Immunotoxins are chimeric proteins consisting of a tumor-specific ligand (antibody, growth factor or peptide) linked to a modified toxin. These molecules bind to cell surface receptors and are subsequently internalized by endocytosis, resulting in cell death. Advances in protein engineering and phage display have enabled the selection of high-affinity targeting moieties. Denileukin diftitox is the only FDA-approved immunotoxin, although others such as BL22 are currently in different phases of development. This review elaborates the key findings of the important clinical studies relating to various chimeric toxins. © 2011 Elsevier Ltd. All rights reserved.

Rama Shanker Verma

Department Of Biotechnology

Swati Choudhary

CD25 ANTIBODY

CINTREDEKIN BESUDOTOX

COMBOTOX

DENILEUKIN DIFTITOX

diphtheria toxin

IMMUNOTOXIN

IMMUNOTOXIN BL22

IMMUNOTOXIN DT388GMCSF

IMMUNOTOXIN ERB38

IMMUNOTOXIN HUM195 RGEL

IMMUNOTOXIN KI 4.DGA

IMMUNOTOXIN LMB2

IMMUNOTOXIN RFT5 DGA

IMMUNOTOXIN SS1P

IMMUNOTOXIN TF CRM107

IMMUNOTOXIN TP38

LEWIS Y ANTIBODY

MESOTHELIN

PSEUDOMONAS EXOTOXIN

RICIN

unclassified drug

antineoplastic activity

B CELL LYMPHOMA

BRAIN EDEMA

BRAIN TUMOR

clinical trial (topic)

CONTINUOUS INFUSION

CUTANEOUS T CELL LYMPHOMA

Cytotoxicity

Fatigue

FLU LIKE SYNDROME

Glioma

HAIRY CELL LEUKEMIA

HEMIPARESIS

HEMOLYTIC UREMIC SYNDROME

HODGKIN DISEASE

Human

HYPERSENSITIVITY REACTION

HYPOALBUMINEMIA

HYPOTENSION

Immunogenicity

liver toxicity

nausea

Nephrotoxicity

neurotoxicity

nonhodgkin lymphoma

nonhuman

RASH

review

seizure

side effect

VASCULAR DISEASE

VASCULAR LEAK SYNDROME

vomiting

Animals

Antineoplastic Agents

CLINICAL TRIALS AS TOPIC

Drug discovery

Humans

IMMUNOTOXINS

Neoplasms

IIT Madras is a public technical and research university located in Chennai, Tamil Nadu. Founded in 1959, it is recognised as an Institute of National Importance.

IIT Madras has been ranked as the top engineering institute in India for four years in a row by the National Institutional Ranking Framework of the MHRD

It currently offers undergraduate, postgraduate and research degrees across 16 disciplines in Engineering, Sciences, Humanities and Management. About 596 faculty belonging to science and engineering departments and centres of the Institute are engaged in teaching, research and industrial consultancy.

IIT Madras

Drug Discovery Today

Autocrine activation of c-kit (KIT receptor tyrosine kinase) has been postulated to be a potent oncogenic driver in small cell lung cancer, neuroblastoma (NB), and poorly differentiated colorectal carcinoma (CRC). Although targeted therapy involving tyrosine kinase inhibitors (TKIs) such as imatinib mesylate is highly effective for gastrointestinal stromal tumor carrying V560G c-kit mutation, it does not show much potential for targeting wild-type KIT (WT-KIT). Our study demonstrates the role of stem cell factor (SCF)-based toxin conjugates for targeting WT-KIT-overexpressing malignancies such as NBs and CRCs. We constructed SCF-based recombinant bacterial toxins by genetically fusing mutated form of natural ligand SCF to receptor binding deficient forms of Diphtheria toxin (DT) or Pseudomonas exotoxin A (ETA') and evaluated their efficacy in vitro. Efficient targeting was achieved in all receptor-positive neuroblastoma (IMR-32 and SHSY5Y) and colon cancer cell lines (COLO 320DM, HCT 116, and DLD-1) but not in receptor-negative breast carcinoma cell line (MCF-7) thereby proving specificity. While dose- and time-dependent cytotoxicity was observed in both neuroblastoma cell lines, COLO 320DM and HCT 116 cells, only an anti-proliferative effect was observed in DLD-1 cells. We prove that these novel targeting agents have promising potential as KIT receptor tyrosine kinase targeting system. © 2015, Springer-Verlag Berlin Heidelberg.

Applied Microbiology and Biotechnology

Targeting c-kit receptor in neuroblastomas and colorectal cancers using stem cell factor (SCF)-based recombinant bacterial toxins

Chemotherapy, radiation, and surgery are the conventional treatment modalities for cancer. The success achieved with these approaches has been limited due to several factors like chemoresistance to drugs, non-specificity leading to peripheral toxicity, and non-resectable tumors. To combat these problems, the concept of targeted therapy using immunotoxins was developed. Immunotoxins are chimeric proteins with a cell-selective ligand chemically linked or genetically fused to a toxin moiety and can target cancer cells overexpressing tumor-associated antigens, membrane receptors, or carbohydrate antigens. Ligands for these receptors or monoclonal antibodies or single chain variable fragments directed against these antigens are fused with bacterial or plant toxins and are made use of as immunotoxins. Pseudomonas exotoxin, anthrax toxin, and diphtheria toxin are the commonly used bacterial toxins. Ricin, saporin, gelonin, and poke weed antiviral protein are the plant toxins utilized in immunotoxin constructs. Several such fusion proteins are in clinical trials, and denileukin difitox is a FDA-approved fusion protein. In spite of the promise shown by bacterial- and plant toxin-based chimeric proteins, their clinical application is hampered by several factors like immunogenicity of the toxin moiety and non-specific toxicity leading to vascular leak syndrome. In order to overcome these problems, a novel generation of immunotoxins in which the cytotoxic moiety is an endogenous protein of human origin like proapoptotic protein or RNase has been developed. This review summarizes the advances in this new class of fusion protein and the future directions to be explored. © 2009 Japanese Cancer Association.

Fulltext

Cancer Science

Humanized immunotoxins: A new generation of immunotoxins for targeted cancer therapy

Journal	Drug Discovery Today
ISSN	13596446
Open Access	No