For applications in autoimmune (AI) diseases, our strategy has focused on antigen-specific modulation and pathway-specific modulation for controlling autoreactive T cell responses. Both approaches complement each other and offer unique opportunities for selective immune re-set of the dysfunctional compartment. The antigen-specific approach is pertinent to diseases with restricted or well-characterized autoantigens and deploys Immuno-STATs to directly modulate the autoreactive T cells. The pathway-specific approach exploits signals that can induce and sustain regulatory T cells, which can then control a broad population of autoreactive T cells. Hence, this approach may be more applicable to diseases with diverse unknown antigens. It is conceivable that the specific signals for Treg induction could be deployed in an Immuno-STAT framework for generation of antigen-specific Tregs.
Approaches to Modulate Autoreactive T Cell Responses
CUE-300 Series: Antigen-Specific Approach
Our CUE-300 framework incorporates class II HLA alleles and is designed to target a broad range of addressable autoimmune diseases by selectively inhibiting the activity of autoreactive CD4+ T cells and/or enhancing the generation and functionality of regulatory T cells (Tregs). Selective targeting of the dysregulated axis in autoimmune diseases should avoid systemic immunosuppression and therefore should not hamper the immune system’s ability to effectively respond to malignancies and infectious organisms.
The CUE-300 Series Immuno-STATs focus on two general strategies:
- Selective inhibition of autoreactive CD4+ T cells by delivering inhibitory signals; or
- Selective expansion of antigen-specific CD4+ regulatory T cells (Tregs) to control aberrant activation of autoreactive T cells
Our lead candidate from the CUE-300 series is CUE-301, a Class II HLA DR0401-based Immuno-STAT that is designed to target and selectively inhibit proinsulin reactive CD4+ T cells in Type 1 diabetes to prevent these cells from injuring or killing insulin-producing beta cells in the pancreas.
CUE-301, contains two copies of the programmed death receptor ligand-1 (PD-L1) (an inhibitory Signal 2) and two copies of a pMHC (Signal 1) comprised of Class II MHC DRB1*0401 complexed with a peptide derived from proinsulin (amino acids 76 to 90), a prohormone precursor to insulin synthesized by beta cells of the islets of Langerhans of the pancreas. Proinsulin has been recognized as an important target antigen in Type 1 diabetes and prior studies have identified T cells from human patients that react against this epitope in the early stages of disease pathogenesis.
This program is a part of our collaboration with Merck & Co., Inc. where we have demonstrated that CUE-301 can selectively inhibit the expansion of proinsulin reactive T cells isolated from the blood of type 1 diabetes patients. In preclinical studies in DR0401-transgenic mice, CUE-301 was shown to inhibit the functional in vivo expansion of proinsulin-specific CD4+ T cells along with a notable reduction in production of pro-inflammatory cytokines.
Selective Suppression of Proins-specific T Cells In Vivo
Untreated Mice / IFNγ ELSIpot
IST Mice / IFNγ ELSIpot
Framework and Selective Suppression of Proins-specific T cells In Vitro
LEGEND: CUE-301 is Cue’s first Immuno-STAT targeting an autoimmune disease, Type 1 diabetes. The CUE-300 series differs from the CUE-100 series in that the pMHC module is comprised Class II MHC with a DRB1*04 HLA allele and an immune checkpoint ligand, programmed death receptor-1 ligand (PD-L1), as the co-regulatory (or co-inhibitory) module.
Additional datasets underscoring our progress with CUE-301 were recently presented at an autoimmune meeting in January 2021.