Our Approach

Harnessing the Immune System

“Restoration of Immune Balance via Harnessing Nature’s Cues”

Immune balance is essential for sustaining human health, while dysregulation and imbalance of the immune system can lead to serious diseases. Susceptibility to cancers and infectious disease can be attributed to inadequate, attenuated, or suppressed immune responses. Conversely, autoimmune diseases result from an overactive immune system that reacts against self-tissue.

Restoring Immune Balance

A key aspect of immune homeostasis is the interplay of two essential components: 1.) a competent effector T cell (Teff) repertoire that can identify and eliminate threats from malignancies and infections, and 2.) the presence of a functional regulatory T cell (Treg) compartment that can control and prevent autoimmune responses. The balance of these two essential components of the adaptive immune system provides our bodies with the ability to selectively marshal a highly effective immune attack, while protecting the body from unwanted collateral harm. A significant number of current therapeutic approaches focus on broad, indiscriminate systemic modulation of the immune system with little to no consideration for specificity or selectivity of the immune response that is relevant to a particular disease. Hence, limited clinical efficacy, coupled with compromised patient safety and tolerability, present considerable drawbacks for many current therapeutic options.

A superior therapeutic strategy would selectively and specifically modulate only disease-relevant T cells, while preserving patient safety and restoring immune homeostasis and balance.This is the core foundational principle that underscores our approach with the Immuno-STAT biologics platform

The Immuno-STAT: A Selective Immune Response, Induced on Cue

Cue Biopharma deploys a rational protein engineering approach to design and develop novel proprietary molecules that build upon the fundamental immunological principles to selectively regulate the activity of disease-relevant T cells. These principles focus on “nature’s cues” for antigen specificity of T cells (Signal 1) together with appropriate secondary activating or inhibitory signals (Signal 2) depending on the disease indication. Cue Biopharma’s innovative platform technologies combine Signal 1 and 2 into a single protein molecule that is stabilized by the Fc portion of a human antibody that serves as the molecule’s backbone and provides manufacturability and structural stability. Cue Biopharma calls its technology platform Immuno-STAT (Selective Targeting and Alteration of T cells).

Immuno-STAT Framework

Signal 1: A stabilized peptide-major histocompatibility complex (pMHC), Class I or II, to selectively engage disease-relevant T cells by incorporating diverse antigenic peptides of interest and choosing different MHC (or HLA) alleles to provide broad coverage for global patient populations.

Signal 2: Distinct co-stimulatory or co-regulatory signals, including cytokines, cell-surface receptors, and other targeting modalities, to control the activity of disease-relevant T cells.

Fc Backbone: Well-characterized protein construct from human antibodies to provide stability and ease of manufacturability that can be engineered to dial in or out biological and effector functions.

A core feature of our Immuno-STAT platform is modularity. Each key component of Immuno-STAT biologics, Signals 1 and 2 and the Fc backbone, can be tailored for various disease indications and desirable biological responses. Much like a “rheostat”, the Immuno-STAT can be deployed effectively to selectively dial up or dial down specific immune responses tailored for diverse diseases. This distinguishing feature enables us to design multiple unique biologics that display a disease-specific antigen (as a stabilized peptide-MHC complex), Signal 1, with an appropriate stimulating Signal 2 to treat cancer and infectious diseases, or an inhibitory or regulatory Signal 2 for autoimmune and inflammatory diseases.

To demonstrate the versatility of the Immuno-STAT framework, Immuno-STATs with five different peptides were designed and synthesized. These included immunogenic peptides derived from:

  • Influenza A virus matrix protein-1 (MP158-66)
  • Cytomegalovirus (CMV) phosphoprotein 65 (pp65495-503)
  • Melanoma associated antigen recognized by T cells (MART-126-35)
  • Wilms’ tumor 1 (WT137-45)
  • Mutated Kirsten rat sarcoma virus (KRAS G12V7-16), a human oncogene

In each case, the co-stimulatory module used in the Immuno-STAT construct is the IL-2 variant utilized in our CUE-100 series Immuno-STATs described below.

Versatility of the Immuno-STAT Framework

Immuno-STATs induce robust proliferation and expansion of antigen specific CD8+ T cells from human peripheral blood mononuclear cells (PBMCs)

We believe our novel and proprietary platform, Immuno-STAT, and its next-generation derivative platform, Neo-STAT, provide superior differentiated solutions to selectively modulate the activity of disease-relevant T cells directly in a patient’s body in order to induce an effective immune response against cancer cells and pathogens. Similarly, Immuno-STATs (as well as Neo-STATs) can be engineered with different Signals 1 and 2 to attenuate or inhibit a debilitating and life-threatening immune response that underlies the pathology of autoimmune diseases.

