On May 6, 2025 CStone Pharmaceuticals ("CStone", HKEX: 2616), an innovation-driven biopharmaceutical company focused on anti-cancer therapies, reported that poster presentations of preclinical data of CS2011 (EGFR/HER3 bispecific antibody), CS5007 (EGFR/HER3 bispecific ADC), CS5005 (SSTR2 ADC) and CS5006 (ITGB4 ADC), key assets in CStone Pipeline 2.0, have been delivered at the 2025 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, CStone Pharmaceauticals, MAY 6, 2025, View Source [SID1234652605]).
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Key Highlights:
CS2011 (EGFR/HER3 bispecific antibody):
EGFR and HER3 are members of the human epidermal growth factor receptor (HER) family and are validated therapeutic targets in advanced solid tumors. EGFR overexpression drives tumor progression in approximately 70% of colorectal cancers (CRC), 60% of lung cancers, and over 90% of head and neck squamous cell carcinomas (HNSCC). Meanwhile, HER3 upregulation frequently emerges as a resistance mechanism to MAPK/PI3K inhibitors, EGFR tyrosine kinase inhibitors (TKIs), and hormone therapies. CS2011 is a bispecific antibody with high binding affinity to both EGFR and HER3. It effectively blocks downstream signaling of both targets, thereby inhibiting tumor growth on EGFR/HER3 positive tumor cells.
1. CS2011 targets almost all HER family signaling except HER2 homodimers, addressing tumor heterogeneity effectively.
2. CS2011 demonstrates potent binding affinity to EGFR and/or HER3 individually and enhanced dual binding affinity to EGFR and HER3 concurrently driven by avidity-based synergy.
3. CS2011 inhibits tumor growth by binding to EGFR and/or HER3-positive tumor cells.
4. CS2011 shows superior in vivo and in vitro anti-tumor activity versus potential major competitors.
（1） Compared to anti-EGFR, anti-HER3 and competing bispecific antibody, CS2011 induces faster and deeper internalization in tumor cells across varying EGFR & HER3 expression levels.
（2） CS2011 demonstrated potent inhibition of EGFR downstream signaling, comparable to anti-EGFR antibodies, and superior inhibition of HER3-mediated signaling compared to competitive bispecific antibody.
（3） CS2011 exhibited robust anti-proliferative activity in tumor cells with diverse EGFR and HER3 expression levels.
（4） In in vivo CDX tumor models, CS2011 demonstrated superior tumor-growth inhibition compared to anti-EGFR or anti-HER3 monoclonal antibodies alone and showed comparable efficacy to the combination treatment.
5. CS2011 exhibited a pharmacokinetic (PK) profile comparable to those of monoclonal antibodies in rodents.
In summary, CS2011 has demonstrated potent blockage activity on EGFR and HER3 and exhibited synergistic effects on their downstream signaling. It thereby shows the potent tumor growth inhibitory effects in in vitro and in vivo experiments. The patent of CS2011 has been filed in March 2025, and its Investigational New Drug (IND) application is expected to be submitted in the near term.
CS5007 (EGFR/HER3 bispecific ADC):
CS5007 is a bispecific ADC targeting both EGFR and HER3, developed with CStone’s proprietary ADC platform. It is composed of EGFR/HER3 bispecific antibody backbone (CS2011), a hydrophilic β-glucuronide linker and a clinically validated topoisomerase I inhibitor, Exatecan. This integrated approach, featuring precise targeting, optimized linker stability, and proven therapeutic payload, positions CS5007 as a potential best-in-class candidate for precision oncology.
1. CS5007 targets almost all human epidermal growth factor receptor (HER) family signaling except for HER2 homodimers, covering broad tumor types and effectively addressing tumor heterogeneity.
2. CS5007 demonstrated high-affinity binding to EGFR single-positive, HER3 single-positive, and EGFR/HER3 double-positive tumor cells.
3. CS5007 triggered high-rate internalization on tumor cells.
4. CS5007 demonstrated potent, antigen-dependent cytotoxicity against tumor cells in vitro across varying EGFR and HER3 expression levels and showed robust tumor-growth inhibition in CDX models.
5. CS5007 exhibited superior in vitro stability compared to ADCs conjugated with tetrapeptide and dipeptide linkers. After 7 days of incubation in human/monkey serum, it retained approximately 70% of its drug payload, indicating a minimal release rate.
6. CS5007 exhibited comparable pharmacokinetic (PK) profile to those ADCs composed of monoclonal antibodies in rodents.
CS5007 demonstrates strong affinity for EGFR- and/or HER3-positive tumor cells and induces efficient internalization. Preclinical studies have shown excellent antitumor activity, favorable safety, and pharmacokinetic profiles. The patent of CS5007 has been filed in March 2025. Preclinical findings support further IND-enabling studies and clinical investigations in various advanced solid tumors.
CS5005 (SSTR2 ADC):
Somatostatin receptor 2 (SSTR2) is a G protein-coupled receptor (GPCR) that is overexpressed in various solid tumors, including neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and small cell lung cancer (SCLC). Due to its tumor-selective expression profile, SSTR2 has emerged as a promising target in the field of precision oncology.
