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Challenges for Therapeutic Application of Pseudomonas Exotoxin-Based Immunotoxins

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Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 6)

Abstract

Immunotoxins are therapeutic molecules that belong to a class of biopharmaceuticals called “Armed antibodies”. Immunotoxins are based on very potent toxins of bacterial or plant origin that lack target-cell specificity. To make them target-cell-specific, the non-specific cell binding domains of the original toxins are replaced with a target-cell-specific binding protein, in most cases a monoclonal antibody or a recombinant antibody fragment. The most clinically-advanced immunotoxins are currently being evaluated in phase II and III clinical studies. Like other targeted and non-targeted therapeutics, immunotoxins too suffer from several limitations that may hinder their therapeutic efficacy. Such limitations include, but are not limited to immunogenicity, modification of the extracellular target to which the targeting antibody binds, modification of the intracellular target upon which the toxin acts to cause cell growth inhibition, and insufficient potency as single agents and off-target toxicity, where non-target cells and organs are affected by the immunotoxin, severely impairing its therapeutic index. This chapter is devoted to a group of immunotoxins in which the toxic moiety is derived from exotoxin A (PE) of the bacterium Pseudomonas aeruginosa. The limitations to the efficacy of PE-based immunotoxins, as well as potential solutions for overcoming such limitations, will be presented. Chapter 2 of this book: “Resistance of tumor cells against antibody-targeted protein toxins” by Ulrich Brinkmann et al. is focused on factors that influence the sensitivity or potential resistances of cancer cells towards recombinant immunotoxins which carry truncated and/or mutated derivatives of Pseudomonas exotoxin as cytotoxic payloads.

Keywords

Immunotoxin(s) Pseudomonas exotoxin A Immunotoxin Monoclonal antibody Immunogenicity De-immunization 

Abbreviations

ADC

Antibody-drug conjugate

APCs

Antigen presenting cells

ATL

Adult T-cell leukemia

BBB

The blood brain barrier

CED

Convection-enhanced delivery

CLL

Chronic lymphocytic leukemia

CTCL

Cutaneous T-cell lymphoma

dsFv

Disulfide-stabilized Fv fragment of an antibody

DT

Diphtheria toxin; E. coli, Escherichia coli bacteria

EGFR

Epidermal growth factor receptor

GBM

Glioblastoma multiforme

HCL

Hairy cell leukemia

IL-13

Interleukin 13

IL-13R

Receptor for IL13

IL-4

Interleukin 4

IL-4R

Receptor for IL4

IT

Immunotoxin

LeY

LewisY carbohydrate antigen

mAb

Monoclonal antibody

NSAIDs

Non-steroidal anti-inflammatory drugs

PBMCs

Peripheral blood mononuclear cells

PDAC

Pancreatic ductal adenocarcinoma

PE (or ETA)

Pseudomonas exotoxin A

PEG

Polyethylene glycol

RICs

Antibody-radionuclide conjugates (radioimmunoconjugates)

RIP

Ribosome-inactivating protein

scFv

Single-chain Fv fragment of an antibody

VLS

Vascular leak syndrome

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Molecular Microbiology and Biotechnology, The George S. Wise Faculty of Life SciencesTel-Aviv UniversityRamat AvivIsrael

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