Known as DuoBody-FAPαxDR4, or GEN1057, this cutting-edge bispecific antibody zeroes in on cancer cells while sparing healthy tissues.
Now in its first human clinical trial, GEN1057 is showing promise as a game-changer, tackling the shortcomings of earlier therapies with a novel approach that’s both potent and precise.
GEN1057 works by targeting two key players in the tumor microenvironment: death receptor 4 (DR4) on cancer cells and fibroblast activation protein alpha (FAPα) on cancer-associated fibroblasts, which are abundant in the supportive tissue of many solid tumors.

Unlike older treatments that triggered DR4 everywhere, risking severe liver damage, GEN1057 only activates DR4 when FAPα is nearby, ensuring it attacks cancer cells specifically in the tumor’s neighborhood. This “conditional activation” sparks a cascade of caspase-8, leading to programmed cell death, or apoptosis, in the cancer cells, leaving healthy cells unharmed.

In lab tests with tumor cell lines and colorectal cancer patient-derived organoids, the drug triggered dose-dependent cell death only when FAPα-expressing cells were present, confirming its targeted action. Crucially, it showed no toxicity in human liver spheroids, sidestepping the hepatotoxicity that plagued earlier DR4-targeting drugs like mapatumumab and lexatumumab. In mouse models, including patient-derived xenografts and a colorectal cancer model with multiorgan metastases, GEN1057 shrank tumors significantly, proving its strength across various tumor types, even those with varying DR4 levels.

Now in a Phase 1 clinical trial (NCT06573294), GEN1057 is being tested for safety and early effectiveness in patients with advanced solid tumors.

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Clinical trial.