is a recombinant humanized CTLA-4 IgG1 monoclonal antibody. In phase I clinical studies, YH001 in combination with PD-1 monoclonal antibody shows a good safety profile and preliminary anti-tumor activity in patients with advanced solid tumors.
In October 2021, Biocytogen/Eucure Biopharma partnered with the US company TRACON (NASDAQ: TCON) to advance the clinical development and commercialization of YH001 in North America for treatment of soft tissue sarcoma and other indications.
The combination regimen was planned as: YH001 (CTLA-4 mAb) + PD-L1 mAb (envafolimab).
In a phase I clinical trial in Australia of YH001 in combination with the anti-PD-1 mAb Tuoyi (Toripalimab) from Junshi Biosciences, YH001 showed good safety and efficacy. Dose escalated from 0.05 mg/kg to 6.0 mg/kg. As of May 2022, 25 patients had been evaluable, of whom five had PR (partial response) and nine had SD (stable disease). The primary study endpoint was met, and the maximum tolerated dose (MTD) of YH001 in combination therapy was determined to be 4.0 mg/kg.
A phase I/II dose escalation trial of YH001 in subjects with advanced solid tumors in China. Dose was modified to escalate from 0.3 mg/kg to 6.0 mg/kg based on the results of the phase I study in Australia. As of May 2022, 14 patients had been evaluable, and four of them had SD (stable disease). The primary study endpoint was met, and the highest dose 6.0 mg/kg set for YH001 single-agent escalation remained safe and tolerable.
Preclinical studies have shown the following findings:
1. When used in combination with PD-1 mAb (pembrolizumab, Keytruda), YH001 showed better anti-tumor activity than ipilimumab (Yervoy) in an in vivo pharmacodynamic tumor model.
2. YH001 showed better blocking activity than ipilimumab (Yervoy) in an in vitro test.
3. As an IgG1 subtype, YH001 showed stronger ADCC and CDC effects than ipilimumab (Yervoy) in an in vitro test. In an in vivo tumor model in mice, YH001 significantly reduced the proportion of Tregs in tumor-infiltrating lymphocytes.
4. YH001 had a better in vivo safety profile than ipilimumab (Yervoy).
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also known as CD152, plays an important regulatory role in the activation of T cells. CTLA-4 is expressed on the surface of regulatory T cells (Tregs), and when bound to B7-1 (CD80) and B7-2 (CD86) on the surface of antigen-presenting cells (APCs), competitively inhibits the binding of B7 to CD28 on the surface of effector T cells, thereby inhibiting the activation of T cells. Therefore, inhibition of CTLA-4 by inhibitory antibodies can block this mechanism, thereby enhancing T cell activity.
Improvement of the patient’s immune response to tumor by blocking the inhibitory signal of human anti-tumor response is considered the most promising tumor immunotherapy at present. CTLA-4 and PD-1 are considered to be two important checkpoints of the immune system and thus the basic targets of tumor immunotherapy as blockage of them can affect different types of T cells and further initiate anti-tumor immune attack.
Currently, the marketed antibody drugs targeting CTLA-4 include CTLA-4 mAb ipilimumab (Yervoy) from BMS and PD-1/CTLA-4 bispecific antibody cadonilimab (trade name: Kaitanni; AK104) from Akeso.
ASCO2022：A first-in-human phase I dose escalation of YH001, an anti-CTLA-4 monoclonal antibody (mAb), in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors