CUE-100 series Advanced Drug Monograph

Name: CUE-100 series Name (English): CUE-100 series

The CUE-100 series is a platform of Immuno-STAT (Selective Targeting Antibody-Agonist Therapeutics) biologics developed by Cue Biopharma. These molecules are engineered to selectively activate and expand antigen-specific T cells for the treatment of cancer and other diseases.

Key Features of CUE-100 Series:

• Mechanism of Action: Immuno-STATs deliver a rationally engineered IL-2 variant (Signal #2) to antigen-specific T cells by binding to the peptide-HLA complex (Signal #1) on antigen-presenting cells (APCs) through a T cell receptor (TCR). This targeted delivery aims to maximize the activation of tumor-specific T cells while minimizing the systemic toxicities associated with untargeted IL-2 therapies and reducing the activation of regulatory T cells (Tregs).
• Engineered IL-2 Variant: The IL-2 component in the CUE-100 series contains mutations that attenuate its binding to the alpha (CD25) and beta (CD122) chains of the IL-2 receptor. This modification reduces the activation of Tregs and non-antigen-specific T cells, enhancing the selectivity for the targeted T cell population.
• Versatility: The modular design of the Immuno-STAT platform allows for the generation of CUE-100 series molecules targeting various disease-associated antigens by swapping out the Signal #1 component. This enables the development of therapeutics for different cancer types, infectious diseases, and autoimmune disorders.

Clinical Development:

Several drug candidates within the CUE-100 series are currently in clinical development:

• CUE-101: This lead candidate targets the HPV16 E7 protein and is being evaluated in Phase 1 and Phase 2 trials for the treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), both as a monotherapy and in combination with pembrolizumab. Early clinical data has shown promising anti-tumor activity. CUE-101 is also being investigated in the neoadjuvant setting for newly diagnosed, locally advanced HPV16+ oropharyngeal squamous cell carcinoma.
• CUE-102: This candidate targets the Wilms' Tumor 1 (WT1) protein and is in a Phase 1 trial for various WT1-expressing cancers, including gastric, pancreatic, ovarian, and colon cancers.
• Other Candidates: Cue Biopharma has presented preclinical data on other CUE-100 series molecules targeting antigens such as MART-1, CMV, FLU virus, and HIV, demonstrating their ability to selectively expand antigen-specific T cells.

Preclinical Findings:

Preclinical studies have demonstrated that CUE-100 series Immuno-STATs can:

• Induce significant expansion of functional, oligoclonal, antigen-specific CD8+ T cells in vitro and in vivo.
• Exhibit reduced proliferation of non-target T cells and Tregs compared to wild-type IL-2.
• Show anti-tumor activity in animal models.

Overall:

The CUE-100 series represents a novel approach to immunotherapy by leveraging targeted delivery of an engineered IL-2 cytokine to enhance the anti-disease immune response while mitigating potential toxicities. Clinical trials are ongoing to evaluate the safety and efficacy of these drug candidates in various indications.