Immunotoxins up to the present day

Abstract

Immunotoxins consist of monoclonal or polyclonal antibodies conjugated to bacterial or plant toxins. The toxins used are typically of the A-B type in which a toxic A chain is coupled to a B chain responsible for cell binding and facilitation of A chain entry into the cytosol. Two broad strategies have been followed: coupling intact toxins, or A chains alone, to antibodies. This review examines current progress in in vitro and in vivo research, including recent clinical studies, concentrating principally on ricin or ricin A chain conjugates. The future role of conjugates using membrane-acting toxins, immunolysins, is also discussed.

Recombinant production of bacterial toxins and their derivatives in the methylotrophic yeast Pichia pastoris

“…Cyt toxins are smaller than the Cry toxins and are further distinguished from the latter by: (1) their highly specific mosquitocidal activity in vivo , (2) their broad cytolytic activity to a variety of invertebrate and vertebrate cells in vitro after solubilisation and activation by proteolytic processing, and (3) their ability to spontaneously insert into membranes containing zwitterionic phospholipids with unsaturated acyl chains [ 37 - 39 ]. This unique combination of features makes Cyt toxins highly suitable for the development of membrane-acting ITs, an alternative idea in the field that was initially explored in our laboratory using chemical conjugation strategies [ 40 , 41 ].…”

Recombinant production of bacterial toxins and their derivatives in the methylotrophic yeast Pichia pastoris

“…Cyt toxins are smaller than the Cry toxins and are further distinguished from the latter by: (1) their highly specific mosquitocidal activity in vivo , (2) their broad cytolytic activity to a variety of invertebrate and vertebrate cells in vitro after solubilisation and activation by proteolytic processing, and (3) their ability to spontaneously insert into membranes containing zwitterionic phospholipids with unsaturated acyl chains [ 37 - 39 ]. This unique combination of features makes Cyt toxins highly suitable for the development of membrane-acting ITs, an alternative idea in the field that was initially explored in our laboratory using chemical conjugation strategies [ 40 , 41 ].…”

Construction of an immunotoxin with the pore forming protein StI and ior C5, a monoclonal antibody against a colon cancer cell line

“…By disrupting the plasma membrane, they might reverse the effects of multidrug resistance. If applied to treat solid tumors, inner cells could be exposed to chemotherapy following lysis of cells located nearer the vasculature [6].…”

Expression of the Bacillus thuringiensis Cyt2Aa1 toxin in Pichia pastoris using a synthetic gene construct

“…In addition to their well‐established role in the biological control of a wide variety of crop pests and human disease vectors [1], B. thuringiensis toxins were also predicted to have great potential for the development of anti‐tumour agents called immunotoxins (ITs) [5], chimaeric molecules consisting of a cell‐binding ligand coupled to a toxin or its subunits [6]. Due to the unique properties described above, Cyt toxins are particularly suited for the development of such membrane‐acting ITs [5], for example by their chemical conjugation with cell‐binding ligands [7]. However, since such chemical conjugation strategies are often characterized with low final yields of heterogeneous products, the use of recombinant expression methods might be better suited for IT production [8], especially for ultimate use in clinical studies.…”

Recombinant production of bacterial toxins and their derivatives in the methylotrophic yeast Pichia pastoris

“…Cyt toxins are smaller than the Cry toxins and are further distinguished from the latter by: (1) their highly specific mosquitocidal activity in vivo , (2) their broad cytolytic activity to a variety of invertebrate and vertebrate cells in vitro after solubilisation and activation by proteolytic processing, and (3) their ability to spontaneously insert into membranes containing zwitterionic phospholipids with unsaturated acyl chains [ 37 - 39 ]. This unique combination of features makes Cyt toxins highly suitable for the development of membrane-acting ITs, an alternative idea in the field that was initially explored in our laboratory using chemical conjugation strategies [ 40 , 41 ].…”

Construction of an immunotoxin with the pore forming protein StI and ior C5, a monoclonal antibody against a colon cancer cell line

“…By disrupting the plasma membrane, they might reverse the effects of multidrug resistance. If applied to treat solid tumors, inner cells could be exposed to chemotherapy following lysis of cells located nearer the vasculature [6].…”

Expression of the Bacillus thuringiensis Cyt2Aa1 toxin in Pichia pastoris using a synthetic gene construct

“…In addition to their well‐established role in the biological control of a wide variety of crop pests and human disease vectors [1], B. thuringiensis toxins were also predicted to have great potential for the development of anti‐tumour agents called immunotoxins (ITs) [5], chimaeric molecules consisting of a cell‐binding ligand coupled to a toxin or its subunits [6]. Due to the unique properties described above, Cyt toxins are particularly suited for the development of such membrane‐acting ITs [5], for example by their chemical conjugation with cell‐binding ligands [7]. However, since such chemical conjugation strategies are often characterized with low final yields of heterogeneous products, the use of recombinant expression methods might be better suited for IT production [8], especially for ultimate use in clinical studies.…”

Recombinant production of bacterial toxins and their derivatives in the methylotrophic yeast Pichia pastoris

“…Cyt toxins are smaller than the Cry toxins and are further distinguished from the latter by: (1) their highly specific mosquitocidal activity in vivo , (2) their broad cytolytic activity to a variety of invertebrate and vertebrate cells in vitro after solubilisation and activation by proteolytic processing, and (3) their ability to spontaneously insert into membranes containing zwitterionic phospholipids with unsaturated acyl chains [ 37 - 39 ]. This unique combination of features makes Cyt toxins highly suitable for the development of membrane-acting ITs, an alternative idea in the field that was initially explored in our laboratory using chemical conjugation strategies [ 40 , 41 ].…”

Construction of an immunotoxin with the pore forming protein StI and ior C5, a monoclonal antibody against a colon cancer cell line

“…By disrupting the plasma membrane, they might reverse the effects of multidrug resistance. If applied to treat solid tumors, inner cells could be exposed to chemotherapy following lysis of cells located nearer the vasculature [6].…”

Expression of the Bacillus thuringiensis Cyt2Aa1 toxin in Pichia pastoris using a synthetic gene construct

“…In addition to their well‐established role in the biological control of a wide variety of crop pests and human disease vectors [1], B. thuringiensis toxins were also predicted to have great potential for the development of anti‐tumour agents called immunotoxins (ITs) [5], chimaeric molecules consisting of a cell‐binding ligand coupled to a toxin or its subunits [6]. Due to the unique properties described above, Cyt toxins are particularly suited for the development of such membrane‐acting ITs [5], for example by their chemical conjugation with cell‐binding ligands [7]. However, since such chemical conjugation strategies are often characterized with low final yields of heterogeneous products, the use of recombinant expression methods might be better suited for IT production [8], especially for ultimate use in clinical studies.…”