PharmaShots Interview: Cue Biopharma's Anish Suri Shares Insights on the Data of CUE-401 Presented at 2021 FOCIS Annual Meeting

In an interview with PharmaShots, Anish Suri, Ph.D., President, and Chief Scientific Officer at Cue Biopharma shared his views on new preclinical data of CUE-401 for the treatment of autoimmune diseases at the 2021 FOCIS Annual Meeting

Shots:

The company has reported the preclinical data of CUE-401 which can induce & expand regulatory T cells in vitro and in vivo & has the potential to be deployed for many chronic autoimmune diseases like lupus, IBD, RA, GVHD & transplant rejection
In vivo data, CUE-401 can effectively induce FOXP3-expressing iTregs from T cells from healthy donors along with patients suffering from RA & IBD. CUE-401 as monothx. was effective at inducing Tregs in mice with active and ongoing autoimmunity
CUE-401 is a bispecific molecule engineered to deliver 2 signals i.e., TGF-ß & IL-2 that is required to induce iTregs

Tuba: Can you please provide a highlight of the data presented at FOCIS 2021?

Anish Suri: Cue Biopharma's strategic focus in autoimmunity and inflammation has centered on two key approaches: (i) for diseases with known or restricted autoantigens we have deployed Immuno-STATs to target antigen-specific pathogenic T cells, and (ii) a pathway-specific approach that focuses on regulatory T cells and pathways that re-set immune balance. To the latter point, Cue Biopharma presented preclinical data on its first drug product candidate from the CUE-400 series, CUE-401, that is designed for selective differentiation and expansion of induced regulatory T cells (iTregs) in a patient's body (CD4+FOXP3+ iTregs). CD4+FOXP3+ Tregs are a critical subset of immune cells involved in the control of immune tolerance by regulating immune homeostasis and limiting self-reactive immune responses.

CUE-401 incorporates rationally engineered cytokines (variants of IL-2 and TGF-ß) that have been known to induce differentiation of naïve T cells to iTregs. Induction of Tregs in vivo is an innovative and potentially effective means of suppressing autoimmune and chronic inflammatory diseases.

Key data highlights from the FOCIS presentation include:

CUE-401-induced Tregs are phenotypically comparable to iTregs generated with soluble forms of TGF-beta and IL-2 found in nature.
In vitro, CUE-401 can effectively induce and expand FOXP3-expressing Tregs from T cells isolated from peripheral blood mononuclear cells (PBMCs) obtained from healthy donors as well as donors with rheumatoid arthritis (RA) and inflammatory bowel diseases (IBD).
CUE-401-induced Tregs additionally demonstrated the ability to functionally suppress the response of effector T cells, hence supporting mechanistic activity.
Studies in in vivo models also demonstrated that a single dose of CUE-401 was effective at inducing and expanding Tregs in mice with active and ongoing autoimmune gastritis. Specifically, seven days following a single dose of CUE-401, an increased percentage of FOXP3+ CD4+ T cells was found in the blood and gastric draining lymph nodes. The increase in Tregs was also accompanied by suppression of autoreactive T cell proliferation.

Tuba: What is CUE-401? How can it induce and expand regulatory T cells in vivo?

Anish Suri: CUE-401 is a novel bispecific molecule engineered to deliver two key immunomodulatory cytokine signals to induce and expand regulatory T cells (Tregs): 1) transforming growth factor-beta (TGF-ß) and 2) interleukin 2 (IL-2). The cytokine signals used in CUE-401 are variants from the versions found in nature with the IL-2 signal modified to have different affinity for IL-2 receptor subunits and TGF-ß modified to reduce TGF-ß receptor binding. (Figure 1)

Delivery of wild-type TGF-ß and IL-2 found in nature has its challenges given that it does not ensure that both signals will engage the same target T cells. In addition, ex vivo delivery can lead to systemic effects and safety liabilities. To this end, CUE-401 provides an elegant solution that can deliver the two key cytokine signals to the same target T cell, and potentially circumvent the safety liabilities.

Tuba: What indications does Cue Biopharma plan to assess CUE-401 on and why?

Anish Suri: Cue-401 has the potential to be deployed for many chronic autoimmune diseases like lupus, IBD (inflammatory bowel diseases), RA (rheumatoid arthritis), and for patients suffering graft versus host disease (GVHD) and even transplant rejection. Cue Biopharma continues its ongoing characterization of CUE-401 in preclinical disease models to identify priority indications.

