B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin has shown substantial antileukemic activity in preclinical SCID mouse models of pediatric B-lineage ALL. Recent evidence indicates that B43-PAP has significant clinical antileukemic activity at doses well tolerated by children with therapy-refractory B-lineage ALL. Further assessment of the clinical potential of B43-PAP immunotoxin may be impeded until we learn more about the factors that determine the probability of therapeutic response in a given patient. 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 (SPECIFIC AIM 1A). The main focus of this specific aim 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.
Under SPECIFIC AIM 1 B, we are 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.
Under SPECIFIC AIM 2, we will 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.
Under SPECIFIC AIM 3, we are proposing to examine the toxicity, disposition, immunogenicity, and antileukemic activity of two novel anti-CD19 immunotoxins that are currently being developed under separate funding, namely scFv(B43)-PAP, which is generated by chemically linking PAP to a genetically engineered single- chain Fv of B43 MoAb, and homogeneous (2:1) B43-PAP containing a single 210 kDa species, which is generated by isolating 210 kDa immunotoxin species using ion exchange chromatography, in phase I/II clinical trials. The knowledge gained from the proposed research may lead to the design of more effective treatment protocols for ALL.
