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Monoclonal Antibodies

Leukemia Insights - Spring 2010

Phase I study of DT2219ARL

Immunotoxins are comprised of a potent toxin linked to a targeting moiety designed to maximize drug delivery to tumor cells, thereby avoiding the nonspecific toxicity typically associated with conventional chemotherapeutic agents. DT2219ARL is a novel recombinant bispecific ligand-directed toxin created with the anti-CD19 hybridoma HD37 and the anti-CD22 hybridoma RFB4. DT2219ARL was constructed using a hybrid gene encoding the first 390 amino acids of the diphtheria toxin (DT390) and the VH and VL regions of anti-CD22 (sFv) and anti-CD19 (sFv). This molecule was genetically enhanced for superior in vivo anti-leukemia activity via reverse orientation of the VH-VL domains and addition of aggregation reducing/stabilizing linkers. CD19 molecules expressing the HD37 epitope and CD22 molecules expressing the RFB4 epitope are present on an average of 80% and 50% of B-lymphoblasts, respectively. A phase I dose escalation study of DT2219ARL is ongoing. Treatment is given intravenously for 4 doses every other day over 4 hours on an inpatient basis.

Phase I study of CMC-544 (inotuzumab ozogamycin) with or without rituximab

CMC-544 is a humanized anti-CD22 monoclonal antibody conjugated to calecheamycin (a potent anthracycline-like cytotoxic agent). CMC-544 ultimately induces apoptosis once internalized. The combination of CMC-544 and rituximab (anti-CD20 monoclonal antibody with significant activity in B-lymphoproliferative disorders either as monotherapy and/or in combination therapy) has demonstrated clinical activity in previously treated follicular and diffuse large B-cell lymphomas [Dang NH, Blood 2009 114:Abstract 584]. In this study, CMC-544 will be given intravenously over 15 minutes for one dose approximately every 4 weeks. Standard-dose rituximab will be co-administered with CMC-544 commencing with the third course if no response (e.g., stable disease or progression) after two courses.


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