Synergy of sequential administration of a deglycosylated ricin A chain-containing combined anti-CD19 and anti-CD22 immunotoxin (Combotox) and cytarabine in a murine model of advanced acute lymphoblastic leukemia

Abstract

The outcome for patients with refractory or relapsed acute lymphoblastic leukemia (ALL) treated with conventional therapy is poor. Immunoconjugates present a novel approach and have recently been shown to have efficacy in this setting. Combotox is a mixture of two ricin-conjugated monoclonal antibodies (RFB4 and HD37) directed against CD19 and CD22, respectively, and has shown activity in pediatric and adult ALL. We created a murine xenograft model of advanced ALL using the NALM/6 cell line to explore whether the combination of Combotox with the cytotoxic agent cytarabine (Ara-C) results in better outcomes. In our model the combination of both low- and high-dose Combotox and Ara-C resulted in significantly longer median survival. Sequential administration of Ara-C and Combotox, however, was shown to be superior to concurrent administration. These findings have led to a phase I clinical trial exploring this combination in adults with relapsed or refractory B-lineage ALL (ClinicalTrials.gov identifier NCT01408160).

Conflict of interest statement

Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

Figures

Figure 1

Lymphoblasts (black arrows) in peripheral blood of a NOD mouse injected with NALM/6 cells on days 7 (a) and 14 (b) after inoculation.

Figure 2

Schema demonstrating administration schedule for each experiment: (A) experiment 1 (concurrent administration of cytarabine [Ara-C] and Combotox), (B) experiment 2 (sequential administration) and (C) experiment 3 (comparison of concurrent and sequential administration). Thin arrows indicate lower doses, whereas bolder arrows indicate higher doses of Ara-C and Combotox (see text).

Figure 3

(a) Concurrent schedule (experiment 1) of Ara-C and Combotox. (b) Sequential schedule (experiment 2) of Ara-C and Combotox. (c) Sequential versus concurrent schedule of Ara-C and Combotox (experiment 3). Ara-C, cytarabine; NS, normal saline; Combo, Combotox.