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

Author:

Kadam Anil H.ORCID,Kandasamy Kathirvel,Buss Tim,Cederstrom Brittany,Yang Chun,Narayanapillai Sreekanth,Rodriguez Juan,Levin Michael D.,Koziol Jim,Olenyuk Bogdan,Borok Zea,Chrastina AdrianORCID,Schnitzer Jan E.ORCID

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.

Funder

NIH

Publisher

Public Library of Science (PLoS)

Subject

Multidisciplinary

Reference64 articles.

1. Paul Ehrlich’s magic bullet concept: 100 years of progress;K Strebhardt;Nature reviews,2008

2. Targeted drug delivery strategies for precision medicines;MT Manzari;Nature Reviews Materials,2021

3. Advanced drug delivery 2020 and beyond: perspectives on the future;YH Bae;Advanced drug delivery reviews,2020

4. Targeting drug delivery in the vascular system: focus on endothelium;PM Glassman;Advanced drug delivery reviews,2020

5. Update on the cellular and molecular basis of capillary permeability;JE Schnitzer;Trends in Cardiovasc Med,1993

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