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.
Preclinical studies have yielded promising results for YH003:
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.