Neo-STAT: The Next-Generation

Our next-generation platform, Neo-STAT, is a derivative of the Immuno-STAT platform and builds upon its core structural framework applications. It is rationally designed and engineered to enable flexibility for targeting a myriad of cancer antigen epitopes, thereby addressing the heterogeneity of many cancers, while also enhancing productivity and efficiencies in the generation of therapeutic molecules. While preserving the basic framework and functional properties of Immuno-STATs pertaining to Signals 1 and 2 and the Fc backbone, Neo-STATs differ in one major and important way. The Signal 1 pMHC portion of Immuno-STATs are produced as fusion proteins such that the peptide antigen of interest occupies the peptide-binding cleft of the MHC as it would in nature. As with all biomolecular drugs such as monoclonal antibodies and bifunctional antibodies (“BiTEs”), this requires a dedicated cell line for each Immuno-STAT targeting a particular epitope. In Neo-STATs, however, the MHC cleft is unoccupied and stabilized such that any disease-relevant peptide antigen of interest can be efficiently and readily attached to the MHC cleft via a chemical reaction.

Next Generation Derivative of the Immuno-STAT Platform

The Neo-STAT platform, shown here with the CUE-100 series construct using an IL-2 variant as the co-stimulatory module, is essentially identical to Immuno-STAT but without a peptide antigen in the MHC peptide binding cleft.

Signal 1: An unoccupied peptide antigen cleft in MHC into which different peptide antigens of interest can be chemically conjugated to create a stabilized pMHC to selectively engage disease-relevant T cells

Signal 2, Fc Backbone, and Peptide Linker: Analogous to the core framework of Immuno-STATs

This innovation has the potential to vastly enhance our reach into the diverse universe of tumor antigens, efficiently address tumor heterogeneity and increase research and development efficiencies. Rather than having to produce a dedicated cell line for each individual Immuno-STAT for each peptide antigen of interest, a single clinical grade Neo-STAT scaffold, with an empty MHC cleft, can be manufactured in bulk using a dedicated production cell line. The Neo-STATs can then be developed into drug candidates by selecting various peptide-antigens of clinical interest by chemically attaching to the empty MHC cleft. Through this stable antigen epitope attachment process, Neo-STATs provide enhancement of productivity and offer the potential for much greater clinical utility including the use of multiple tumor antigens for multi-antigen based cocktail therapy, post-translationally modified peptides, difficult to manufacture peptides or altered peptide ligands, and tumor neo-antigens for personalized cancer immunotherapy.

Therapeutic Application of Immuno-STATs and Neo-STATs

Cue Biopharma is actively exploring the therapeutic potential of Immuno-STATs and Neo-STATs to treat cancer, infectious diseases, and autoimmune diseases.

  • In the context of cancer and infectious disease, Immuno-STATs and Neo-STATs are designed to selectively activate disease-relevant T cells.
  • For the treatment of autoimmune disease, Immuno-STATs are designed to selectively inhibit pathogenic autoreactive T cells.

Notably in oncology, Immuno-STATs do not antagonize, i.e., shut off or block, a specific enzymatic reaction, biochemical pathway, or receptor-ligand interaction as many chemotherapeutic and targeted agents, as well as most antibody-based therapeutics. Rather, Immuno-STATs act as an agonist, i.e., to stimulate and activate an adaptive immune response, including targeted anti-tumor T cells for eradication of cancers. In this way, Immuno-STATs (as well as Neo-STATs) modulate the patient’s own immune system to address the underlying disease.

CUE-101: Cue Biopharma’s Leading Drug Candidate is Currently in Clinical Trials: A Phase 1 Monotherapy (2L+) and a Combination (1L) Clinical Trial

Our lead compound, CUE-101, representative of the IL-2 based CUE-100 series, is designed to specifically engage and activate T cells that recognize a peptide antigen (epitope) derived from the E7 protein of human papilloma virus (HPV). According to the National Cancer Institute (NCI), HPV is an oncogenic (i.e., cancer causing) virus linked to about 5% of all cancers worldwide, including most cervical, vulvar, vaginal, penile, anal and certain types of head and neck cancers (i.e., oropharyngeal). It is estimated that HPV is linked to approximately 70% of all Head and Neck Squamous Cell Carcinoma cancer. Tumor cells of these cancers express the viral E7 protein, which we believe can be recognized and selectively eliminated by CUE-101 stimulated T cells.

In September 2019, we commenced a dose-escalation and expansion Phase 1 clinical trial of CUE-101 as second-line, or later, therapy in heavily pre-treated patients with progressive recurrent or metastatic HPV-driven head and neck cancer (NCT03978689). In this monotherapy study, we anticipate enrolling up to 50 patients to evaluate safety and tolerability, pharmacokinetics and pharmacodynamics, and to assess signs of therapeutic efficacy, as well as determine a recommended dose for expanding one of the dose cohorts to 20 patients. The data emerging from this monotherapy trial has been encouraging to date with evidence of tolerability at therapeutically promising relevant dose levels, demonstrating dose proportional exposure pharmacokinetics (PK) and associated pharmacodynamic (PD) activity. Furthermore, this dose escalation/patient expansion trial has demonstrated evidence of anti-tumor activity with confirmed stable disease in several patients despite still being in the dose escalation part of the study. Based upon the information provided by this trial to date, we believe the data from CUE-101 has reduced the risk profile and enhanced the potential value potential of the CUE-100 series. Furthermore, the mechanistic evidence emerging from this trial supports the potential for mechanistic synergy in combination with checkpoint inhibitors, such as pembrolizumab.

