公开(公告)号：US20220073626A1

公开(公告)日：2022-03-10

申请号：US17420537

申请日：2020-01-02

申请人： INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHECHE MÉDICALE (INSERM) ,  ASSISTANCE PUBLIQUE - HÔPITAUX DE PARIS ,  FONDATION IMAGINE ,  CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE ,  UNIVERSITÉ DE PARIS ,  UNIVERSITÉ PARIS-SACLAY

发明人： Olivier HERMINE ,  Julien ROSSIGNOL ,  Zakia BELAID-CHOUCAIR ,  Guillemette FOUQUET ,  Lucile COURONNE ,  Michael DUSSIOT ,  Rachel RIGNAULT-BRICARD ,  Tereza COMAN ,  Flavia GUILLEM ,  Yves LEPELLETIER ,  Amédée RENAND ,  Pierre MILPIED

IPC分类号： C07K16/28 ,  A61K38/17 ,  A61P35/00 ,  C12N5/0783 ,  A61K35/17

摘要： Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by unleashing exhausted CD8+ T-cell thereby restoring anti-tumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Here, the inventors show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T-cells, interacts and enhances PD-1 activity. In mice, CD8+ T-cell specific deletion of Nrp1 improves spontaneous and anti PD1 antibody anti-tumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T-cells QI predicts poor outcome of patients treated with anti-PD1 (e.g. pembrolizumab). Finally, the combination of anti-NRP1 and anti-PD1 antibodies is synergistic in human, specifically in CD8+ T-cells anti-tumor response. Thus the therapeutic inhibition of NRP1 alone or combined with an immune checkpoint inhibitor (e.g. anti-PD1 antibody) could efficiently repress tumor growth in human cancer. The present invention also relates to multispecific antibodies comprising at least one binding site that specifically binds to an immune checkpoint molecule (e.g. PD-1), and at least one binding site that specifically binds to NRP-1. The present invention also relates to a population of cells engineered to express a chimeric antigen receptor (CAR) and wherein the expression of NRP-1 in said cells is repressed.