CTLA-4をターゲットとするYH001モノクローナル抗体は、腫瘍細胞に対する免疫応答を高め、腫瘍微小環境における制御性T細胞（Regulatory T cells or Tregs）の除去を強化することで多種多様の腫瘍を治療します。抗腫瘍反応の抑制信号をブロックして患者の腫瘍に対する免疫応答を強化するこの方法は、現在最も期待できるがん免疫療法であるとみなされています。開発チームは抗CTLA-4抗体の開発コンセプトを再革新し、同種移植ヒト化マウスモデルに基づいた抗体のin vivo薬効評価という「黄金律」を採用し、スクリーニングの結果YH001抗体を獲得しました。YH001は前臨床研究において非常に高い親和性と安全性を示し、動物を使った薬効試験においても併用薬としての大きな潜在力があることが証明されました。
YH001 is a promising recombinant humanized CTLA-4 IgG1 monoclonal antibody that has shown preliminary anti-tumor activity and a good safety profile in combination with PD-1 monoclonal antibodies.
Clinical Progress
We have reached an agreement with Tracon in the United States to explore indications such as sarcoma and other indications. The Phase I/II clinical trial of YH001 in combination with envafolimab (PD-L1 mAb) and doxorubicin for the treatment of soft tissue sarcoma patients was approved by FDA in August 2022, and dosed the first patient in November 2022.
YH001, in combination with the anti-PD-1 mAb Tuoyi (Toripalimab) from Junshi Biosciences, demonstrated promising safety and efficacy in a phase I clinical trial conducted in Australia. The trial involved dose escalation ranging from 0.05 mg/kg to 6.0 mg/kg. As of the data as cut-off date of December 31, 2022, Among 26 evaluable patients out of 29 enrolled patients, 5 showed partial response (PR) while 11 had stable disease (SD). The study achieved its primary endpoint, and the maximum tolerated dose (MTD) of YH001 in combination therapy was determined to be 4.0 mg/kg.
Trial #：YH001002
NCT #：NCT04357756
A phase I/II dose escalation trial of YH001 for subjects with advanced solid tumors was conducted in China. Based on the results of the phase I study in Australia, the dose was modified to escalate from 0.3 mg/kg to 6.0 mg/kg. As of May 2022, 14 patients had been evaluated, with four showing stable disease (SD). The primary study endpoint was achieved, and the highest dose of 6.0 mg/kg for YH001 as a single-agent escalation remained safe and tolerable.
Trial #：YH001003
NCT #：NCT04699929
We received the U.S. FDA approval in June 2021, the Taiwan FDA approval in October 2021 and the NMPA approval in November 2021 for the Phase II clinical trial.
Several preclinical studies have demonstrated the effectiveness and safety of YH001:
1.In an in vivo pharmacodynamic tumor model, YH001 showed superior anti-tumor activity when used in combination with the PD-1 mAb pembrolizumab (Keytruda) compared to ipilimumab (Yervoy).
2.In vitro tests showed that YH001 exhibited better blocking activity and stronger antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) effects than ipilimumab.
3. In a mouse model, YH001 significantly reduced the proportion of Tregs in tumor-infiltrating lymphocytes.
4.YH001 displayed a more favorable in vivo safety profile compared to ipilimumab.
CTLA-4 Target
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also known as CD152, plays a crucial regulatory role in T cell activation. CTLA-4 is expressed on the surface of regulatory T cells (Tregs), and it competitively inhibits the binding of B7 to CD28 on the surface of effector T cells when bound to B7-1 (CD80) and B7-2 (CD86) on the surface of antigen-presenting cells (APCs). Consequently, T cell activation is inhibited. Inhibitory antibodies that target CTLA-4 can block this mechanism and enhance T cell activity, thus improving the patient's immune response to tumors.
Blocking the inhibitory signal of the human anti-tumor response is currently considered the most promising tumor immunotherapy. CTLA-4 and PD-1 are critical checkpoints of the immune system and are thus key targets of tumor immunotherapy. By blocking them, different types of T cells can be affected, leading to the initiation of anti-tumor immune attack.
Currently, marketed antibody drugs targeting CTLA-4 include the CTLA-4 mAb ipilimumab (Yervoy) from BMS and the PD-1/CTLA-4 bispecific antibody cadonilimab (trade name: Kaitanni; AK104) from Akeso.
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