In February 2021, we treated the first patient in an ongoing dose-escalation and expansion Phase 1 clinical trial of CUE-101 in combination with pembrolizumab (KEYTRUDA®) as first-line therapy in newly diagnosed patients with recurrent or metastatic head and neck cancer (NCT03978689). We expect to enroll up to 35 additional patients to evaluate tolerability, pharmacokinetics and pharmacodynamics, and to evaluate the therapeutic efficacy of this drug combination. We believe the combination of CUE-101 with pembrolizumab has the potential for synergistic therapeutic benefit in these patients, as the mechanism of action for the two drugs should be complimentary in their effect. Pembrolizumab is approved for first line (1L) therapy in these patients and provides therapeutic benefit by blocking a key defense mechanism utilized by the cancer cells, thereby evading the attempts of the patient’s activated T cells from accessing the tumor cells. In essence, the therapeutic benefit from pembrolizumab comes from an existing HPV specific T cell population in the patient’s body attempting to attack the cancer but being modulated by the PD1 – PDL-1 checkpoint signal. Treatment with concurrent CUE-101 should increase this population of HPV specific T cells, potentiating the efficacy of pembrolizumab.

In addition to CUE-101, we have a growing pipeline of preclinical programs that deploy the IL-2 based CUE-100 series with additional well-characterized tumor antigens.

Commercialization Advantages

In addition to the selective modulation of T cell activity directly in the patient’s body, we believe Immuno-STATs and Neo-STATs offer several key points of potential differentiation over competing approaches:

  • Broad Disease Coverage – Access to a growing set of disease associated targets (extracellular and intracellular peptide antigens) and access to diverse patient populations based on their HLA (MHC) types to provide broad patient coverage and reach.
  • Manufacturability – Utilizes established industry standard development and production processes to support a cost-of-goods and supply chain similar to that of monoclonal antibodies. Immuno-STATs and Neo-STATs are stable, off-the-shelf biologics for use by treating physicians.
  • Conveniently Administered – Standard delivery format by intravenous (IV) injection entailing an intermittent dosing schedule (once every 3 weeks) that can be administered by specialists and community-based physicians

Leveraging Immuno-STATs to Address Tumor Resistance Mechanisms

A significant and ongoing challenge in tumor immunotherapy pertains to tumor resistance or escape mechanisms whereby a subset of tumors is able to evade T cell detection, by suppressing or downregulating the production of proteins involved in antigen processing and presentation of tumor antigens/epitopes to the adaptive immune system, including T cells. Among the escape mechanisms are changes or mutations of the antigen processing compartment (e.g., TAP transporters) or antigen presentation molecules (such as HLA or ß2-microglobulin), which make the tumor invisible to the anti-tumor T cells. The loss of immunogenicity of the tumor is an adaptive evolution of the cancer to avoid immune detection – a stage defined as the escape phase of cancer immuno-editing. It is estimated that upwards of 20%-30% of patients may have tumor cells utilizing this escape mechanism.

Our approach to addressing this escape mechanism takes advantage of related observations from detailed cellular analysis of human cancer tissues revealing the significant presence of CD8+ T cells that are not specific for the tumor antigens but instead recognizing viral antigens (such as EBV, flu or CMV). In other words, a significant fraction of the protective memory anti-viral T cell repertoire localizes to the tumor tissue, likely in response to chemotactic signals that are agnostic of specificity of the T cells. Hence, we have investigated the opportunity to leverage the Immuno-STAT platform to generate therapeutic molecules to re-direct or “trick” the viral T cell repertoire present in the tumor environment to recognize and kill the cancer cells, including those that have lost the expression of HLA molecules or the ability to present antigen effectively. The schematic below describes the generation of viral-specific Immuno-STATs, or RDI-STATs that can be tethered to a tumor cell via binding to tumor cell-surface antigens (e.g., Trop2, PSMA, mesothelin etc.). Thus, in this manner the tumor is coated with a viral Immuno-STAT to make it appear like a virally infected cancer cell, which can then be recognized by the anti-viral T cells that populate the host and the tumor tissue and become activated by the Immuno-STAT IL-2 to kill the tumor cell.

Viral T Cell Redirection via RDI-STATs: Immuno-STAT Framework with Tumor Targeting TAA

  • Harnesses a pre-existing and robust viral T cell repertoire present in high frequency
  • Superior specificity: avoids systemic activation of ALL T cells
  • Superior safety: minimizes cytokine release
  • De-risked by CUE-101 clinical experience