BHB810's CDH17 Bet: Novel Target, Zero Clinical Data, Rising Comparator Bar

BigHat Biosciences Doses First Patient in Phase I BHB810 Trial

BigHat Biosciences has initiated a Phase I clinical trial for BHB810, an AI-designed VHH-Fc antibody-drug conjugate targeting Cadherin-17 (CDH17). The first patient with advanced gastric or gastroesophageal tumours has been dosed. This trial aims to assess the drug's safety, tolerability, pharmacokinetics, and preliminary anti-tumour activity, initially focusing on patients with CDH17-expressing tumors. Preclinical studies showed BHB810 achieved complete or near-complete tumor clearance across various models and demonstrated a promising safety profile. This marks a significant step for BigHat's AI platform in advancing novel therapeutics to human studies.

• BigHat Biosciences has successfully dosed the first patient in its Phase I clinical trial for BHB810, an AI-designed VHH-Fc antibody-drug conjugate. This milestone validates the company's AI platform's capability to translate antibody designs into clinic-ready therapeutics, marking its first program to enter human studies. The trial will initially focus on patients with advanced gastric and gastroesophageal tumours expressing Cadherin-17 (CDH17).
• BHB810 is an antibody-drug conjugate specifically designed to target Cadherin-17 (CDH17), a protein often expressed in gastrointestinal malignancies. Preclinical investigations demonstrated significant efficacy, with BHB810 inducing complete or near-complete tumour clearance in approximately 30 patient-derived and cell-derived tumour models, including those with low and heterogeneous CDH17 expression. This suggests a broad potential for anti-tumour activity.
• The drug candidate, BHB810, exhibited a promising safety profile in animal studies, attributed to its compact antibody structure and stable payload technology. The Phase I trial's primary objectives include evaluating the drug's safety, tolerability, and pharmacokinetics, alongside its preliminary anti-tumour activity, which are crucial for further development in addressing difficult-to-drug targets like CDH17 in GI cancers.

Addressing the Unmet Needs in Advanced Gastric Cancers

Despite meaningful advances in HER2-targeted and immune checkpoint-based strategies, the treatment of advanced gastric and gastroesophageal cancers remains constrained by a set of persistent and interrelated challenges that limit durable clinical benefit across patient populations.

• Trastuzumab resistance: Acquired resistance to trastuzumab is a well-recognized limitation in HER2-positive gastric cancer. Mechanisms include increased glutamine metabolism driven by GLS1 overexpression, GLS1 microvesicle-mediated M2 macrophage polarization, and pro-angiogenic reprogramming of the tumor microenvironment — all of which contribute to environment-mediated drug resistance that is distinct from tumor-cell-intrinsic mechanisms.

• Failure of successive HER2-directed agents to displace trastuzumab: Attempts to improve upon trastuzumab-based chemotherapy by adding or substituting agents — including lapatinib, high-dose trastuzumab, pertuzumab, and trastuzumab emtansine — did not displace trastuzumab-based therapy as the first-line standard, underscoring the difficulty of improving on the ToGA regimen through HER2 pathway intensification alone.

• Limited efficacy of immune checkpoint inhibitors in peritoneal dissemination: While anti-PD-1 and anti-CTLA-4 therapies demonstrate activity in gastric cancer, their efficacy diminishes in the context of peritoneal dissemination. Resistant tumors display abnormal activation of the JAK-STAT pathway alongside infiltration of macrophages, neutrophils, and Tregs, and CD8+ T cells in these tumors exhibit an exhaustion phenotype despite their presence.

• Immunosuppressive tumor microenvironment limiting ICI response: A large proportion of patients with T-cell-inflamed tumor microenvironments do not respond to PD-1/PD-L1 blockade. High stromal scores — associated with activation of transforming growth factor and epithelial-mesenchymal transition — are linked to T-cell suppression and resistance to PD-1/PD-L1 therapy, and represent an independent negative indicator of overall survival.

• HER2 heterogeneity and low HER2 expression: Current evidence cannot recommend trastuzumab for patients with IHC1+ HER2 low expression gastric cancer, leaving this subpopulation without an established HER2-directed option. Whether patients with low HER2 expression could benefit from HER2-directed therapies remains an active area of investigation.

• Limited systemic efficacy in peritoneal metastatic disease: The efficacy of second-line systemic chemotherapy in recurrent gastric cancer with peritoneal metastasis is limited, necessitating evaluation of additive local approaches such as pressurized intraperitoneal aerosol chemotherapy (PIPAC) and cytoreductive surgery, which remain investigational in this setting.

