Monoclonal immunotoxins

A-chain immunotoxins, however, may not be quite as cytotoxic as conjugates formed from intact toxin molecules (Manske et al., 1989). In an alternative approach to A chain use, the intact toxin of two-subunit proteins is directly conjugated to a monoclonal without isolation of the A chain. Conjugation of an antibody with intact A-B chain toxins can be done without a cleavable linker, as long as the A chain can still separate from the B chain once it is internalized. Therefore, it is important to avoid intramolecular crosslinking during the conjugation process which can prevent release of the A-B complex. In addition, since the B chain... 

Ghetie, V., Ghetie, M.-A., Uhr, J.W., and Vitetta, E.S. (1988) Large scale preparation of immunotoxins constructed with the Fab fragment of IgGl murine monoclonal antibodies and chemically deglyco-sylated ricin A chain./. Immunol. Meth. 112, 267-277. 

The antileukemic efficacy of an immunotoxin composed of a monoclonal anti-Thy-1 antibody disulfide linked to the ribosome-inactivating protein gelonin. Cancer Immunol. Immunother. 25, 31. 

Lambert, J. M., Senter, P. D., Yau-Young, A., Blattler, W. A., and Goldmacher, V.S. (1985) Purified immunotoxins that are reactive with human lymphoid cells monoclonal antibodies conjugated to the ribosome-inactivating proteins gelonin and the pokeweed antiviral proteins./. Biol. Chem. 260,12035—12041. 

Scott, C. J., Jr., Goldmacher, V. S., Lambert, J. M., Chari, R. V., Bolender, S., Gauthier, M. N., and Blattler, W. A. (1987) The antileukemic efficacy of an immunotoxin composed of a monoclonal anti-Thy-1 antibody disulfide linked to the ribosome-inactivating protein gel-onin. Cancer Immunol. Immunother. 25, 31. 

Ricin is a type II toxin. The A chain (ricin A) contains 267 amino acid residues, and the B chain (ricin B) 262 residues. Ricin A is exceptionally toxic, and it has been estimated that a single molecule is sufficient to kill an individual cell. This peptide can be prepared by genetic engineering using Escherichia coli. The potent action of this material on eukaryotic cells has been investigated in anticancer therapy. Ricin A has been coupled to monoclonal antibodies and successfully delivered specifically to the tumour cells. However, in vitro toxicity of ricin A-based immunotoxins is enhanced significantly if ricin B is also present. 

The development of monoclonal antibodies (mAbs) has revolutionized cancer treatment, and several mAbs are today approved for clinical use. Treatment resistance is often a problem in mAbs-treatment where multiple treatment series are necessary [100]. Dmg response can be increased by binding mAbs to cytotoxic compounds, such as protein toxins, forming immunotoxins (ITs) [101]. The historical problems with first and second generation ITs are largely solved by the use of recombinant DNA technology where chimeric proteins consisting of the Fv-ffagment of an antibody and... 

Human monoclonal antibodies are on the market both for therapeutic and diagnostic purposes. Why is it then necessary to develop immunotoxins ... 

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