The pharmacological functions of bispecific antibodies (BsAbs) can be broadly categorized into three core mechanisms: Cell-engagers, Non-cell bridging, and Receptor-ligand blockade. These three categories constitute the fundamental framework for the design and functional implementation of bispecific antibody therapeutics.
1. Cell-Engaging Therapies
In cell-engaging strategies, T cell engagers (TCEs) physically link activating receptors on the surface of T cells (e.g., CD3) or NK cell-associated receptors to tumor-specific antigens (e.g., BCMA, CD19) on malignant cells. This cross-bridging triggers the activation of T cell cytotoxicity, leading to the release of perforin and granzyme to directly eliminate tumor cells. This mechanism has become a representative therapeutic modality in hematological malignancies.
Canonical TCEs primarily initiate T cell activation via CD3 signaling, while alternative designs deliver co-stimulation as Signal 2 to synergize with tumor cell-derived Signal 1. To expand targetability, ImmTAC technology has been developed, which employs high-affinity TCRs to recognize intracellular peptides presented by HLA molecules, redirecting polyclonal T cells toward tumors.
NK cell engagers (NKCEs) recruit the intrinsic cytolytic capacity of NK cells by targeting activating receptors such as CD16a and NKG2D, forming BiKE or TriKE therapeutic formats. Macrophage engagers function by simultaneously blocking the CD47-SIRPα immune checkpoint and triggering Fcγ receptor-mediated antibody-dependent cellular phagocytosis (ADCP). To mitigate on-target/off-tumor toxicities such as anemia induced by CD47 inhibition, novel bispecific designs adopt a high-affinity binding profile for tumor-associated antigens (TAAs) and low-affinity binding for CD47. Meanwhile, these molecules activate receptors including CD40 to repolarize macrophages into a pro-inflammatory, anti-tumor phenotype.
Representative Case: Blinatumomab
Targets: CD3 / CD19
Mechanism: T cells are recruited and juxtaposed with tumor cells via CD3 engagement, forming immunological synapses and releasing cytotoxic factors to exert tumoricidal effects.
Clinical Application: Blinatumomab significantly improves the complete remission rate in acute lymphoblastic leukemia (ALL) and has been established as a standard immunotherapeutic agent.
2. Non-Cell Bridging Therapies
In non-cell bridging modalities, bispecific antibodies modulate immune checkpoints, co-stimulation signals and the tumor microenvironment (TME) to potentiate anti-tumor immunity. Dual immune checkpoint inhibitors co-targeting molecules such as PD-1 and CTLA-4 exert synergistic immunostimulatory effects and help overcome therapeutic resistance. Co-stimulatory receptor agonists (e.g., OX40 / 4-1BB) provide the secondary signal required for full T cell activation, yet carry the risk of systemic excessive immune activation.
Accordingly, this therapeutic strategy preferentially adopts TAA-restricted combinatorial formats (e.g., TAA/CD28, TAA/4-1BB) to achieve spatially controlled immune activation.
Moreover, tumor cells rely on multiple signaling pathways to sustain proliferation and immune evasion, and mono-target inhibition is frequently compromised by compensatory pathway activation. Bispecific antibodies in this category can concurrently bind and block two oncogenic signaling cascades (e.g., EGFR/MET), achieving synergistic suppression, reducing drug resistance risk and enhancing therapeutic efficacy. In addition, TME-targeted bispecific antibodies focus on reversing the immunosuppressive state, with representative candidates including PD-L1/VEGF and TGF-β/PD-L1. Such combinations comprehensively dismantle the inhibitory constraints of the TME on anti-tumor immune responses.
Representative Case: Amivantamab
Targets: EGFR / MET
Mechanism: Simultaneously blocks EGFR and MET signaling cascades, preventing tumor escape through alternative pathway activation.
Clinical Application: For non-small cell lung cancer (NSCLC) harboring EGFR Exon 20 insertion mutations, Amivantamab binds to the extracellular domains of both receptors to break through drug resistance bottlenecks, becoming the world’s first approved targeted therapy for this specific NSCLC subtype.
3. Receptor-Ligand Blockade
The core principle of the receptor-ligand blockade strategy is to directly interfere with pathological receptor-ligand interactions and ablate downstream signaling activation, while alleviating tissue inflammation and vascular leakage.
Bispecific antibodies in this class can concurrently inhibit multiple oncogenic signaling pathways critical for tumor progression (e.g., EGFR/MET), blocking redundant or compensatory cascades to surmount therapeutic resistance. Additionally, some bispecific molecules target two distinct epitopes on the same receptor (e.g., HER2/HER2), inducing robust receptor crosslinking, internalization and degradation. Other designs prevent receptor heterodimerization (e.g., HER2/HER3), thereby silencing downstream oncogenic signaling. Certain bispecific antibodies simultaneously bind to both a receptor and its ligand to form stable inactive complexes, leading to thorough suppression of pathological signaling and tumor regression.
Representative Case: Faricimab
Targets: VEGF-A / Angiopoietin-2 (Ang-2)
Mechanism: VEGF-A drives pathological angiogenesis, whereas Ang-2 destabilizes blood vessels and exacerbates inflammation by inhibiting Tie2 signaling. Faricimab dually neutralizes VEGF-A and Ang-2, exerting combined effects of anti-angiogenesis, vascular stabilization and anti-inflammation.
Clinical Application: In neovascular age-related macular degeneration and diabetic macular edema, Faricimab demonstrates durable efficacy and favorable safety profiles, substantially reducing the risk of disease progression.
Summary
Bispecific antibody therapeutics achieve multi-dimensional intervention against tumors and pathological microenvironments via three fundamental mechanisms: cell engagement, non-cell bridging, and receptor-ligand blockade. Each mechanism corresponds to distinct molecular design strategies and specific clinical indications. Representative agents including Blinatumomab, Amivantamab and Faricimab fully illustrate the broad clinical potential of bispecific antibodies in hematological malignancies and other refractory diseases. With advances in molecular engineering and mechanistic immunology, future bispecific antibody development will integrate multiple functional mechanisms to deliver more potent and long-lasting anti-tumor therapeutic outcomes.
