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Efficacy of compartmental administration of immunotoxin LMB-1 (B3-LysPE38) in a rat model of carcinomatous meningitis.

Publication ,  Journal Article
Bigner, DD; Archer, GE; McLendon, RE; Friedman, HS; Fuchs, HE; Pai, LH; Herndon, JE; Pastan, IH
Published in: Clin Cancer Res
December 1995

LMB-1 (B3-LysPE38) is an immunotoxin composed of the tumor-reactive monoclonal antibody B3 and a genetically engineered form of Pseudomonas exotoxin. Monoclonal antibody B3 reacts with a carbohydrate epitope that is found on a number of solid tumors (e.g., breast, ovarian, and lung carcinomas) that frequently invade the intrathecal space, causing neoplastic meningitis. The Pseudomonas exotoxin has been engineered to remove the binding domain to eliminate nonspecific binding. A model of human neoplastic meningitis using rats bearing the human epidermoid carcinoma A431 was used for therapeutic studies of immunotoxin LMB-1. Therapy was initiated 3 days after injection of the tumor cells, which was one third of the median survival time of untreated rats. A single intrathecal injection of 40 microgram increased median survival from 9 days with saline injection to 16 days (78%, P < 0.001), and a single dose of 200 microgram increased median survival to 25 days (188%, P < 0. 001). Three doses of 40 or 200 microgram given on days 3, 6, and 8 significantly increased the median survival of 9.5 days associated with saline injection to 40.5 days (326% increase) and 33.0 days (247% increase), respectively, with two long-term survivors (191-day survival) in each treatment group. LMB-1 had no therapeutic effect on the treatment of two B3 antigen-negative neoplastic meningitis models. Treatment of the antigen-positive A431 neoplastic meningitis with B3 alone or a nonspecific monoclonal, MOPC, coupled to the engineered Pseudomonas exotoxin produced no survival effects. Nontumor-bearing athymic rats showed no toxicity with a single dose of either 40 microgram or 200 microgram, or 3 doses of 40 microgram. However, when they were given three doses of 200 microgram, these rats showed weight loss and loss of neurological function, and two of eight animals died. These studies indicate that, in the range of the most therapeutically effective dosage, the immunotoxin LMB-1 is tolerated in the intrathecal space and should be considered for human intrathecal trials.

Duke Scholars

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

December 1995

Volume

1

Issue

12

Start / End Page

1545 / 1555

Location

United States

Related Subject Headings

  • Virulence Factors
  • Tumor Cells, Cultured
  • Rats, Nude
  • Rats
  • Pseudomonas aeruginosa Exotoxin A
  • Oncology & Carcinogenesis
  • Meningeal Neoplasms
  • Lewis Blood Group Antigens
  • Immunotoxins
  • Humans
 

Citation

APA
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MLA
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Bigner, D. D., Archer, G. E., McLendon, R. E., Friedman, H. S., Fuchs, H. E., Pai, L. H., … Pastan, I. H. (1995). Efficacy of compartmental administration of immunotoxin LMB-1 (B3-LysPE38) in a rat model of carcinomatous meningitis. Clin Cancer Res, 1(12), 1545–1555.
Bigner, D. D., G. E. Archer, R. E. McLendon, H. S. Friedman, H. E. Fuchs, L. H. Pai, J. E. Herndon, and I. H. Pastan. “Efficacy of compartmental administration of immunotoxin LMB-1 (B3-LysPE38) in a rat model of carcinomatous meningitis.Clin Cancer Res 1, no. 12 (December 1995): 1545–55.
Bigner DD, Archer GE, McLendon RE, Friedman HS, Fuchs HE, Pai LH, et al. Efficacy of compartmental administration of immunotoxin LMB-1 (B3-LysPE38) in a rat model of carcinomatous meningitis. Clin Cancer Res. 1995 Dec;1(12):1545–55.
Bigner, D. D., et al. “Efficacy of compartmental administration of immunotoxin LMB-1 (B3-LysPE38) in a rat model of carcinomatous meningitis.Clin Cancer Res, vol. 1, no. 12, Dec. 1995, pp. 1545–55.
Bigner DD, Archer GE, McLendon RE, Friedman HS, Fuchs HE, Pai LH, Herndon JE, Pastan IH. Efficacy of compartmental administration of immunotoxin LMB-1 (B3-LysPE38) in a rat model of carcinomatous meningitis. Clin Cancer Res. 1995 Dec;1(12):1545–1555.

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

December 1995

Volume

1

Issue

12

Start / End Page

1545 / 1555

Location

United States

Related Subject Headings

  • Virulence Factors
  • Tumor Cells, Cultured
  • Rats, Nude
  • Rats
  • Pseudomonas aeruginosa Exotoxin A
  • Oncology & Carcinogenesis
  • Meningeal Neoplasms
  • Lewis Blood Group Antigens
  • Immunotoxins
  • Humans