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CD40 agonistic antibody is emerging as a front-line immunotherapy for patients with cancer. However, despite its remarkable curative effects, serious immune-related adverse reactions limit the clinical application of CD40 agonists. Crosslinking-dependent activation is one of the promising approaches to diminish the adverse effects of CD40 agonists. Agonistic CD40 stimulation on antigen presenting cells (APCs) not only promotes activation of T cells, but also results in PD-L1 upregulation on APCs, thus creating a negative feedback loop to dampen the anti-tumor immune response. Therefore, we hypothesized that the combination of CD40 agonist and blockade of PD-1/PD-L1 interaction may further induce a synergistic effect on T cell activation and anti-tumor activity. Here, we report a novel PD-L1xCD40 Bispecific Antibody (BsAb) designed to have synergistic curative effects as well as improved safety profiles. The PD-L1/CD40 BsAb was generated using the Harbour HBICE࣪® platform. It exhibited superior binding activities to both PD-L1 and CD40, respectively. CD40 activation was fully relied on the PD-L1 crosslinking. The PD-L1xCD40 BsAb showed potent tumor growth inhibition in preclinical efficacy models. Meanwhile, it showed much improved safety profile compared to a reference anti-CD40 agonistic antibody in the preclinical tox models. Overall, the PD-L1xCD40 BsAb demonstrated remarkable in vivo anti-tumor efficacy and improved safety profiles in preclinical models, which presents it as a promising candidate for the development of next-generation cancer immune therapeutics. Citation Format: Haishan luo, Zihong Meng, Jimmy Rong, Yuandong Wang, Yunxing Yang, Fei Chen, Youhong Wang, Victor Chen, Gang Deng, Yebo He, Xin Gan, Yiping Rong. Development of a novel PD-L1xCD40 bispecific antibody with excellent efficacy and safety profile for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5559.