YH003은 면역세포 표면의 TNF receptor superfamily중 하나인 CD40을 타겟으로 하는 새로운 인간화 항체입니다. 이는 CD40 수용체의 신호통로를 특이적으로 활성화시켜, 수지상세포등의 선천적인 면역 세포를 활성화하고, 항종양 T세포의 효력과 활성을 증대시킵니다. 저희 바이오사이토젠은 이전까지의 in vitro 약효 스크리닝 모델의 극복할 수 없는 단점을 고려하여, YH003 개발 프로젝트에서는 규모화된 in vivo 약효 스크리닝과 체내 독성 분석 모델을 채용하여 후보물질을 선별하는 전략을 사용하였습니다. 여러 종류의 종양 세포와 CD40 인간화 마우스를 사용하여 동종이식 종양 동물 모델을 구축하였으며, 그 후 여러 종류의 항체 후보물질 주사액을 접종하여, 종양 성장에의 영향을 관찰하여, 동물 체내에서의 신약 후보물질의 안전성과 종양억제의 유효성을 평가하였습니다. 전임상 연구 데이터를 통하여, CD40항체와 화학요법, 방사능 요법, 여타 면역항암제와의 높은 병용 투여 잠재력을 확인할 수 있습니다.
우리는 미국과 호주에서 YH003의 2상 MRCT를 시작하고 있습니다. 2021년 6월 FDA로부터 IND 승인을 받았고, 대만 FDA와 NMPA로부터 CTN/IND 승인을 신청하고 있습니다.
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.
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).
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.
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 (pembrolizumab) in subjects with advanced solid tumors. It is being conducted in Australia, China and other countries.
A phase II clinical trial of a combination therapy YH003 (CD40 mAb) + PD-1 mAb (pembrolizumab) + standard chemotherapy (albumin-bound paclitaxel) in China as the first-line treatment for mucosal melanoma
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.
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.