These findings suggest that there is additional room for improvement in terms of the safety and tolerability of the combination treatment. hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was decided to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. == Conclusions == QL1706 was well tolerated and exhibited promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is usually currently being evaluated in randomized phase II (NCT05576272,NCT05179317) and phase III (NCT05446883,NCT05487391) trials. Trial RegistrationClinicalTrials.gov Identifier:NCT04296994andNCT05171790. == Supplementary Information == The online version contains supplementary material available at 10.1186/s13045-023-01445-1. Keywords:Bifunctional PD-1, CTLA4 antibody, MabPair, Phase I trial, Nasopharyngeal carcinoma, Cervical cancer == Background == Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are key immune checkpoint inhibitors of the T-cell immune response. The combination of anti-PD-1 and anti-CTLA-4 antibodies has been tested extensively in multiple tumor types in clinical trials [14]. The addition of an anti-CTLA-4 antibody to PD-1 blockade increases the objective response rate (ORR), which can often be translated into a longer duration of response (DoR) and survival [4,5]. Thus, CRL2 the combination of nivolumab and ipilimumab has been approved for the treatment of many advanced solid tumors such as melanoma, renal carcinoma, colorectal cancer (CRC), non-small-cell lung cancer (NSCLC), and hepatocellular carcinoma (HCC) [2,68]. However, the combined inhibition of both PD-1 and CTLA-4 can lead to an increase of immune-related adverse events (irAEs) compared to anti-PD-1 monotherapy [9]. A previous Talampanel study using different doses of nivolumab and ipilimumab in the Talampanel combination therapy has exhibited that the severity level of irAEs is usually more associated with the dose of ipilimumab than that of nivolumab [10], so the current strategy to manage the elevated toxicity is usually to reduce the dose and frequency of ipilimumab [11]. Nevertheless, the frequency of grade 3 or 4 4 adverse events (AEs) is still much higher with the combination therapy than with anti-PD-1 monotherapy [6]. Interestingly, in a recent study of quavonlimab (an anti-CTLA-4 IgG1 molecule) in combination with pembrolizumab (an anti-PD-1 antibody) in NSCLC patients, a low dose of CTLA-4 antibody (25 mg every 6 weeks plus 200 mg of anti-PD-1 every 3 weeks) exhibited a better safety profile with an equal efficacy; therefore, this dose was selected as the recommended phase II dose (RP2D) for further studies [12,13]. These findings suggest that there is additional room for improvement in terms of the safety and tolerability of the combination treatment. Another alteration of dual PD1 and CTLA4 blockade is the use of a bispecific antibody by binding two antigens or one antigen with different epitopes, which has demonstrated a promising efficacy [14]. However, the safety and efficacy of a bispecific antibody need to be further evaluated. QL1706 was generated by using MabPair (patent No. US20190276542A1 in the USA, details in the Additional file1), a new technological platform that enables the production of two antibodies close to their natural forms from a single host cell line and is manufactured as one Talampanel product [15]. QL1706 contains a mixture of anti-PD-1 IgG4 and anti-CTLA-4 IgG1 that were produced together in a fixed ratio. Each antibody was individually optimized to achieve desirable target coverage and antibody effector functions. In particular, the anti-CTLA-4 antibody was designed to have a shorter elimination half-life (t1/2) to reduce its exposure and lower.