BHB810: Targeting CDH17 with an AI-Designed ADC

Recent research in gastric and gastroesophageal cancer has identified several emerging therapeutic targets that are reshaping the precision medicine landscape. Fibroblast growth factor receptor 2 isoform IIIb (FGFR2b) has gained considerable clinical interest, with the selective monoclonal antibody bemarituzumab currently under phase 3 investigation in the first-line advanced gastric cancer setting. FGFR2b protein overexpression, together with its function in oncogenic signaling pathways, positions it as an attractive target, though its translation into routine treatment selection is complicated by variability in immunohistochemistry staining intensity, intratumoral heterogeneity, and the distinction between FGFR2b protein expression, FGFR2 amplification, and true pathway dependency. Claudin 18.2 (CLDN18.2), a highly tissue-specific target abnormally overexpressed in gastric and gastroesophageal junction cancer with limited overlap with HER2 positivity or PD-L1 CPS ≥5, has also advanced significantly. Zolbetuximab, a CLDN18.2-targeted monoclonal antibody, demonstrated superior progression-free survival and overall survival when combined with chemotherapy across the SPOTLIGHT and GLOW trials, with the FAST trial showing median overall survival extending from 8.4 months to 13.2 months (HR, 0.72; P < .01). CLDN18.2-targeted CAR T cell therapy (CT041) has additionally shown an overall response rate of 48.6% and disease control rate of 73.0% in a phase 1 trial of previously treated CLDN18.2-positive digestive system cancers.

Immune checkpoint targets beyond PD-1 represent another active area of investigation. The CD155/TIGIT signaling axis has been shown to inhibit CD8+ T-cell metabolism and effector functions in gastric cancer, with combined targeting of TIGIT and PD-1 further enhancing CD8+ T-cell activation and improving survival in tumor-bearing mice. Single-cell RNA sequencing analyses have identified NKG2A as a distinct immune checkpoint mediating anti-PD-1 resistance, with NKG2A-expressing CD8+ T cells (defined as ICEP2) associated with resistance potentially driven by LGMN macrophage recruitment through the CXCL16-CXCR6 signaling pathway. In the broader PD-1-based bispecific antibody space, 121 interventional clinical trials have been registered globally through April 17, 2026, with CTLA-4 as the most frequent non-PD-1 co-target, followed by VEGF, TIGIT, and LAG3.

Mesothelin represents an additional emerging target in gastroesophageal adenocarcinoma, with expression observed in 50.4% of tumors in one western patient cohort — substantially exceeding HER2-neu IHC 3+ positivity (7.1%) and c-met positivity (6.6%) in the same series. High mesothelin expression has been independently associated with poor recurrence-free survival, overall survival, and peritoneal recurrence in advanced gastric cancer, particularly in stage III and diffuse/mixed-type disease. Antibody-drug conjugates (ADCs) have emerged as a broader platform of interest across solid tumors including gastric cancer, with HER2, trophoblast cell-surface antigen, mesothelin, delta-like ligand 3, and nectin-4 identified as major ADC targets in bibliometric analyses of the field.

Unpacking the Phase I Study Design for BHB810

Several pivotal trials across gastric and gastroesophageal malignancies have evaluated distinct therapeutic strategies — immunotherapy combinations, perioperative chemotherapy, and HER2-targeted regimens — each with defined patient populations, intervention arms, and primary endpoints. The table below consolidates the key study design parameters and efficacy outcomes reported across these trials.

BHB810's Position in the ADC Landscape for GI Cancers

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AI-Designed ADC Targets Aggressive Gastric Cancers

The entry of BHB810 into Phase I clinical trials represents a pivotal moment, not just for BigHat Biosciences, but for the broader field of oncology, particularly in the challenging landscape of advanced digestive system cancers. This AI-designed VHH-Fc antibody-drug conjugate targets Cadherin-17 (CDH17), a membrane protein consistently found to be overexpressed in aggressive gastric and colorectal cancers, correlating with poorer patient outcomes. The literature strongly supports CDH17 as an attractive therapeutic target, with studies demonstrating that its inhibition can suppress tumor progression by downregulating key signaling pathways like Wnt/β-catenin.

This development underscores the growing impact of artificial intelligence in accelerating drug discovery, moving from computational design to human trials. The VHH-Fc format, utilizing single-domain antibodies, offers potential advantages in terms of size, stability, and tumor penetration, which could be critical for effective drug delivery. However, as with any novel therapeutic, particularly one targeting an antigen also present in healthy tissues, careful consideration of potential risks is paramount. While preclinical data for BHB810 showed promising efficacy and safety, the transition to human studies will rigorously evaluate these aspects. The potential for on-target, off-tumor toxicity, given CDH17's expression in healthy colon, will be closely monitored. Furthermore, the inherent heterogeneity of CDH17 expression within tumors, while potentially manageable, could influence patient selection and overall treatment response. Success in this early phase could validate a powerful new approach to drug development and offer a much-needed therapeutic option for patients battling these aggressive malignancies.