Ascepion Pharmaceuticals (China)

ABSTRACT Aberrant redox homeostasis owing to overproduction of reactive oxygen species (ROS) within the ocular microenvironment is critically implicated in the pathogenesis of various inflammatory ocular disorders or injuries. Previously reported antioxidant strategies, such as small‐molecule ROS scavengers or nano‐enzymes, are challenged by rapid tear turnover. Herein, we demonstrate that by decomposing hydrogen peroxide, the most stable form of ROS, catalase (CAT) shows superior ability in mitigating oxidative stress compared to the widely‐applied antioxidant enzyme superoxide dismutase (SOD), and is able to effectively clear different types of ROS to restore redox homeostasis. We then developed a thiolation strategy for CAT, and the obtained CAT‐SH could form cleavable disulfide bonds with mucins on the ocular surface to allow greatly prolonged retention and sustained ROS scavenging. Such CAT‐SH eyedrop treatment significantly improves prognosis in acute corneal alkali burn model, and demonstrates compelling efficacy in treating allergic conjunctivitis by effectively stabilizing mast cells and attenuating allergic responses. In both models, CAT‐SH eyedrops offer improved therapeutic performances compared to respective clinically used eyedrop therapies. Meanwhile, such CAT‐SH eyedrops exhibit exceptional safety profiles. Our work thus offers a highly promising yet simple eyedrop therapy to treat ocular surface injuries or inflammatory diseases with significant translational potential.

This study investigated the safety and efficacy of an anti-CTLA-4 monoclonal antibody (CS1002) as monotherapy and in combination with an anti-PD-1 monoclonal antibody (CS1003) in patients with advanced/metastatic solid tumors. The phase 1 study involved phase 1a monotherapy dose-escalation (part 1) and phase 1b combination therapy dose escalation (part 2) and expansion (part 3). Various dosing schedules of CS1002 (0.3, 1, or 3mg/kg every 3 weeks, or 3mg/kg every 9 weeks) were evaluated with 200mg CS1003 every 3 weeks in part 3. Parts 1, 2, and 3 included a total of 13, 18, and 61 patients, respectively. No dose-limiting toxicities or maximum tolerated doses were observed. Treatment-related adverse events (TRAEs) were reported in 30.8%, 83.3%, and 75.0% of patients in parts 1, 2, and 3, respectively. Grade ≥3 TRAEs were experienced by 15.4%, 50.0%, and 18.3% of patients in each part. Of 61 patients evaluable for efficacy, 23 (37.7%) achieved objective responses in multiple tumor types. Higher objective response rates were observed with conventional and high-dose CS1002 regimens (1mg/kg every 3 weeks or 3mg/kg every 9 weeks) compared to low-dose CS1002 (0.3mg/kg every 3 weeks) in microsatellite instability-high/mismatch repair-deficient tumors, melanoma, and hepatocellular carcinoma (50.0% vs. 58.8%, 14.3% vs. 42.9%, and 0% vs. 16.7%). CS1002, as monotherapy, and in combination with CS1003, had a manageable safety profile across a broad dosing range. Promising antitumor activities were observed in patients with immune oncology (IO)-naive and IO-refractory tumors across CS1002 dose levels when combined with CS1003, supporting further evaluation of this treatment combination for solid tumors. CS1002 is a human immunoglobulin (Ig) G1 monoclonal antibody that blocks the interaction of CTLA-4 with its ligands and increases T-cell activation/proliferation. CS1003, now named nofazinlimab, is a humanized, recombinant IgG4 monoclonal antibody that blocks the interaction between human PD-1 and its ligands. In this original article, we determined the safety profile of CS1002 as monotherapy and in combination with CS1003. Furthermore, we explored the antitumor activity of the combination in anti-programmed cell death protein (ligand)-1 (PD-[L]1)-naive microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) pan tumors, and anti-PD-(L)1-refractory melanoma and hepatocellular carcinoma (HCC). CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising antitumor activities across CS1002 dose levels when combined with CS1003. This supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.