Domain II of Pseudomonas Exotoxin Is Critical for Efficacy of Bolus Doses in a Xenograft Model of Acute Lymphoblastic Leukemia

Müller F, Cunningham T, Beers R, Bera TK, Wayne AS, Pastan I (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Toxins MDPI

Book Volume: 10

Journal Issue: 5

DOI: 10.3390/toxins10050210

Abstract

Moxetumomab pasudotox is a fusion protein of a CD22-targeting antibody and Pseudomonas exotoxin. Minutes of exposure to Moxetumomab achieves similar cell killing than hours of exposure to a novel deimmunized variant against some acute lymphoblastic leukemia (ALL). Because blood levels fall quickly, Moxetumomab is more than 1000-fold more active than the deimmunized variant in vivo. We aimed to identify which part of Moxetumomab increases in vivo efficacy and generated five immunotoxins, tested time-dependent activity, and determined the efficacy in a KOPN-8 xenograft model. Full domain II shortened the time cells had to be exposed to die to only a few minutes for some ALL; deimmunized domain III consistently extended the time. Against KOPN-8, full domain II accelerated time to arrest protein synthesis by three-fold and tripled PARP-cleavage. In vivo efficacy was increased by more than 10-fold by domain II and increasing size, and therefore half-life enhanced efficacy two- to four-fold. In summary, in vivo efficacy is determined by the time cells have to be exposed to immunotoxin to die and serum half-life. Thus, domain II is most critical for activity against some ALL treated with bolus doses; however, immunotoxins lacking all but the furin-cleavage site of domain II may be advantageous when treating continuously.

Authors with CRIS profile

Fabian Müller Department of Medicine 5 – Haematology and Oncology

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

J059: CD22-targeting immunotoxin initiates systemic anti-lymphoma immunity in syngeneic mice July 1, 2017 - June 30, 2020

Involved external institutions

National Cancer Institute (NCI) US United States (USA) (US) University of Southern California (USC) US United States (USA) (US)

How to cite

APA:

Müller, F., Cunningham, T., Beers, R., Bera, T.K., Wayne, A.S., & Pastan, I. (2018). Domain II of Pseudomonas Exotoxin Is Critical for Efficacy of Bolus Doses in a Xenograft Model of Acute Lymphoblastic Leukemia. Toxins, 10(5). https://dx.doi.org/10.3390/toxins10050210

MLA:

Müller, Fabian, et al. "Domain II of Pseudomonas Exotoxin Is Critical for Efficacy of Bolus Doses in a Xenograft Model of Acute Lymphoblastic Leukemia." Toxins 10.5 (2018).

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