Cue Biopharma, Inc. (CUE)

Executive Summary / Key Takeaways

• Cue Biopharma is leveraging its Immuno-STAT platform, designed for selective T-cell modulation, across oncology and autoimmune diseases, aiming for enhanced efficacy and reduced toxicity compared to broader approaches.
• Recent strategic prioritization has shifted focus towards autoimmune programs (CUE-401, CUE-500 series) and seeking partnerships for oncology assets (CUE-100 series) to manage capital and accelerate development.
• A significant collaboration with Boehringer Ingelheim for CUE-501, a B cell depletion therapy, provides a $12 million upfront payment and potential milestones, validating the platform's autoimmune application and extending the cash runway.
• Despite promising clinical data for oncology candidates CUE-101 and CUE-102 showing signs of enhanced efficacy and tolerability, further development is contingent on securing strategic alliances.
• The company faces substantial financial challenges, including recurring losses and a going concern risk, necessitating significant additional funding beyond the current runway into Q2 2026, compounded by a recent Nasdaq minimum bid price deficiency.

The Promise of Precision: Cue Biopharma's Immuno-STAT Platform

Cue Biopharma is a clinical-stage biopharmaceutical company dedicated to developing a novel class of injectable biologics designed to selectively engage and modulate disease-specific T cells directly within the patient's body. At its core is the proprietary Immuno-STAT platform, which seeks to translate nature's intricate signaling mechanisms into therapeutic proteins. This approach represents a fundamental departure from conventional immunotherapies that often broadly activate the immune system, leading to unwanted side effects. By focusing on selective modulation, Cue Biopharma aims to enhance therapeutic efficacy while minimizing off-target effects, potentially establishing new standards of care in areas of high unmet medical need.

The Immuno-STAT platform is engineered for flexibility and modularity. It utilizes biologics that present two key signals, or "cues," to T cells: a stabilized peptide-MHC (pMHC) complex that selectively binds to T cells expressing a specific T-cell receptor (TCR) relevant to the disease, and a functional immune-modulating signal like an attenuated cytokine. This design ensures that only the targeted, disease-relevant T cells receive the activation or modulation signal. The platform's modularity allows for different peptide-HLA complexes and immune signals to be swapped into the core framework, enabling the development of a diverse pipeline targeting various diseases and patient populations. This inherent flexibility also offers potential advantages in manufacturing and regulatory pathways, as demonstrated by the regulatory efficiency gained with the CUE-102 IND filing, which leveraged clinical and safety data from CUE-101 due to their 99% sequence identity, bypassing the need for repeat preclinical toxicology studies and accelerating clinical entry.

Strategic Evolution and Pipeline Prioritization

Cue Biopharma's journey began with foundational technology licensed from Albert Einstein College of Medicine in 2015, which underpins its core platform. Early efforts focused on building out the Immuno-STAT technology and initiating clinical development in oncology. The company has historically funded its operations through equity financings and collaborations, facing recurring losses and the continuous need for additional capital inherent to the clinical-stage biotech model.

Facing challenging capital market conditions, Cue Biopharma recently underwent a strategic restructuring to optimize its path forward. The company has prioritized the development of its autoimmune programs, specifically the CUE-400 and CUE-500 series, for near-term focus and resource deployment. Concurrently, it is actively seeking third-party support through partnerships and collaborations to advance its CUE-100 series oncology programs, including CUE-101 and CUE-102. This strategic pivot aims to reduce capital requirements, extend the cash runway, and leverage external resources and expertise to accelerate pipeline development across multiple fronts.

Validating the Platform: Clinical Insights and Autoimmune Momentum

Clinical validation of the Immuno-STAT platform has primarily come from the CUE-100 series in oncology. While these programs are now being positioned for partnerships, the data generated to date are foundational to the platform's investment thesis. CUE-101, targeting HPV-associated cancers, has been evaluated in Phase 1b trials. In the first-line setting in combination with KEYTRUDA for HPV+ recurrent metastatic head and neck squamous cell carcinoma (HNSCC) patients (CPS > 1), the combination demonstrated an overall response rate (ORR) of 46%, significantly higher than the 19% historical ORR observed with pembrolizumab monotherapy. Notably, in patients with low CPS scores (1-19), the combination achieved a 50% ORR compared to approximately 15% historically with pembrolizumab alone. The median progression-free survival (PFS) was 5.8 months versus 3.2 months historically, and the 12-month overall survival (OS) for CPS > 1 patients was 90% compared to 51% historically, with a median OS of 21.8 months versus 12.3 months. In the monotherapy setting for heavily pretreated (2L+) HPV+ HNSCC, CUE-101 showed a median OS of 20.8 months (4mg/kg cohort) and 24.8 months (2mg/kg cohort), compared to historical median OS of approximately 8 months with checkpoint inhibitors in the second line.

CUE-102, targeting WT1-expressing cancers (colorectal, gastric, ovarian, pancreatic), is in a Phase 1b monotherapy dose escalation trial. Early signs of anti-tumor activity and disease control have been observed across multiple indications, which is particularly encouraging given that these cancers have historically shown limited response to checkpoint inhibitors. While these oncology programs are now being advanced via potential partnerships, the clinical data underscore the platform's ability to selectively activate tumor-specific T cells and generate anti-tumor responses.

