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Targeting caveolae to pump bispecific antibody to TGF-β into diseased lungs enables ultra-low dose therapeutic efficacy


Anil H. Kadam, Kathirvel Kandasamy, [...], and Jan E. Schnitzer

PLOS ONE, 2022


The long-sought-after “magic bullet” in systemic therapy remains unrealized for disease targets existing inside most tissues, theoretically because vascular endothelium impedes passive tissue entry and full target engagement. We engineered the first “dual precision” bispecific antibody with one arm pair to precisely bind to lung endothelium and drive active delivery and the other to precisely block TGF-β effector function inside lung tissue. Targeting caveolae for transendothelial pumping proved essential for delivering most of the injected intravenous dose precisely into lungs within one hour and for enhancing therapeutic potency by >1000-fold in a rat pneumonitis model. Ultra-low doses (μg/kg) inhibited inflammatory cell infiltration, edema, lung tissue damage, disease biomarker expression and TGF-β signaling. The prodigious benefit of active vs passive transvascular delivery of a precision therapeutic unveils a new promising drug design, delivery and therapy paradigm ripe for expansion and clinical testing.

Results from nanoScan® SPECT/CT

  • Authors showed that caveolae pumping in the vascular endothelium can pump therapeutic antibody into diseased lung to achieve unprecedented precision therapeutic targeting and efficacy
  • Whole body SPECT imaging showed robust lung uptake after 24 or 48 h injected 125I-833c&Freso intravenously (iv)
  • Neither the mutant 125I-833cX&Freso nor 125I-fresolimumab, which both lack APP binding, targeted the lungs even after 24 



Publication on PLoS One

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