Multispecific Antibodies: Focus on VEGF–PD-L1 Bispecific Agents

Multispecific antibodies (MsAbs), represent an advanced class of engineered immunoglobulins capable of binding two or more distinct antigens or epitopes simultaneously. The term “multispecific antibodies” emphasizes the capacity of a single molecule to engage multiple targets, offering improved therapeutic potential in complex diseases such as cancer. By contrast to conventional monoclonal antibodies (mAbs) that bind a single target, MsAbs may combine immune-modulation, blockade of signalling pathways, or cell-bridging functionalities in one construct.

In oncology, the development of multispecific antibodies has surged in recent years because tumours exploit multifactorial mechanisms such as immune evasion, angiogenesis, and stromal support networks, that may not be fully addressed by single-target therapies. Hence, MsAbs allow the simultaneous disruption of multiple tumour-promoting axes while potentially coordinating synergistic effects. For example, combining checkpoint blockade with angiogenesis inhibition addresses both immune suppression and tumour vascular supply.

In this article we focus on MsAbs in oncology with particular attention to agents targeting the vascular endothelial growth factor (VEGF) axis together with immune‐checkpoint ligand-1 (PD-L1) (and in some cases PD-1). These VEGF–PD(L)1 multispecific antibodies are emerging as a compelling strategy to intersect anti-angiogenic therapy with immunotherapy in solid tumour

The mechanism of action (MoA) of multispecific antibodies hinges on their ability to simultaneously engage two (or more) discrete antigens. This dual (or multi) engagement can be leveraged in several ways:

1. Dual signalling blockade: One arm of the antibody blocks pathway A (e.g., VEGF signalling) while another arm blocks pathway B (e.g., PD-L1/PD-1 immune checkpoint). The combined blockade may yield additive or synergistic antitumour effects.
2. Tumour-targeting plus immune-effector recruitment: Some MsAbs can bind a tumour antigen and a T-cell activating receptor (for instance CD3), thereby physically redirecting immune effectors to tumour cells (so-called T-cell engager bispecifics).
3. Conditional activation or preferential targeting: By requiring simultaneous binding of both antigens for optimal affinity/avidity, MsAbs can enhance tumour-selectivity, reduce off-target toxicity, and promote intra-tumour accumulation.

In the case of MsAbs targeting VEGF (or VEGF-A/VEGFR axis) and PD-L1 (or PD-1), the proposed mechanistic rationale is particularly strong. The two pathways cross-link tumour angiogenesis, immune suppression and the tumour microenvironment (TME) in the following ways:

• VEGF promotes tumour vascular growth, but also establishes an immunosuppressive microenvironment by impairing dendritic cell maturation, promoting regulatory T-cells (Tregs), inhibiting effector T-cell infiltration, and up-regulating checkpoints such as PD-1/PD-L1.
• PD-L1 on tumour cells (and on other cells in the TME) binds PD-1 on T cells to inhibit T-cell activation and permit immune evasion.
• By combining VEGF inhibition with PD(L)1 blockade in a single molecule, one achieves: (a) anti-angiogenic effect, normalising vasculature and enhancing T-cell infiltration; (b) direct checkpoint inhibition re-activating T-cells; (c) potentially improved tumour localisation of the bispecific (if one arm binds PD-L1 expressed in tumour). For example, one bispecific engineered to bind both PD-L1 and VEGF showed enhanced tumour binding and internalisation in the presence of VEGF and PD-L1 double expression.
• In some designs, increased local binding and internalisation may concentrate the drug in the tumour microenvironment, improving therapeutic index. For example, HLX37 (PD-L1×VEGF bispecific) showed enhanced tumour enrichment compared to the combination of separate anti-PD-L1 + anti-VEGF mAbs.

Thus, the mechanism of VEGF–PD(L)1 multispecific antibodies combines vascular modulation and immune checkpoint reactivation in one modality, a rational way to overcome resistance mechanisms seen with single-agent approaches.

