Recombinant immunotoxins

Tsutsumi, Y., M. Onda, S. Nagata, B. Lee, R.J. Kreitman, and I. Pastan, Site-specific chemical modification with polyethylene glycol of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) improves antitumor activity and reduces animal toxicity and immunogenicity. Proc Natl Acad Sci USA,... 

Brinkmann, U., Recombinant antibody fragments and immunotoxin fusions for cancer therapy. In Vivo, 2000.14(1) 21-7. 

Kreitman, R.J., Wilson, W.H., White, J.D., Stetler-Stevenson, M., Jaffe, E.S., Giardina, S. etal. (2000) Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J. Clin. Oncol., 18, 1622-1636. 

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... 

As previously discussed, CD25 is a component of the IL-2 receptor on activated T cells. A recombinant anti-CD25 immunotoxin, LMB-2, contains fused Fv and Pseudomonas exotoxin A sequences and is currently in clinical trials (186). 

Pai-Scherf, L. H., Villa, J., Pearson, D., Watson, T., Liu, E., Willingham, M. C., and Pastan, I. (1999). Hepatotoxicity in cancer patients receiving erb-38, a recombinant immunotoxin that targets the erbB2 receptor. Clin. Cancer Res. 5, 2311-2315. 

Reiter, Y., and Pastan, I. (1998). Recombinant Fv immunotoxins and Fv fragments as novel agents for cancer therapy and diagnosis. Trends Biotechnol., 16, 513-520. 

Toxic effects of metabolites from drug degradation do not need to be monitored for immunotoxins (per IHC S6). As a recombinant protein, immunotox-ins entering the human body are quickly degraded to small peptides and amino acids in the blood by proteases that specifically target foreign proteins and are cleared by the kidney. 

Immunotoxins continue to be actively investigated as viable alternatives to conventional therapies for a variety of diseases. An array of different recombinant, antibody formats are now available for use in immunotoxins. While these design changes have improved the overall in vitro and preclinical in vivo efficacy of immunotoxins, increased potency does not address either of the two major concerns for drugs of this type immunogenicity and toxicity. As such, immunotoxins in their current form may have limited application other than to those disease conditions either where the patients are immunocompro-... 

Brinkmann U. Recombinant immunotoxins protein engineering for cancer therapy. Mol Med Today 1996 439-46. 

Di Paolo C, Willuda J, Kubetzko S, Lauffer I, Tschudi D, Waibel R, Pluckthun A, Stahel RA, Zangemeister-Wittke U. A recombinant immunotoxin derived from a humanized epithelial cell adhesion molecule-specific single-chain antibody fragment has potent and selective antitumor activity. Clin Cancer Res 2003 9 2837-48. 

Kreitman RJ, Pastan I. Accumulation of a recombinant immunotoxin in a tumor in vivo fewer than 1000 molecules per cell are sufficient for complete responses. Cancer Res 1998 58 968-75. 

Kreitman RJ, Wilson WH, Bergeron K, Raggio M, Stetler-Stevenson M, FitzGerald DJ, Pastan I. Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N Engl J Med 2001 345 241-7. 

Reiter Y. Recombinant immunotoxins in targeted cancer cell therapy. Adv Cancer Res 2001 81 93-124. 

Fig. 3.3. Principle of design of immunotoxin conjugates by chemical coupling of toxins, or through their recombinant synthesis as fusion proteins. The antibody components which are parts of the Fah fusion and single-chain fusion are shown in Fig. 3.4.

Wawrzynczak, E.J., Cumber, A.J., Henry, R.V. and Parnell, G.D. (1991) Comparative biochemical, cytotoxic and pharmacokinetic properties of immunotoxins made with native ricin A chain, ricin Al chain and recombinant ricin A chain. Int J Cancer, 47, 130-135. 

Buchner, J., Pastan, I., and Brinkmann, U. (1992) A method for increasing the yield of properly folded recombinant fusion proteins single chain immunotoxins from renaturation of bacterial inclusion bodies. Anal. Biochem. 205, 263-270. 

Zverev, V., Sidorov, A., Zdanovsky, A., Malushova, V., Zdanovska, N., Shukhmina, N., Anjaparidze, O., Pille, E., and Melnikova, N. (1992) Inhibition of the infectivity of HIV by different forms of CD4-diphtheria recombinant immunotoxins. VIII International Conference on AIDS, Amsterdam, The Netherlands, p. 45. 

First-generation immunotoxins were hybrid molecules of bacterial toxins covalently linked to antibodies. In a number of studies, these turned out to be insufficient, with dose-limiting toxicides such as vascular leak syndrome, thrombocytopenia, and organ damage. Modern immunotoxins are recombinant fusion products of, for example, the variable domain (Fv) of a MAb, and a truncated bacterial toxin [121]. Recombinant immunotoxins are currendy being developed to target a number of... 

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