How Our Understanding of CEACAM6 Has Evolved in the Last 12 Months

What Is CEACAM6?

CEACAM6 is a cell-surface protein involved in cellular adhesion and signaling, and is expressed at low levels in healthy tissues. In a number of aggressive solid tumors, however, it becomes markedly overexpressed, particularly in pancreatic, lung (non-small cell lung cancer, NSCLC), and gastrointestinal malignancies such as colorectal, gastric, and esophageal cancers.

In cancer, elevated levels of CEACAM6 are consistently associated with:
· Advanced tumor stage
· Poor differentiation
· Shorter progression-free survival
· Reduced overall survival

In colorectal adenocarcinoma, high CEACAM6 expression correlates with significantly shorter progression-free survival, meaning that the disease tends to progress sooner. Notably, large multicenter analyses involving over 300 patients have identified CEACAM6 as an independent prognostic factor, with a hazard ratio of 9.516 for overall survival, meaning that patients with high CEACAM6 expression face more than nine times the risk of death compared to those with lower levels.

In other words, elevated CEACAM6 does not just track with worse outcomes, it predicts them, even when other clinical factors are taken into account.[1]

This shift in understanding is critical: CEACAM6 is not just a marker of aggressive disease; it is an active driver of it.

Driving Tumor Growth and Spread

Cancer progression is not random. Tumor cells acquire specific capabilities that enable them to grow, invade, and spread, and CEACAM6 supports several of these hallmarks.

It promotes epithelial–mesenchymal transition (EMT), a process that increases cellular mobility and invasiveness. Through EMT, tumor cells lose adhesion to neighboring cells and gain the ability to migrate.

CEACAM6 also enhances resistance to anoikis, a form of programmed cell death triggered when cells detach from their native environment. By evading anoikis, cancer cells can survive in circulation and seed metastases.

At the molecular level, CEACAM6 activates key oncogenic pathways, including:
· PI3K/AKT
· RAS/MAPK
· Src–FAK signaling

These pathways regulate proliferation, survival, migration, and angiogenesis (the formation of new blood vessels that feed tumors), collectively reinforcing a more aggressive and metastatic tumor phenotype.[1][2]

Shaping the Immune Microenvironment

A key aspect of CEACAM6 biology is its role in shaping an immunosuppressive tumor microenvironment.

Tumors exist within a dynamic immune environment, some of which are infiltrated by immune cells, while others actively exclude or suppress them. High CEACAM6 expression has been associated with a distinctly immunosuppressive microenvironment.

Studies show inverse correlations between CEACAM6 and anti-tumor immune populations such as:
· CD3+ T cells
· CD8+ cytotoxic T cells
· CD45RO+ memory T cells
· Th1 helper T cells
· M1 macrophages

At the same time, CEACAM6 expression correlates positively with immunosuppressive cell types, such as:
· FOXP3+ regulatory T cells (Tregs)
· Myeloid-derived suppressor cells (MDSCs)

Spatial transcriptomics analyses of colorectal liver metastases further show that CEACAM6 is linked to immune exclusion, where immune cells are physically prevented from accessing tumor regions. It also upregulates PD-L1 expression, reinforcing checkpoint-mediated immune suppression.[1][2]

This has direct clinical implications, as immune context is a key determinant of response to immunotherapy.

A Driver of Therapy Resistance

CEACAM6 expression has been associated with resistance to multiple treatment modalities, including chemotherapy and immunotherapy.

By promoting EMT and remodeling the tumor microenvironment, CEACAM6 contributes to chemoresistance, enabling cancer cells to become more adaptable and less sensitive to cytotoxic agents.

At the same time, its role in immune suppression and PD-L1 upregulation may reduce responsiveness to immune checkpoint inhibitors. Tumors with high CEACAM6 may be intrinsically less susceptible to PD-1/PD-L1 blockade due to pre-existing immune exlclusion.