Tuba: In addition to CUE-401, CUE Biopharma is advancing a pipeline of therapeutics leveraging its Immuno-STAT (Selective Targeting and Alteration of T cells) platform. Can you explain how the platform works?

Anish Suri: The Immuno-STAT' (Selective Targeting and Alteration of T cells) platform creates stable, off-the-shelf molecules referred to as Immuno-STATs, designed to selectively engage and modulate disease-relevant T cells within the patient's body without the need for ex vivo manipulation. The key benefit is the ability to provide targeted therapies for both cancers and autoimmune diseases with the potential for higher efficacy while avoiding the negative side effects of global systemic approaches.

Immuno-STATS are reverse engineered to mimic the natural mechanism that antigen-presenting cells (APCs) use to engage T cells during an immune response. This is done through the simultaneous presentation of two different signals or 'cues'that lead to selective T cell activation against the disease target of choice:

Signal #1 enables specificity and selectivity of T cells. It consists of the target disease antigenic peptide presented by stabilized MHC molecules (also known as HLA molecules in humans). The peptide-HLA complex engages only the disease-relevant T cells via their T cell receptor (TCR).
Signal #2 consists of a key immune-regulatory signal to enable selective activation or inhibition of disease-specific T cells for the treatment of cancer or autoimmune disease, respectively.

Tuba: How do Immuno-STAT biologics selectively modulate disease-associated T cells to fight cancer?

Anish Suri: Immuno-STAT cancer-specific molecules leverage a modified immune-activating molecule, interleukin 2 (IL-2), that has been uniquely engineered to achieve preferential selective activation of the cancer-killing T cells (CD8+ cytotoxic T-cells). Signal #1 varies for each specific drug product program, as it provides specificity for each tumor type.

For instance, CUE-101, Cue Biopharma's lead drug product candidate in development for the treatment of patients with human papillomavirus-positive recurrent/metastatic head and neck squamous cell carcinoma (HPV+ R/M HNSCC) includes the HPV E7 protein, as its Signal #1. This enables specificity against HPV+ tumors.

CUE 101 has already demonstrated clinical potential in Phase 1 clinical trial as monotherapy in late-stage cancer patients, including a confirmed partial response with an approximate 50% tumor reduction and six stable disease responses, as of June of 2021' a rarity for the immuno-oncology space in which very few immunotherapies show single-agent clinical benefit.

Tuba: What next steps should we expect from Cue Biopharma in terms of clinical programs, collaborations, and other aspects?

Anish Suri: In terms of CUE-401, we continue an ongoing characterization of the biologic in preclinical disease models to identify priority indications. Our research program with Merck to develop clinical Immuno-STAT candidates from our CUE-300 series for selected autoimmune diseases has provided favorable pre-clinical results, with our lead candidate, CUE-301.

We continue to make progress in our immuno-oncology programs with our CUE-101 Phase 1a/b monotherapy dose-escalation and expansion trials in patients with HPV+ second line and beyond (2L+) head and neck squamous cell carcinoma. In addition, CUE-101 is being evaluated in Phase 1 dose-escalation trial as first-line treatment in combination with Merck's anti-PD-1 therapy, KEYTRUDA® (pembrolizumab) in the same patient population. In parallel, we continue our work to further develop and optimize our platform technologies and our pipeline, including CUE-102, our next clinical candidate, targeting the Wilms' tumor 1 (WT1) antigen for cancer treatment. CUE-102 is on track for IND filing in 2022. Beyond that, we have very exciting data demonstrating the activity of Immuno-STATs with mutated KRAS epitopes that can be harnessed for cancers with specific KRAS driver mutations. We continue to move these novel molecules forward with much enthusiasm.

Tuba: Are you open to additional collaborations to advance the development and delivery of your Immuno-STAT Biologics?

Anish Suri: We are open to exploring strategic partnerships and collaborations selectively with potential partners that have the depth of scientific understanding and complementary capabilities that allow us to rapidly move our assets into the clinic and help maximize the fullest potential of our platform. The modularity and flexibility of our technology allow us to generate vast numbers of therapeutic molecules in a relatively short period, hence enabling partnerships that expedite execution of our R&D strategy is of the highest importance to our objectives.

Source: Bradford Today

About Author: Anish Suri is the President and Chief Scientific Officer. He received his Ph.D. in immunology from Washington University in St Louis, Missouri. He is an immunologist with extensive experience in basic and translational research focused on immuno-oncology, autoimmune disorders, transplantation rejection, and inflammation.