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HER3 and EpCAM are two of the most promising, yet historically elusive, targets in oncology. HER3 is broadly expressed across multiple epithelial tumors and has been implicated in tumor progression, metastasis, and resistance to targeted therapies.1-3 EpCAM is highly expressed in a wide range of epithelial malignancies and is associated with tumor proliferation and poor prognosis.4
Importantly, HER3 and EpCAM exhibit clinically relevant co-expression across major epithelial malignancies—including colorectal, non-small cell lung (NSCLC), breast, pancreatic, and gastric cancers (Figure 1). Together, these indications represent an immense, multi-billion-dollar therapeutic market.
Yet, despite this massive clinical potential, both HER3 and EpCAM remain underexploited therapeutic targets. While HER3-directed therapies have advanced clinically, significant unmet need remains across epithelial cancers, and EpCAM-targeted ADCs have yet to demonstrate broad clinical success.5,6
Figure 1. Co-expression of HER3 and EpCAM in multiple major cancer types. (In-house analysis)
While both HER3 and EpCAM are highly overexpressed on cancer cells, standalone ADCs against these targets have historically struggled. The clinical landscape is currently defined by a few key benchmarks, but they face significant roadblocks:
While HER2 is one of the most famous targets in oncology, it is also one of the most crowded, dominated by entrenched standard-of-care drugs like Enhertu and Herceptin. HER3, part of the same receptor family, presents a massive, underexplored "blue ocean" for bispecific ADCs with three key advantages:
To bridge the gap between high efficacy and clinical safety, Biocytogen has developed BCG044— a novel, fully human common light chain HER3 × EpCAM bispecific ADC (bsADC).
BCG044 is conjugated to our proprietary topoisomerase I (TOP1) inhibitor linker-payload, BLD1102. By utilizing a "dual-key" cooperative binding mechanism, BCG044 selectively targets cells expressing both antigens. Dual-targeting strategies have emerged as a promising approach to improve tumor selectivity while reducing toxicity associated with single-antigen targeting.8 This strategy expands the therapeutic window by mitigating historical EpCAM-associated toxicities while enhancing payload delivery into tumors.
By targeting two highly expressed tumor antigens with limited therapeutic options and substantial unmet clinical need, BCG044 is uniquely positioned to capture massive, underserved patient populations across CRC, NSCLC, and breast cancers.
BCG044 requires simultaneous engagement of HER3 and EpCAM to trigger rapid internalization. This cooperative avidity minimizes interactions with single-antigen normal tissues—effectively bypassing historical EpCAM toxicities while driving fast, efficient internalization in dual-positive tumor cells.
In EpCAM-humanized mouse models, a cross-reactive surrogate of BCG044 demonstrated markedly improved tolerability and reduced systemic toxicity, compared with both parental EpCAM-targeting constructs and leading clinical benchmarks.
Built on our proprietary common light chain RenLite® platform utilizing a knobs-into-holes (KIH) design, BCG044 effectively eliminates the chain-mispairing issues that historically challenge bispecific manufacturing. This ensures favorable physicochemical properties and seamless downstream scale-up.
Figure 2. In vivo antitumor efficacy of BCG044 across pancreatic and colorectal cancer PDX models. (All vcMMAE-ADCs with DAR~4; BLD1102-ADCs with DAR~8)
Figure 3. Enhanced in vivo safety and tolerability in EpCAM-humanized mice. (BCG044 dose: 60 mg/kg)
By targeting two highly expressed tumor antigens with limited therapeutic options and substantial unmet clinical need, BCG044 offers first-in-class, blockbuster potential to capture highly unmet patient populations. With its optimized safety profile, robust efficacy against clinical benchmarks, and clean manufacturability, BCG044 represents a highly optimized asset ready to redefine treatment paradigms for epithelial tumors.
BCG044 solves the specific clinical and manufacturing hurdles that have historically sidelined these high-value targets, offering partners a true first-in-class opportunity:
Although EpCAM is broadly expressed across many epithelial cancers, its expression on normal epithelial tissues has historically complicated therapeutic development. Several EpCAM-targeted approaches have encountered challenges related to therapeutic window, gastrointestinal toxicity, and on-target/off-tumor effects, highlighting the need for improved targeting strategies.
Although HER3 has emerged as an important therapeutic target and multiple HER3-directed programs have advanced clinically, challenges related to efficacy, resistance mechanisms, and patient selection continue to leave substantial unmet need across HER3-positive tumors. HER3 is a known driver of tumor metastasis and treatment resistance, single-target HER3 ADCs frequently battle suboptimal internalization efficiency, limiting their ability to drop payloads into the cell. Furthermore, leading single-target HER3 candidates have recently faced major clinical and regulatory setbacks (such as failing to improve overall survival), leaving this massive patient population without a targeted option.
BCG044 overcomes single-target hurdles through synergy-driven tumor selectivity. By requiring both HER3 and EpCAM to bind effectively, the bispecific ADC avoids interacting with healthy single-antigen tissues, successfully bypassing EpCAM-associated toxicity. Simultaneously, this dual-engagement triggers rapid cellular internalization, solving the delivery issues that have historically plagued HER3-only assets.
BCG044 is designed to target major epithelial malignancies where HER3 and EpCAM are broadly co-expressed. This includes massive, underserved patient populations in colorectal cancer (CRC), non-small cell lung cancer (NSCLC), breast cancer, pancreatic cancer, and gastric cancer.
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