YH001은 CTLA-4을 타겟으로 하는 단일클론항체로서, 암세포에 대한 신체의 면역응답성을 높이고, 종양미세환경 중에서의 Treg세포의 감소를 이끌어내어, 다양한 종양치료의 목적을 달성할 수 있도록 합니다. 체내의 항종양 활성을 억제하는 신호를 차단하여, 환자의 종양에 대한 면역응답성을 개선하는 치료법은 현재 가장 유망한 면역요법으로서 인식되고 있습니다. 연구개발팀은 CTLA-4항체의 개발 전략을 새롭게 설계하고, 동종이식 종양 동물 모델을 통하여 항체 후보물질의 in vivo 약효 스크리닝의 “Golden standard”를 도입, 최종적으로 YH001 항체를 선별해내었습니다. 전임상 연구개발 단계에서, YH001은 매우 높은 친화력과 안전성을 보였으며, 동물 모델을 이용한 약효 실험에서 병용 투여 요법에 대한 높은 잠재력을 보였습니다. 2020년 5월, YH001은 Junshi Biosciences의 PD-1 단일클론항체인 투오이(Tuoyi™)와의 병용 투여 요법으로 호주에서 임상 1상을 정식으로 개시하였습니다.
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.
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.
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.
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.
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.