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

Beyond its critical roles in development and tissue homeostasis, TGFβ signaling promotes key aspects of cancer progression and is a primary driver of fibrosis. Although blocking TGFβ signaling has great therapeutic potential for cancer and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), preclinical and clinical studies revealed that non-specific alteration of the pathway can have severe adverse consequences; therefore, inhibiting TGFβ signaling in a cell-type specific manner may avoid systemic toxic effects while preserving potential therapeutic effects. The parasitic helminth Heligmosomoides polygyrus has evolved cell-type-targeted modulators of TGFβ signaling. With insights from the development of other targeted signaling modulators and using the worm proteins as a guide, we sought to develop a human-fibroblast-targeted TGFBR2 antagonist. Here, we report mechanistic insights into the targeted worm TGFBR2 antagonist TGM6 and fusion proteins containing the TGM6 targeting domains. We created a bispecific antibody TGFBR2 antagonist that binds PDGFRA as a targeting receptor and demonstrates cell selectivity and enhanced potency in fibroblasts. Our findings suggest a viable path for developing targeted TGFβ signaling antagonists as therapeutics for cancer and tissue fibrosis.