The data in this graph was taken from the Beacon Oncology Database.

• VEGF;PD-L1 and VEGF;PD-1 bispecific antibodies dominate the landscape, with 17 and 15 assets, respectively
• The majority of assets are in the clinical and preclinical phases, with only a small portion having reached approved status
• Trispecific antibodies are less common, VEGF;PDL-1;CTLA-4 and VEGF;PDL-1;TGFB having 5 and 4 assets, respectively

Preclinical studies have provided proof-of-concept for VEGF–PD(L)1 bispecifics (a subset of “multispecific antibodies”). Key examples:

• The bispecific antibody HB0025 (VEGFR1 domain fused to anti-PD-L1 mAb) demonstrated in preclinical models that dual blockade of VEGF/VEGFR and PD-L1 led to greater tumour growth inhibition compared to either single agent alone.
• Another study of JS207 (anti-PD-1/VEGFA bispecific) found high binding affinity, potent T-cell activation, and significant anti-tumour efficacy in mouse MC38 colon and A375 melanoma models. The authors emphasised that a bispecific approach offered improved pharmacokinetics and simplified dosing versus combination therapy.
• HLX37 (PD-L1/VEGF bispecific) was shown in humanised CDX models (MDA-MB-231, NCI-H292) to achieve dose-dependent tumour volume reduction, superior to the combination of anti-PD-L1 + anti-VEGF mAbs, and displayed favourable PK and safety in cynomolgus monkeys.
• CVL006 (anti-PD-L1 VHH + humanised IgG1 anti-VEGF) outperformed benchmark anti-PD-L1 + anti-VEGF in preclinical efficacy (greater tumour growth inhibition, higher cytokine release, stronger T-cell reactivation) in in vivo models.

These preclinical data support the concept that a single bispecific antibody targeting both angiogenesis and immune checkpoint pathways can deliver improved anti-tumour efficacy, potentially better tissue penetration and simplified dosing.

Mechanistic studies also supported the interdependence of VEGF signalling and immune suppression: VEGF blockade can enhance dendritic cell function, T-cell infiltration and reduce T-reg mediated suppression, thus increasing the effectiveness of checkpoint inhibitors.

Overall, the preclinical foundation for VEGF–PD(L)1 multispecific antibodies is robust, demonstrating dual‐pathway inhibition, favourable in vivo efficacy, and acceptable preclinical safety.

While many multispecific antibodies remain in early development, the VEGF–PD(L)1 class is entering clinical proof-of-concept and later stage trials

• BNT327 (PD-L1/VEGF bispecific) is being evaluated in combination therapy: A current study (NCT06892548) is recruiting to assess the efficacy and safety of BNT327 (a PD-L1 and VEGF bispecific antibody) combined with BNT324 (a B7-H3 ADC) in patients with advanced/metastatic or relapsed/progressive small-cell and non-small-cell lung cancer, including establishing recommended Phase 2 dose levels and expansion cohorts.
• BNT327 is also under investigation in combination with chemotherapy: The registered phase II trial (NCT06449209) is active (not recruiting) to evaluate safety and preliminary effectiveness of BNT327 in participants with small-cell lung cancer (both untreated extended-stage and progressed disease cohorts), exploring its activity across disease settings.
• HB0025 (PD-L1/VEGF bispecific) has been studied in a Phase 1 dose escalation/expansion trial: The multicenter, open-label Phase 1 study (NCT04678908) is designed to evaluate safety, toxicity, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity of HB0025 monotherapy in advanced solid tumors with no effective standard options.

These registered multispecific antibody trials reflect emerging clinical development of VEGF/PD-L1 dual-targeting strategies in oncology, with ongoing dose optimization and efficacy assessments across solid tumor indications.

