First-in-human study of ZGGS15, a dual specific antibody targeting LAG-3 and TIGIT, as monotherapy in patients with advanced solid tumors.

e14678 Background: ZGGS15 is a recombinant humanized bispecific antibody composed of a monoclonal antibody against LAG-3 and TIGIT. It can specifically bind LAG-3 and TIGIT. It reverses LAG-3 and TIGIT immune suppression to T and NK cells, relieves suppression of Treg to T and NK cells, promotes the activation and proliferation of T and NK cells, and cytokines release. ZGGS15 restores T and NK cell functions to kill tumor cells. In non-clinical studies, we found that ZGGS15 had significant anti-tumor effects and synergistic anti-tumor effects with Anti-PD-1 antibody. Therefore, we conducted a Phase 1 clinical study to assess the tolerability, safety, and preliminary efficacy of this drug as monotherapy in patients with advanced solid tumors. Methods: During the dose escalation stage, an accelerated titration design (ATD) in the first dose (1 subject if ≤Grade 2 treatment-related adverse event occurred) 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 30 (0.3, 1, 3, 10, 20, 30) 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 ZGGS15 until treatment discontinuation criteria were met. Tumor response was assessed by RECIST1.1 and iRECIST. Pharmacokinetics (PK) and receptor occupancy (RO) profiles were also assessed in this study. Results: A total of 12 patients (4 males and 8 females) completed the DLT observation in the first four dose groups (0.3 to 10 mg), with a median age of 57 years. Eight (66.7%) of them received at least 3 lines of antineoplastic therapies, and five (41.7%) have been exposed to PD-1 or PD-L1 inhibitors. There was no DLT event observed. Thirty-eight treatment-related adverse events (TRAEs) occurred. Up to now, TRAEs were all grade 1 ~ 2. The most frequent TRAEs were proteinuria (33.3%, 4/12), hypokalemia (25%, 3/12), hypoalbuminemia (25%, 3/12), and hypertriglyceridemia (25%, 3/12). The C max and AUC increased from 0.3-1 mg/kg approximately in dose proportion. Nearly complete and sustained RO of T and NK cells in PBMCs was observed at 1 mg/kg dose of ZGGS15 for at least 3 weeks. Conclusions: The first four dose levels of ZGGS15 were very well tolerated. A good PK profile, and a long-lasting RO were observed in this escalation study. It is anticipated that this product could provide an additional benefit only when use in combination with an anti-PD-1 antibody. Clinical trial information: NCT05864573 .