Chinese biotech Leads Biolabs is challenging for the world’s first approval of a 4-1BB-targeting therapy, a target that global pharmaceutical companies had abandoned one after another due to toxicity concerns. The strategy involves using bispecific antibody technology to activate 4-1BB only in the vicinity of cancer cells, overcoming the limitations of previous therapies.
According to biotech industry sources on the 28th, Leads Biolabs has filed for regulatory approval in China for Opartystomig, a bispecific antibody that simultaneously targets PD-L1 and 4-1BB. The drug has been designated for priority review and will undergo evaluation within 130 days. If approved, it would become the world’s first 4-1BB-targeting therapy.
However, since key clinical efficacy data has not yet been disclosed, the extent to which the safety issues—the biggest limitation of previous 4-1BB therapies—have been improved will likely be the decisive factor in actual approval and market viability.
4-1BB is an immune-activating receptor that promotes the activation and proliferation of immune T cells. If PD-1, a protein on the surface of cancer cells, acts as a brake that suppresses immune responses, then 4-1BB functions as an accelerator that enhances the attacking power of immune cells. Targeting PD-L1 and 4-1BB simultaneously helps the immune system recognize and attack cancer cells more effectively.
While the anti-cancer efficacy is potent, systemic activation of 4-1BB has been a chronic problem, causing severe side effects including liver toxicity.
Indeed, global big pharma companies repeatedly entered 4-1BB therapy development but failed to overcome the safety barrier. After U.S.-based Pfizer and Bristol Myers Squibb discontinued development, Switzerland’s Roche also announced in its first-quarter earnings this year that it was halting development of englumafusp alfa, a bispecific antibody targeting both CD19 and 4-1BB. Roche had already discontinued development of three 4-1BB candidates last year and is currently conducting a Phase 1 trial of Clesitomig, a 4-1BB trispecific antibody, in solid tumors.
4-1BB-based bispecific antibodies work by simultaneously targeting a cancer cell surface protein and 4-1BB, boosting immune cell attack power only where cancer cells are present. This strategy aims to overcome the limitations of previous therapies, such as liver toxicity, by reducing systemic 4-1BB activation, and development competition has recently intensified. Approximately 80 4-1BB-related programs are currently known to be in development globally.
South Korean companies are also entering the 4-1BB market with bispecific antibodies.
ABL Bio is developing Javastomig (ABL111) and Rajistomig (ABL503), both based on its proprietary 4-1BB bispecific antibody platform Grabody-T. Javastomig simultaneously targets Claudin18.2, a cancer cell surface protein, and 4-1BB, and has demonstrated anti-cancer efficacy and tolerability in a Phase 1b trial. Rajistomig, like Leads Biolabs’ candidate, simultaneously targets PD-L1 and 4-1BB and is currently preparing to enter Phase 1 trials. Both drugs are being co-developed by ABL Bio and U.S. biotech firm Novabridge Biosciences.
Hanmi Pharmaceutical is also conducting a global Phase 1 trial of BH3120, a bispecific antibody targeting PD-L1 and 4-1BB. The trial is evaluating the drug as both monotherapy and in combination with Merck’s (MSD) Keytruda in patients with advanced or metastatic solid tumors in South Korea and the United States. BH3120 incorporates Hanmi Pharmaceutical’s Pentambody bispecific antibody platform, designed to activate immune cells while selectively attacking cancer cells.
YH32367 (Nesprotamig), co-developed by Yuhan Corporation and ABL Bio, is another next-generation bispecific antibody candidate utilizing 4-1BB. It simultaneously targets HER2, which is expressed in major solid tumors, and 4-1BB. Phase 1/2 trials are currently underway, with development targeting conditional approval in South Korea by 2028 and final approval by 2032.
A South Korean industry official said, “4-1BB therapies were once considered a target that had hit a wall as big pharma companies abandoned development one after another. However, with the emergence of a new approach that activates 4-1BB only around tumors using bispecific antibodies, it is re-emerging as a key competitive field for next-generation immuno-oncology drugs.”