R01AI164475

New Way in Delivering Immunomodulatory Drugs in T1D

With no effective therapy to date, the ongoing Type 1 Diabetes (T1D) epidemic continues to be a major health problem. While immune therapeutics hold great promise for the treatment of T1D, their inadequacy, serious toxicity, side effects, and morbidity have limited research efforts in the lifelong immunosuppression approach. This shortcoming has prompted investigators to search for alternative approaches.

Targeted nanomedicine using polymeric nanoparticles (NPs) holds particular promise to enhance the delivery of immune therapeutics to treat T1D. This strategy can minimize the undesirable side effects of immune therapeutics by delivering them to diseased tissues, where they can undergo sustained release.

In this multidisciplinary project, we aim to develop an innovative, targeted nanodelivery method for immune therapeutics for T1D. Although progress has been made in developing new formulations, a method of targeted delivery of NPs to specific tissue sites following systemic administration remains to be developed.

The priming and activation of autoreactive T cells occur in the pancreatic lymph nodes (PLNs), where naive T cells enter through lymph node (LN)-restricted vasculature known as high endothelial venules (HEVs) and encounter autoantigens from the pancreas presented by dendritic cells. Activated T cells traffic subsequently to the pancreas, causing insulitis and autoimmune diabetes. Notably, we have found that HEVs are also formed in the pancreas during the onset of diabetes in NOD mice.

Here, for the first time, we have developed a nanodelivery of therapeutics to PLN and pancreata of NOD mice targeting HEV with intravenous injection. We have generated a novel monoclonal antibody (MAB) and single-chain variable fragment (scFv) against the peripheral node addressin (PNAd), a glycoprotein family expressed only by endothelial cells of the HEV. We also provide human data that supports the clinical applicability of our delivery platform. Moreover, our preliminary data shows that delivery of anti-CD3 antibody using our HEV-targeted approach unprecedentedly increases the efficacy of anti-CD3 in suppressing autoimmune diabetes in NOD mice.

Our main hypothesis is that targeted delivery of anti-CD3 to the pancreatic lymph nodes (PLNs) and pancreata will increase its efficacy and decrease toxicity by reducing systemic dosing significantly.

In Aim 1, we will examine and optimize the stability, binding efficacy, and biodistribution of anti-HEV MAB-conjugated NPs in NOD mice.

In Aim 2, we will assess the clinical efficacy and the mechanisms by which the delivery of anti-CD3 using anti-HEV MAB-conjugated NPs reverses autoimmune diabetes in NOD mice.

In Aim 3, we plan to test the binding capacity to the PLNs and pancreata of human T1D patients of our optimized anti-HEV MAB-conjugated NPs.

This multidisciplinary, collaborative approach will lay the groundwork for the introduction of an innovative, targeted delivery method of immune therapeutics for T1D.

Los Angeles University Of California

NOT APPLICABLE

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Los Angeles, California 900958361 United States

Single Zip Code

Change of Recipient Organization (Type 7 Parent Clinical Trial Optional) (PA-24-254)

Amendment Since initial award the total obligations have increased 382% from $635,857 to $3,067,019.