Friday, May 17, 2024
5/17/2024
Project summary/abstract Modern medicine has created precision drugs blocking a single therapeutic target like TGF-ß with high affinity and specificity. Yet treating lung diseases remains challenging in part because lung microvascular endothelium represents a key restrictive barrier to effective drug delivery. Current systemic therapeutics rely solely on convection and diffusion to extravasate passively into the tissue interstitium where disease targets and cells can readily be reached and directly treated. The goal of this research proposal is to design, develop and test a novel drug delivery system for immunotherapeutics that overcomes this key barrier by targeting caveolae to facilitate active and specific transcytosis into lungs after intravenous injection. The ideal is to deliver the entire therapeutic dose inside the lung tissue with all other tissues minimally exposed. We attempt to approach this ideal by achieving robust transendothelial pumping precisely into lung tissue to comprehensively block the therapeutic target TGF-ß, which regulates inflammation and remodeling in diseased tissues. Because TGF-ß also exerts various homeostatic effects in many organs, caution is necessary when systemic targeting of its function is attempted. Precision lung targeting proposed here will maximize efficacy and therapeutic indices by minimizing dosages, eliminating toxicities, and reducing cost of treatment. To that end, we have genetically engineered the first “dual precision” immunotherapeutics, namely bispecific antibodies in quad format with one arm pair mediating precise binding/delivery to and penetration of lung tissue via caveolae pumping and the other pair constituting the precision therapeutic modality that blocks TGF-ß effector function. Active transendothelial delivery improved precision lung targeting by 100-fold over standard passive transport. Delivering most of the injected dose into lungs within 1 hour enhanced therapeutic potency by >1000-fold in a rat pneumonitis model. Now our goal is to expand this promising preliminary work and further improve and rigorously test this drug delivery system to treat key lung diseases at distinct stages ranging from early acute inflammation to chronic and progressive fibrosis. We will optimize lung targeting of our dual precision immunotherapeutics and study their specific lung delivery, penetration, accumulation, localization, and therapeutic impact in rats using multiple imaging techniques (SPECT-CT, IVM, EM, and IHC). Therapeutic effects will be assessed in a rat bleomycin model that reproduces pathological hallmarks of many fatal human diseases including ALI, ARDS, COVID, pneumonias, and fibrosis. Our specific aims are: 1) to engineer and evaluate distinct caveolae-targeted antibody constructs for precision active delivery into normal lung tissue, 2) to quantify targeting and optimize delivery of bispecific immunotherapeutics in lung disease, 3) to test efficacy of bispecific immunotherapeutics to ameliorate lung disease and block TGF-ß pathways. This work sets a foundation for caveolae-targeted therapies and could begin a paradigm shift from passive to active drug delivery for many diseases.
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