Charles Rodolphe Brupbacher Symposium 2017 - Posterpreis
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Frau Natalia Arenas Ramirez für ihr Poster "Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2"
Natalia Arenas Ramirez, PhD
Interleukin (IL)-2 is an essential cytokine for the homeostasis and activation of T cells. It can stimulate cells expressing different levels of dimeric or trimeric IL-2 receptors (IL-2Rs). The administration of IL-2 at high doses proved its benefit for patients with advanced cancer through the stimulation of cells expressing high levels of dimeric IL-2Rs (CD8+ T cells and NK cells). By contrast, most of the IL-2-related side effects observed in patients treated with IL-2 have been associated to the binding of the cytokine to its IL-2 receptor-α (CD25) subunit, preferentially expressed by immunosuppressive CD4+ T regulatory cells. Currently, no mAb specific to human (h) IL-2 suitable for clinical development in cancer immunotherapy is available. In order to cover this clinical need, Natalia Arenas-Ramirez and colleagues developed a rational approach to generate and identify high affinity anti-hIL-2 antibodies specifically blocking the CD25 binding site. The best monoclonal antibody (mAb), termed NARA1, was isolated and fully characterized. Surface plasmon resonance analysis showed that NARA1 was efficiently blocking the CD25 binding site of hIL-2 therefore acting as a high affinity CD25-mimobody. X-ray crystallography in complex with hIL-2 depicted the binding epitope of NARA1. Residues of hIL-2 contacting NARA1 are clearly involved in the binding to CD25. In vivo, hIL-2/NARA1 complexes preferentially expand CD8+ T cells and NK cells, while the expansion of immunosuppressive CD4+ T regulatory cells remains low. The immuno-stimulatory effect of hIL-2/NARA1 complexes leads to potent anti-tumor responses correlating with higher levels of CD8+ T cells in the tumor site. The anti-tumor effect observed was clearly dependent on CD8+ T cells that remain less exhausted that the ones generated upon conventional hIL-2 immunotherapy. Moreover, hIL-2/NARA1 complexes lead to favorable benefit to adverse effect ratios, as shown treating Tyr::N-RasQ61K Ink4a–/– mice which developed less skin melanoma nodules and lung metastases while tolerating well several cycles of hIL-2/NARA1 complexes. NARA1 is the first anti-hIL-2 mAb able to potentiate the immuno-stimulatory properties of hIL-2, thus meriting further investigation for clinical development.