First-in-human study of ZG005, a dual specific antibody targeting TIGIT and PD-1, as monotherapy in patients with advanced solid tumors.
Authors: Qin Shukui , Cheng Ying , Wu Lihua , Chai Xiaoli , Wang Qiming , Liu Qinghua , Fan Lianlian , Shi Jianhua 
Published: June 2023

e14504 Background: Multiple groups have shown that TIGIT contributes to immune-tolerance by inhibiting immune responses mediated by T cells and NK cells through binding its ligand, CD155 (PVR), on antigen-presenting cells and a variety of non-hematopoietic cell types including tumor cells. ZG005, a PD-1 and TIGIT dual specific antibody, is a promising immunotherapy for tumors as blocking these two pathways could synergistically activate T cells and enhance the anti-tumor activity of NK cells. We have conducted a Phase 1 clinical study to assess the tolerability, safety, preliminary efficacy of this drug. Methods: During the dose escalation stage, an accelerated titration design (ATD) in the first dose and the standard "3+3" design in the rest doses were used. Subjects were patients with advanced solid tumors who failed to the available standard treatments. The dose groups were set from 0.3 to 20 (0.3, 1, 3, 10, 20) mg/kg, intravenous infusion, once every 3 weeks. The first 21-day-period was defined as the dose-limiting toxicity (DLT) observation period. Subjects could continue to receive ZG005 until treatment discontinuation criteria were met. Tumor response was assessed by RECIST1.1 and iRECIST. Pharmacokinetics and receptor occupancy (RO) profiles were also assessed in this study. Results: A total of 16 subjects (6 males and 10 females) completed the DLT observation, with median age of 59 years. Nine (56.3%) of them received at least 3 lines of antineoplastic therapies, and six (31.6%) have been exposed to PD-1 or PD-L1 inhibitors. There was one DLT event found in the 1 mg/kg dose group, showing a grade 3 hepatic function abnormal (immune-mediated). No other DLT event was observed. Forty-nine treatment-related adverse events (TRAEs) including the aforementioned DLT event occurred. TRAEs were basically grade 1 or 2, except one female who suffered from rectal cancer unfortunately died at home. Due to limited information gathered, the investigators considered that the death was mostly related to the underlying condition, but the cause of the study drug could not be completely excluded. The most frequent TRAEs were increases in alanine aminotransferase, lipase, blood creatine phosphokinase MB, blood alkaline phosphatase and blood lactate dehydrogenase, with an incidence of 18.8% (3/16). Of the 10 evaluable cases, 1 had PR, 6 had SD and 3 had PD. The longest duration of administration was in a subject with intrahepatic cholangiocarcinoma who received 9 cycles and is still remaining in this study. The Cmax and AUC increased from 0.3-20 mg/kg approximately in dose proportion. Complete and sustained RO of T cells in PBMCs was observed at ≥ 3 mg/kg doses of ZG005 for at least 3 weeks. Conclusions: ZG005 demonstrates good safety and tolerance in this escalation study. It also demonstrates preliminary antitumor effects in patients with solid tumors, a good PK profile and long-lasting RO. Clinical trial information: ChiCTR20220021 .