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- Title
Targeting caveolae to pump bispecific antibody to TGF-β into diseased lungs enables ultra-low dose therapeutic efficacy.
- Authors
Kadam, Anil H.; Kandasamy, Kathirvel; Buss, Tim; Cederstrom, Brittany; Yang, Chun; Narayanapillai, Sreekanth; Rodriguez, Juan; Levin, Michael D.; Koziol, Jim; Olenyuk, Bogdan; Borok, Zea; Chrastina, Adrian; Schnitzer, Jan E.
- Abstract
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.
- Subjects
BISPECIFIC antibodies; CAVEOLAE; TREATMENT effectiveness; VASCULAR endothelium; LUNGS; IMMUNE response
- Publication
PLoS ONE, 2022, Vol 17, Issue 11, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0276462