ADC-1013, an agonistic CD40 antibody optimized for local immunotherapy of cancer

Abstract

Local administration of immune activating antibodies may increase the efficacy and reduce the immunerelated adverse events associated with systemic immunotherapy of cancer. Here we report the development of a fully human agonistic CD40 antibody (IgG1), ADC1013, which has been optimized for local immunotherapy by increasing potency and tumor retention. ADC1013 activates CD40 receptors on antigen-presenting cells such as dendritic cells, resulting in up-regulation of the co-stimulatory molecules CD80 and CD86, and induction of IL-12. In addition, ADC-1013 induces direct tumor killing of CD40+ tumors, e.g. via antibodydependent cellular cytotoxicity (ADCC). The anti-tumor effects of ADC-1013 were first assessed in a bladder cancer model (EJ) in immunodeficient NSG mice. Significant anti-tumor responses were demonstrated, and further augmented in mice repopulated with human moDCs/T cells. To study the anti-tumor effects related to the immune activating properties of ADC-1013 in more detail, a human CD40 positive transgenic mouse (hCD40tg) in C57/BL-6 background was used. This transgenic mouse strain has an intact immune system and fully functional dendritic cells that are activated upon ADC-1013 treatment. Furthermore, the dendritic cells obtained from this strain are able to induce antigen specific T cell activation in vitro upon stimulation with ADC-1013. Importantly, treatment with ADC-1013 in a syngeneic bladder cancer (MB49) model, which is hCD40 negative, demonstrated that ADC-1013 induce significant tumor protection and long term immunity independent of direct tumor targeting. In addition, the anti-tumor immunity was shown to be T-cell dependent. To our knowledge, ADC-1013 represents the first immunomodulatory antibody optimized for local immunotherapy of cancer. It is currently in late pre-clinical development and will enter clinical trials in 2014.

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@inproceedings{Mangsbo2013ADC1013AA, title={ADC-1013, an agonistic CD40 antibody optimized for local immunotherapy of cancer}, author={Sara M. Mangsbo and Sissela Broos and Erika Gustafsson and Christina Furebring and Niina Veitonm{\"a}ki and Eva Dahl{\'e}n and Per Norl{\'e}n and Malin Lindstedt and Thomas H. T{\"{o}tterman and Peter Ellmark}, year={2013} }