Targeting NKG2DLs with an ADCC enhanced fusion protein for induction of NK cell reactivity against ovarian cancer — ASN Events
  1. Schedule
  2. Poster Session One
  3. Targeting NKG2DLs with an ADCC enhanced fusion protein for induction of NK cell reactivity against ovarian cancer

Targeting NKG2DLs with an ADCC enhanced fusion protein for induction of NK cell reactivity against ovarian cancer (#135)

Ilona Hagelstein 1 2 , Kevin Wang 1 2 , Helmut R. Salih 1 2 3 , Martina S. Lutz 1 2
  1. Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
  2. Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
  3. German Cancer Consortium (DKTK), partner site Tübingen, a partnership between DKFZ and University Hospital Tübingen, Tübingen, Germany

Ligands for the activating immune receptor NKG2D (NKG2DLs) are frequently overexpressed on malignant cells while being largely absent in healthy tissues. Analysis of mRNA levels using The Cancer Genome Atlas (TCGA) identified elevated expression of various NKG2DLs in ovarian cancer, one of the most lethal gynecologic malignancy amongst others due to disease relapse and the emergence of chemoresistance. Despite the advent of monoclonal antibodies (mAbs) in cancer therapy more than two decades ago, patients with ovarian cancer have not yet experienced benefits of this treatment modality. Natural killer (NK) cells play a crucial role for the therapeutic efficacy of antitumor mAb by mediating antibody-dependent cellular cytotoxicity (ADCC) because of which many efforts are aimed at enhancing this pivotal antibody function by modifications to the Fc region, aiming to improve NK cell-mediated ADCC.

Here we aimed to utilize the rather tumor-specific expression of NKG2DLs by employing them as targets for an Fc-optimized NKG2D-Ig fusion protein (NKG2D-ADCC) to induce NK cell ADCC against ovarian cancer. The NKG2D-ADCC construct has been modified in the Fc part by introducing the S239D/I332E mutations, thereby enhancing the binding affinity to the Fc receptor CD16.

Flow cytometric analysis revealed a diverse range of expression patterns for NKG2DLs across all tested ovarian cancer cell lines, with at least two NKG2DLs present in each sample. Functional testing demonstrated that NKG2D-ADCC effectively activated NK cells against cancer cells, resulting in degranulation and release of IFN-γ. Control constructs with unrelated specificity did not exhibit similar effects, thereby affirming the targeted nature of our approach. Finally, NKG2D-ADCC profoundly induced NK lysis of ovarian cancer cells in both short- and long-term cytotoxicity assays.

Together, our findings show that our NKG2D-ADCC fusion protein robustly enhances NK cell reactivity against ovarian cancer cells, representing a promising avenue for immunotherapeutic intervention.