Antigen-Specific Suppression of Experimental Autoimmune Encephalomyelitis by a Novel Bifunctional Peptide Inhibitor: Structure Optimization and Pharmacokinetics

Abstract

The objective of this study was to optimize the in vivo activity of proteolipid protein (PLP)-bifunctional peptide inhibitor (BPI) molecule to suppress experimental autoimmune encephalomyelitis (EAE) in SJL/J mice and evaluate pharmacokinetic profiles of PLP-BPI. PLP-BPI is constructed via conjugation of myelin PLP 139-151 with CD11a 237-246 -derived peptide (LABL) via a spacer. The hypothesis is that PLP-BPI binds simultaneously to major histocompatibility complex-II and intercellular adhesion molecule-1 on the antigen-presenting cell (APC) and inhibits the formation of the immunological synapse during T-cell and APC interactions. In this study, the structure of BPI was modified by varying the spacer and was evaluated in the EAE model.Intravenous injections of BPI derivatives inhibited the onset, severity, and incidence of EAE more effectively and induced a lower incidence of anaphylaxis than that produced by unmodified PLP-BPI. As anticipated, production of interleukin-17, a proinflammatory cytokine commonly found in elevated levels among multiple sclerosis (MS) patients, was significantly lower in Ac-PLP-BPI-PEG6-or Ac-PLP-BPI-NH 2 -2-treated mice than in phosphate-buffered saline-treated mice. These results suggest that BPI-type molecules can be modified to achieve more efficient and better tolerated BPI-based derivatives for the treatment of MS.

Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis

“…Previously, a bifunctional peptide inhibitor (BPI) demonstrated the importance of co-delivering both antigenic peptide and a peptide inhibiting T cell activation by blocking immune cell adhesion (22,23,(26)(27)(28). Applying this codelivery approach of autoantigen and peptide inhibitor to a multivalent delivery vehicle (SAgA PLP:LABL ), i.e., multiple copies of peptide per therapeutic molecule, has also suppressed EAE (24,25).…”

“…Addition of antigen specificity to such an approach may reduce undesired side effects associated with global immunosuppression that accompanies many of the current immunomodulatory therapies available (4-7). Indeed, several groups have begun investigating antigen-specific immunotherapies to treat autoimmune disorders (22)(23)(24)(25)(26)(27)(28)(32)(33)(34)(35)(36).…”

“…The creation of an antigen-specific treatment capable of suppressing the immune response by co-delivery of autoantigen and immune inhibitor may improve the safety and efficacy of autoimmune therapies. Several previous studies have shown that co-delivering autoantigen and immune inhibitory peptide can inhibit autoimmune disease in animal models (22)(23)(24)(25)(26)(27)(28).…”

Peptides and Proteins for Treatment and Suppression of Type 1 Diabetes

“…EAE is an animal model for multiple sclerosis (MS). PLP-BPI derivatives are able to suppress EAE better than the parent PLP peptide (PLP 139-151 ), indicating that the presence of LABL peptide alters the mechanisms of action of PLP-BPI compared to PLP peptide alone (Kobayashi et al, 2008;Kobayashi et al, 2007;Ridwan et al, 2010;Zhao et al, 2010). Cytokine studies indicated that PLP-BPI treatment induced the differentiation and proliferation of T-reg and Th2 cells and suppressed the proliferation of Th17 cells.…”

“…Using the distance estimate, a combination of glycine (G) and amino caproic acid (Acp) was used to connect LABL to GAD peptides. In general, BPI molecules are effective in suppressing different autoimmune diseases; for example, GAD-BPI, PLP-BPI, and CII-BPI molecules (Table 1) have excellent efficacy to suppress T1D (Murray et al, 2007), EAE (Kobayashi et al, 2008;Kobayashi et al, 2007;Ridwan et al, 2010;Zhao et al, 2010), and RA, respectively. The central hypothesis is that binding of BPI molecules simultaneously to MHC-II and ICAM-1 on the surface of APC blocks the immunological synapse formation at the interface of APC-T cells.…”