This may help explain why some patients do not respond to therapies that are otherwise effective in biomarker-selected populations.[1][2]

A New Therapeutic Opportunity

Recognizing CEACAM6 as an active biological driver has created new opportunities for targeted therapeutic strategies, with Helix at the forefront of translating this biology into clinical development.

The last 12 months have brought meaningful momentum across the CEACAM6 space. In the clinic, EBC-129 (an ADC directed against a tumor-specific glycosylated epitope on CEACAM5/6) received FDA Fast Track Designation for pancreatic ductal adenocarcinoma (PDAC) in May 2025, with updated Phase 1 data highlighting clinical activity in heavily pretreated patients with PDAC and a biomarker assay showing expression across multiple solid tumors, including pancreatic, gastric, esophageal, lung, colorectal, and appendiceal cancers.[4]

At the same time, not all CEACAM6-targeting approaches have translated successfully. The anti-CEACAM6 antibody tinurilimab (BAY 1834942) was discontinued in 2025 following a Phase I study in advanced solid tumors due to an unfavorable benefit-risk profile, with no objective responses observed and clinically significant toxicities reported.[5]

This divergence highlights an important point: the clinical potential of CEACAM6 depends not only on the target itself, but on how it is engaged. Helix’s lead candidate, Tumor Defense Breaker™ L-DOS47, is an antibody-enzyme conjugate (AEC) targeting CEACAM6 that delivers urease directly to the tumor microenvironment, locally converting urea into ammonia and increasing pH. This mechanism is designed to disrupt the acidic conditions that tumors rely on for growth, immune evasion, and resistance to therapy. L-DOS47 has demonstrated a favorable safety profile across multiple clinical studies in NSCLC, both as a monotherapy and in combination with chemotherapy, with no maximum tolerated dose reached and limited dose-limited toxicities reported.[6]

Importantly, promising early efficacy signals have also been observed. In a Phase I/II study evaluating L-DOS47 as monotherapy, no tumor shrinkage was observed, but patients receiving higher doses experienced a statistically significant delay in disease progression (improvement in progression-free survival, PFS), with median PFS reaching 4.1 months in the highest dosing group (p=0.0203). This is particularly meaningful given that over 90% of patients had already received two or more prior lines of therapy. For context, median PFS with pembrolizumab monotherapy (an immune checkpoint inhibitor widely used as the standard of care in NSCLC) has been reported in the range of approximately 2 to 6 months in previously treated NSCLC populations, depending on PD-L1 expression levels.[6]

While the study was not designed to demonstrate definitive efficacy, the relationship between dose and outcome, together with consistent disease control, suggests that targeting CEACAM6 through this mechanism may have real clinical potential. Taken together, these findings reinforce that CEACAM6 is a viable therapeutic target, and that recent setbacks reflect the challenges of therapeutic design rather than the validity of the target itself.

In a second Phase I/II study of L-DOS47 in combination with pemetrexed and carboplatin in patients with advanced non-squamous NSCLC, a clinical benefit rate of 75% was observed, including partial responses and stable disease. These outcomes are notable in a heavily pretreated population and compare favorably with historical response rates reported for chemotherapy alone.[7] Across all patients, the median duration of response was 197 days, with progression-free survival extending beyond six months. Notably, one heavily pre-treated patient achieved near-complete remission, highlighting the potential for meaningful clinical responses in selected cases.

Together, these clinical findings suggest that CEACAM6 can be safely and effectively targeted in the clinic, with emerging evidence that modulating the tumor microenvironment may translate into meaningful therapeutic benefit. Building on this, a clinical study evaluating L-DOS47 in combination with pembrolizumab in first-line NSCLC is planned, with the aim of assessing whether this approach can enhance response to immune checkpoint inhibition.