The future for multispecific antibodies, and specifically VEGF–PD(L)1 bispecifics, is highly promising but also will face key scientific, clinical and regulatory challenges and opportunities. Some of the future directions include:

1. Broader tumour-type expansion
   Given the broad expression of VEGF and PD-L1 (or PD-1) and the general relevance of angiogenesis + immune suppression in many solid tumours, these bispecifics may extend beyond lung cancer into breast, colorectal, hepatocellular carcinoma, renal cell carcinoma, and others. Preclinical models such as HLX37 included breast cancer (MDA-MB-231) and lung carcinoma (NCI-H292) cell lines.
2. Combination strategies
   Multispecific antibodies may serve as backbone agents in combination with chemotherapy, other immunotherapies (e.g., CTLA-4 inhibitors, 4-1BB agonists), targeted therapies, or antibody-drug conjugates (ADCs).
3. Refinement of engineering and specificity
   Future MsAbs may incorporate improved tumour-targeting moieties, enhanced stability, reduced immunogenicity, and conditional activation mechanisms (e.g., requirement of tumour-antigen binding for Fc activation). As one example, HLX37 was engineered with an exposed PD-L1 VHH nanobody and optimized interdomain linker for enhanced tumour deposition.
4. Biomarker-driven patient selection
   As with single-agent checkpoint inhibitors, biomarkers such as PD-L1 expression, tumour mutational burden, VEGF/VEGFR expression or angiogenic signatures may refine which patients benefit most. In addition, dual-pathway engagement might require assessment of both immune and angiogenic biomarkers.
5. Overcoming resistance mechanisms
   One of the rationales for multispecific antibodies is to pre-empt or overcome resistance to monotherapy agents. For instance, tumours resistant to anti-PD-1 may still rely on angiogenesis for immune exclusion; combining with VEGF blockade may restore sensitivity. Further research will focus on mechanisms of primary/ acquired resistance and how multispecifics can address them.
6. Global regulatory and commercial pathways
   As the bispecific field matures, regulatory frameworks must adapt to the complexity of these agents (for example, how to evaluate dual blockade versus combination therapy). Pricing, reimbursement and manufacturing scalability will also become key considerations.
7. Toxicity management
   Combining two mechanisms inherently risks overlapping or additive toxicity (e.g., immune-related adverse events + hypertension/bleeding from anti-VEGF). Future MsAb design must focus on improved safety profiles, possibly via tumour-selective binding, Fc engineering (to reduce unwanted effector functions), and biomarker-based risk stratification.
8. Next-generation multispecifics
   Beyond VEGF + PD(L)1, other combinations may emerge (e.g., angiogenesis + metabolic modulator, immune checkpoint + stromal target, tumour antigen + T-cell engager). The multispecific antibody platform is a versatile scaffold with many future permutations.

Multispecific antibodies represent a transformative paradigm in oncology, allowing the simultaneous targeting of multiple tumour-promoting mechanisms within a single molecular entity. Among the most compelling of these are bispecific antibodies targeting VEGF (or VEGF-A/VEGFR) together with PD-L1 (or PD-1). By combining angiogenesis inhibition and immune checkpoint blockade, VEGF–PD(L)1 multispecific antibodies address both the vascular and immune escape components of the tumour microenvironment.

Preclinical studies of these agents (e.g., HB0025, JS207, HLX37, CVL006) have demonstrated potent dual-pathway blockade, enhanced T-cell activation, tumour infiltration and inhibition of angiogenesis. Early clinical trials are underway, with Ivonescimab (PD-1/VEGF-A) already approved in China and several other candidates advancing through global phase II/III programmes.

The future for multispecific antibodies in oncology is rich with opportunity, expanding indications, refined engineering, combinatorial strategies, biomarker-driven selection and improved safety-efficacy balance. As these agents mature, they may become front-line therapies in solid tumours, offering improved outcomes over monotherapy approaches.

For clinicians, researchers and industry alike, the keyword “Multispecific Antibodies” will increasingly represent a frontier technology in cancer treatment. The VEGF–PD(L)1 bispecific class is among the first wave to demonstrate clinical translation of the multispecific concept, and serves as a model for the broader application of this platform