Abstract |
We have constructed a single-chain immunotoxin consisting of the variable H and L chains of the carcinoma-reactive mAb BR96, fused to the binding defective protein toxin, PE40. This molecule, BR96 sFv-PE40, has been shown to be extremely cytotoxic toward a variety of BR96 Ag-expressing tumor cell lines. When administered i.v. into athymic mice carrying L2987 tumor xenografts, BR96 sFv-PE40 was cleared rapidly from the blood with a half-life of approximately 30 min. This is in comparison to a chemical conjugate, chiBR96-LysPE40, that remained in the blood for almost 2 h. In addition, the smaller single-chain immunotoxin (67 kDa) penetrates the tumor faster than the larger chemical conjugate (190 kDa). Using a variety of administration schedules and doses, we treated established human tumor xenografts in athymic mice with both the single-chain immunotoxin BR96 sFv-PE40 and the chemical conjugate chiBR96-LysPE40. In both L2987 lung carcinoma and MCF-7 breast carcinoma models, we found that BR96 sFv-PE40 completely regressed the tumor xenografts. With an administration schedule of q4dx5, the tumors were totally regressed and did not reappear. The chiBR96-LysPE40 conjugate produced partial tumor regressions, although at near maximum tolerated dose. These results show that the single-chain immunotoxin, BR96 sFv-PE40, is a potent antitumor agent.
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Authors | P N Friedman, D F Chace, P A Trail, C B Siegall |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 150
Issue 7
Pg. 3054-61
(Apr 01 1993)
ISSN: 0022-1767 [Print] United States |
PMID | 8454873
(Publication Type: Journal Article)
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Chemical References |
- Antibodies, Monoclonal
- Antineoplastic Agents
- BR96 sFv-PE40
- Bacterial Toxins
- Exotoxins
- Immunotoxins
- Recombinant Fusion Proteins
- Virulence Factors
- ADP Ribose Transferases
- Pseudomonas aeruginosa exotoxin A
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Topics |
- ADP Ribose Transferases
- Animals
- Antibodies, Monoclonal
(therapeutic use, toxicity)
- Antineoplastic Agents
(pharmacology, toxicity)
- Bacterial Toxins
- Exotoxins
(therapeutic use, toxicity)
- Female
- Humans
- Immunotoxins
(therapeutic use, toxicity)
- Lung Neoplasms
(therapy)
- Mammary Neoplasms, Experimental
(therapy)
- Mice
- Mice, Nude
- Neoplasm Transplantation
- Pseudomonas aeruginosa
(chemistry, genetics, immunology)
- Recombinant Fusion Proteins
(therapeutic use, toxicity)
- Structure-Activity Relationship
- Tissue Distribution
- Virulence Factors
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