对于首次完全缓解（CR）移植的新诊断的AML患者，治愈率仍然只有60-65%，对于直接使用放射标记的抗cd45抗体和SCT的复发性AML患者，治愈率仍然只有20-30%。由于血液中放射性标记抗体的循环半衰期长，RIT的疗效目前受到非特异性辐射递送到正常组织的限制。本提案的主要目标是开展学术研究事业，开发创新方法

Radioimmunotherapy (RIT) using radiolabeled anti-CD20 monoclonal antibodies (Ab) induces remissions in 50-90% of relapsed lymphoma (NHL) patients; however, most patients eventually succumb to recurrent lymphoma. Our group has documented the promise of radiolabeled anti-CD45 monoclonal Abs administered in the setting of allogeneic stem cell transplantation (SCT) for acute myeloid leukemia (AML), but toxicity remains high and cure rates are still only 60-65% for patients with newly diagnosed AML transplanted in first complete remission (CR) and 20-30% for relapsed AML using directly radiolabeled anti-CD45 Ab and SCT. The efficacy of RIT is currently limited by non-specific delivery of radiation to normal tissues, as a result of the long circulating half-life of radiolabeled antibodies in the bloodstream. The primary objective of this proposal is to launch an academic research career developing innovative approaches to optimize the efficacy of RIT using a two-step streptavidin(SA)-biotin pretargeting strategy to target the anti-CD20 and anti-CD45 antigens on the surface of NHL and AML tumor cells, respectively. In Aim 1, we will compare and contrast the pharmacokinetics, tumor localization, and therapeutic efficacies obtained with directly radiolabeled anti-CD20 Ab (1F5) and pretargeted RIT using an anti-CD20 tetravalent single chain (scFv)4SA fusion protein followed by escalating doses of radiolabeled DOTA-biotin in murine lymphoma xenograft and disseminated lymphoma transplant models. In dim 2, we will compare the pharmacokinetics, tumor localization, and therapeutic efficacies of leukemia bearing mice treated with radiolabeled anti-human (h)CD45 Ab using conventional RIT, and optimized two-step pretargeting KIT utilizing non-radiolabeled anti-hCD45 (scFv)4SA followed by 90y-DOTA-biotin. In Aim 3, we will assess the toxicities of anti-CD45 pretargeting in a murine syngeneic leukemia model in which the target antigen is present on both leukemia cells as well as normal hematopoietic tissues. In Aim 4, we will conduct a phase I clinical study to investigate the feasibility, tolerability, and potential efficacy of pretargeted KIT for patients with relapsed indolent NHL or mantle cell NHL. We hypothesize that targeting radiation specifically to malignant cells using anti-CD20 (scFv)4SA and anti-CD45 (scFv)4SA fusion proteins will augment the efficacy and decrease the toxicity of therapy compared with conventional RIT regimens employing directly radiolabeled Abs. We anticipate that these interventions will ultimately enhance the prognosis for patients with relapsed lymphomas and advanced AML by increasing the response and survival rates, while simultaneously minimizing toxicities.