First-in-class anti-PVR mAb NTX1088 restores DNAM1 expression and enhances antitumor immunity
نویسندگان
چکیده
NTX1088 is a humanized, hinge-stabilized IgG4 mAb that binds PVR with sub-nM affinity and blocks all known interacting receptors single nM EC-50. (CD155), cell surface protein, highly upregulated on tumor cells, across multiple cancer types. has been associated worse patient outcomes, due to its role in immune suppression. impact cells mediated through interaction the key stimulatory receptor, DNAM1 (CD226), T NK leading internalization degradation of DNAM1. additionally, ligand for inhibitory checkpoint receptors, TIGIT CD96. Accordingly, blocking multi-faceted immune-stimulating role, namely, restoration expression activation function, while simultaneously neutralizing CD96 signals cells. Importantly, downmodulation was recently identified as resistance mechanism approved ICIs, by unique MoA, not shared other therapies. In vitro, NTX1088, monotherapy, significantly increased activation, superior TIGIT, CD112R, PD1 antibody blockade, immune-mediated killing, IFNg release, CD137 induction. Importantly only able restore settings. Synergy observed when combined blockers or anti-CD112R mAb, NTX2R13, line expression. Numerous humanized murine xenograft models were investigated. monotherapy exhibited robust growth inhibition PDAC line, HPAFII, co-engrafted human PBMC NOD/SCID mice. The effect improved inhibitor. Furthermore, strong NSG mice engrafted PBMCs NSCLC A549, whereas failed this setting. Tumor-infiltrating lymphocytes, harvested from these mice, demonstrated higher prevalence CD137+, DNAM1+, CD8+ vivo toxicity toxicokinetic studies cynomolgus monkeys revealed well tolerated up high exposure level, equivalent over 60 times EC90 values. Moreover, ability induce non-specific cytokine release ruled out tested vitro. an open IND, enrolling patients locally advanced metastatic solid tumors NCT05378425. No conflict interest.
منابع مشابه
Oncolytic adenovirus coexpressing interleukin-12 and shVEGF restores antitumor immune function and enhances antitumor efficacy
Tumor microenvironment is extremely immunosuppressive, preventing efficient induction of antitumor immunity. To overcome tumor-mediated immunosuppression and enhance the potency of immunogene therapy, oncolytic adenovirus (Ad) co-expressing interleukin (IL)-12 and vascular endothelial growth factor (VEGF)-specific short hairpin ribonucleic acid (shVEGF; RdB/IL12/shVEGF) was generated. Intratumo...
متن کاملSTAT1-Induced HLA Class I Upregulation Enhances Immunogenicity and Clinical Response to Anti-EGFR mAb Cetuximab Therapy in HNC Patients.
The goal of this study was to characterize the molecular mechanisms underlying cetuximab-mediated upregulation of HLA class I antigen-processing machinery components in head and neck cancer (HNC) cells and to determine the clinical significance of these changes in cetuximab-treated HNC patients. Flow cytometry, signaling studies, and chromatin immunoprecipitation (ChIP) assays were performed us...
متن کاملChemotherapy enhances vaccine-induced antitumor immunity in melanoma patients.
Combination of chemotherapy with cancer vaccines is currently regarded as a potentially valuable therapeutic approach for the treatment of some metastatic tumors, but optimal modalities remain unknown. We designed a phase I/II pilot study for evaluating the effects of dacarbazine (DTIC) on the immune response in HLA-A2(+) disease-free melanoma patients who received anticancer vaccination 1 day ...
متن کاملIL-2 in vivo activities and antitumor efficacy enhanced by an anti-IL-2 mAb.
IL-2 is a potent immunostimulant and has been tested for clinical use, including in immunotherapy for cancers and HIV infection. Here we show that a widely used neutralizing anti-murine IL-2 mAb (S4B6) exhibits unexpected activities that enhance the treatment effects of IL-2 in vivo. Coinjection of the anti-IL-2 mAb with a plasmid carrying murine IL-2 cDNA significantly increased the serum IL-2...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
ژورنال
عنوان ژورنال: European Journal of Cancer
سال: 2022
ISSN: ['0959-8049', '1879-0852']
DOI: https://doi.org/10.1016/s0959-8049(22)00987-x