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• W2912373397 abstract "3728 Immunotoxins are a class of anti-cancer therapies that are hybrid proteins composed of a tumor-targeting monoclonal antibody and a cell-killing toxin moiety. CAT-8015 (formerly HA22) is a second generation immunotoxin consisting of disulfide bond stabilized Fv fragments of RFB4, an anti-CD22 monoclonal antibody, and the translocating and ADP-ribosylating domains of Pseudomonas exotoxin A (PE38). The biological activity of CAT-8015 was examined in vitro on the EHEB, CA46, Mec1, Daudi and JD38 B-cell lines using two different cytotoxicity assays; a cell viability-based assay and an inhibition of protein synthesis-based assay. The range of IC50s in both assays for the various cell lines was 0.1 - 10 ng/ml. Time course studies demonstrated that exposure to the immunotoxin for as little as 4 hr was sufficient to induce a significant amount of cell killing. Pharmacokinetic studies with CAT-8015 were conducted in mice, rats and cynomolgus monkeys and the data were analyzed using a compartmental model. The t1/2 values were calculated to be 0.42, 0.61 and 0.78 hr and the Vss values were 1.37, 10.6 and 123.1 ml in mice, rats and monkeys, respectively. The in vivo anti-tumor activity of CAT-8015 was examined in a subcutaneous tumor model using the CD22-expressing Burkitt’s lymphoma cell line JD38. When the average tumor volume reached 100-200 mm3, increasing doses of the immunotoxin were administered intravenously at 48 hr intervals for a total of three doses. Treatment with 12.5 μg/kg resulted in a cytostatic response. At higher doses, ≥ 25 μg/kg, a rapid reduction in tumor volume occurred that reached a nadir within 7 days, and complete remissions were achieved with doses ≥ 75 μg/kg. In additional experiments, rapid shrinkage of larger tumors, up to approximately 800 mm3, was also achieved following CAT-8015 administration. In contrast, CAT-3888 (formerly BL22) administration induced a cytostatic response even at doses as high as 150 μg/kg and a rebound in tumor growth was observed within 2 - 3 weeks at all the doses tested. As an additional comparison, animals bearing JD38 tumors were administered rituximab every four days for 3 doses. Treatment with rituximab at doses as high as 5 mg/kg resulted in only a transitory inhibition of tumor growth. In summary, CAT-8015 is a highly efficacious CD22-directed immunotoxin that induced complete remission of tumors in a mouse xenograft lymphoma model at doses that were well tolerated by the mice." @default.
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• W2912373397 date "2006-04-15" @default.
• W2912373397 modified "2023-09-25" @default.
• W2912373397 title "Characterization of CAT-8015: A Pseudomonas exotoxin based immunotoxin for the treatment of CD22-related hematological malignancies" @default.
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