Codelivery of antigen and an immune cell adhesion inhibitor is necessary for efficacy of soluble antigen arrays in experimental autoimmune encephalomyelitis

Abstract

Autoimmune diseases such as multiple sclerosis (MS) are typified by the misrecognition of self-antigen and the clonal expansion of autoreactive T cells. Antigen-specific immunotherapies (antigen-SITs) have long been explored as a means to desensitize patients to offending self-antigen(s) with the potential to retolerize the immune response. Soluble antigen arrays (SAgAs) are composed of hyaluronic acid (HA) cografted with disease-specific autoantigen (proteolipid protein peptide) and an ICAM-1 inhibitor peptide (LABL). SAgAs were designed as an antigen-SIT that codeliver peptides to suppress experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Codelivery of antigen and cell adhesion inhibitor (LABL) conjugated to HA was essential for SAgA treatment of EAE. Individual SAgA components or mixtures thereof reduced proinflammatory cytokines in cultured splenocytes from EAE mice; however, these treatments showed minimal to no in vivo therapeutic effect in EAE mice. Thus, carriers that codeliver antigen and a secondary “context” signal (e.g., LABL) in vivo may be an important design criteria to consider when designing antigen-SIT for autoimmune therapy.

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

“…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).…”

“…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). In this study, multivalent SAgA technology was used as a foundation to synthesize new SAgAs (SAgA PLP:B7AP , SAgA PLP:CD80-CAP , SAgA PLP:sF2 ) that target the B7 signaling pathway and co-deliver PLP autoantigen for the treatment of EAE.…”

“…SAgAs targeting the B7 pathway were created by co-grafting to hyaluronic acid polymers (HA) both autoantigen (PLP 139-151 ) and B7-binding peptides (B7AP, CD80-CAP, or sF2) as previously reported (15,24,25). For a positive control, an ICAM-1-targeted SAgA (SAgA PLP:LABL ) was created containing autoantigen (PLP [139][140][141][142][143][144][145][146][147][148][149][150][151] ) and the cell adhesion peptide LABL derived from leukocyte function associated antigen-1 (LFA-1), which has previously shown efficacy in EAE (24,25).…”

“…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).…”

“…We grafted to hyaluronic acid both a myelin sheath antigenic peptide (PLP [139][140][141][142][143][144][145][146][147][148][149][150][151] ) and peptides capable of binding B7 signaling pathway surface receptors by following previously reported procedures (15,24,25). The resulting soluble antigen arrays (SAgAs) act as a carrier to co-deliver multiple copies of the autoantigen and a peptide from the B7 pathway.…”