Drug – bio-affecting and body treating compositions – Conjugate or complex of monoclonal or polyclonal antibody,... – Conjugated to proteinaceous toxin or fragment thereof
Patent
1997-12-01
2000-06-06
Chan, Christina Y.
Drug, bio-affecting and body treating compositions
Conjugate or complex of monoclonal or polyclonal antibody,...
Conjugated to proteinaceous toxin or fragment thereof
4241301, 4241331, 4241341, 4241351, 4241411, 4241431, 4241441, 4241531, 4241731, 4241781, 4241921, 435328, 435343, 4353431, 5303871, 5303873, 5303882, 53038822, 5303887, 53038873, 5303911, 5303917, A61K 39395, C07K 1628, C12N 512
Patent
active
060715197
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to compositions and methods of treating diseases of the immune system. In particular, this invention relates to methods of preventing allograft rejection and methods of treating autoimmune diseases and various malignancies of lymphoid origin.
BACKGROUND OF THE INVENTION
Immunotoxins (IT's) are chimeric molecules in which cell-binding ligands are coupled to toxins or their subunits. The ligand portion of the immunotoxin is usually a monoclonal antibody (Mab) that binds to selected target cells. The toxin portion of the immunotoxin can be derived form various sources. Most commonly, toxins are derived from plants or bacteria, but toxins of human origin or synthetic toxins (drugs) have been used as well. Toxins used for immunotoxins derived from plants or bacteria all inhibit protein synthesis of eukaryotic cells. Unlike chemotherapeutic molecules, these toxins kill both resting and dividing cells. The toxins share a number of common features: (i) they are synthesized as single chain proteins and are processed either post translationally or in the target cell to which they are delivered into two-chain molecules with interchain disulfide bonds; (ii) the disulfide bond linking the two chains is critical for cytotoxicity; and (iii) all toxins have separate subunits or domains devoded to binding to cells, translocation across membranes, and the destruction of protein synthesis in the target cell. These domains can be separated or genetically manipulated to delete those that are unwanted.
The most widely used plant toxins ricin and abrin, consist of two disulfate-linked polypeptides A and B (Olsnes et al., in Molecular Action of Toxins and Viruses p51-105 (1982)). Another group of plant-derived toxins used in immunotoxins are the ribosome inactivating proteins (RIPs). These molecules are single-chain proteins frequently found in plants and have similar enzymatic properties as the A-chain of ricin (reviewed in Stirpe and Barbieri FEBS 195:1 (1986)). The cross-linker used to join the Mab and the toxin must remain stable extracellularly, but labile intracellularly so that the toxin fragment can be released in the cytosol. The choice of cross-linker depends on whether intact toxins, A-chains or RIPs are used. A-chains and RIPs are generally coupled to the Mab using linkers that introduce a disulfide bond between the ligand and the A-chain (Myers et al., J. Immunol. Meth. 136:221 (1991)). Bonds that cannot be reduced render these immunotoxins much less toxic or nontoxic, probably because the A-chain must be released from the ligand by reduction to be cytotoxic. Intact toxins are usually linked to ligands using non-reducible linkages (such as thioether) to prevent release of the active free toxin in vivo.
RIPs, efficiently inhibit eukaryotic protein synthesis. Gelonin is a type I RIP (single catalytic chain), which has an advantage above type II RIPs in that type II RIPs have in addition to the catalytic chain, a cell-binding lectin-like B-chain. Because gelonin has no cell-binding lectin-like B-chain, it is unable to bind to cell membranes in the absence of a targeting agent and therefore has a low nonspecific toxicity. Even in comparison with another type I RIP (saporin), LD50 studies in mice have shown that native gelonin is approximately 10-fold less toxic than saporin, and thus may be particularly suitable for therapeutic applications. Moreover, immuno-conjugates with gelonin when targeted to cells have low IC50 values, inhibit a greater percentage of target cells and require less exposure time in comparison to other toxins. For these reasons, the low native toxicity and the high specific toxicity, the therapeutic window is very high for gelonin. Gelonin is among the most promising toxins used for the construction of ITs. In direct comparison experiments, gelonin was superior to two of the most popular toxins, ricin A chain and Pseudomonas exotoxin A (Fishwild et al Clin Exp Immunol 97:10 (1994)). The cDNA of gelonin was recently isolated (Better et al J Biol Chem 2
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de Boer Mark
De Gast Gijsberi
Chan Christina Y.
Gambel Phillip
Innogenetics N.V.
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