Beginner-Friendly Series｜Bispecific Antibody Drug Vol.3：Strategic Considerations in Selecting Targets for Bispecific Antibody Drugs

In this third installment of our Beginner-Friendly Bispecific Antibody Drug series, we delve into the crucial question: “Which targets should be selected?” Target selection is a core strategic decision in bispecific antibody development, directly influencing efficacy, specificity, safety, and eventual clinical success. This article breaks down key considerations with examples to help beginners navigate the target selection process.

1. Why Target Selection Matters in Bispecific Antibody Development

Unlike monoclonal antibodies, bispecific antibodies (bsAbs) must engage two targets simultaneously. This dual-targeting mechanism can lead to synergistic effects but also poses complex challenges in choosing appropriate antigens. The right target combination can result in enhanced tumor specificity, improved immune cell redirection, or blockade of redundant signaling pathways.

2. General Classification of Target Types

• Tumor-Associated Antigens (TAAs): Expressed primarily on tumor cells, such as HER2, EGFR, and CEA.
• Immune Cell Surface Markers: Including CD3 (T-cell activation), CD16 (NK cells), or CD28 (costimulatory signal).
• TME (Tumor Microenvironment) Targets: Such as PD-L1 or VEGF, which regulate immune evasion and angiogenesis.
• Novel Tumor-Specific Epitopes: Discovered through neoantigen profiling and spatial omics techniques.

3. Key Considerations When Selecting Targets

3.1 Target Expression and Tumor Selectivity

Targets should ideally have high and homogeneous expression on tumor cells while being absent or minimal in healthy tissues. For example, BCMA in multiple myeloma is a popular target due to its tumor-specific expression.

3.2 Internalization Rate and Accessibility

Targets that allow antibody internalization (e.g., EGFR) can be suitable for delivering cytotoxic payloads, while surface-anchored targets with minimal endocytosis are better for immune redirection approaches.

3.3 Functionality and Mechanistic Complementarity

Combining a tumor antigen with an immune cell activator (e.g., CD3 x GPC3) enhances immune engagement. Alternatively, dual blockade of receptors like HER2 x HER3 can suppress compensatory signaling.

3.4 Cross-Reactivity and Off-Tumor Toxicity

Antigens also expressed in normal tissues (e.g., HER2 in the heart) can lead to dose-limiting toxicities. Carefully balancing efficacy and safety through target density thresholds or conditional activation designs is essential.

4. Target Combinations: Strategic Approaches

• Tumor Antigen x Immune Activator (T-cell/NK): Most common format, e.g., CD3 x BCMA (Elranatamab).
• Dual Tumor Antigens: Increases tumor selectivity, e.g., EGFR x cMET.
• Inhibitory Receptor x Co-stimulatory Molecule: Combines checkpoint blockade with immune activation, e.g., PD-L1 x CD28.

5. Emerging Tools for Rational Target Selection

• Spatial Transcriptomics: Maps gene expression in tissue context to identify tumor-restricted targets.
• Single-cell RNA-seq: Dissects tumor heterogeneity and reveals subclonal targets.
• Proteomics and Cell Surfaceome Profiling: Helps verify surface protein abundance.

6. Case Study: Target Selection in Elranatamab

Pfizer’s Elranatamab targets BCMA (on myeloma cells) and CD3 (on T cells). The selection of BCMA was based on its high expression in multiple myeloma and low expression in normal tissues. CD3 ensures robust T-cell engagement. This combination demonstrates how rational target pairing can enhance antitumor efficacy with manageable toxicity.

7. Summary

Target selection in bispecific antibody design is a strategic exercise requiring an understanding of tumor biology, immune engagement, and safety profiles. As technology evolves, target discovery will become increasingly data-driven, enabling more precise and effective bsAb therapies.

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This article was produced by the Morningglorysciences Editorial Team.