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Different toxicity profiles for drug-versus radionuclide-conjugated BR96 monoclonal antibodies in a syngeneic rat colon carcinoma model

Nilsson, Rune LU ; Eriksson, Sophie LU ; Sjögren, Hans Olof LU and Tennvall, Jan LU (2011) In Acta Oncologica 50(5). p.711-718
Abstract
Background. One of many approaches being evaluated in experimental models and in the clinic for the treatment of cancer is the use of antibodies conjugated to various drugs or radionuclides. The aim of the present study was to compare the toxicity profiles of radioimmunoconjugates and drug-immunoconjugates based on the same monoclonal antibody, evaluated in the same experimental model, that much resembles human studies. The pattern of dose-limiting toxicity of a monomethylauristatinconjugated monoclonal antibody (BR96) was compared to that of the same antibody conjugated with lutetium-177, and to the same non-conjugated antibody. Material and methods. Rats with established colon carcinoma were injected with monomethylauristatin-conjugated... (More)
Background. One of many approaches being evaluated in experimental models and in the clinic for the treatment of cancer is the use of antibodies conjugated to various drugs or radionuclides. The aim of the present study was to compare the toxicity profiles of radioimmunoconjugates and drug-immunoconjugates based on the same monoclonal antibody, evaluated in the same experimental model, that much resembles human studies. The pattern of dose-limiting toxicity of a monomethylauristatinconjugated monoclonal antibody (BR96) was compared to that of the same antibody conjugated with lutetium-177, and to the same non-conjugated antibody. Material and methods. Rats with established colon carcinoma were injected with monomethylauristatin-conjugated mAb-BR96, 177 Lu-BR96, or non-conjugated BR96. Liver, kidney, and myelotoxicity were assessed for 100 days by analysis of blood parameters. Body weight and therapeutic effects was also monitored. Results. Myelotoxicity was found to be dose limiting for the radionuclide BR96 conjugate. The dose-limiting factor was prolonged suppression of leukocytes (> 28 days) with increased risk of infections. For monomethylauristatin-conjugated BR96, liver toxicity was dose limiting, whereas no dose-limiting toxicity was observed with non-conjugated BR96. Both the drug-immunoconjugate and the radioimmunoconjugate resulted in decreased platelet counts, but the time to nadir and duration differed. Conclusion. The two conjugates resulted in different patterns of toxicity. By using the two conjugates of BR96 in a sequential therapeutic design it could be possible to increase the therapeutic window and hence probably the efficacy without significantly increasing the toxicity. This concept is regarded as valid regardless of conjugate or model chosen. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Acta Oncologica
volume
50
issue
5
pages
711 - 718
publisher
Taylor & Francis
external identifiers
  • wos:000290631600014
  • scopus:79956146296
ISSN
1651-226X
DOI
10.3109/0284186X.2010.547215
language
English
LU publication?
yes
id
0f00b423-4566-443f-9297-082760bf53ad (old id 1986576)
date added to LUP
2011-07-01 09:15:45
date last changed
2017-01-01 05:28:42
@article{0f00b423-4566-443f-9297-082760bf53ad,
  abstract     = {Background. One of many approaches being evaluated in experimental models and in the clinic for the treatment of cancer is the use of antibodies conjugated to various drugs or radionuclides. The aim of the present study was to compare the toxicity profiles of radioimmunoconjugates and drug-immunoconjugates based on the same monoclonal antibody, evaluated in the same experimental model, that much resembles human studies. The pattern of dose-limiting toxicity of a monomethylauristatinconjugated monoclonal antibody (BR96) was compared to that of the same antibody conjugated with lutetium-177, and to the same non-conjugated antibody. Material and methods. Rats with established colon carcinoma were injected with monomethylauristatin-conjugated mAb-BR96, 177 Lu-BR96, or non-conjugated BR96. Liver, kidney, and myelotoxicity were assessed for 100 days by analysis of blood parameters. Body weight and therapeutic effects was also monitored. Results. Myelotoxicity was found to be dose limiting for the radionuclide BR96 conjugate. The dose-limiting factor was prolonged suppression of leukocytes (> 28 days) with increased risk of infections. For monomethylauristatin-conjugated BR96, liver toxicity was dose limiting, whereas no dose-limiting toxicity was observed with non-conjugated BR96. Both the drug-immunoconjugate and the radioimmunoconjugate resulted in decreased platelet counts, but the time to nadir and duration differed. Conclusion. The two conjugates resulted in different patterns of toxicity. By using the two conjugates of BR96 in a sequential therapeutic design it could be possible to increase the therapeutic window and hence probably the efficacy without significantly increasing the toxicity. This concept is regarded as valid regardless of conjugate or model chosen.},
  author       = {Nilsson, Rune and Eriksson, Sophie and Sjögren, Hans Olof and Tennvall, Jan},
  issn         = {1651-226X},
  language     = {eng},
  number       = {5},
  pages        = {711--718},
  publisher    = {Taylor & Francis},
  series       = {Acta Oncologica},
  title        = {Different toxicity profiles for drug-versus radionuclide-conjugated BR96 monoclonal antibodies in a syngeneic rat colon carcinoma model},
  url          = {http://dx.doi.org/10.3109/0284186X.2010.547215},
  volume       = {50},
  year         = {2011},
}