The strategic shift towards autoimmune diseases has quickly yielded a significant partnership. The CUE-400 series includes CUE-401, designed to induce and expand regulatory T cells (Tregs) for autoimmune conditions. Although the collaboration with Ono Pharmaceutical Co., Ltd. (OPHLY) for CUE-401 was terminated in March 2025, Cue Biopharma retained all rights and is continuing IND-enabling studies, targeting an IND filing in the third quarter of 2026, with human proof-of-mechanism data anticipated in the first half of 2027, subject to funding. The CUE-500 series focuses on targeted cell depletion. CUE-501, aimed at depleting autoimmune disease-causing B cells by redirecting anti-viral memory T cells, became the subject of a strategic collaboration and license agreement with Boehringer Ingelheim (BI) in April 2025. This agreement provides Cue Biopharma with a $12 million upfront payment and eligibility for up to approximately $345 million in success-based milestones plus royalties. BI has received an exclusive worldwide license and is responsible for all future development and commercialization of CUE-501, while Cue Biopharma is restricted from developing B cell depletion molecules during the four-year research term. This partnership represents a crucial validation of the Immuno-STAT platform's potential in autoimmune disease and provides significant non-dilutive funding.

Financial Position and Outlook

As a clinical-stage company, Cue Biopharma has not generated commercial revenue and has a history of operating losses and negative cash flows. For the three months ended March 31, 2025, collaboration revenue was $421,000, a decrease from $1.717 million in the same period of 2024, primarily due to the termination of the Ono collaboration. Research and development expenses decreased to $8.547 million from $10.199 million, reflecting reduced clinical trial costs for the CUE-100 series as activities shifted to patient monitoring. General and administrative expenses remained relatively consistent. The net loss for Q1 2025 was $12.257 million, comparable to $12.347 million in Q1 2024.

As of March 31, 2025, the company had cash and cash equivalents of $13.1 million. However, subsequent events in April 2025 significantly bolstered its liquidity. The underwritten public offering generated approximately $18.0 million in net proceeds, and the BI collaboration provided a $12.0 million upfront payment. Based on these funds and current operating plans, management believes existing resources will enable the company to fund operations into the second quarter of 2026.

Despite this extended runway, the company explicitly states that it will need substantial additional financing to fund future operations and remain a going concern. This need for capital raises substantial doubt about its ability to continue operations beyond the current runway. Future financing is expected to come from a combination of equity offerings, collaborations, and other strategic alliances. The volatility in capital markets poses a significant risk to securing necessary funding on acceptable terms.

Competitive Landscape and Risks

Cue Biopharma operates in a highly competitive biotechnology landscape, facing established pharmaceutical companies like Merck & Co., Inc. (MRK), Bristol Myers Squibb Company (BMY), F. Hoffmann-La Roche AG (RHHBY), and Gilead Sciences, Inc. (GILD), as well as numerous other biotech firms developing immunotherapies. While larger competitors possess vast financial resources, extensive pipelines, and established market presence, Cue Biopharma's competitive edge lies in the precision and modularity of its Immuno-STAT platform. The ability to selectively target disease-relevant T cells offers a potential differentiation in efficacy and tolerability compared to the broader mechanisms of action employed by many existing therapies, including checkpoint inhibitors and pan-T cell engagers. For instance, the CUE-500 series is positioned as significantly differentiated from other B cell depletion approaches like antibody-drug conjugates or CAR-T therapies, aiming for CAR-T like efficacy with a more manageable biologic format and potentially better safety profile.

However, Cue Biopharma's smaller scale and limited financial resources are significant disadvantages. Its R&D spending, while substantial for a company its size, is dwarfed by the budgets of large pharma, potentially impacting the speed and scale of development. The reliance on partnerships, while strategic for funding and capacity, means relinquishing certain rights and potential future revenue streams.

Key risks facing the company include the substantial doubt about its ability to continue as a going concern due to recurring losses and the need for significant future financing. The success of its drug candidates is uncertain and dependent on the outcomes of future preclinical and clinical trials, which may not replicate earlier promising results. Regulatory approval pathways are complex and costly. The company relies on third parties for clinical trial conduct and manufacturing, introducing execution risks. Furthermore, the company recently received a notice from Nasdaq regarding non-compliance with the minimum bid price requirement, which could lead to delisting and negatively impact its stock price and ability to raise capital.

Conclusion

Cue Biopharma's investment thesis is centered on the potential of its differentiated Immuno-STAT platform to deliver precision immunotherapy with enhanced efficacy and tolerability across oncology and autoimmune diseases. The recent strategic pivot, prioritizing autoimmune programs and seeking oncology partnerships, is a pragmatic response to resource constraints and market dynamics, aimed at leveraging the platform's modularity for broader development and securing crucial funding. The collaboration with Boehringer Ingelheim for CUE-501 provides significant validation and financial support for the autoimmune pipeline, while the promising clinical data from the CUE-100 series in oncology highlight the platform's potential, albeit dependent on future partnerships for advancement. While the company's technology offers a compelling competitive differentiation, particularly in targeted T-cell modulation and potential manufacturing advantages, it faces substantial financial headwinds, including the need for significant additional capital and the challenge of maintaining its Nasdaq listing. The successful execution of its partnership strategy and the achievement of key clinical and regulatory milestones, such as the planned CUE-401 IND filing, will be critical determinants of Cue Biopharma's ability to navigate these challenges and realize the potential of its innovative platform.