B43 (ANTI-CD19)-POKEWEED ANTIVIRAL PROTEIN IMMUNOTOXIN

该研究的长期目标是开发新的 和高效的免疫化疗方案， 治疗预后不良的B系急性淋巴细胞白血病（ALL） 患者 这是我们的核心工作假设， 使用B43（抗-CD 19）-美洲商陆抗病毒剂的免疫化疗方案 蛋白（PAP）免疫毒素将改善穷人的无事件生存 B系ALL患者预后。 我们提出的第一个主要目标是 进行B43（抗CD 19）-PAP免疫毒素在复发性 B系ALL患者。 该项目的主要重点将是 检查患者的临床反应与 B43-PAP治疗复发性B系ALL的疗效观察 B43-PAP对同一患者的原发性原始细胞。 为此我们 将检查B43-PAP对原发性原始细胞的抗白血病疗效 从使用体外白血病细胞的患者中， 祖细胞（LPC）测定系统以及体内SCID小鼠 模型系统 我们还将尝试将初始LPC负担 以及第14天的残留LPC负荷， 实现了缓解。 我们进一步建议研究 全身免疫毒素分布的患者间差异 B43（抗CD 19）的毒性、免疫原性和抗白血病活性 PAP免疫毒素。 我们将研究的有效性和毒性 使用B43（抗-CD 19）-PAP的联合免疫化疗方案 免疫毒素在人B系ALL临床前SCID小鼠模型中的作用， 随后实施具有最高治疗指数的方案， I/II期临床试验。 我们还将研究B43的影响 （抗CD 19）-PAP免疫毒素治疗移植前残留 急性淋巴细胞白血病高危缓解期患者白血病负荷与预后 接受骨髓移植 从拟议的研究中获得的知识，如 在临床项目I和II以及实验室项目I和II中概述， 可能会导致设计更有效的治疗方案。 此外，我们预计，新一代的抗CD 19 免疫毒素如均质210 kDa B43-PAP和单链Fv B43- PAP，将在预计的 补助期。

The long-term goal of the proposed research is the development of novel and highly effective immunochemotherapy protocols for more successful treatment of poor prognosis B-lineage acute lymphoblastic leukemia (ALL) patients. It is our central working hypothesis that combinative immunochemotherapy regimens employing B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin will improve event-free survival of poor prognosis B-lineage ALL patients. We propose as our first major goal to conduct a phase II study of B43 (anti-CD19)-PAP immunotoxin in relapsed B-lineage ALL patients. The main focus of this project will be the examination of the correlation between the clinical response of a relapsed B-lineage ALL patient to B43-PAP therapy and the efficacy of B43-PAP against primary blasts from the same patient. To this end, we will examine the anti-leukemic efficacy of B43-PAP against primary blasts from patients on this protocol using both the in vitro leukemic progenitor cell (LPC) assay system as well as the in vivo SCID mouse model system. We will also attempt to correlate the initial LPC burden as well as the residual LPC burden on day 14 with the duration of the achieved remission. We are further proposing to examine the effects of the interpatient differences in immunotoxin disposition on systemic toxicity, immunogenicity and anti-leukemic activity of B43 (anti-CD19)- PAP immunotoxin. We will examine the efficacy and toxicity of combinative immunochemotherapy regimens employing B43 (anti-CD19)-PAP immunotoxin in a preclinical SCID mouse model of human B-lineage ALL and subsequently implement regimens with the highest therapeutic index in phase I/II clinical trials. We will also examine the impact of B43 (anti-CD19)-PAP immunotoxin therapy on the pretransplant residual leukemia burden and outcome of high risk remission ALL patients undergoing BMT. The knowledge gained from the proposed research, as outlined under CLINICAL PROGRAMS I & II and LABORATORY PROGRAMS I & II, may lead to the design of more effective treatment protocols for ALL. Furthermore, we anticipate that a new generation of anti-CD19 immunotoxins such as homogeneous 210 kDa B43-PAP and single chain Fv B43- PAP, will become available for clinical studies during the projected grant period.