YH004은 면역세포 표면의 TNF receptor superfamily중 하나인 4-1BB를 타겟으로 하는 새로운 인간화 항체로서 독특하게도 IgG1 isotype을 베이스로 하고 있습니다. 4-1BB는 주로 T세포, 수지상세포, 단핵세포, B세포, 비만세포, NK세포와 호중성 과립구에서 발현됩니다. YH004는 4-1BB의 활성화제로서, 면역세포의 증식등을 통한 체내 면역 반응의 활성등을 유도합니다. 마우스에서의 전임상 in vivo 실험은 YH004의 단일 투여 및 병용투여시 대조군에 비하여 명확하고 균일한 약효를 보여주고 있습니다. 수많은 전임상, 임상시험 데이터들은 4-1BB가 종양 면역치료요법에 있어서 거대한 잠재력을 갖고 있음을 보여주고 있습니다. 하지만, 여러 4-1BB 활성화제들은 간독성 때문에 임상 단계의 개발 진전이 가로막힌 상태입니다. 저희 바이오사이토젠은 YH004의 in vitro 기능 분석을 통하여 YH004의 인간과 원숭이의 4-1BB에 대한 결합력과 친화력이 상당히 높음을 알 수 있었으며, 영장류를 이용한 체내 독성 실험에서 간독성이 관찰되지 않았습니다.2021년 6월 TGA로부터 CTN 승인을 받았고 호주에서 임상 1상을 시작하고 있다.
YH004 is a recombinant humanized agonistic 4-1BB IgG1 monoclonal antibody with a favorable safety profile. It effectively eliminates Treg cells with high expression of 4-1BB through ADCC effects and activates CD8+ T cells.
YH004, a potential therapeutic for advanced solid tumors and relapsed/refractory non-Hodgkin’s lymphoma (r/r NHL), is currently undergoing a phase I dose escalation study in Australia as monotherapy. The study was approved under the CTN scheme by the Australian Therapeutic Goods Administration (TGA) in June 2021 and we have completed the dosing of the first patient in December 2021. As of December 31, 2022, 8 subjects were enrolled and received 0.01 mg/kg (n=1), 0.03 mg/kg (n=1), 0.1 mg/kg (n=3), and 0.3 mg/kg (n=3) dosing. 2 subjects had a best efficacy assessment of SD. All adverse events associated with YH004 were mild or moderate (Grade 1 or 2).
We have also received IND approval from the U.S. FDA in October 2021.
We have received the approval for the IND applications by the NMPA on January 7, 2022.
Preclinical studies have yielded several key findings on the potential of YH004 as a therapeutic agent:
1.In an in vivo toxicology study in cynomolgus monkeys, no hepatotoxicity was observed even at the highest tested dose of 30 mg/kg. In the B-h4-1BB syngeneic model, YH004 was significantly safer than urelumab.
2.YH004 had similar antitumor activity to urelumab in the humanized syngeneic 4-1BB MC38 colorectal cancer model at a dose of 1.0 mg/kg. However, YH004 showed better antitumor efficacy than urelumab when used in combination with a PD-1 antibody.
3.YH004 specifically eliminates Tregs, which have high levels of 4-1BB expression, through ADCC.
4.In vitro studies revealed that YH004 has a higher binding affinity to human 4-1BB than urelumab.
5.YH004 promotes the proliferation of CD8+ T cells and the release of IL-2 by activating 4-1BB.
4-1BB is a member of the tumor necrosis factor receptor superfamily (TNFRSF) and is expressed in activated T cells within the tumor microenvironment. Antibody-mediated stimulation of 4-1BB can enhance the release of CD8+ T cell effectors through costimulatory signals, promote cell proliferation while inhibiting apoptosis, and ultimately improve the anti-tumor immune response.
Bristol-Myers Squibb's urelumab (BMS-663513) is the first therapeutic drug targeting 4-1BB that has entered clinical trials. However, there are currently no 4-1BB drugs on the market.