Immunotoxins for targeted cancer therapy

Abstract

Immunotoxins are proteins that contain a toxin along with an antibody or growth factor that binds specifically to target cells. Nearly all protein toxins work by enzymatically inhibiting protein synthesis. For the immunotoxin to work, it must bind to and be internalized by the target cells, and the enzymatic fragment of the toxin must translocate to the cytosol. Once in the cytosol, 1 molecule is capable of killing a cell, making immunotoxins some of the most potent killing agents. Various plant and bacterial toxins have been genetically fused or chemically conjugated to ligands that bind to cancer cells. Among the most active clinically are those that bind to hematologic tumors. At present, only 1 agent, which contains human interleukin-2 and truncated diphtheria toxin, is approved for use in cutaneous T-cell lymphoma. Another, containing an anti-CD22 Fv and truncated Pseudomonas exotoxin, has induced complete remissions in a high proportion of cases of hairy-cell leukemia. Refinement of existing immunotoxins and development of new immunotoxins are underway to improve the treatment of cancer.

Attempts to Express the A1-GMCSF Immunotoxin in the Baculovirus Expression Vector System

“…However, despite a report on the expression of recombinant DT-GMCSF immunotoxin by the BEVS, the recombinant A1 derived fusion proteins could not be expressed by this system. This might have been due to the difference in the mechanisms of action of the two bacterial toxin conjugates, since the diphtheria toxin acts on eukaryotic elongation factor 2, 3) whereas the Shiga toxin directly inhibits the formation of eukaryotic ribosomal assembly by removing the glycoside group of A4324 on the 28s rRNA. 19) However, the susceptibility of insect cells to the toxicity induced by diphtheria toxin has been confirmed by Valdizan et al 20) and Dai et al 21) The first group showed that ectopic expression of diphtheria toxin receptor on the surface of Sf9 insect cells followed by exposure of them to intact diphtheria toxin resulted in cell death, and the second group found that cytosolic expression of recombinant diphtheria toxin in insect cells resulted in cell death.…”

“…3) Another bacterial toxin that can be used for this purpose is Shiga toxin. 4,5) One of the cell-surface receptors that can be used for targeting of immunotoxins to cancer cells is the receptor for granulocyte macrophage colony-stimulating factor (GM-CSF receptor, GMR).…”

Suppression of hepatoma tumor growth by systemic administration of the phytotoxin gelonin driven by the survivin promoter

“…Currently toxins have been selected to treat cancers [12][13][14][15][16]. Gelonin obtained from the seeds of Gelonium multiflorum is a kind of ribosome inactivating proteins (RIPs) that interacted with eukaryotic ribosomal 60S subunit to cause an irreversible inactivation, thereby blocking protein synthesis.…”

Chondroitin Sulfate as a Molecular Portal That Preferentially Mediates the Apoptotic Killing of Tumor Cells by Penetratin-directed Mitochondria-disrupting Peptides

“…The targeted delivery of toxic moieties to tumor cells by attaching them to antibodies, antibody fragments, or ligands that recognize overexpressed cell surface markers is a promising approach (1,2). However, the use of biomacromolecules, such as peptide-, protein-, and nucleic acid-based drugs, as targeted therapeutic agents is made difficult by their limited ability to permeate the plasma membrane (3).…”