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Targeted Cancer Therapy: History and Development of Immunotoxins

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Resistance to Immunotoxins in Cancer Therapy

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

Abstract

Though a number of new drugs have been and are being formulated to treat cancer, newer therapeutic approaches are needed due to increased instances of drug resistance and toxic side effects. One relatively new approach for treatment is immunotherapy, using antibodies or ligands to cell surface molecules as vehicles to deliver toxins to specific cells, thus increasing the efficacy of the treatment by several folds. Such conjugates, of antibodies and toxins termed ‘immunotoxins’ are generated either as chemical conjugates using hetero-bifunctional cross-linkers that link the antibody to the toxin, or as ‘fusion proteins’, wherein, the gene for the antibody and the gene for the toxin are cloned together as one construct into bacterial expression systems and expressed as recombinant proteins. Several toxins, mainly the inhibitors of translation, are being explored for preparing immunotoxins. This chapter provides an overview of the treatment modalities adopted to date for the cancer management and introduces the field of immunotherapy. The chapter also focuses on the different toxins used in generating immunotoxins and on those that have made it to clinical trials.

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Abbreviations

5-FU:

5-fluorouracil

ADCC:

Antibody-dependent cellular cytotoxicity

bsAb:

Bispecific antibody

BiTE:

Bispecific T cell engager

CT:

Cancer-testis

CEA:

Carcinoembryonic antigen

CLL:

Chronic lymphocytic leukemia

CD:

Cluster of differentiation

CDC:

Complement dependent cytotoxicity

CDR:

Complementarity determining region

CTCL:

Cutaneous T-cell lymphoma

CTL:

Cytotoxic T lymphocyte

CTLA4:

Cytotoxic T lymphocyte-associated antigen 4

DC:

Dendritic cells

DMSO:

Dimethyl sulfoxide

DT:

Diphtheria toxin

ER:

Endoplasmic reticulum

EPHA3:

Ephrin receptor A3

EGF:

Epidermal growth factor

EpCAM:

Epithelial cell adhesion molecule

ERAD:

ER-associated degradation

eEF2:

Eukaryotic elongation factor 2

FATE-1:

Fetal and adult testis-expressed transcript 1

FAP:

Fibroblast activation protein

GBM:

Glioblastomamultiformes

GM-CSF:

Granulocyte-macrophage colony stimulating factor receptor

HCL:

Hairy cell leukemia

HGFR:

Hepatocyte growth factor receptor

HER2:

Human epidermal growth factor receptor 2

Ig:

Immunoglobulin

IT:

Immunotoxin

ITAM:

Immunotyrosine-activating motif

IGF1R:

Insulin-like growth factor 1 receptor

IL-10:

Interleukin 10

IL-2R:

Interleukin-2 receptor

MHC:

Major histocompatibility complex

MART-1:

Melanocyte antigen recognized by T-cells 1

MAC:

Membrane-attack complex

MMP:

Mitochondrial membrane potential

mAb:

Monoclonal antibody

NK:

Natural killer

NHS:

N-hydroxysuccinimide

SPDP:

N-succinimidyl 3-(2-pyridyldithio) propionate

SMPT:

Succinimidyloxycarbonyl-C-methyl-C-(2-pyridyldithio) toluene

PARP:

Poly-ADP ribose polymerase

PE:

Pseudomonas exotoxin

ROS:

Reactive oxygen species

RANKL:

Receptor activator of nuclear factor-xB ligand

RNA:

Ribonucleic acid

rRNA:

ribosomal RNA

RIP:

Ribosome inactivating protein

SAGE-1:

Sarcoma antigen 1

ST:

Shiga toxin

scFv:

Single chain Fv

SAPK:

Stress Activated Protein Kinase

(scFv)2 :

Tandem scFv

TRAIL1:

TNF-related apoptosis inducing ligand 1

TGF:

Transforming growth factor

TEM:

Triethylenemaleamine

TNF:

Tumor necrosis factor

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

VAMP:

Vincristine, Amethopterin, 6-mercaptopurine, Prednisone.

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Acknowledgements

The authors would like to thank the Council for Scientific and Industrial Research (CSIR) for funding their research work. Sudarshan Gadadhar acknowledges CSIR for his fellowship.

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  1. Department of Biochemistry, Indian Institute of Science, 560012, Bangalore, Karnataka, India

    Sudarshan Gadadhar & Anjali A. Karande

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  1. Sudarshan Gadadhar
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  2. Anjali A. Karande
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Correspondence to Anjali A. Karande .

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  1. Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India

    Rama Shanker Verma

  2. Department of Microbiology, Immunology,, University of California of Los Angeles, Los Angeles, California, USA

    Benjamin Bonavida

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Gadadhar, S., Karande, A. (2015). Targeted Cancer Therapy: History and Development of Immunotoxins. In: Verma, R., Bonavida, B. (eds) Resistance to Immunotoxins in Cancer Therapy. Resistance to Targeted Anti-Cancer Therapeutics, vol 6. Springer, Cham. https://doi.org/10.1007/978-3-319-17275-0_1

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