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553 CUE-100 series Immuno-STATs from concept to the clinic: Leveraging protein engineering to stimulate and selectively deliver affinity-attenuated IL-2 to antigen-specific T cells
  1. Alex Histed1,
  2. Natasha Girgis1,
  3. Miguel Moreta1,
  4. Jonathan Soriano1,
  5. BS Luke Witt1,
  6. Zohra Merazga1,
  7. Fulvio Diaz1,
  8. Fan Zhao1,
  9. Melissa Kemp1,
  10. Paige Ruthardt1,
  11. Dharma Thapa1,
  12. Anish Suri1,
  13. Ronald Seidel1,
  14. Kenneth Pienta2,
  15. Mary Simcox1,
  16. Steven Quayle1,
  17. John Ross1 and
  18. Saso Cemerski1
  1. 1CUE Biopharma, Cambridge, MA, USA
  2. 2Johns Hopkins University School of Medic, Baltimore, MD, USA


Background Activation of T cells requires a specific peptide/HLA (human leukocyte antigen) signal presented by an interacting immune or target cell along with engagement of co-stimulatory molecules or cytokine receptors. Cue Biopharma has developed a proprietary biologics platform, termed Immuno-STAT™ (Selective Targeting and Alteration of T cells), wherein a singular protein framework incorporates peptide/HLA complexes and co-stimulatory or cytokine signals. The CUE-100 series Immuno-STATs selectively deliver rationally engineered IL-2 molecules to antigen-specific T cells. The IL-2 molecules in the CUE-100 series Immuno-STATs contain mutations that attenuate binding to IL-2 receptors alpha and beta, which minimizes activation of regulatory T cells (Tregs) and the irrelevant non-antigen-specific T cell repertoire. We have demonstrated that CUE-100 series Immuno-STATs specific for different antigenic peptides (from HPV16, WT1, MART-1, CMV, Flu, and HIV) induce expansion of functional, oligoclonal, antigen-specific repertoires from human PBMCs. The lead clinical candidate CUE-101, presenting the E711-20 peptide from HPV-16 in the context of HLA-A*02:01, is currently being tested in a Phase 1 clinical trial in recurrent/metastatic head and neck cancer patients with evidence of dose-proportional PK, early pharmacodynamic effects and signals of clinical activity.

Methods CUE-100 series Immuno-STATs were tested with human PBMCs to demonstrate specific T cell activation and expansion. Expanded T cell clonality was assessed by single cell TCR sequencing. Responses of T cells to peptide-presenting targets was evaluated by cytokine staining and by assessing their ability to kill target cells. In vivo activity of CUE-100 series Immuno-STATs was assessed in HLA-A2 transgenic mice.

Results Data demonstrate that the CUE-100 series Immuno-STATs selectively activate antigen-specific CD8+ T cells. Signaling, cell-based assays and cytokine release studies confirmed functional attenuation of the IL-2 components of the CUE-100 series, which allows for a favorable safety and selectivity profile. Immuno-STATs demonstrated robust expansion of CD8+ T cells after primary stimulation of unprimed hPBMCs, or re-stimulation of hPBMCs after initial cognate peptide stimulation. In addition, CUE-100 series Immuno-STATs expanded CD8+ T cells in naïve HLA-A*02 transgenic mice. In both cases the expanded T cells exhibited a polyfunctional response upon challenge with peptide-presenting target cells.

Conclusions The presented data suggests that CUE-100 series Immuno-STATs have the potential to enhance anti-tumor immune responses by inducing a robust antigen-specific, oligoclonal, polyfunctional T cell repertoire. Early validation of CUE-100 series Immuno-STATs is obtained through the emerging signs of pharmacodynamic and clinical activity in the ongoing Phase I trial with CUE-101.


  1. Quayle SN, Girgis N, Thapa DR, et al. CUE-101, a Novel HPV16 E7-pHLA-IL-2-Fc Fusion protein, enhances tumor antigen specific T cell activation for the treatment of HPV16-driven malignancies. Clin Cancer Res 2020;26:1953–64.

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