On March 25, 2025 CStone reported that it will showcase its latest preclinical studies on five internally developed innovative candidates, including the trispecific antibody CS2009, the bispecific antibody CS2011, and three novel antibody-drug conjugates (ADCs) developed from CStone’s proprietary ADC platform: CS5006, CS5007, and CS5005 (Press release, CStone Pharmaceauticals, MAR 25, 2025, View Source [SID1234651423]). The abstracts will be published in Cancer Research, the official journal of AACR (Free AACR Whitepaper), on April 11 (ET).
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CS2009 is a trispecific antibody targeting PD-1, VEGFA, and CTLA-4. Its innovative molecular design is expected to enhance anti-tumor efficacy by preferentially targeting PD-1/CTLA-4 double positive T cells in tumor microenvironment (TME) while reducing systemic toxicity by sparing CTLA-4 single positive cells, making it a potential first-in-class (FIH) or best-in-class (BIC) next-generation immuno-oncology backbone. Preclinical studies have demonstrated that CS2009 induces more potent tumor growth inhibition (TGI) than its potential competitors, such as PD-1/CTLA-4 bispecific antibodies, PD-1/VEGF bispecific antibodies, and PD-1/CTLA-4 combination therapies, along with an outstanding safety profile. CS2009 is currently evaluated in a global multicenter Phase I clinical trial in patients with late-stage cancers, including non-small cell lung cancer (NSCLC), ovarian cancer (OC), renal cell carcinoma (RCC), cervical cancer (CC), hepatocellular carcinoma (HCC), gastric adenocarcinoma (GAC), etc.
CS5006 is a first-in-class ADC targeting the novel antigen ITGB4, whose expression pattern holds broad application potential in solid tumors, including NSCLC, squamous cell carcinoma of the head and neck (SCCHN), and esophageal squamous cell carcinoma (ESCC). Preclinical studies demonstrated that ITGB4 ADCs were potent to inhibit tumor growth in multiple animal models and well tolerated, thus supporting further preclinical development toward clinical evaluation of this promising FIC molecule.
CS2011 (EGFR/HER3 bispecific antibody) is the bispecific antibody backbone of CS5007 (EGFR/HER3 bispecific ADC). CS2011 enables synergistic blocking of EGFR and HER3 signaling for enhanced therapeutic effects, while minimizing toxicity in normal tissues. CS5007 is built on CStone’s proprietary ADC platform, demonstrating best-in-class potential. Both CS2011 and CS5007 target indications include NSCLC, SCCHN, and colorectal cancer (CRC).
CS5005 is a first-in-class ADC targeting SSTR2, enabling precise targeting of SSTR2-positive tumors, including small cell lung cancer (SCLC), neuroendocrine carcinoma (NEC), and neuroendocrine tumors (NETs). CS5005 is composed of CStone’s proprietary anti-SSTR2 antibody with high affinity and selectivity, CStone’s proprietary hydrophilic beta-glucuronide linker, and potent TOP1 inhibitor. It has demonstrated encouraging anti-tumor activity in vitro and in vivo. Meanwhile, leveraging CStone’s proprietary ADC platform, we are accelerating the development of a bispecific ADC targeting SSTR2/DLL3 (CS5008). By simultaneously targeting SSTR2 and DLL3 that frequently co-express in SCLC, NECs, NETs and others, CS5008 aims to overcome tumor heterogeneity, a challenge faced by mono-specific therapies.
Detailed information on the research topics and poster presentations selected for AACR (Free AACR Whitepaper) 2025 are as follows:
Title: CS2009: A first-in-class trispecific antibody targeting PD-1, CTLA-4, and VEGFA with potential to be a next-generation backbone therapy with combined checkpoint inhibition and anti-angiogenesis
Session Title: Overcoming Checkpoint Inhibition and Tumor Suppression
Presentation Type: Poster
Abstract Number: 7299
Time: Wednesday, April 30, 2025, 9:00 AM – 12:00 PM ET
Location: Poster Section 39, Board #14
Key Findings: In the proof of mechanism studies, CS2009 demonstrated strong synergy between the PD-1 and CTLA-4 arms, and the checkpoint inhibitory activity from the PD-1/CTLA4 arms was also greatly enhanced through crosslinking between its anti-VEGF arms with VEGFA dimers. DMPK/toxicology study in cynomolgus monkeys demonstrated that the highest non-severely toxic dose (HNSTD) and the no observed adverse effect level (NOAEL) of CS2009 were 100 mg/kg. CS2009 exhibited a PK profile comparable to those of monoclonal antibodies and demonstrated dose-dependent T-cell activation in cynomolgus monkeys.
Title: CS5006: A novel integrin β4-targeted antibody-drug conjugate (ADC) with robust antitumor activity in preclinical studies
Session Title: Growth Factor Receptors and Other Surface Antigens as Targets for Therapy 2
Presentation Type: Poster
Abstract Number: 2953
Date & Time: Monday, April 28, 2025, 2:00 PM – 5:00 PM ET
Location: Poster Section 18, Board #5
Key Findings: CS5006 (ITGB4 ADC) demonstrated promising therapeutic potential by effectively killing tumor cells in both in vivo and in vitro studies, while maintaining a PK profile comparable to those of monoclonal antibodies.
Title: CS2011: A novel bispecific antibody targeting EGFR and HER3 that demonstrates promising antitumor activity in preclinical evaluation
Session Title: Growth Factor Receptors and Other Surface Antigens as Targets for Therapy 1
Presentation Type: Poster
Abstract Number: 2927
Date and Time: Monday, April 28, 2025, 2:00 PM – 5:00 PM ET
Location: Poster Section 17, Board #1
Key Findings: CS2011 (an EGFR/HER3 bispecific antibody), composed of anti-EGFR and anti-HER3 arms with balanced affinity, effectively and synergistically inhibits EGFR/HER3 downstream signaling, leading to further inhibition of tumor growth. Its lead compound demonstrated favorable stability and a PK profile comparable to those of monoclonal antibodies.
Title: CS5007: A novel EGFR and HER3 dual-targeted antibody-drug conjugate (ADC) with potent antitumor activity in preclinical studies
Session Title: Growth Factor Receptors and Other Surface Antigens as Targets for Therapy 2
Presentation Type: Poster
Abstract Number: 2954
Date and Time: Monday, April 28, 2025, 2:00 PM – 5:00 PM ET
Location: Poster Section 18, Board #6
Key Findings: CS5007 (EGFR/HER3 ADC) inhibited tumor growth by blocking downstream EGFR/HER3 signaling and releasing chemotherapeutic molecules in a target-dependent manner. Its lead compound demonstrated favorable stability and a PK profile comparable to those of monoclonal antibodies.
Title: CS5005: A novel SSTR2-targeted antibody-drug conjugate (ADC) with robust antitumor activity in preclinical studies
Session Title: Molecular, Preclinical, and Clinical Endocrinology
Presentation Type: Poster
Abstract Number: 4751
Date & Time: Tuesday, April 29, 2025, 9:00 AM – 12:00 PM ET
Location: Poster Section 35, Board #18
Key Findings: CS5005 (SSTR2 ADC) demonstrated promising therapeutic potential by effectively killing tumor cells in both in vivo and in vitro studies, while maintaining a PK profile comparable to those of monoclonal antibodies. Additionally, a dual-target ADC against DLL3 and SSTR2 also exhibited potential as a therapeutic agent.