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
occurs 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 intra venous injection. We have generated a novel mAb and 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 unprecedently 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 reverse 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.

Grant Number: 7R01AI164475-05
NIH Institute/Center: NIH
Principal Investigator: Reza Abdi