Background: Immune checkpoint inhibitors (ICI) PD-1/PD-L1 antibody are key drugs for the treatment of non-small cell lung cancer (NSCLC). Bispecific antibody is one of the strategies aimed at the clinical needs for NSCLC patients who are resistant to or refractory from ICI treatment. Tim-3, one of the next generation of ICB targets, is co-expressed on exhausted T cells with PD-1. It is also expressed by innate immune populations, including NK and DC. Dual blocking PD-1 and Tim-3 not only on T cells but also on DC, NK cells may achieve better clinical benefit. Methods: A bivalent to both Tim-3 and PD-1 bispecific antibody (Bis5) was developed and is in Phase I clinical trials for NSCLC patients who are resistant to or refractory from PD-1 antibody treatment. Results: Bis5 showed affinity of 5-8 nM to both Tim-3 and PD-1. Moreover, Bis5 showed better cell activity than Tim-3 and PD-1 antibody combination to activated T cell as well as NK and DC. Bis5 showed 77%-88% tumor inhibition which is close to PD-1 antibody alone in MC38 model. Neither PD-1 antibody or PD-1 and Tim-3 antibody combination show any activity in CT26 model while Bis5 showed significant tumor inhibition activity and doubled the survival rate. The highest non-severe toxicity dose (HNSTD) was 200mpk in monkeys. ADA were 33.3% (2/6), 83.3% (5/6), and 0.0% (0/6) at doses of 2, 10, and 50 mpk, respectively. The T1/2 were 31.7-66.5 h for doses 2-50 mpk. Conclusions: A Phase I, multicenter, open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary efficacy of Bis5 in patients with advanced and/or metastatic solid tumors has started. Seven cohorts (0.1, 0.3, 1, 3, 6, 10, 15 mg/kg) are planned to be enrolled sequentially in the dose escalation part. In the expansion part, a cohort group of 10 patients is planned for post PD-1 treated NSCLC as the second or third line treatment.