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YH003は、免疫細胞マーカーである腫瘍壊死因子受容体スーパーファミリーメンバーCD40をターゲットとしたヒト化抗体です。この医薬品はCD40受容体の信号伝達経路を特に活性化することにより抗原提示細胞である樹状細胞(DC)などを通じて自然免疫の活性化を促進し、抗腫瘍T細胞の免疫反応を効果的に加速させます。従来のin vitroスクリーニング技術には不可避の欠陥があることを考慮し、YH003プロジェクトの前期開発ではハイスループットin vivo薬効研究と毒性試験を結合したスクリーニング戦略が採用されました。様々な種類の腫瘍細胞をCD40ヒト化マウスに接種することでSyngeneic腫瘍モデルを確立し、異なるリード抗体分子を注入して腫瘍の生長への影響を観察することで、最終的に確定された抗体医薬品候補は、対照薬より高い安全性と薬効を持つことになります。前臨床研究の総合データによれば、YH003は、化学療法、放射線療法、分子標的治療、免疫調整剤との相性が非常に良いことが証明されました。

2020年7月、YH003は上海君実生物の抗PD-1モノクローナル抗体Toripalimab Injectionと併用され、オーストラリアでの第1相臨床試験を順調に終え、2021年5月第2相臨床試験を開始しました。

YH003 is a promising recombinant humanized agonistic CD40 IgG2 monoclonal antibody that has shown good safety and preliminary efficacy in phase I clinical studies when used in combination with PD-1 monoclonal antibody (mAb) for patients with advanced solid tumors. Notably, there were no cytokine storm-related adverse reactions or significant transaminase elevation or hepatic toxicity observed.

Clnical Progress

Currently, a multi-regional phase II clinical study is underway to evaluate the antitumor activity of YH003 in combination with toripalimab (PD-1 mAb) with or without chemotherapy in subjects with unresectable/metastatic pancreatic ductal adenocarcinoma (PDAC).

Trial #:YH003004

NCT #:NCT05031494

In a phase I clinical trial conducted in Australia, YH003 was combined with the anti-PD-1 mAb Toripalimab from Junshi Biosciences and demonstrated excellent safety and efficacy. As of April 3, 2022, the study had enrolled a total of 26 subjects with advanced solid tumors who had either progressed after standard treatment or were intolerant to it. The patients had received a median of three lines of treatments (range: 1-7 lines), and eleven out of the twenty-six enrolled patients had previously undergone immunotherapy (PD-1, PD-L1 or PD-1/CTLA-4 bispecific antibody). During dose escalation from 0.03 mg/kg to 3.0 mg/kg, YH003 did not reach its maximum tolerated dose. Only two patients experienced Grade 3 adverse events related to YH003 - neutropenia and transaminase elevation - while no ≥ Grade 4 AE occurred. In all subjects, only one dose-limiting toxicity event was observed without any drug-related serious adverse events occurring. Of the nineteen radiographically evaluable subjects, three achieved partial response (ORR =15.8%) while four showed stable disease (DCR =36.8%). The primary endpoint was met successfully as recommended phase II dose (RP2D) was determined to be at a dosage level of 0.3 mg/kg for further studies on this combination therapy's efficacy against advanced solid tumors that have failed standard treatment options or are intolerant towards them.

Trial #:YH003002

NCT #:NCT04481009

We also obtained the IND approval from the NMPA for a Phase I clinical trial of YH003 in advanced solid tumor patients in China.

A multicenter, open-label, international phase I dose escalation study of the safety, tolerability and pharmacokinetics of YH003 (CD40 mAb) + YH001 (CTLA-4 mAb) + PD-1 mAb in subjects with advanced solid tumors. It is being conducted in Australia, China and other countries.

Trial #:YH003005

NCT #:NCT05176509

A phase II clinical trial of a combination therapy YH003 (CD40 mAb) + PD-1 mAb + standard chemotherapy (albumin-bound paclitaxel) in China as the first-line treatment for mucosal melanoma

Trial #:YH003006

NCT #:NCT05420324

Preclinical studies have yielded promising results for YH003:

1. In the B-hCD40 syngeneic model, YH003 demonstrated a superior safety profile compared to selicrelumab at doses of 0.3 mg/kg, 3 mg/kg or 30 mg/kg as it did not show any hepatotoxicity.

2.YH003 exhibited strong dose-dependent efficacy in multiple tumor models when administered alone or in combination with PD-1 antibodies. In fact, complete tumor response was observed with combination treatment of YH003 and PD-1 antibody during preclinical studies.

3.The IgG2 subtype design of YH003 avoids the antibody-dependent cellular cytotoxicity (ADCC) effect which leads to an expanded treatment window and longer in vivo half-life.

CD40 Target

The CD40 target is crucial for effective tumor immunotherapy as it promotes activation of innate immune cells such as dendritic antigen presenting cells (DCs), and positively regulates effector activity of anti-tumor T cells. Studies have shown that CD40 activation can transform cold tumors lacking immune cell infiltration into hot tumors that respond well to immunotherapy. To overcome limitations associated with traditional in vitro drug screening processes, early stage development for YH003 involved high-throughput in vivo efficacy and safety studies to ensure optimal therapeutic outcomes are achieved while minimizing adverse effects in patients.


November 1, 2022 | Eucure Biopharma, a Subsidiary of Biocytogen, Announces Partnership with ISU ABXIS for the Development of Tri-specific Antibodies using YH003 Antibody Sequence
April 7, 2022 | Biocytogen Subsidiary Eucure Biopharma Completes First Patient Dosing for Phase I Clinical Trial of YH003 (Anti-CD40 mAb) Triple Combination Therapy
December 8, 2021 | Biocytogen/Eucure Biopharma Announce the Completion of First Patient Dosing for Phase II Clinical Trial of YH003 in Australia
November 2, 2021 | Biocytogen/Eucure Biopharma's YH003 (Anti-CD40 Monoclonal Antibody) Approved for Phase II Multi-Regional Clinical Trial by China National Medical Products Administration

Poster Downloads

ASCO 2024: A phase II, multi-center, open-label study to evaluate the safety and efficacy of YH003 in combination with Toripalimab (anti-PD-1 mAb) in patients with unresectable/metastatic pancreatic ductal adenocarcinoma

ESMO2023:Phase I open-label, dose escalation and expansion study of YH003, an anti-CD40 agonist monoclonal antibody in combination with Toripalimab in patients (pts) with advanced solid tumours

ASCO2022:A phase I open-label dose escalation of YH003 (CD40 mAb) in combination with toripalimab (PD-1 mAb) in patients with advanced solid tumors

AACR2020:In vivo drug screening platform accelerates anti-hCD40 antibody drug discovery