Key result
FAP-targeted bispecific antibodies accelerate cardiac deterioration and increase scar size via IFNg and CD40L signaling.
Why the study?
Cardiac fibrosis drives heart-failure progression without approved targeted therapies, prompting evaluation of FAP+ fibroblast depletion and FAP-directed bispecific T-cell-engaging antibodies after cardiac injury.
Do FAP-directed bispecific T-cell-engaging antibodies improve cardiac remodeling and function in a model of cardiac ischemia-reperfusion injury?
Do FAP-directed bispecific T-cell-engaging antibodies improve cardiac remodeling and function in a model of cardiac ischemia-reperfusion injury?
FAP-targeted BiTE molecules successfully deplete fibrotic cells but paradoxically worsen cardiac function post-myocardial infarction via IFNg signaling, revealing a critical need to block collateral inflammation to unmask their cardioprotective effects.
Targeting FAP+ fibroblasts may limit post-injury fibrosis; leaves open whether this alters clinical heart-failure progression.
Introduction Cardiac fibrosis is a major driver of heart-failure progression, yet no approved therapies directly target fibrotic remodeling. Recent work has identified a population of activated, non-myofibroblast cardiac fibroblasts marked by fibroblast activation protein (FAP). These FAP+ fibroblasts arise after injury through inflammatory signaling and contribute to pathological fibrosis. Methods We utilized an echo guided model of cardiac ischemia reperfusion injury to investigate the effects of of FAP+ fibroblast depletion. We also evaluated the therapeutic feasibility of FAP-directed bispecific T-cell—engaging antibodies (BiTE® molecules) to eliminate FAP+ fibroblasts and profiled downstream signaling pathways. Finally, we investigated strategies for reducing harmful collateral inflammation from BiTE® molecule treatment while preserving the cardioprotective effects of FAP+ fibroblast depletion. Results We demonstrate the potential benefits of FAP+ fibroblast depletion following myocardial infarction. Unexpectedly, while FAP targeted bispecific T-cell engaging antibodies (BiTE® molecules) effectively eliminate FAP+ fibroblasts from the heart, they surprisingly lead to accelerated deterioration of cardiac function, enhanced adverse remodeling, and increased scar size. FAP BiTE® molecules elicit a robust cytokine response within the heart with prominent activation of interferon gamma (IFNg) and CD40 ligand pathways. Target cell killing was independent of IFNg and CD40L signaling and blockade of these pathways was sufficient to unmask the protective therapeutic effects of FAP+ fibroblast depletion. Conclusion We reveal that IFNg signaling to fibroblasts drives the differentiation of an independent lineage of activated fibroblasts not typically found in the infarcted heart, which are responsible for the harmful effects of FAP BiTE® molecules. Collectively, these findings highlight a previously unrecognized cardiac liability of BiTE® molecules and inform the design of the next generation of therapeutics.
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Yang et al. (2026) studied Cardiac fibrosis. FAP-directed bispecific T-cell-engaging antibodies (BiTE molecules) was evaluated on Cardiac function, adverse remodeling, and scar size. FAP-targeted bispecific T-cell engaging antibodies eliminated FAP+ fibroblasts but accelerated deterioration of cardiac function and increased scar size via collateral IFNg and CD40 ligand signaling.
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