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Recombinant immunotoxins

Over the last few years Pharmedartis has in collaboration with the Fraunhofer IME (PPD group) intensively worked on the development, construction, expression and characterization of recombinant immunotherapeutics. Natural ligands, antibodies as well derivatives and antibody fragments are genetically fused to several cell toxic components such as a deletion mutant of Pseudomonas aeruginosa exotoxin A. Functional expression in the periplasm of E.coli was realized by a novel method (Barth et al., Appl. Environ. Microbiol., 2000), also filed as patent application (WO 00/28050). The biological activity of the proteins was verified both in vitro and in vivo.

By using angiogenin a novel, completely human immunotoxin was developed. By fusing it to human CD30 ligand the recombinant fusion protein showed strong cytotoxic activity against CD30-positive lymphoma cells (Huhn et al., Cancer Res., 2001).

This work was extended using other human enzymes like e.g. granzyme B (EP01/04514).

Thus, all prerequisites to focus on more effective human enzymes have been established and are the ideal basis to develop the next generation of human immunotherapeutics. The biotechnological knowledge accumulated during the last few years will be used to continue preclinical testing and push recombinant pharmaceuticals into clinical application with different clinical partners (University hospitals of Aachen, Cologne, Munich, Maastricht and Utrecht).

 

Selection of Recombinant immunotoxins so far developed

Binder

Target antigen

Disease

Reference

Ki-4

CD30 receptor

Hodgkin’s lymphoma

Klimka et al., Br. J. Cancer, 1999
Barth et al., Blood, 2000
Stöcker et al., Prot. Expr. Purif., 2003

Ki-3

CD30 receptor

Hansen et al., Int. J. Cancer, 2002

CD30L

CD30 receptor

Barth et al., Cytok. Cell. Molec. Ther., 1999
Huhn et al., Cancer Res., 2001

HAK30

CD30 receptor

Klimka et al., Br. J. Cancer, 2000

RFT5

CD25 receptor

Barth et al., Int. J. Molec. Med., 1998
Barth et al., Int. J. Cancer, 2000

IL-9

IL-9 receptor

Klimka et al., Cytok. Mol. Ther., 1996

IL-4

IL-4 receptor

In preparation

14.18

GD2 antigen

Neuroblastoma

Tur et al., Int. J. Molec. Med., 2001

h22

CD64 receptor

AML

Tur et al., Cancer Res., 2003

425

EGF receptor

Pancreatic carcinoma

Bruell et al., Int. J. Oncol., 2003
Bruell et al., Int. J. Molec. Med., 2004

Phl p 5 b

B-cell receptor

Allergy

Stöcker, Klockenbring et al. J Allergy Clin Immunol 2005
Wicklein et al.,  Clin. Exp. Allergy, 2006