is a recombinant humanized agonistic CD40 IgG2 monoclonal antibody. Phase I clinical studies have showed that YH003 in combination with PD-1 monoclonal antibody (mAb) has good safety and preliminary efficacy in patients with advanced solid tumors. There is hardly any transaminase elevation or hepatic toxicity and no cytokine storm-related adverse reaction.
At present, a multi-regional phase II clinical study of YH003 is ongoing, which is aimed to evaluate the efficacy and safety of YH003 in combination with PD-1 mAb as the first-line treatment in patients with PD-(L)1-resistant unresectable/metastatic melanoma, in combination with PD-1 mAb as the second-line treatment in patients with unresectable/metastatic pancreatic ductal adenocarcinoma (PDAC), and in combination with PD-1 mAb and chemotherapy as the first-line treatment in patients with unresectable/metastatic PDAC.
In a phase I clinical trial in Australia, YH003 in combination with the anti-PD-1 mAb Toripalimab from Junshi Biosciences showed good safety and efficacy. As of April 3, 2022, a total of 26 subjects with advanced solid tumor who had progressed after or were intolerant to standard treatment had been enrolled. The patients had received three lines (median) of treatments (range, 1-7 lines) and 11 of the 26 enrolled patients had received immunotherapy (PD-1, PD-L1 or PD-1/CTLA-4 bispecific antibody, etc.). YH003 did not reach the maximum tolerated dose when escalating from 0.03 mg/kg to 3.0 mg/kg. Only two patients experienced Grade 3 adverse events (AEs) related to YH003, neutropenia and transaminase elevation. No ≥ Grade 4 AE occurred. In all subjects, only one dose-limiting toxicity (DLT) event was observed and no drug-related serious adverse event (SAE) occurred. Of the 19 radiographically evaluable subjects, three had PR (ORR = 15.8%) and four had SD (DCR = 36.8%). The primary endpoint was met, and the recommended phase II dose (RP2D) was determined to be 0.3 mg/kg.
A multicenter, open-label, phase I dose escalation study of the safety, tolerability and pharmacokinetics of YH003 monotherapy in subjects with advanced solid tumors.
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 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 + standard chemotherapy (albumin-bound paclitaxel) in China as the first-line treatment for mucosal melanoma
Preclinical studies have shown the following findings:
1. In the B-hCD40 syngeneic model, YH003 did not show hepatotoxicity at the dose of 0.3 mg/kg, 3 mg/kg or 30 mg/kg, showing a better safety profile than selicrelumab.
2. YH003 demonstrated strong dose-dependent efficacy in multiple tumor models, whether alone or in combination with PD-1 antibodies. In preclinical studies, complete tumor response was observed with combination treatment of YH003 and PD-1 antibody.
3. The IgG2 subtype design avoids the antibody-dependent cellular cytotoxicity (ADCC) effect, resulting in a longer in vivo half-life of YH003 and an expanded treatment window.
CD40 is a member of the tumor necrosis factor receptor superfamily (TNFRSF) on the surface of immune cells. This drug promotes the activation of innate immune cells, such as dendritic antigen presenting cells (DCs), and positively regulates the effector activity of anti-tumor T cells by specifically activating the CD40 receptor signaling pathway. To date, studies have shown that CD40 activation is a key regulatory point for tumor immunotherapy, effectively transforming cold tumors lacking immune cell infiltration into hot tumors that respond well to tumor immunotherapy.
Considering the inevitable defects of the traditional in vitro drug screening process, the YH003 project adopted the screening strategy of high-throughput in vivo efficacy studies combined with the investigation of side effects and toxicity in vivo in the early stages of development.
AACR2020：In vivo drug screening platform accelerates anti-hCD40 antibody drug discovery
ASCO2022：A phase I open-label dose escalation of YH003 (CD40 mAb) in combination with toripalimab (PD-1 mAb) in patients with advanced solid tumors