B7-H3 antibody discovery for next-generation immunotherapies

In 2026, how can we design anti-B7-H3 antibodies that stand out for their efficacy, safety, and intellectual property profiles? Monoclonal, bispecific, ADC, or novel formats, which approach should we choose to compete with the first wave of clinical candidates and the next-generation molecules already in development?

In this article, we will discuss the role of B7-H3, the antibodies already developed against this target and recent approaches to designing high-performing candidates. We will also emphasize the differentiation criteria useful for R&D, licensing and competitive positioning.

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What is B7-H3 and what is its role in the immune response?

B7-H3 (CD276) is a member of the B7 family of immune regulatory molecules. It is a type I transmembrane glycoprotein expressed on the surface of various cell types, including antigen-presenting cells, T cells, and, most notably, a wide range of tumor cells. Unlike its B7 family relatives B7-1 (CD80) and B7-2 (CD86), which are primarily expressed on professional antigen-presenting cells, B7-H3 displays a broader expression pattern that extends to non-hematopoietic tissues and, at particularly high levels, to many solid tumors.

The function of B7-H3 in immune regulation remains an area of active investigation. In non-malignant tissues, B7-H3 has been reported to exert predominantly inhibitory effects on T cell activation and proliferation, contributing to immune tolerance. In the tumor context, B7-H3 expression is associated with immune evasion, as it suppresses tumor antigen-specific T cell responses and promotes a protumorigenic microenvironment. Beyond its immunological role, B7-H3 also drives non-immunologic protumorigenic processes, including cell migration, invasion, angiogenesis, chemoresistance, and metabolic reprogramming.

Key mechanisms of B7-H3 in tumor biology:

• immune checkpoint activity, suppressing T cell activation and promoting immune evasion in the tumor microenvironment;
• interaction with NKp30 (NCR3), an activating receptor on natural killer cells, where 4Ig-B7-H3 can protect tumor cells from NK-mediated lysis;
• engagement of TLT-2 (TREML2) on CD8+ T cells, which can enhance T cell activation and IFN-γ production;
• promotion of tumor cell migration, invasion, and angiogenesis through non-immunologic signaling pathways;
• contribution to chemoresistance and endothelial-to-mesenchymal transition.

Structurally, B7-H3 is a type I transmembrane glycoprotein encoded by the CD276 gene on chromosome 15. The full-length 4Ig isoform (isoform 1) comprises four extracellular immunoglobulin-like domains arranged in a V1-C2-1-V2-C2-2 configuration, a single transmembrane segment (residues 467–487), and a cytoplasmic tail (residues 488–534). A shorter 2Ig isoform (isoform 2) lacks the first V-C2 pair. The protein is N-glycosylated at ASN-322 and ASN-407. The 4Ig isoform is the predominant form on the cell surface and is the primary target of most therapeutic antibodies.

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Why target B7-H3 in therapy?

In many solid tumors, B7-H3 is overexpressed on both tumor cells and tumor-associated vasculature, while its expression in most normal tissues remains low or undetectable. This favorable expression profile, combined with its role in immune evasion and tumor progression, makes B7-H3 an attractive target for antibody-based immunotherapy. B7-H3 expression is detected in approximately 60% of over 25,000 tumor samples across multiple cancer types, with particularly high levels in small cell lung cancer, nasopharyngeal carcinoma, glioblastoma, and several other malignancies.

Anti-B7-H3 antibodies thus have two main objectives:

• blockade of B7-H3-mediated immune suppression to restore anti-tumor T cell and NK cell responses;
• direct targeting of B7-H3-expressing tumor cells through effector functions (ADCC, ADC) or payload delivery (ADCs).

Approved indications and combinations B7-H3

No anti-B7-H3 antibody has received regulatory approval to date. However, the target has been extensively validated in the clinic, with multiple molecules in phase 1/2 and phase 3 trials.

The most advanced clinical-stage molecules are predominantly antibody-drug conjugates (ADCs). YL201, a B7H3-targeting ADC with a tumor microenvironment-activable linker and a topoisomerase 1 inhibitor payload, demonstrated an objective response rate of 63.9% in extensive-stage small cell lung cancer (ES-SCLC) and 48.6% in nasopharyngeal carcinoma (NPC) in a phase 1/1b trial enrolling 312 patients. Phase 3 trials for SCLC and NPC have been initiated. Similarly, HS-20093 (GSK5764227), another B7-H3 ADC, showed a confirmed ORR of 52.3% in ES-SCLC and 22.4% in NSCLC in the ARTEMIS-001 phase 1a/b trial (306 patients), with 8.0 mg/kg selected for phase 3 development. IBI343, an Fc-glycan-specific B7H3 ADC from Innovent, has also shown promising results in phase 1 trials and is advancing into phase 3 studies.

Beyond ADCs, radiolabeled antibodies such as omburtamab (131I-omburtamab) have been evaluated in phase I trials for diffuse intrinsic pontine glioma (DIPG) using convection-enhanced delivery, demonstrating locoregional control in pediatric patients. Bispecific antibodies, including the CD276×CD3 T cell engager CC-3 (phase I, NCT05999396) and the B7-H3×CD28 costimulatory bispecific XmAb808, represent additional clinical-stage approaches.

