On March 3, 2025 CStone Pharmaceuticals ("CStone", HKEX: 2616), an innovation-driven biopharmaceutical company focused on the research and development of anti-cancer therapies, reported that the first patient has been successfully dosed in the global multicenter Phase I clinical trial of its novel PD-1/VEGF/CTLA-4 trispecific antibody, CS2009, with no infusion reactions or other adverse events observed (Press release, CStone Pharmaceauticals, MAR 3, 2025, View Source [SID1234650855]).
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This trial aims to evaluate the clinical potential of CS2009 in a wide range of advanced solid tumors including, but not limited to, non-small cell lung cancer, hepatocellular carcinoma, gastric adenocarcinoma, endometrial cancer, ovarian cancer, renal cell carcinoma, and cervical cancer, in efforts to advance the development of innovative tumor immunotherapies.
CS2009, an innovative trispecific antibody designed and developed by CStone, combines three clinically validated targets—PD-1, VEGFA, and CTLA-4—and exerts multidimensional anti-tumor effects through synergistic actions. Specifically, anti-PD-1 activity that reverses T cell exhaustion, anti-CTLA-4 activity that promotes T cell activation and proliferation, while anti-VEGFA activity blocks tumor angiogenesis and improves the tumor micro-environment (TME). In the TME, anti-PD-1 and anti-CTLA-4 activities are significantly enhanced by crosslinking with VEGFA. Meanwhile, CS2009 preferentially blocks PD-1 and CTLA-4 on double-positive tumor-infiltrating T cells while minimizing interference with CTLA-4 regulation in peripheral T cells, thus potentially offering enhanced efficacy with lower systemic toxicity.
In preclinical studies, CS2009 demonstrated superior anti-tumor activity compared to potential competitors. By combining CTLA-4 inhibition with PD-1 and VEGFA blockade, CS2009 may further enhance benefits for patients with low or negative PD-L1 expression, who respond poorly to PD-(L)1 therapies. This well positions CS2009 as a next-generation, first- or best-in-class immunotherapy backbone, with the potential to replace current anti-PD-(L)1-based therapies.
Dr. Jason Yang, CEO, President of R&D, and Executive Director at CStone, stated, "The initiation of the first-in-human study for CS2009 marks a breakthrough in our clinical development. Our robust preclinical data have confirmed CS2009’s potential across a wide range of solid tumor indications. In in vitro studies, CS2009 demonstrated its ability to effectively and specifically activate tumor-infiltrating T cells, as well as robust synergistic effect with anti-VEGF activity; in immunocompetent mouse models, CS2009 showed stronger anti-tumor effects than both PD-1/CTLA-4 and PD-1/VEGF bispecific antibodies; and in toxicology studies, CS2009 exhibited a safety margin which was greater than the PD-1/CTLA-4 bispecific antibody and comparable to the PD-1/VEGF bispecific antibody. These results give us confidence in CS2009’s clinical potential. We look forward to sharing additional clinical data that will further validate its safety and anti-tumor activity, paving the way for a new era in cancer immunotherapy."
Dr. Qingmei Shi, Chief Medical Officer of CStone, added, "We are pleased to achieve the first-patient-dosed milestone for CS2009, an innovative trispecific antibody that can potentially offer balanced efficacy and safety while addressing the unmet medical needs in patients with low or negative PD-L1 expression. We expect to see rapid and encouraging progress in this study and are committed to bringing improved treatment options to patients with solid tumors worldwide. We appreciate the exceptional efforts of our clinical team, who managed through the entire process—from submitting the clinical trial application in Australia to dosing the first patient—in two months that overlapped with major holidays in China and Australia. This is another testament to CStone’s outstanding clinical development efficiency and unwavering commitment to serving patients."
Currently, the multicenter Phase I clinical trial of CS2009 is being conducted in Australia, with plans to expand into China and the United States in the near future.
About CS2009 (PD-1/VEGF/CTLA-4 Trispecific Antibody)
CS2009 is a trispecific antibody targeting PD-1, VEGFA, and CTLA-4, with the potential to be first- or best-in-class for major tumor types. Its differentiated molecular design combines three clinically validated targets, preferentially invigorating exhausted tumor infiltrating lymphocytes (TILs) while demonstrating VEGF neutralization comparable to existing anti-VEGF antibodies. CS2009 covers a wide range of cancers, including but not limited to non-small cell lung cancer, hepatocellular carcinoma, gastric adenocarcinoma, endometrial cancer, ovarian cancer, renal cell carcinoma, and cervical cancer.
In November 2024, CStone presented preclinical data for CS2009 at the 39th SITC (Free SITC Whitepaper) Annual Meeting. These results show that CS2009 exhibits superior anti-tumor activity compared to potential competitors, including PD-1/CTLA-4 bispecific antibodies, PD-1/VEGF bispecific antibodies, and PD-1/CTLA-4 combination therapies.