A targeted bispecific TGFBR2 antagonist antibody demonstrates cell selectivity and enhanced potency on human fibroblasts

TGFβ signaling is essential for development and tissue homeostasis, but it also drives cancer progression and is a primary mediator of fibrosis. Broadly blocking TGFβ has therapeutic potential for cancer and idiopathic pulmonary fibrosis (IPF), yet non-specific pathway alteration has caused severe adverse effects in preclinical and clinical studies, motivating cell-type-specific inhibition.

Guided by the parasitic helminth Heligmosomoides polygyrus, which has evolved cell-type-targeted modulators of TGFβ signaling, the authors studied the worm TGFBR2 antagonist TGM6 and fusion proteins containing its targeting domains. They engineered a bispecific antibody TGFBR2 antagonist that binds PDGFRA as a targeting receptor on human fibroblasts.

The bispecific antibody demonstrated cell selectivity and enhanced potency on fibroblasts, suggesting that targeted TGFβ inhibition could preserve therapeutic effects while minimizing systemic toxicity.

These findings indicate a viable path for developing targeted TGFβ signaling antagonists as therapeutics for cancer and tissue fibrosis such as IPF.