The ultimate goal of the Antibody-targeted Therapeutics Core is to generate novel, injectable, targeted biologics and drug delivery vehicles that efficiently target and penetrate the lung. The core will enable the caveolae-based delivery system to be used in all 3 projects by provide purified antibodies, recombinant antibodies and antibody fragments, hetero-bifunctional immunocomplexes, antibody-linked nanoparticles, and antibody fusion proteins. Intact antibodies will be purified from hybridoma supernatant; recombinant antibodies, fragments and fusion proteins will be expressed in mammalian tissue culture expression systems. Once purified, they will be conjugated to other antibodies, proteins or novel drug delivery nanoparticles. The reagents provided to each project will be characterized biophysically to ensure their integrity and unaltered kinetic properties, such as target binding and drug binding/release. We will use a novel technology platform to study the real-time label-free kinetics of antibody, protein and nanoparticle conjugates in comparison to unconjugated antibodies. We will generate individual conjugates between antibodies against APP2 (mAPP2; targeting moiety) and either neutralizing versions of TGF antibody or recombinant Thy protein or its molecular derivatives (therapeutic moiety), followed by purification and formulation for subsequent injection. We will also generate optimized targeted delivery systems for rapamycin and troglitazone to prevent or treat fibrosis. Specifically, we will produce an immunoconjugate consisting of mAPP2's lung targeting moiety and polymeric nanogel as carrier for either rapamycin or troglitazone. Nanogels will be prepared from methacrylate copolymer with oligoethylene glycol and pyridyldisulfide moieties in the side chains, which forms micelles of controlled sizes. These micelles are cross-linked into nanogels in the presence of drug molecules in aqueous/organic buffers to encapsulate the drugs upon cross-linking. Drug capacity and rates of drug release from nanogels can be varied in a broad range and will be fine-tuned for specific applications. This core will provide services critical to all aims in all 3 projects and will be instrumental in providing characterization of the new retargeted therapeutic reagents for eventual clinical translation.
CORE B NARRATIVE Our goal is to generate new therapeutics that can be injected into the IPF animal models and ultimately patients and that will deliver anti-fibrotic drugs and biologics to the lung to treat IPF. Targeted delivery of therapeutics to the lung can treat the many diseases that can affect lung function and patient health. It can also reduce serious side effects of current drugs by delivering therapeutic doses to the lung but not to other organs.
|Prasad, Priyaa; Molla, Mijanur Rahaman; Cui, Wei et al. (2015) Polyamide Nanogels from Generally Recognized as Safe Components and Their Toxicity in Mouse Preimplantation Embryos. Biomacromolecules 16:3491-8|