This combination strategy is further supported by preclinical data. In pancreatic cancer models, where a highly immunosuppressive and acidic tumor microenvironment limits response to therapy, L-DOS47 has been shown to increase tumor pH and, when combined with pembrolizumab, this translated into sustained tumor growth inhibition for up to four weeks compared to either treatment alone.[8] These findings suggest that targeting CEACAM6 to modulate the tumor microenvironment may enhance the effectiveness of immunotherapy, particularly when used in combination strategies to overcome resistance in otherwise refractory tumors.

Preclinical development across the broader CEACAM6 field is expanding in parallel. In March 2025, Eisai researchers reported that the CEACAM6-targeted ADC 84-EBET produced marked tumor regression across colorectal, lung, and breast cancer models and showed strong synergy with PD-1 blockade in resistant mouse models, while also remodeling the tumor microenvironment. In gastroesophageal junction cancer, a 2025 multi-omics study identified CEACAM6 (also “CD66c”) as a promising ADC target and showed that a new CD66c-DXd conjugate selectively killed tumor cells and drove durable tumor regression in vivo with limited activity in non-malignant cells.[3]

Looking Ahead

CEACAM6 is emerging as a therapeutically actionable target with multiple avenues for intervention. Recent clinical and preclinical findings suggest that its relevance lies not only in tumor biology, but in how it can be leveraged to reshape the tumor microenvironment and influence response to therapy.

What is becoming increasingly clear is that the future of CEACAM6 targeting will be defined by combination strategies and modality selection. Approaches that can modulate the tumor microenvironment, whether through AECs, ADCs, or other targeted platforms, may help overcome resistance to existing therapies, particularly immune checkpoint inhibition.

This is especially relevant in tumors characterized by immune exclusion and metabolic adaptation, where CEACAM6 expression contributes to both disease progression and therapeutic resistance. In these settings, targeting CEACAM6 may not act in isolation, but rather as a means of enhancing the effectiveness of other treatments.

As the field advances, the focus is shifting from whether CEACAM6 is a viable target to how best to engage and leverage it, through the right combination of biology, modality, and clinical strategy. At Helix BioPharma, we are advancing this approach by exploring CEACAM6-targeted strategies designed to modulate the tumor microenvironment and improve responses to therapy, with the goal of applying smarter, more strategic approaches that build on what already works to bring better outcomes to patients, faster.

References:

1. Jin L, Tao C, Pan Z, Zhang P. Integrative Omics Analysis Reveals the Potential Value of CEACAM6 in Pan-Gastrointestinal Cancers. Immun Inflamm Dis. 2026;14(2):e70327. doi:10.1002/iid3.70327

2. Liu Y, Ye J, Ma J and Pan X: Multicenter validation of CEACAM6 and FOXP3 as robust prognostic biomarkers in colon cancer: Combined immunohistochemical and transcriptomic analysis. Mol Clin Oncol 23: 102, 2025.

3. Kogai H, Tsukamoto S, Koga M, et al. Broad-Spectrum Efficacy of CEACAM6-Targeted Antibody-Drug Conjugate with BET Protein Degrader in Colorectal, Lung, and Breast Cancer Mouse Models. Mol Cancer Ther. 2025;24(3):392-405. doi:10.1158/1535-7163.MCT-24-0444

4. Fabbricatore R. EBC-129 receives FDA fast-track designation for PDAC. CancerNetwork. May 28, 2025. Accessed March 18, 2026. https://www.cancernetwork.com/view/ebc-129-receives-fda-fast-track-designation-for-pdac

5. Siu LL, Hong DS, Döcke WD, et al. A Phase I Study of the Anti-CEACAM6 Antibody Tinurilimab (BAY 1834942) in Patients with Advanced Solid Tumors. Target Oncol. 2025;20(4):637-649. doi:10.1007/s11523-025-01154-4

6. Ramlau R, Kowalski DM, Szczęsna A, et al. Safety of unconventional antibody-drug conjugate L-DOS47 in a phase I/II monotherapy study targeting advanced NSCLC. Front Oncol. 2025;15:1544967. Published 2025 Aug 11. doi:10.3389/fonc.2025.1544967

