A vaccine-like administration of PLP-PEG-B7AP and MOG-PEG-B7AP to control EAE in relapse-remission and chronic progressive animal models of multiple sclerosis:
Bifunctional peptide inhibitors as peptide-based therapeutic vaccines
JOHN STEWART1, AHMED H. BADAWI2, PAUL KIPTOO3, TERUNA J. SIAHAAN3*
*Corresponding author
1. Current Address: MedImmune, LLC, Gaithersburg, MD 66047, USA
2. Current Address: Kansas University Medical Center, Kansas City, KS 66160, USA
3. The University of Kansas, Department of Pharmaceutical Chemistry, Simons Research Laboratories, 2095 Constant Ave., Lawrence, Kansas 66047, USA
Abstract
Most current therapies for treatment of multiple sclerosis or other autoimmune diseases work by suppressing the general immune response. Normally they treat the symptoms but do not address the underlying change in the immune system balance. In this study, PLP-PEG-B7AP and MOG-PEG-B7AP, new bifunctional peptide inhibitors or BPI molecules, were evaluated for suppressing experimental autoimmune encephalomyelitis (EAE) in relapse-remission (RRMS) and chronic progressive (CPMS) animal models for multiple sclerosis, respectively, when administered in a vaccine-like manner. PLP-PEG-B7AP and MOG-PEG-B7AP are conjugates between an antigenic peptide (PLP139-151 or MOG38-50 peptide) and a B7 antisense peptide (B7AP) derived from a CD28 receptor linked via a pegylated moiety. When administered as a vaccine-like treatment, PLP-PEG-B7AP was effective in suppressing EAE in the RRMS animal model while MOG-PEG-B7AP was effective in suppressing EAE in the CPMS animal model. Both BPI molecules were more effective than their respective parent antigenic peptides alone (i.e., PLP139-151 or MOG38-50). Vaccination with the PLP-PEG-B7AP molecule produced a long-term suppression of pro-inflammatory cytokine IFN-γ.
INTRODUCTION
A breakdown in the host immune system is one of the contributing factors that cause autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes (T1D), and rheumatoid arthritis (RA), amongst others (1-3). In MS, the host immune cells infiltrate the central nervous systems (CNS) and attack the myelin sheath of the neurons to expose the underlying axons, so they cannot translate signals within neurons (4). As a result of this neuronal damage, MS patients suffer from symptoms of neurological disorders such as sensory loss, loss of vision, and varying degrees of paralysis. MS patients can be classified as relapsing-remitting (RRMS), primary progressive (PPMS), secondary progressive (SPMS), and progressive-relapsing (PRMS), depending on the clinical stage of the disease. About 80-90% of MS patients initially exhibit symptoms of RRMS typified by episodes of relapses and remission (5, 6). But as the disease progresses, RRMS is transformed into chronic progressive MS (CPMS) (6, 7). Most of the current therapies for MS mitigate the symptoms of the disease, and they do not cure the underlying causes of myelin-specific neuronal damages. Thus, t ...
