A Chinese biotech is vying for the world's first approval of a therapy targeting "4-1BB," a program global drugmakers had halted over toxicity concerns. Its strategy is to use bispecific antibody technology to activate 4-1BB only around cancer cells to overcome the toxicity seen with existing treatments. In Korea, ABL Bio(298380), Hanmi Pharmaceutical(128940), and Yuhan(000100) are also entering development of 4-1BB-based bispecific antibodies.
On the 28th, the biotech industry said Leads Biolabs has filed for approval in China for the bispecific antibody "Opartystomig," which targets PD-L1 and 4-1BB simultaneously. The drug has been designated for priority review and is expected to be assessed within 130 days. If approved, it would be the world's first 4-1BB–targeted therapy.
However, with key clinical efficacy data yet to be disclosed, how much it has improved on the safety issues—the biggest limitation of earlier 4-1BB therapies—is expected to be crucial to actual approval prospects and marketability.
4-1BB is an immune-activating receptor that promotes activation and proliferation of T cells. If PD-1, a cancer cell surface protein, lifts the "brake" on immune responses, 4-1BB serves as the "accelerator" that boosts immune cell attack power. Targeting PD-L1 and 4-1BB at the same time helps the immune system recognize and attack cancer cells more easily.
While 4-1BB has strong anticancer effects, a chronic problem has been that systemic activity can trigger serious side effects, including liver toxicity.
In fact, global big pharma companies also rushed into 4-1BB therapy development but failed to overcome safety issues. After Pfizer in the United States and Bristol Myers Squibb (BMS) halted development, Roche of Switzerland said in its first-quarter earnings release this year that it had stopped developing "Englumafusp alpha," a bispecific antibody targeting CD19 and 4-1BB simultaneously. Roche also halted development of three 4-1BB candidates last year. Roche is currently conducting a phase 1 trial in solid tumors for the 4-1BB trispecific antibody "Clesitomig."
Bispecific antibodies based on 4-1BB target a cancer cell surface protein and 4-1BB at the same time to enhance immune cell attack power where cancer cells are present. The strategy is to reduce systemic activation of 4-1BB to overcome limitations of earlier therapies, such as liver toxicity. Competition in 4-1BB therapy development has recently ramped up again. There are believed to be about 80 4-1BB–related programs in development in and outside Korea.
Korean corporations are also entering the 4-1BB market with bispecific antibodies at the forefront.
ABL Bio(298380) is developing "Javastomig (ABL111)" and "Rajistomig (ABL503)" using its own 4-1BB–based bispecific platform "Grabody-T." Javastomig targets claudin 18.2, a cancer cell surface protein, and 4-1BB simultaneously, and demonstrated anticancer efficacy and tolerability in a phase 1b trial. Rajistomig, like Leads Biolabs, targets PD-L1 and 4-1BB at the same time. It is currently preparing to enter a phase 1 trial. Both Jivastomig and Rajistomig are being co-developed by ABL Bio and U.S. biotech Novabridge Biosciences.
Hanmi Pharmaceutical(128940) is also conducting a global phase 1 trial of "BH3120," a bispecific antibody targeting PD-L1 and 4-1BB. In Korea and the United States, it is evaluating monotherapy and combination therapy with Merck's Keytruda in patients with advanced or metastatic solid tumors. BH3120 employs Hanmi Pharmaceutical's "Pentambody" bispecific platform, designed to activate immune cells while selectively attacking cancer cells.
"YH32367 (Nesprotamig)," co-developed by Yuhan(000100) and ABL Bio, is also a next-generation bispecific candidate leveraging 4-1BB. It targets HER2, which is expressed in major solid tumors, and 4-1BB simultaneously. It is currently in phases 1 and 2, with a goal of conditional approval in Korea in 2028 and final approval in 2032.
A domestic industry official said, "4-1BB therapies were once viewed as a target that hit a wall as big pharma repeatedly abandoned development. But a new approach—'turning on 4-1BB only around cancer' through bispecifics—has emerged, and the field is reemerging as a core competitive area for next-generation immuno-oncology."