Paclitaxel synergizes with exposure time adjusted CD22-targeting immunotoxins against B-cell malignancies

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.

5-Azacytidine prevents relapse and produces long-term complete remissions in leukemia xenografts treated with Moxetumomab pasudotox

“…Thus, the reduction of the intracellular pool of CD22 may affect the internalization of Moxe over time. In accord with our previous data showing that CD22-targeted immunotoxins are more active the longer the cells are exposed (20,44), the reduction of intracellular CD22 suggests that the resistant cells must be exposed to Moxe longer for them to die. Because Moxe has a short 20-min half-life in mice, the drug concentration after a bolus dose falls rapidly to low levels not capable of killing the resistant cells (20,44).…”

“…In accord with our previous data showing that CD22-targeted immunotoxins are more active the longer the cells are exposed (20,44), the reduction of intracellular CD22 suggests that the resistant cells must be exposed to Moxe longer for them to die. Because Moxe has a short 20-min half-life in mice, the drug concentration after a bolus dose falls rapidly to low levels not capable of killing the resistant cells (20,44). Even though suggested by our data, CD22 expression levels and Moxe activity does not necessarily correlate (45) and CD22-targeted immunotoxin can be highly active against ALL that expresses little CD22 (34).…”

Antiviral Immunotoxin Against Bovine herpesvirus-1: Targeted Inhibition of Viral Replication and Apoptosis of Infected Cell

“…There is growing interest in developing immunotoxins for use in cancer treatment, and lately, the development of a variety of immunotoxins has been reported with the ability to inhibit virus replication and dissemination along with destruction and clearance of infected cells ( Mazor et al, 2012 ; Denton et al, 2014 ; Chandramohan et al, 2017 ; Lim et al, 2017 ; Polito et al, 2017 ). The major beneficial effect of antibody-conjugated immunotoxins is that they are selective and provide targeted delivery of toxins with minimal side effects to the host ( Cai and Berger, 2011 ; Hou et al, 2016 ; Müller et al, 2017 ). Therefore, the target molecule is the major element within the immunotoxin and plays a vital role in targeting virus-infected cells.…”

Synergistic immunotoxin-paclitaxel combination against lymphoma

“…Paclitaxel was identified as a potent enhancer of bolus doses of mesothelin-targeted immunotoxin in vivo resulting in a new clinical trial testing the combination against solid tumors (NCT02810418) [7]. In line with these results, the combination of paclitaxel and CD22-targeted immunotoxin achieved a long-lasting durable remission in 60% of the mice bearing a systemic ALL xenograft and the efficacy of continuously administered immunotoxin was enhanced substantially by 100-fold in a systemic MCL mouse model [5]. These striking effects of the combination of continuously administered immunotoxin and paclitaxel strongly support future clinical trials in patients with B-cell malignancies [5].…”

“…The area under the curve (AUC) however is similar possibly explaining the similar off-target toxicity in mice which do not express human CD22 [5]. In patients, the blood counts of healthy B-cells remain unchanged after bolus doses of CD22-targeted immunotoxin [3].…”