ITGB6 × B7-H3 Dual-Payload Bispecific ADC (BCG048)

ITGB6 × B7-H3 Dual-Target ADC Strategy

• Tumor-selective target profile: Integrin β6 (ITGB6) and B7-H3 (CD276) are overexpressed in multiple solid tumors with limited expression in normal tissues, offering a favorable therapeutic window for ADC development.
• Broad solid tumor relevance: ITGB6 and B7-H3 are co-expressed across esophageal carcinoma, head and neck squamous cell carcinoma, bladder carcinoma, non-small cell lung cancer, and pancreatic adenocarcinoma.  
• Complementary mechanisms: ITGB6 promotes tumor invasion and immune exclusion, while B7-H3 mediates immunosuppression, enabling cooperative targeting of biologically distinct yet clinically relevant tumor pathways.  
• Improved binding and payload delivery: Both antigens enable specific antibody binding; ITGB6 supports efficient internalization and B7-H3 provides clinically validated ADC tractability.
• Overcoming tumor heterogeneity: Dual targeting is designed to address antigen heterogeneity and broaden tumor-cell coverage compared with single-target ADC strategies.
• Competitive differentiation: B7-H3 is an established ADC target; adding ITGB6 introduces mechanistic depth and strategic differentiation.

BackboneRenLite® Fully Human Common Light Chain Antibody Backbone

Built on the RenLite® platform, BCG048 uses common light-chain technology to simplify assembly, reduce manufacturing complexity, and provide a developable antibody backbone for the ITGB6 × B7-H3 dual-target ADC design.    

Dual-Payload ADC Design with vcMMAE and BLD1102

BCG048 integrates vcMMAE (DAR=2) with our proprietary BLD1102 linker–payload system (BCPT02, DAR=4)—a highly potent topoisomerase I (TOP1) inhibitor with greater cytotoxic activity than DXd, addressing the limitations of single-payload ADCs.

• Resistance mitigation: By combining distinct cytotoxic mechanisms—tubulin polymerization inhibition (vcMMAE) and TOP1-mediated DNA damage (BLD1102)—this dual-payload pairing may help mitigate single-payload resistance, particularly the MDR1-mediated efflux typically associated with MMAE.
• Synergistic potency: The vcMMAE and BLD1102 pairing is designed to support broader tumor cell killing through complementary payload activity. The hydrophilic properties of BLD1102 may help improve solubility and reduce aggregation risk, supporting the developability of the BCG048 dual-payload ADC format.

Robust Antitumor Efficacy Profile

• The ITGB6 × B7-H3 bsAb (unconjugated) shows enhanced internalization in dual-positive tumor cells (Figure 4).
• The ITGB6 × B7-H3 bsAb (vcMMAE-conjugated) demonstrated improved efficacy in CDX models as proof of concept for dual targeting.
• BCG048 (dual-payload) shows synergistic effects over single-payload ADCs and outperforms benchmark ADC comparators in vivo (Figure 5).

IP Status and Potential Indications

• A PCT patent application has been filed.
• BCG048 is being evaluated for ITGB6/B7-H3-expressing solid tumors, with potential indications including NSCLC, pancreatic, TNBC, colorectal, gastric cancers.

The preclinical data supporting BCG048 include target co-expression analysis, dual-payload conjugation feasibility, dual-payload pharmacokinetics, bispecific antibody backbone internalization, and antitumor efficacy in a colorectal PDX model, supporting the development of BCG048 as an ITGB6 × B7-H3 dual-payload bispecific ADC for broad potential solid tumor indications.

ITGB6 and B7-H3 Are Co-expressed Across Multiple Solid Tumor Types

Figure 1. Co-expression analysis of ITGB6 and B7-H3 in solid tumors based on TCGA transcriptomic data. Expression levels of ITGB6 and B7-H3 were evaluated using log2-transformed TPM values from the TCGA database. These data demonstrate a positive correlation between the two targets, supporting the rationale for evaluating ITGB6 × B7-H3 dual-targeting strategies in selected solid tumors, including esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), bladder urothelial carcinoma (BLCA), lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), and pancreatic adenocarcinoma (PAAD).

Dual-Payload Conjugation Maintains Antigen Binding Activity

Figure 2. Antigen binding analysis of a trastuzumab-based dual-payload ADC in HCC1954 cells. The trastuzumab-vcMMAE-BLD1102 ADC (red line) retained HER2 binding activity comparable to both unconjugated trastuzumab and the single-payload trastuzumab-vcMMAE ADC, confirming that dual-payload conjugation does not compromise antigen affinity.

Dual-Payload ADC Shows a Favorable Pharmacokinetic Profile

Figure 3. Pharmacokinetic (PK) profile of a vcMMAE and BLD1102 dual-payload ADC. Following a single intravenous administration at 3 mg/kg, plasma concentrations of the dual-payload ADC, single-payload controls, and free payloads were quantified over time. The dual-payload ADC (yellow line) exhibited a PK profile comparable to that of the single-payload controls, confirming sustained systemic ADC exposure after dual-payload conjugation with vcMMAE and BLD1102.

BCG048 Bispecific Antibody Backbone Shows Enhanced Internalization

Figure 4. Internalization kinetics of the BCG048 ITGB6 × B7-H3 bispecific antibody backbone in tumor cells. Internalization was evaluated across HCC70, HCC1954, and BXPC-3 cells with different ITGB6 and B7-H3 expression levels. The BCG048 bsAb-5 clone (green line) demonstrated rapid, progressive internalization over time, outperforming single-target ITGB6 or B7-H3 parental antibody analogs and mutant controls, confirming enhanced internalization driven by the ITGB6 × B7-H3 bispecific antibody design.

BCG048 Demonstrates Antitumor Efficacy in a Colorectal PDX Model

Figure 5. Antitumor efficacy of BCG048 dual-payload ADC in the BP0847 colorectal PDX model. BCG048 (red line) showed superior antitumor efficacy compared with single-payload ADCs (A) and benchmark ADCs (B), supporting the antitumor potential of the ITGB6 × B7-H3 dual-targeting and dual-payload ADC design in this preclinical model.

Biocytogen welcomes partnership discussions to further evaluate the development potential of BCG048.

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