CS5005 is a first-in-class, SSTR2-targeting ADC, composed of CStone’s proprietary anti-SSTR2 antibody with high affinity and selectivity, hydrophilic β-glucuronide linker, and potent topoisomerase I inhibitor, Exatecan. In preclinical studies, CS5005 demonstrated potent, antigen-dependent tumor growth inhibition that was not affected by co-administration with SSA-derived therapies. Additionally, CS5005 exhibited superior stability, monoclonal antibody-like pharmacokinetic (PK) properties, and favorable tolerability in preliminary non-human primate toxicity studies.
1. CS5005 demonstrated high affinity to SSTR2-positive cell lines and induced high-rate internalization on tumor cells.
2. CS5005 exhibited cross-reactivity with SSTR2-expressing cells in non-human primates and demonstrated selective binding to SSTR2 with minimal interaction with other SSTRs.
3. CS5005 demonstrated potent antigen-dependent cytotoxic activity against tumor cells in vitro and robust tumor-growth inhibition in CDX tumor model.
4. The antitumor activity of CS5005 (SSTR2-DXd) is not compromised by concomitant ligand-derived treatments (e.g., octreotide, Lutathera), thereby avoiding drug-drug interference commonly observed with current anti-SSTR2 therapies.
5. CS5005 demonstrated superior in vitro stability due to its proprietary linker, outperforming ADCs conjugated with well-validated dipeptide and tetrapeptide linkers.
6. Superior pharmacokinetic (PK) properties of CS5005 in rodents.
7. Bioinformatics analysis of SCLC samples supports DLL3/SSTR2 dual targeting as a strategy to overcome tumor heterogeneity and expand the treatable patient population.
In summary, CS5005 is a first-in-class, SSTR2-targeting ADC designed to selectively eliminate SSTR2-positive tumors, including small cell lung cancer, neuroendocrine carcinoma, and neuroendocrine tumors. It is composed of CStone’s proprietary high-affinity, high-selectivity anti-SSTR2 antibody, CStone’s proprietary hydrophilic β-glucuronide linker, and potent TOP1 inhibitor payload. CS5005 has demonstrated robust antitumor activity in both in vitro and in vivo studies, supporting its progression toward IND submission and clinical development. The patent of de novo antibody backbone of CS5005 has been filed in the first half of 2024. CS5008, an SSTR2/DLL3 bispecific ADC is under development. By simultaneously targeting SSTR2 and DLL3 that frequently co-express in SCLC, NETs, NECs and others, CS5008 aims to overcome tumor heterogeneity, a challenge faced by mono-specific therapies.
CS5006 (ITGB4 ADC):
CS5006 is a first-in-class antibody-drug conjugate (ADC) targeting the novel antigen integrin β4 (ITGB4), developed using CStone’s proprietary ADC platform. Leveraging an internally developed machine learning-based bioinformatics algorithm alongside rigorous in-house experimental validation, CStone identified elevated ITGB4 expression across multiple tumor types—including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC), and head and neck squamous cell carcinoma (HNSCC)—with minimal expression observed in normal tissues. Preclinical in vivo and in vitro studies have demonstrated CS5006’s promising therapeutic potential, highlighting its ability to effectively killing tumor cells.
1. Bioinformatics analysis identified high ITGB4 expression in colorectal tumor tissues, supporting ITGB4 as a promising tumor-associated antigen for CRC. In the tumor microenvironment, ITGB4 was selectively overexpressed on tumor cells while remaining low expression in normal tissues.
2. Immunohistochemistry (IHC) staining confirmed limited ITGB4 expression in normal tissue but high expression in tumor tissues from patients with CRC, sq-NSCLC, HNSCC and ESCC.
3. ITGB4 antibody demonstrated high affinity and internalization rate.
4. CS5006 preclinical proof-of-concept models using ITGB4-vedotin and ITGB4-DXd showed potent antitumor activity in both in vitro and in vivo studies, along with favorable pharmacokinetic (PK) profiles.
（1） ITGB4-vedotin exhibited strong antigen-dependent cytotoxicity in ITGB4-positive tumor cell lines in vitro and demonstrated potent antigen-dependent tumor inhibition in CDX models in vivo.
（2） ITGB4-DXd also exhibited potent antigen-dependent cytotoxicity in vitro and strong tumor-inhibitory effects in vivo CDX tumor models.
（3） Both ITGB4-vedotin and ITGB4-DXd exhibited favorable PK characteristics.
In summary, CS5006 is a first-in-class ADC targeting the novel tumor antigen ITGB4 and is currently undergoing comprehensive preclinical evaluation. Preclinical data have demonstrated strong antitumor activity across multiple animal models, particularly in solid tumors such as non-small cell lung cancer, head and neck squamous cell carcinoma, and esophageal squamous cell carcinoma. The compound also exhibited good tolerability, providing strong support for its further clinical development. The patent of CS5006 has been filed in April 2023.
Poster Information:
Poster Title
Poster Number
CS2011: A novel bispecific antibody targeting EGFR and HER3 that
demonstrates promising anti-tumor activity in preclinical evaluation
2927
CS5007: A novel EGFR and HER3 dual-targeted antibody-drug
conjugate (ADC) with potent antitumor activity in preclinical studies
2954
CS5005: A novel SSTR2-targeted antibody-drug conjugate (ADC) with
robust anti-tumor activity in preclinical studies
4751
CS5006: A novel integrin β4-targeted antibody-drug conjugate (ADC)
with robust antitumor activity in preclinical studies
2953