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Local activation of costimulatory pathways by e.g. CD40 activation has been shown to generate powerful systemic anti-tumor responses. Here we report significant anti-tumor effects obtained with an optimized fully human agonistic CD40 antibody, ADC-1013, in two syngeneic tumor models.
An hCD40 transgenic mouse (hCD40tg) strain was used to evaluate the immune mediated anti-tumor effects of ADC-1013. Dendritic cells obtained from hCD40tg mice were hCD40 positive and could be activated by stimulation with ADC-1013 to a similar extent as human monocyte derived dendritic cells. Furthermore, stimulation of dendritic cells from hCD40tg mice in vitro, with ADC-1013, induced antigen specific T cell activation.
Two different syngeneic tumor models, hCD40 negative MB49 bladder cancer and hCD40 positive B16.F10.hCD40+ melanoma, was used to demonstrate anti-tumor effects. Subcutaneous tumors from both models were characterized by flow cytometry and immunohistochemistry in hCD40tg mice. Treatment of the bladder cancer model (MB49) with ADC-1013 resulted in significant anti-tumor response and long term tumor immunity. The anti-tumor immunity was shown to be T cell dependent and naïve mice were protected from tumor challenge by transplantation of splenocytes from cured hCD40tg mice. In addition, significant anti-tumor effect was demonstrated in a subcutaneous B16.F10.hCD40+ melanoma model.
The human CD40 agonistic antibody ADC-1013 is the first costimulatory antibody optimized for local immunotherapy of cancer. Strong immune mediated anti-tumor effects were demonstrated. ADC-1013 is currently in late pre-clinical development.