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BR96 sFv-PE40 Immunotoxin: Nonclinical Safety Assessment
H.G. Haggerty
Department of Drug Safety Evaluation, Bristol-Myers Squibb, Syracuse, New York 13221, Bristol-Myers Squibb, PO. Box 4755, Syracuse, New York 13221-4755, haggerth{at}bms.com.
W.A. Warner
Department of Drug Safety Evaluation, Bristol-Myers Squibb, Syracuse, New York 13221
C.R. Comereski
Department of Drug Safety Evaluation, Bristol-Myers Squibb, Syracuse, New York 13221
W.M. Peden
Department of Drug Safety Evaluation, Bristol-Myers Squibb, Syracuse, New York 13221
L.E. Mezza
Department of Drug Safety Evaluation, Bristol-Myers Squibb, Syracuse, New York 13221
B.D. Damle
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Lawrenceville, New Jersey 08543
C.B. Siegall
Seattle Genetics, Bothell, Washington 98021
T.J. Davidson
Department of Drug Safety Evaluation, Bristol-Myers Squibb, Syracuse, New York 13221
BR96 sFv-PE40, a recombinant DNA-derived fusion protein composed of the heavy- and light-chain variable region domains of the monoclonal antibody BR96 and the translocation and catalytic domains of Pseudomonas exotoxin A, is being developed for the treatment of solid tumors expressing cell surface Lewisy-related antigens. Single- and repeat-dose intravenous toxicity studies in rats and dogs and a comparative ex vivo tissue-binding study with rat, dog, and human tissues were conducted to assess the toxicity of BR96 sFv-PE40 and to estimate a safe starting dose in humans. Additional studies were performed to investigate the prevention of pulmonary vascular-leak syndrome, the dose-limiting toxicity of BR96 sFv-PE40 in rats, and the immunogenicity of BR96 sFv-PE40. In single-dose studies in rats, the vascular leak appeared to be primarily confined to the lungs; however, with a repeat-dose regimen (every other day for 5 doses) other organs including the brain and heart were involved at lethal doses (12-15 mg/m2 cumulative). Single doses of 1.8 mg/m2 and a cumulative 3.8 mg/m2 dose (0.75 mg/m2, every other day for 5 doses) were generally well tolerated in rats. These doses are significantly greater than doses required to cure rodents bearing human tumor xenografts. In dogs, the major target organ following single or repeated doses (every 3 days for 5 doses) was the pancreas. Morphologic changes in the exocrine pancreas ranged from atrophy with single-cell necrosis to diffuse acinar necrosis. After a 1-mo dose-free observation period, no residual pancreatic toxicity was observed in dogs given single doses up to 6.0 mg/m2 or 5 doses of 2.4 mg/m2 (12 mg/m2 cumulative). No significant pancreatic toxicity was observed at doses <0.6 mg/m2 in high Lewisy-expressing dogs. Assessment of trypsinlike immunoreactivity was useful in monitoring changes in pancreatic function. The immunogenicity of BR96 sFv-PE40 could be inhibited by combined treatment with an immunosuppressant in dogs, thus maintaining exposure to BR96 sFv-PE40.
Key Words: BR96 sFv-PE40 • immunotoxin • safety
References
- Amlot PL, Stone MJ, Cunningham D., Fay J., Newman J., Collins R., May R., McCarthy M., Richardson J., Ghetie V., Ramilo O., Thorpe PE, Uhr JW, and Vitteta ES (1993). A phase I study of an anti-CD22 deglycosylated ricin A chain immunotoxin in the treatment of B-cell lymphomas resistant to conventional therapy. Blood 9: 2624-2633.
