4-1BB (CD137) is a co-stimulatory receptor that stimulates the function of multiple immune cells. Its ability to induce potent anti-tumor activity makes 4-1BB an attractive target for immuno-oncology. However, clinical development of a monospecific 4-1BB agonistic antibody has been hampered by dose-limiting hepatic toxicities. To minimize systemic toxicities, we have developed a novel Claudin18.2 (CLDN18.2) x 4-1BB bispecific antibody, TJ-CD4B (ABL111) that stimulates 4-1BB pathway only when it engages with Claudin 18.2, a tumor-associated antigen specifically expressed in gastrointestinal cancers. Previous data have shown that TJ-CD4B/ABL111 binds with high affinity to CLDN18.2, including in tumor cells that express a low level of CLDN18.2. Moreover, 4-1BB was induced to trigger T cell activation in a CLDN18.2-dependent manner, leading to a strong and long-lasting antitumor effect. The pharmacologic and safety profiles support the further development of TJ-CD4B/ABL111.