Abstract
CD22-targeted recombinant immunotoxins (rIT) are active in hairy cell leukemia or acute lymphoblastic leukemia (ALL), but not in mantle cell lymphoma (MCL) patients. The goal was to enhance rIT efficacy in vivo and to define a strong combination treatment. Activity of Moxetumomab pasudotox (Moxe) and LR combined with paclitaxel was tested against MCL cell lines in vitro and as bolus doses or continuous infusion in xenograft models. In the KOPN-8 ALL xenograft, Moxe or paclitaxel alone was active, but all mice died from leukemia; when combined, 60% of the mice achieved a sustained complete remission. Against MCL cells in vitro, LR was more active than Moxe and the cells had to be exposed to rIT for more than 24 hours for them to die. To maintain high blood levels in vivo, LR was administered continuously by 7-day pumps achieving a well-tolerated steady plasma concentration of 45 ng/ml. In JeKo-1 xenografts, continuously administered LR was 14-fold more active than bolus doses and the combination with paclitaxel additionally improved responses by 135-fold. Maintaining high rIT-plasma levels greatly improves responses in the JeKo-1 model and paclitaxel substantially enhances bolus and continuously infused rIT, supporting a clinical evaluation against B-cell malignancies.
Highlights
We have developed recombinant immunotoxins which consist of an antibody fragment fused to a truncated Pseudomonas exotoxin A [1]
Three i.v. bolus doses of 0.4 mg/kg Moxetumomab pasudotox (Moxe) QOD given from day 8 resulted in an abrogation of the bioluminescence signal on day 19 but the bioluminescence recurred in all these mice indicating expected leukemia relapse
With the goal to test the efficacy of this combination in an mantle cell lymphoma (MCL) xenograft, we found in vitro (i) that LR was more active than Moxe against MCL cells and that (ii) MCL cells had to be exposed to CD22-targeting recombinant immunotoxins (rIT) for a highly variable time for them to die
Summary
We have developed recombinant immunotoxins (rIT) which consist of an antibody fragment fused to a truncated Pseudomonas exotoxin A [1]. The first CD22targeting rIT BL22 (CAT-3888) is active against B-cell non-Hodgkin lymphoma (B-NHL) cell lines in vitro [2] and achieves an objective response rate of 81% in patients with hairy cell leukemia (HCL) [3]. The affinity matured BL22variant HA22 or Moxetumomab pasudotox (Moxe) [5] is 10-fold more potent than BL22 in vitro and achieves an overall response rate of 86% in HCL patients [6] and of 33% in pediatric B-ALL [7]. Moxe regularly develop neutralizing antibodies which likely reduce the anti-leukemic activity in these patients [6]. LR is more active than Moxe or BL22 against various ALL and lymphoma cell lines and against patient-derived chronic lymphocytic leukemia (CLL) [8].
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