- Friedman PN, McAndrew SJ, Gawlak SL, Chace D., Trail PA, and Siegall CB (1993). BR96 sFv-PE40, a potent single-chain immunotoxin that selectively kills carcinoma cells. Cancer Res. 53: 334.[Abstract/Free Full Text]
- Ghetie V. and Vitetta E. (1994). Immunotoxins in the therapy of cancer: From bench to clinic. Pharmacol. Ther. 63: 209-234.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Grossbard ML, Freedman AS, Ritz J., Coral F., Goldmacher VS, Eliseo L., Spector N., Dear K., Lambert JM, Blattler WA, Taylor JA, and Nadler LM (1992). Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: A phase I trial of daily bolus infusion. Blood 79: 576-585.[Abstract/Free Full Text]
- Grossbard ML, Lambert JM, Goldmacher VS, Spector NL, Kinsella J., Eliseo L., Coral F., Taylor JA. Blättler WA, Epstein CL, and Nadler LM (1993). Anti-B4-blocked ricin: A phase I trial of 7-day continuous infusions in patients with B-cell neoplasms. J. Clin. Oncol. 11: 726-737.[Abstract]
- Hellström I., Garrigues HJ, Garrigues U., and Hellström KE (1990). Highly tumor-reactive, internalizing, mouse monoclonal antibodies to Ley-related cell surface antigens. Cancer Res. 50: 2183.[Abstract/Free Full Text]
- Keller ET (1990). High serum trypsin-like immunoreactivity secondary to pancreatitis in a dog with exocrine pancreatic insufficiency. J. Am. Vet. Med. Assoc. 196: 623-626.[Web of Science][Medline]
[Order article via Infotrieve]
- LeMaistre CR, Meneghetti C., Rosenblum M., Reuben J., Parker K., Shaw J., Deisseroth A., Woodworth T., and Parkinson DR (1992). Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptor. Blood 79: 2547-2554.[Abstract/Free Full Text]
- Levitt MD and Eckfeldt JH (1993). Diagnosis of acute pancreatitis. In: The Pancreas: Biology, Pathobiology, and Disease, Vlw Go, E Lebenthal, EP Di Magno, HA Reber, JD Gardner and GA Scheele (eds). Raven Press, New York, pp. 613-635.
- Siegall CB, Chace D., Mixan B., Garrigues U., Wan H., Paul L., Hellström I., and Hellström KE (1994). In vitro and in vivo characterization of BR96 sFv-PE40, single-chain immunotoxin fusion protein that cures human breast carcinoma xenografts in athymic mice and rats. J. Immunol. 152: 2377.[Abstract]
- Siegall CB, Haggerty HG, Warner GL, Chace D., Mixan B., Linsley P., and Davidson TJ (1997). Prevention of immunotoxin-mediated immunogenicity by blockade of CD28-B7 mediated co-stimulation using CTLA4-Ig. J. Immunol. 159: 5168-5173.[Abstract]
- Siegall CB, Liggitt D., Chace D., Mixan B., Sugar J., Davidson T., and Stains M. (1997). Characterization of vascular leak syndrome induced by the toxin component of Pseudomonas exotoxin-based immunotoxins and its potential inhibition with nonsteroidal antiinflammatory drugs. Clin. Cancer Res. 3: 339-345.[Abstract]
- Siegall CB, Liggitt D., Chace D., Tepper MA, and Fell HP (1994). Prevention of immunotoxin-mediated vascular leak syndrome in rats with retention of antitumor activity. Proc. Natl. Acad. Sci. USA 91: 9514-9518.[Abstract/Free Full Text]
- Spitler LE, del Rio M., Khentigan A., Wedel NI, Brophy NA, Miller LL, Harkonen WS, Rosendorf LL, Lee HM, Misschak RP, Kawahata RT, Stoudemire JB, Fradkin LB, Bautista EE, and Scannon PJ (1987). Therapy of patients with malignant melanoma using a monoclonal antimelanoma antibody-ricin A chain immunotoxin. Cancer Res. 47: 1717-1723.[Abstract/Free Full Text]
- Vitteta ES, Stone M., Amlot P., Fay J., May R., Till M., Newman J., Clark P., Collins R., Cunningham D., Ghetie V., Uhr JW, and Thorpe PE (1991). Phase I immunotoxin trial in patients with B-cell lymphoma. Cancer Res. 51: 4052-4058.[Abstract/Free Full Text]
- Williams DA (1987). New tests of pancreatic and small intestinal function. Compend. Cont. Educ. Pract. Vet. 9: 1167-1175.
- Williams DA and Batt RM (1983). Diagnosis of canine exocrine pancreatic insufficiency by the assay of serum trypsin-like immunoreactivity. J. Small Anim. Pract. 24: 583-588.[Web of Science]
Toxicologic Pathology, Vol. 27, No. 1,
87-94 (1999)
DOI: 10.1177/019262339902700116
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