Abstract
Systemic administration of bio-therapeutics can result in only a fraction of drug reaching targeted tissues, with the majority of drug being distributed to tissues irrelevant to the drug’s site of action. Targeted delivery to specific organs may allow for greater accumulation, better efficacy, and improved safety. We investigated how targeting plasmalemma vesicle-associated protein (PV1), a protein found in the endothelial caveolae of lungs and kidneys, can promote accumulation in these organs. Using ex vivo fluorescence imaging, we show that intravenously administered αPV1 antibodies localize to mouse lungs and kidneys. In a bleomycin-induced idiopathic pulmonary fibrosis (IPF) mouse model, αPV1 conjugated to Prostaglandin E2 (PGE2), a known anti-fibrotic agent, significantly reduced collagen content and fibrosis whereas a non-targeted PGE2 antibody conjugate failed to slow fibrosis progression. Our results demonstrate that PV1 targeting can be utilized to deliver therapeutics to lungs and this approach is potentially applicable for various lung diseases.
Highlights
Systemic administration of bio-therapeutics can result in only a fraction of drug reaching targeted tissues, with the majority of drug being distributed to tissues irrelevant to the drug’s site of action
It is imperative for many therapeutic monoclonal antibodies (mAbs) to distribute to and accumulate in a specific organ or tissue
We demonstrate that a mousespecific high-affinity αPV1 monoclonal antibody can be used to deliver disease-modulating therapeutics to lungs and kidneys of mice and show similar target expression of PV1 in human normal and diseased lungs
Summary
Systemic administration of bio-therapeutics can result in only a fraction of drug reaching targeted tissues, with the majority of drug being distributed to tissues irrelevant to the drug’s site of action. These authors jointly supervised this work: The use of monoclonal antibodies (mAbs) as therapeutics continues to expand for the treatment of cancer, inflammatory, autoimmune, cardiovascular, and infectious diseases. For proper efficacy, it is imperative for many therapeutic mAbs to distribute to and accumulate in a specific organ or tissue. We conjugated an anti-fibrotic small molecule to an anti-PV1 (αPV1) antibody and observe substantial reduction in the development of lung fibrosis (compared to an isotype control antibody) in an idiopathic pulmonary fibrosis (IPF) mouse model This finding was confirmed using both immunohistochemistry (IHC) for alpha-1 type I collagen (Col1a1) and second harmonics imaging microscopy for fibrillar collagen. We demonstrate that a mousespecific high-affinity αPV1 monoclonal antibody can be used to deliver disease-modulating therapeutics to lungs and kidneys of mice and show similar target expression of PV1 in human normal and diseased lungs
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