Routes of Administration and Dose Optimization of Soluble Antigen Arrays in Mice with Experimental Autoimmune Encephalomyelitis

Abstract

Soluble Antigen Arrays (SAgAs) were developed for treating mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. SAgAs are composed of hyaluronan with grafted EAE antigen and LABL peptide (a ligand of ICAM-1). SAgA dose was tested by varying injection volume, SAgA concentration, and administration schedule. Routes of administration were explored to determine the efficacy of SAgAs when injected intramuscularly, subcutaneously, intraperitoneally, intravenously, or instilled into lungs. Injections proximal to the central nervous system (CNS) were compared to distal injection sites. Intravenous dosing was included to determine if SAgA efficiency results from systemic exposure. Pulmonary instillation was included since reports suggest T cells are licensed in the lungs before moving onto the CNS1,2. Decreasing the volume of injection or SAgA dose reduced treatment efficacy. Treating mice with a single injection on day 4, 7, or 10 also reduced efficacy compared to injecting on all three days. Surprisingly, changing the injection site did not lead to a significant difference in efficacy. Intravenous administration showed efficacy similar to other routes, suggesting SAgAs act systemically. When SAgAs were delivered via pulmonary instillation, however, EAE mice failed to develop any symptoms, suggesting a unique lung mechanism to ameliorate EAE in mice.

Pulmonary Administration of Soluble Antigen Arrays Is Superior to Antigen in Treatment of Experimental Autoimmune Encephalomyelitis

“…Multiple sclerosis (MS) is an autoimmune disease in which immune cells attack and degrade the myelin sheath surrounding neurons, thus interrupting the transmission of electrical signals 3,4,10,11 . Many of the current therapies approved for MS focus on treating inflammation or neurological symptoms such as loss of balance, degrees of paralysis, and a loss of coordination.…”

“…Many of the current therapies approved for MS focus on treating inflammation or neurological symptoms such as loss of balance, degrees of paralysis, and a loss of coordination. Recently, researchers have aimed to correct the underlying immune response using ASIT 4,12,13 . There are different forms of this disease: secondary progressive, primary progressive, progressive relapsing, and relapsing-remitting, the latter of which affects a majority of patients, approximately 80% 4,10,11 .…”

“…Recently, researchers have aimed to correct the underlying immune response using ASIT 4,12,13 . There are different forms of this disease: secondary progressive, primary progressive, progressive relapsing, and relapsing-remitting, the latter of which affects a majority of patients, approximately 80% 4,10,11 . If the autoimmunity is not corrected, patients can experience progressive cycles of remission and relapse, where periodic symptoms are followed by remission, but the patient does not fully recover to the previous baseline, as is experienced in relapsing-remitting MS.…”

“…If the autoimmunity is not corrected, patients can experience progressive cycles of remission and relapse, where periodic symptoms are followed by remission, but the patient does not fully recover to the previous baseline, as is experienced in relapsing-remitting MS. Experimental autoimmune encephalomyelitis (EAE), a murine model of relapsing and remitting MS, is induced by a single proteolipid protein epitope (PLP 139–151 ) and serves as a useful model for studying ASIT approaches to autoimmune diseases 3,4,14 .…”

Conjugates of Cell Adhesion Peptides for Therapeutics and Diagnostics Against Cancer and Autoimmune Diseases

“…Similar to BPI molecules, the development of soluble antigen arrays (SAgAs; Figure 5) was inspired by a combination of the BPI concept and Dintzis’ rules, which have been shown to induce immune stimulation or tolerance [100–106]. Dintzis’ rules indicated that induced immune responses are influenced by particle size, solubility, flexibility, antigen valency, spacing, and binding avidity.…”