7. Piha-Paul S, Simon G, Belani CP, et al. A Phase 1, Open-Label, Dose-Escalation Study of L-DOS47 in Combination With Pemetrexed Plus Carboplatin in Patients With Stage IV Recurrent or Metastatic Nonsquamous NSCLC. JTO Clin Res Rep. 2022;3(11):100408. Published 2022 Sep 16. doi:10.1016/j.jtocrr.2022.100408

8. Jardim-Perassi BV, Irrera P, Oluwatola OE, et al. L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy. Biomedicines. 2024;12(2):461. Published 2024 Feb 19. doi:10.3390/biomedicines12020461

Jacek Antas

Chief Executive Officer

Jacek Antas is a shareholder of the Company, has spent more than 25 years in the financial services industry holding various positions in sales and consulting.

Mr. Antas obtained a master’s degree from the Warsaw School of Economics and has served as a board member of various
companies throughout his career.

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James B. Murphy

Chief Financial Officer

Mr. Murphy is a certified public accountant with over thirty years of experience in finance and operations management. He is currently a consultant with Danforth Advisors LLC (“Danforth”), a leading provider of outsourced strategic and operational specialists across functions in the life sciences industry. While at Danforth, Mr. Murphy has served over fifteen private and publicly held life sciences companies as CFO and CFO Advisor, helping them secure over USD 0.5 billion in financing and successfully execute pivotal asset transactions. Mr. Murphy functions as a consultant to Helix pursuant to a consulting agreement between the Company and Danforth.

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Thomas Mehrling

Medical Adviser

Thomas Mehrling (PhD in Pharmacology and MD) has over 20 years’ experience in multinational Pharma companies developing novel oncology compounds from preclinical research through to registration. Prior to entering the industry, he spent 13 years as an MD at the University Hospital in Frankfurt, working on preclinical and translational projects. He served as Director of European Oncology at Mundipharma International (2003–2013), building the company’s first European oncology business from the ground up out of Cambridge, UK, and completing the clinical development, registration and launch of two major products in Europe, DepoCyte® and Levact® (Ribomustin® and Treanda®). In 2013, he led the establishment of the Mundipharma Group’s start-up, Mundipharma EDO, developing anti-cancer therapeutics for solid tumours out of Basel, Switzerland.

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Kim Gaspar

Director Quality Assurance

Kim is the Director of Quality Assurance at Helix BioPharma Corp. An experienced quality assurance professional with expertise in Canadian, US, and EU regulations, she has been involved in all aspects of Phase I/II biopharmaceutical product development over the years, including regulatory submissions, QC laboratory compliance, tech transfer and third-party oversight of CMC activities, clinical QA, and bioanalytical data analysis. Kim joined Helix in 2000, transitioning into QA in 2003. She holds a B.Sc in Biochemistry and a Ph.D in Veterinary Physiological Sciences, both from the University of Saskatchewan.

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Brenda Lee

Director Clinical Operations

Brenda is the Clinical Operations Director at Helix Biopharma Corp. A clinical research operations professional with 25 years of experience managing clinical trials, ranging from early Phase I to late Phase IIIb/IV studies, she brings experience in clinical study protocol writing and development, trial start-up and vendor management, and a proven track record in planning and managing clinical trials to quality standards, timelines and budget. Brenda joined Helix Biopharma Corp. in 2018, working to advance the clinical program of L-DOS47. She holds B.Sc and M.Sc. degrees from the University of Toronto, specializing in Nutritional Sciences and Human Biology.

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Jerzy Leszczynski

Director

Jerzy Leszczynski is a shareholder of the Company, has spent more than 35 years developing businesses and has served in the capacity of board member of various real estate development companies. Mr. Leszczynski obtained his Master of Science in Chemistry from the Warsaw Institute of Technology.

