Adecto's ADAM8 Antibody Dies Unfunded: Novel Target, Zero Clinical Data, Patent the Sole Survivor

Adecto Pharmaceuticals Ceases Operations Due to Funding Challenges

Adecto Pharmaceuticals, a Boston-based biotech founded in 2014, officially ceased operations on September 30. The company, which was developing a monoclonal antibody targeting ADAM8 for cancers unresponsive to conventional immunotherapy, cited a risk-averse fundraising environment and a lack of clinical data for new therapeutic targets as reasons for running out of financial runway. Despite the closure, Adecto's CEO hopes to advance its work, having filed a provisional patent on its lead ADAM8 antibody.

• Adecto Pharmaceuticals, focused on developing treatments for immunotherapy-resistant cancers, officially closed its doors on September 30. The company's CEO attributed the closure to a challenging fundraising landscape that was hesitant to back new therapeutic targets without prior clinical data, leading to a depletion of financial resources.
• Founded in 2014 by Tufts University researchers, Adecto was developing a monoclonal antibody designed to inhibit the cell surface protein ADAM8. This mechanism aimed to reprogram lymphoid and myeloid cells to generate a more potent antitumor immune response, with the belief that ADAM8-targeted therapies could become a standard of care in cancer.
• Despite ceasing operations, Adecto's leadership is committed to ensuring its research continues. The company has filed a provisional patent for its lead ADAM8 antibody and is actively exploring various avenues to advance its development, underscoring the perceived importance of its therapeutic approach.

Addressing the Unmet Need in Immunotherapy-Resistant Cancers

Despite the transformative impact of immune checkpoint inhibitors (ICIs) across multiple tumor types, a substantial proportion of patients derive no durable benefit — a challenge rooted in both tumor-intrinsic and microenvironmental mechanisms of resistance. Primary and acquired resistance to PD-1/PD-L1 inhibitors remain critical unresolved problems in clinical practice, and the complexity of the tumor immune landscape continues to limit the reach of current immunotherapeutic strategies.

• Discordance between predictive biomarkers: dMMR and MSI-H status are considered equivalent predictors of ICI efficacy, yet a 19.3% discrepancy between MMR immunohistochemistry and MSI PCR testing has been observed across cancer cohorts. The discrepancy between dMMR and MSI-high status was high within the entire cohort (60.9%) and in colorectal (58.6%) and non-colorectal (68%) subcohorts, with classical dMMR showing only ~60% correlation with MSI-high status and unusual dMMR showing less than 10% correlation. Preanalytical factors strongly influence both MMR IHC and MSI PCR results, calling into question the current dogma that dMMR phenotype and genetic MSI status are equivalent predictive markers for immunotherapies.

• Primary resistance even in biomarker-selected populations: Approximately half of patients with dMMR/MSI-H gastrointestinal cancer derive no benefit from ICIs. AKT1 and CDH1 mutations have been identified as independent predictors of poor progression-free survival and primary resistance to ICIs in this population. The combined IOpred biomarker (mutant AKT1 or CDH1) identified 52.4% of dMMR/MSI-H patients with primary resistance, with a positive predictive value of 91.7% in the discovery cohort and 80% in the validation cohort. Among IOpred-wild-type patients, those with TMB ≤26.19 mutations per megabase had a significantly higher primary resistance rate (34.8% vs 6.7%, p=0.014) and poorer PFS (HR=3.46, p=0.008) and OS (HR=4.42, p=0.047) than TMB-high patients.

• Immunosuppressive tumor microenvironment (TME): Myeloid-derived suppressor cells (MDSCs) function as major negative regulators within the TME, facilitating tumor immune evasion by modulating various immune cells and promoting tumor growth and metastasis through non-immunological mechanisms such as angiogenesis and the formation of pre-metastatic niches. TNFR2 — highly expressed on regulatory T cells, MDSCs, cancer-associated fibroblasts, and malignant cells — orchestrates a coordinated network driving immune evasion and contributing to resistance to immune checkpoint blockade.

• Limited efficacy of ICI monotherapy and the need for combination strategies: PD-1/PD-L1 inhibitors induce sustained responses in only a limited number of patients, and broad clinical efficacy is constrained by low response rates, immune-related adverse events, and the pervasive challenge of primary or acquired resistance. Multi-target combination therapy — including co-targeting of VEGF, CTLA-4, and LAG-3, as well as approaches targeting cancer-associated fibroblasts or utilizing antibody-drug conjugates — has emerged as an essential strategy for overcoming resistance, though the optimal combinations remain under investigation.

• Disease-specific resistance contexts: In metastatic castration-resistant prostate cancer, checkpoint inhibitor therapy has shown limited efficacy even in the dMMR/MSI-H subset, which represents only approximately 3–5% of cases. Re-sensitization to pembrolizumab following PSMA-CD3 bispecific T-cell engager therapy (JNJ-081) has been reported in a single case, representing a potential but as yet unvalidated strategy for reversing acquired resistance in this setting.

Exploring Novel Targets Like ADAM8 for Resistant Cancers

Recent research has intensified focus on reprogramming immunosuppressive "cold" tumor microenvironments (TMEs) — characterized by poor effector cell infiltration, high immunosuppressive cell burden, and upregulated checkpoint axes — as the central challenge in cancers resistant to conventional immunotherapy. Multiple novel and emerging therapeutic targets are under active investigation across tumor types.

