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.
Clinical Progress
- YH003 - Collaboration with Syncromune
In 2022, we entered into a licensing agreement with Syncromune. Syncromune obtained the rights to an intratumoral immunotherapy comprising YH002 and other active ingredients. Subsequently, both parties agreed to include YH001 and YH003 as selected active components within the collaboration scope. Currently, Syncromune has initiated clinical trials of the SyncrovaxTM therapy in Mexico and has obtained promising preliminary clinical data demonstrating anti-tumor activity.
On June 28, 2024, Syncromune was granted Fast Track designation by the U.S. FDA for the SYNC-T SV-102 therapy, which is its lead candidate for treating patients with metastatic castration-resistant prostate cancer (mCRPC). As of March 9, 2024, interim data from the Phase I study of SV-102 in mCRPC patients showed an objective response rate (ORR) of 85% among the 13 evaluated out of 15 enrolled patients, with good safety and tolerability and no occurrence of Grade 3 or 4 autoimmune adverse events. Among these patients, 5 achieved complete response (CR), 6 achieved partial response (PR), and 2 had stable disease (SD). Notably, 7 out of the 13 evaluated patients (53.8%) experienced complete resolution of bone metastases.
The composition of SYNC-T SV-102 includes the CTLA-4 monoclonal antibody (YH001) and CD40 agonistic monoclonal antibody (YH003), all of which were licensed from Biocytogen's subsidiary, Eucure Biopharma.
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). The first patient in this trial received the initial dose in December 2021 in Australia. As of June 30, 2024, a total of 92 PDAC (pancreatic ductal adenocarcinoma) patients were enrolled and received at least one dose of the investigational drug. This includes 47 patients in the first-line treatment cohort and 45 patients in the second-line and beyond treatment cohorts. The study results demonstrated good safety and tolerability of YH003 in combination with toripalimab and nab-paclitaxel + gemcitabine for both first-line and second-line treatment in PDAC patients.
In the first-line cohort, 43 patients (including 10 Caucasians) underwent at least one post-treatment tumor assessment. Among them, 1 patient achieved complete response (CR), 11 patients achieved partial response (PR), and 23 patients had stable disease (SD).
In the second-line and beyond cohort, 40 patients underwent at least one post-treatment tumor assessment. Among these, 4 patients achieved partial response (PR), and 10 patients had stable disease (SD).
Trial #：YH003004
NCT #：NCT05031494
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.
Trial #：YH003002
NCT #：NCT04481009
The multicenter, open-label, international Phase I dose-escalation study evaluating the safety, tolerability, and pharmacokinetics of the combination of YH003 (CD40 monoclonal antibody), YH001 (CTLA-4 monoclonal antibody), and PD-1 monoclonal antibody (pembrolizumab) in patients with advanced solid tumors has been completed. The study was conducted in countries including Australia and China. As of June 22, 2023, a total of 15 patients were enrolled and treated with YH003 in combination with pembrolizumab and YH001, with no drug-related deaths occurring during the study.
Trial #：YH003005
NCT #：NCT05176509
China Phase II Clinical Trial of YH003 (CD40 Monoclonal Antibody) + PD-1 Monoclonal Antibody (Pembrolizumab) + Standard Chemotherapy (Nab-Paclitaxel) for First-Line Treatment of Mucosal Melanoma.
As of June 30, 2024, a total of 20 patients were enrolled and received treatment with YH003 in combination with pembrolizumab and nab-paclitaxel, and all underwent at least one post-treatment tumor assessment. Among them, 7 patients achieved partial response (PR), and 7 patients had stable disease (SD). The results of this Phase II study indicate that the combination of YH003, pembrolizumab, and nab-paclitaxel has good safety.
Trial #：YH003006
NCT #：NCT05420324
CD40 Target
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.
Leveraging Biocytogen’s humanized mouse model resources and unique in vivo drug screening strategy, the CD40 humanized syngeneic tumor transplant model, developed in-house by Biocytogen, was extensively utilized during the preclinical antibody screening Phase. This enabled the rapid identification of the monoclonal antibody YH003, which completely inhibited tumor growth in mice without causing liver toxicity or other adverse effects.
News
AACR2020：In vivo drug screening platform accelerates anti-hCD40 antibody drug discovery
