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The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T cell dependent tumor immunity.

Mangsbo, Sara M; Broos, Sissela; Fletcher, Erika; Veitonmaki, Niina; Furebring, Christina; Dahlen, Eva; Norlén, Per LU ; Lindstedt, Malin; Totterman, Thomas H and Ellmark, Peter (2015) In Clinical Cancer Research 21(5). p.1115-1126
Abstract
Purpose: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013. Experimental Design: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 has been investigated in human and murine in vitro models. The in vivo effect has been investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse. Results:... (More)
Purpose: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013. Experimental Design: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 has been investigated in human and murine in vitro models. The in vivo effect has been investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse. Results: Activation of dendritic cells (DCs) by ADC-1013 results in up-regulation of the co-stimulatory molecules CD80 and CD86, and secretion of IL-12. ADC-1013 also activates dendritic cells from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated dendritic cells induce antigen-specific T cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant anti-tumor effects and long-term tumor-specific immunity. Further, ADC-1013 demonstrates significant anti-tumor effects in a human bladder cancer transplanted into immunodeficient NSG mice. Conclusions: Our data demonstrate that ADC-1013 induces long-lasting anti-tumor responses and immunological memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
21
issue
5
pages
1115 - 1126
publisher
American Association for Cancer Research
external identifiers
  • pmid:25316820
  • wos:000351982800025
  • scopus:84928811075
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-14-0913
language
English
LU publication?
yes
id
480d2e8b-781e-4a9b-820d-ac1e9aa4b3a1 (old id 4736906)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25316820?dopt=Abstract
date added to LUP
2014-11-09 21:08:56
date last changed
2017-03-05 03:22:36
@article{480d2e8b-781e-4a9b-820d-ac1e9aa4b3a1,
  abstract     = {Purpose: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013. Experimental Design: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 has been investigated in human and murine in vitro models. The in vivo effect has been investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse. Results: Activation of dendritic cells (DCs) by ADC-1013 results in up-regulation of the co-stimulatory molecules CD80 and CD86, and secretion of IL-12. ADC-1013 also activates dendritic cells from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated dendritic cells induce antigen-specific T cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant anti-tumor effects and long-term tumor-specific immunity. Further, ADC-1013 demonstrates significant anti-tumor effects in a human bladder cancer transplanted into immunodeficient NSG mice. Conclusions: Our data demonstrate that ADC-1013 induces long-lasting anti-tumor responses and immunological memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer.},
  author       = {Mangsbo, Sara M and Broos, Sissela and Fletcher, Erika and Veitonmaki, Niina and Furebring, Christina and Dahlen, Eva and Norlén, Per and Lindstedt, Malin and Totterman, Thomas H and Ellmark, Peter},
  issn         = {1078-0432},
  language     = {eng},
  number       = {5},
  pages        = {1115--1126},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T cell dependent tumor immunity.},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-14-0913},
  volume       = {21},
  year         = {2015},
}