The clinical validation of B7-H3 as a target is therefore strong, but the absence of an approved antibody means that the competitive landscape is still being defined. The molecules that will establish the standard of care in B7-H3-positive tumors are yet to be determined.

The challenges of projects involving anti-B7-H3 antibodies

Today, projects using anti-B7-H3 solutions face several constraints:

• a rapidly growing and crowded clinical landscape, with multiple ADCs, bispecifics, and radiolabeled antibodies already in phase 1/2 or phase 3 trials, making differentiation essential;
• the lack of a fully characterized B7-H3 receptor, which complicates the design of purely blocking antibodies and has pushed the field toward effector-function-based formats (ADCs, bispecifics, radioimmunoconjugates);
• the need to balance tumor targeting with the low but non-zero expression of B7-H3 in certain normal tissues (e.g., placenta, testis, and some vascular beds), which can limit the therapeutic window;
• intellectual property considerations, as the most advanced molecules (YL201, HS-20093, IBI343) are protected by active patents on their antibody sequences, linkers, and payloads.

The challenge is therefore to design a differentiated antibody with a novel epitope, an optimized format (ADC, bispecific, or next-generation construct), and a strong IP position that distinguishes it from the existing clinical pipeline.

👉 Explore our pipeline to identify untapped opportunities and competitive positioning.

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Overview of anti-B7-H3 antibodies, from the first to the second generation

First-generation anti-B7-H3 antibodies

No anti-B7-H3 antibody has been approved to date. The first-generation landscape is defined by the most advanced clinical-stage molecules, which are predominantly antibody-drug conjugates.

YL201 (MediLink Therapeutics) is a B7H3-targeting ADC that couples a novel topoisomerase 1 inhibitor to a tumor microenvironment-activable, protease-cleavable linker. In its phase 1/1b trial (NCT05434234, NCT06057922), YL201 demonstrated an acceptable safety profile and encouraging anti-tumor activity, with objective response rates of 63.9% in ES-SCLC, 48.6% in NPC, and 54.2% in lymphoepithelioma-like carcinoma. Phase 3 trials for SCLC and NPC have been initiated.

HS-20093 (GSK5764227, Hansoh/GSK) is a B7-H3-targeted ADC evaluated in the ARTEMIS-001 phase 1a/b trial (NCT05276609) in 306 patients with previously treated advanced solid tumors. The maximum tolerated dose was established at 12.0 mg/kg, and 8.0 mg/kg was selected for phase 3 trials. Confirmed ORRs were 52.3% in ES-SCLC and 22.4% in NSCLC.

IBI343 (Innovent Biopharma) is an Fc-glycan-specific B7H3 ADC that uses the conserved Fc N-glycan as the anchor point for site-specific conjugation, improving ADC homogeneity and pharmacokinetics. It has demonstrated promising results in phase 1 trials and is advancing into phase 3 studies.

Omburtamab is a B7-H3-targeting antibody that has been evaluated as a radioimmunoconjugate (131I-omburtamab) in phase I trials for pediatric diffuse intrinsic pontine glioma (DIPG) using convection-enhanced delivery (NCT01502917), demonstrating locoregional control in the brainstem.

Next-generation anti-B7-H3 antibodies

The second wave of anti-B7-H3 antibodies broadens the therapeutic index through novel formats and combination strategies.

Examples include:

• T cell-engaging bispecific antibodies, such as CC-3 (CD276×CD3, phase I, NCT05999396), which redirects T cells to B7-H3-expressing tumor cells and has shown potent T cell activation, degranulation, and target cell lysis in endometrial cancer models;
• costimulatory bispecific antibodies, such as XmAb808 (B7-H3×CD28), which combines B7-H3 targeting with CD28 co-stimulation to enhance T cell activation in the tumor microenvironment;
• bispecific ADCs, such as DB-1419 (B7-H3×PD-L1), which simultaneously targets B7-H3 and PD-L1 to deliver a cytotoxic payload while releasing a checkpoint-inhibitory effect;
• B7-H3 bispecific antibodies for glioblastoma, such as MGD009, designed to engage immune effectors in the CNS;
• engineered Fc variants and pH-sensitive designs that modulate effector functions (ADCC, CDC) to optimize the therapeutic window in the context of low-level B7-H3 expression in normal tissues.

Several questions arise from these trends. Which isotype and Fc effector function profile best suits a given format? Should the antibody target the 4Ig or 2Ig isoform, or both? Which extracellular domains (V1, C2-1, V2, C2-2) should be engaged to maximize tumor selectivity while avoiding cross-reactivity with normal tissue? How can the linker-payload combination in ADCs be optimized to minimize off-target toxicity?

👉 With no approved anti-B7-H3 antibody yet, the IP landscape is still being shaped. The first molecules to reach phase 3 and regulatory review will define the standard of care, creating a window for differentiated candidates with novel epitopes, optimized formats, and strong patent positions. The key is to position ahead of the first approvals.

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Why choose MAbSilico to design anti-B7-H3 antibodies?

The available data allow us to understand the biology and clinical aspects of the B7-H3 protein. In contrast, the design of a competitive anti-B7-H3 antibody requires a comprehensive range of structures, experimental data, and the intellectual property landscape.