The patent's assignee for patent number 8530637 is Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus (
News editors obtained the following quote from the background information supplied by the inventors: "Epithelial cells of most organs typically express the ErbB2 (HER2) receptor tyrosine kinase at low levels. However, in several types of carcinomas, ErbB2 expression is strongly enhanced, often as a result of gene amplification. Due to this preferential expression in many tumors of epithelial origin, its accessibility from the extracellular space, and its involvement in the transformation process, the ErbB2 receptor tyrosine kinase is a preferred target for directed cancer therapy.
"Based on a truncated Pseudomonas exotoxin A derivative lacking the toxin's endogenous cell binding domain, a recombinant toxin was developed that employs a single-chain Fv antibody fragment of the ErbB2-specific monoclonal antibody FRP5 for targeting of the toxin to ErbB2 (1). In in vitro cell killing experiments, this bacterially expressed scFv(FRP5)-ETA molecule displayed potent antitumoral activity against a wide range of established and primary human tumor cells, including breast and ovarian carcinomas (1-3), squamous cell carcinomas (4, 5) and prostate carcinomas (6). In experimental animals scFv(FRP5)-ETA effectively inhibited growth of established human tumor xenografts (1, 3-5) and murine and rat tumor cells stably transfected with human c-erbB2 constructs (7, 8). In cancer patients, intratumoral injection of scFv(FRP5)-ETA into cutaneous lesions of ErbB2 expressing tumors resulted in a response rate of 60%, with complete regression of injected tumor nodules observed in 40%, and partial reduction in the size of injected tumors in another 20% of patients (9). In a recent phase I clinical study, maximum tolerated dose (MTD), dose limiting toxicity and pharmacokinetic parameters of intravenously injected scFv(FRP5)-ETA were determined (10). Thereby three out of 18 patients showed stable disease, and in another three patients clinical signs of activity in terms of signs and symptoms were observed."
As a supplement to the background information on this patent, NewsRx correspondents also obtained the inventors' summary information for this patent: "Preparations of therapeutic proteins for the treatment of human patients must meet very high standards of purity and homogeneity to qualify for approval by regulatory authorities. By-products contaminating preparations of the active compound may cause adverse events in a patient, such as toxic reactions, and/or the induction of undesired immune responses. Therefore, such by-products must be removed to the extent technically possible, and for any remaining by-products, possible biological activities or the absence thereof must be individually demonstrated. As a consequence, production costs will dramatically increase due to the requirement for sophisticated and expensive purification techniques used to remove such undesired by-products, and/or due to additional testing that is required if a particular by-product cannot be removed.
"For production of the scFv(FRP5)-ETA antibody-toxin for in vivo applications, so far mainly the bacterial expression vector pSW220-5 was used (7). This plasmid encodes a fusion protein composed of the ErbB2-specific scFv antibody fragment scFv(FRP5) derived from monoclonal antibody FRP5 (11, 12), genetically fused to truncated Pseudomonas exotoxin A (ETA), representing amino acid residues 252-613 of the wildtype toxin. In addition, the scFv(FRP5)-ETA expression unit in plasmid pSW220-5 includes sequences for two hexahistidine clusters (His.sub.6) and an N-terminal FLAG tag for purification and detection of the protein (FIG. 1A). Protein preparations from bacterial expression cultures transformed with pSW220-5 contain a major product corresponding to full-length scFv(FRP5)-ETA, and a major by-product (about 10%) that migrates directly below the main band. Both protein bands can be detected in purified protein preparations by Coomassie-staining of SDS-PAA gels (see FIG. 2A, left lane), and with ETA-specific antibodies in immunoblot experiments (data not shown). Also previous immunoblot experiments revealed that the by-product is being recognized by antibodies to the exotoxin A portion of scFv(FRP5)-ETA. This by-product has therefore been thought to be generated during or after expression by protein degradation of full-length scFv(FRP5)-ETA by bacterial proteases. Using standard protein purification techniques, it has not been possible so far to remove this truncated protein fragment."
For additional information on this patent, see: Wels, Winfried S.; Daelken, Benjamin;
Keywords for this news article include: Antibodies, Oncology, Peptides, Carcinoma, Immunology, Amino Acids,
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