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Janusz Grabski

Director, Chair of Audit Committee

Janusz (John) Grabski is a lawyer specialized in corporate and real estate law with over twenty years of experience.

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Malgorzata Laube

Director

Malgorzata Laube has over 19 years of experience in nuclear medicine. In her last role with Alberta Health Services, she was the Department Supervisor, Nuclear Medicine at Royal Alexandra Hospital. Ms. Laube obtained a MSc degree in Environmental Engineering from the Warsaw University of Technology and is based in Edmonton, Alberta, Canada.

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Jacek Antas

Chairman of the Board

Jacek Antas is a shareholder of the Company, has spent more than 25 years in the financial services industry holding various positions in sales and consulting.

Mr. Antas obtained a master’s degree from the Warsaw School of Economics and has served as a board member of various
companies throughout his career.

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Jonathan Davis

Advisor, ADC Discovery

Jonathan Davis received his Ph.D. from University of California, San Francisco, where he studied protein structure and function using NMR. After a post-doc at Harvard Medical School exploring RNA selection and structure in the labs of Jack Szostak and Gerhard Wagner, he went to work at EMD Serono, where his work involved improving antibody-based therapeutics, inventing a platform technology for generating heterodimeric Fcs as a basis for multifunctional molecules, and developing a novel scaffold based on an artificially-designed protein from David Baker’s lab. In 2008 he took a job at Bristol-Myers Squibb in Waltham/Cambridge MA, working on antibody discovery and platform development in a wide range of therapeutic areas, with a particular focus on multispecific therapeutics. He moved to Madison, WI in 2019 to take on the role of VP of Innovation and Strategy at Invenra, a biotech focused on bispecific antibodies, and where he is currently head of the Scientific Advisory Board. In early 2024 he left the corporate world to found Creative Antibodies, a consulting firm that helps guide companies to successful antibody discovery and development projects, from mAbs to multispecifics, ADCs, and other formats. Outside of science, Jonathan is a conservatory trained cellist, plays numerous other instruments, and founded the UCSF Orchestra (now Symphony Parnassus) in San Francisco, where he was Music Director for six years.

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Davide Guggi

Advisor, CMC

Davide graduated as a pharmacist and received his PhD in Pharmaceutical Technology and Biotechnology from the University of Vienna. He has over 20 years of experience in the pharmaceutical industry, principally in the field of oncology. At the beginning of his career, Davide led oncology business units and commercial departments at Mundipharma and Gilead across Austria and Eastern Europe. Since over 10 years he has been working as a CMC expert, covering operational and regulatory CMC functions on behalf of over 20 different small- and medium-sized biotech companies across the world. He has served as CMC Director and CSO/CTO for several years, developing both small molecules and biologics (mABs, Fab, ADCs and Radio-immuno-conjugates) from early discovery to NDA/BLA in the US, EU and Canada, with a focus on First-in-Human and Phase I/II studies in oncology indications.

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Tumor Defense Breaker™, L-DOS47

L‑DOS47 is a first‑in‑class, clinical-stage antibody‑enzyme conjugate designed to deliver a game-changing assist to anti-cancer immunity and today’s leading cancer immunotherapies for the treatment of prevalent, hard-to-treat solid tumors. The compound precisely targets CEACAM6, a cell-surface protein overexpressed in non‑small cell lung cancer (NSCLC) and other aggressive tumors, where it delivers an enzymatic payload that raises the extracellular pH of the acidic tumor microenvironment (TME). By neutralizing tumor acidity, L-DOS47 restores immune cell infiltration and activity, helps turn immunologically “cold” tumors “hot”, and enhances the therapeutic reach of immune checkpoint inhibitors. With patented composition-of-matter coverage through 2036 and demonstrated synergy with PD-1 inhibitor, pembrolizumab, L-DOS47 is poised to significantly increase the efficacy of immune checkpoint blockade and unlock broader and more durable responses in NSCLC and other aggressive solid tumors.



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