The long-term aim of to limit disease in man. Toward this goal, we will take advantage of: the restricted nature of 13(IV) collagen (13(IV) and its available epitopes with the kidney;the availability of a unique panel of human monoclonal antibodies (mAb) that bind to 13(IV) within glomeruli in vivo, and our experience in Ab engineering, protein expression, and experimental models of nephritis, to create human fusion proteins that bind to the kidney, in vivo. The experimental approach will involve modification of human m anti-13(IV) Ab, whereby their antigen binding for 13(IV) is maintained, so that they bind to the GBM in vivo, in mice. However their Fc regions will be altered, so that instead of promoting inflammation, they will constructed so that they have the potential to deliver either anti-inflammatory or anti-fibrotic signals to glomeruli. Initially, this will involve, selection expression and purification of candidate human m anti-13(IV) minibodies, in vitro. Subsequently, further selection and optimization of candidates will be carried out in normal, and then in nephritic mice, to identify the ideal reagents for delivery to glomeruli, with the long-term goal to deliver disease modifying agents. These technologies, along with the aforementioned panel of reagents, will be used to pursue the following Specific Aims: 1: To produce and characterize recombinant human anti-13(IV)Ab fragments with linkers, and 2: To evaluate the capacity of the human Ab fragments to deliver reagents to the kidney, in vivo, during health and disease. Once conditions are optimized, the reagents will be used in future studies to test the hypothesis that modified human anti-13 (IV) Ab will efficiently deliver drugs to the kidney to limit local inflammation, without systemic side effects. If successful, a major advantage of this approach and technology is that it will have application to all forms of glomerulonephritis. Furthermore, since the reagents are derived from human Ab sequences, they have the potential of being directly evaluated to treat human glomerulonephritis, with limited modification.
The overall goal of these studies is develop more effective, less toxic therapy for glomerulonephritis. For this purpose, human antibodies that bind to the kidney will be modified, so they have the potential to localize in the kidney and deliver anti- inflammatory and anti-fibrotic agents, to modify the course of nephritis. Although the proposed studies will be performed in mice, since the reagents will be based on human sequences, they will have the potential to be directly applied to various forms of human glomerulonephritis in the future.
| Chaudhary, Kapil; Shinde, Rahul; Liu, Haiyun et al. (2015) Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy. J Immunol 194:5713-24 |
| Kvirkvelia, Nino; McMenamin, Malgorzata; Chaudhary, Kapil et al. (2013) Prostaglandin E2 promotes cellular recovery from established nephrotoxic serum nephritis in mice, prosurvival, and regenerative effects on glomerular cells. Am J Physiol Renal Physiol 304:F463-70 |
