Localizing Therapeutics to Target Lung Myofibroblasts and Reverse Fibrosis - Project Summary/Abstract
Lung diseases are a global public health problem with significant morbidity, inadequate therapies and a very
high burden to society. Of these, idiopathic pulmonary fibrosis (IPF) is particularly challenging to treat as existing
therapeutics, Nintedanib and Pirfenidone, only slow progression but do not reverse fibrosis. One of the reasons
is in part due to the fact that the vascular endothelium represents a key barrier to effective delivery of anti-fibrotic
drugs into lung tissue. Current systemic lung therapies rely on passive transvascular transport to move circulating
drugs from the bloodstream and into the target tissue. Hoverer, only minute fractions of the injected doses
actually reach the lung tissue, diminishing efficacy and often necessitating dose escalation. The ideal goal is to
deliver the entire dose of therapeutic into the lung with the minimal exposure of other tissues. We attempt to
approach this ideal goal by pumping unique immunotherapeutics precisely into lung tissue to comprehensively
block activation and differentiation of MF, the key driver of profibrotic extracellular matrix (ECM) deposition and
activation of survival cascades, leading to progressive scarring. The goal of this project is to develop and test
novel lung precision drug delivery system (LPDDS) targeting endothelial cells caveolae that are actively and
specifically pump myofibroblasts (MF)-directed antifibrotics into lungs at microdoses after intravenous (iv)
injection. We have identified the cell surface protein Thy-1 a precision therapeutic and a major modulator of MF
activation and differentiation and characterized its role in resolving fibrosis via synergistic engagement of multiple
profibrotic signaling pathways. Based on this, we engineered the first “dual precision” bispecific therapeutic
mAPP:Thy-1 with antibody mediating precise binding/delivery to and penetration of lung tissue via caveolae
transcytosis and the other – mediating Thy-1’s fibrosis-resolving activity in the lung interstitium where the loss of
Thy-1 promotes a dysregulated MF phenotype driving fibrosis. To further potentiate antifibrotic effect, we
designed mAPP:FAP-Nintedanib immunoconjugates, where concerted action of Thy-1 and Nintedanib in the
lung parenchyma has even greater power to concentrate their fibrosis-resolving activities at the site of action,
potentially reversing fibrosis. Our goal is to explore transendothelial pumping via caveolae to improve therapy of
lung diseases at various stages from very early inflammatory to fibrotic. We will optimize lung targeting of our
LPDDS through engineering and chemistry and will study their specific lung delivery, penetration, accumulation,
and therapeutic impact using multiple imaging techniques (SPECT-CT, IVM, EM, and IHC). Therapeutic effects
will be determined in two rat models that can reproduce many pathological hallmarks of inflammatory and fibrotic
disease stages. Our specific aims are 1) to generate and test in vitro activity of caveolae- and myofibroblast-
targeting therapeutics, 2) to assess the lung targeting, imaging and tissue processing of caveolae- and
myofibroblast-targeting therapeutics in rodent models of fibrosis, and 3) to test the therapeutic efficacy of
caveolae/myofibroblast-targeting therapeutics in lung fibrosis. This work sets a foundation for caveolae-targeted
therapies and could begin a paradigm shift from passive to active delivery for many pulmonary diseases.
