YH004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4-1BBをターゲットとしたヒト化抗体で、独特なIgG1アイソタイプを採用しています。4-1BBは主としてT細胞、DC細胞、単核細胞、B細胞、肥満細胞、NK細胞、好中球に発現します。YH004は4-1BBアゴニストとして免疫細胞の増殖を誘導し、生体の免疫反応を加速することができます。In vivoマウス実験によれば、YH004の単独投与と併用効果はいずれも対照薬より高い結果が得られました。多数の前臨床および臨床データは、4-1BBが、がん免疫治療に非常に有望であることを示しています。しかしながら4-1BBアゴニストが肝毒性を引き起こしたため、臨床開発が相次いで中止されました。YH004のin vitroタンパク質間相互作用の解析によれば、これは人・サルの間で4-1BB結合親和性が似ています。またカニクイザルのin vivo毒性試験ではYH004の肝毒性は観察されませんでした。2021年6月にTGAからCTNの承認を取得し、オーストラリアで第I相臨床試験を開始しています。

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.

Clinical Progress

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).

Trial #：YH004002

NCT #：NCT05040932

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 Target

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.

Poster Downloads

AACR2020: Optimization of novel anti-4-1BB antibodies on Biocytogen’s in vivo drug screening platform

AACR2019: Novel in vivo durg screening platform accelerated 4-1BB agonistic antibody development