• TIGIT/PVR (CD155) axis: TIGIT is an inhibitory immune checkpoint expressed on NK cells and T cells that competes with the activating receptor CD226 (DNAM-1) for the ligands CD155 (PVR/poliovirus receptor) and CD112 (Nectin-2/PVRL2). Its role in tumor immunosuppression is analogous to the PD-1/PD-L1 axis, and anti-TIGIT antibodies have demonstrated synergy with anti-PD-1/PD-L1 antibodies in pre-clinical models. In the B16F10 cold tumor model, MHC-II-restricted neoantigen vaccination upregulated the PVR-TIGIT checkpoint axis, and combining vaccination with TIGIT blockade achieved synergistic anti-tumor efficacy by enhancing antigen-specific CD4 T cell function, promoting effector memory differentiation, and delaying CD8 T cell exhaustion.

• MHC-II-restricted neoantigen vaccines: Vaccination with MHC-II-restricted neoantigens promoted inflammatory signaling within the TME, enhanced infiltration of both CD4 and CD8 T cells, and increased interferon (IFN)-γ production in cold tumor models. This approach provides a prerequisite for immune checkpoint inhibitor (ICI) response by converting an immunosuppressive TME into one permissive to checkpoint blockade, particularly when combined with TIGIT inhibition.

• Recombinant human Cyclophilin A (rhCypA): rhCypA, an analog of proinflammatory secretory CypA, has been identified as a stimulator of the antitumor immune response and a modulator of the immune TME. In the melanoma B16 model in vivo, rhCypA treatment increased the proportion of activated CD4+CD25+ T cells and CD8+ T cells with upregulated activation markers CD44, CD25, and co-stimulatory CD28, while upregulating PD-1 and CTLA-4 and downregulating exhaustion markers KLRG-1 and LAG-3 in tumor-infiltrating NK cells. Treated tumors showed increased perforin and granzyme B production and TNFα-producing CD4+ cells.

• VEGF/VEGFR pathway inhibition combined with ICIs: The VEGF/VEGFR pathway drives cold tumor phenotype formation in gynecologic malignancies — including ovarian, endometrial, and cervical cancers — through vascular abnormalities, elevated interstitial fluid pressure, impaired T cell infiltration, expansion of Tregs and myeloid-derived suppressor cells (MDSCs), and impaired dendritic cell antigen presentation. Combining VEGF/VEGFR inhibitors with ICIs leverages vascular normalization and immunosuppression reversal synergistically to convert cold tumors to hot ones.

• Metabolic reprogramming targets — GLUT1 and glycolysis: Aberrant glycolytic reprogramming contributes to the immunosuppressive TME in cold tumors. A biomimetic dual-targeting nanomodulator (CM-cRGD@PBG) incorporating the GLUT1 inhibitor BAY-876 reversed lactate-driven immunosuppression by inhibiting M2-like macrophage polarization and Treg expansion. Gemcitabine was repurposed within this platform as an immunomodulatory agent to selectively deplete MDSCs and Tregs, while mesoporous polydopamine-mediated photothermal therapy elicited immunogenic cell death, facilitating dendritic cell maturation and antigen presentation in pancreatic and lung cancer models.

• Emerging checkpoint receptors — LAG-3, TIM-3, and TIGIT in lung cancer: Beyond PD-1/PD-L1 and CTLA-4, inhibitory receptors including LAG-3, TIGIT, and TIM-3 contribute additional layers of immune regulation and resistance in lung cancer, highlighting opportunities for combinatorial therapeutic strategies across the disease continuum.

• Immunosuppressive cytokine and metabolic byproduct targeting in breast cancer: The breast TME is dominated by immunosuppressive cytokines including IL-10, TGF-β, and IL-35 — the latter produced by both regulatory T cells and breast cancer cells — alongside metabolic byproducts such as lactate, reactive oxygen species (ROS), and ammonia that impair T cell function. Targeting these pathways through combination strategies involving checkpoint blockade, CAR-T cell therapies, and microbiome modulation is proposed to facilitate the cold-to-hot TME transition.

ADAM8: A Promising Oncology Target's Uphill Battle

The recent closure of Adecto Pharmaceuticals, a biotech focused on an ADAM8-targeting monoclonal antibody for immunotherapy-resistant cancers, serves as a stark reminder of the formidable hurdles in novel drug development. Despite the scientific community's growing interest in ADAM8 as a therapeutic target, the company's inability to secure further funding underscores the intense pressure on early-stage ventures to demonstrate compelling clinical data.

Research has consistently highlighted ADAM8's significant role in various aggressive cancers. Studies indicate that high ADAM8 expression is associated with poor prognosis in hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC), where its inhibition has shown promise in reducing tumor burden and metastasis in preclinical models. Furthermore, ADAM8 contributes to the aggressive bone metastatic phenotype of lung cancer through novel spliced isoforms and mediates temozolomide chemoresistance and enhanced invasiveness in glioblastoma (GBM). More recently, it has been implicated in the metastasis of chemoresistant colon cancer cells, linking it to TrkB/C-induced HOXC6 activation.

However, the path to clinical translation for ADAM8 is not without complexity:

• Dual Biological Roles: While promoting cancer progression, ADAM8 has also been shown to dampen airway inflammation in asthma models, suggesting a nuanced physiological function that requires careful consideration for therapeutic targeting.

• Target Specificity: The presence of alternatively spliced isoforms in cancer, such as Delta18a and Delta14' in lung cancer, means that any therapeutic agent must be highly specific to the pathogenic forms to avoid unintended consequences.

Adecto's provisional patent on its lead ADAM8 antibody could still hold value, potentially attracting larger pharmaceutical entities looking to acquire de-risked assets in oncology. However, this event reinforces the market's demand for robust preclinical validation and, crucially, early human data to mitigate the inherent risks of novel target development. The scientific interest in ADAM8 remains strong, but its journey from promising target to approved therapy clearly requires significant investment, strategic precision, and a higher threshold of clinical evidence than Adecto was able to achieve.