CD276 Overview

CD276 is a type I transmembrane glycoprotein and a member of the B7 family. It was first identified in 2001.

The CD276 gene is located on chromosome 15 and encodes a protein consisting of 316 amino acids, with a relative molecular weight ranging from 45 to 66 kDa. The full-length CD276 protein comprises four regions: a predicted signal peptide, extracellular V- and C-like immunoglobulin domains (IgV and IgC), a transmembrane domain, and a cytoplasmic tail. There are two isoforms: 2Ig CD276 and 4Ig CD276, with the latter being the predominant form.

Structure of CD276

Some studies have shown that CD276 exhibits both co-stimulatory and inhibitory functions in the immune system within non-malignant tissues. On one hand, CD276 acts as a co-stimulatory molecule, promoting T cell activation, proliferation, and the secretion of cytokines such as IFN-γ and IL-2. On the other hand, CD276 also plays a co-inhibitory role in certain adaptive immune responses, enabling tumor cells to evade immune surveillance and suppressing NK cell–mediated cytolysis.

Signaling Pathways of CD276

Studies have shown that CD276 is overexpressed in various tumor types, including non-small cell lung cancer, pancreatic cancer, and primary liver cancer. Its elevated expression in tumor tissues is often associated with poor prognosis, shorter overall survival (OS), and reduced progression-free survival (PFS). In lung cancer—particularly small cell lung cancer—approximately 65% of patients exhibit high CD276 expression in their tumors. This overexpression correlates with poor clinical outcomes, highlighting CD276 as a promising therapeutic target.

Expression of CD276 in Cancer Tissues

Current Research Landscape of CD276

To date, no CD276 ADC products have been approved for market release worldwide. The research and development landscape for CD276 ADCs differs from that of other therapeutic areas. Despite challenges encountered during development, global companies continue to make persistent efforts to advance this field.

According to research, there are currently seven CD276 ADC candidates in clinical development worldwide, targeting a broad range of cancers, including neuroblastoma with CNS involvement, lung cancers, sarcoma, head and neck cancers, as well as other advanced or recurrent solid tumors.

Inatuzumab Deruxtecan

Co-developed by Daiichi Sankyo and Merck & Co., this antibody-drug conjugate has entered a global Phase III clinical trial for prostate cancer, becoming the first CD276-targeting ADC to reach this stage of development.

Built on Daiichi Sankyo’s proprietary DXd platform, the candidate represents a significant advancement in the field and highlights the growing momentum in the global CD276 ADC landscape.

HS-20093

HS-20093 is a CD276-targeting antibody-drug conjugate (ADC) that utilizes a clinically validated topoisomerase inhibitor (TOPOi) as its cytotoxic payload.

On December 20, 2023, GSK entered into a licensing agreement with Hansoh Pharma, securing the ex-China rights to HS-20093. The deal includes an upfront payment of $185 million, with potential milestone payments of up to $1.525 billion. Following the agreement, GSK has initiated two Phase III clinical trials, focusing on small cell lung cancer and osteosarcoma.

As of April 18, 2025, the Chinese Drug Clinical Trial Registry (CTR20251474) indicates that Hansoh has registered a Phase III clinical trial comparing HS-20093 injection with gemcitabine plus docetaxel in patients with osteosarcoma who have failed second-line treatment. This marks the first Phase III osteosarcoma trial initiated for this candidate.

Recently, HS-20093 has entered a Phase I clinical trial in combination with a PD-L1 antibody as a first-line maintenance therapy for small cell lung cancer. This combination strategy is expected to enhance response rates through immune-synergistic mechanisms, offering a potential new treatment option for tumors with low immunogenicity.

Conclusion

CD276 has rapidly gained attention as a compelling target in oncology, driven by its high expression in a range of solid tumors and its role in immune modulation. Although no CD276-targeting ADCs have been approved to date, several candidates, including Inatuzumab deruxtecan 

 and HS-20093, have advanced into late-stage clinical development, signaling strong momentum in the field. With ongoing innovations in payload design and combination strategies, CD276 ADCs hold significant potential to become an important therapeutic option for difficult-to-treat cancers.

Reference

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