Current status of immunological therapies for rheumatoid arthritis with a focus on antigen-specific therapeutic vaccines.

Rheumatoid arthritis (RA) is recognized as an autoimmune joint disease driven by T cell responses to self (or modified self or microbial mimic) antigens that trigger and aggravate the inflammatory condition. Newer treatments of RA employ monoclonal antibodies or recombinant receptors against cytokines or immune cell receptors as well as small-molecule Janus kinase (JAK) inhibitors to systemically ablate the cytokine or cellular responses that fuel inflammation. Unlike these treatments, a therapeutic vaccine, such as CEL-4000, helps balance adaptive immune homeostasis by promoting antigen-specific regulatory rather than inflammatory responses, and hence modulates the immunopathological course of RA.

Restoring the Balance between Pro-Inflammatory and Anti-Inflammatory Cytokines in the Treatment of Rheumatoid Arthritis: New Insights from Animal Models.

Rheumatoid arthritis (RA) and other autoimmune inflammatory diseases are examples of imbalances within the immune system (disrupted homeostasis) that arise from the effects of an accumulation of environmental and habitual insults over a lifetime, combined with genetic predispositions. This review compares current immunotherapies-(1) disease-modifying anti-rheumatic drugs (DMARDs) and (2) Janus kinase (JAK) inhibitors (jakinibs)-to a newer approach-(3) therapeutic vaccines (using the LEAPS vaccine approach). The Ligand Epitope Antigen Presentation System (LEAPS) therapies are capable of inhibiting ongoing disease progression in animal models.

Vaccination by Two DerG LEAPS Conjugates Incorporating Distinct Proteoglycan (PG, Aggrecan) Epitopes Provides Therapy by Different Immune Mechanisms in a Mouse Model of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) can be initiated and driven by immune responses to multiple antigenic epitopes including those in cartilage proteoglycan (PG, aggrecan) and type II collagen. RA is driven by T helper 1 (Th1) or Th17 pro-inflammatory T cell responses. LEAPS (Ligand Epitope Antigen Presentation System) DerG peptide conjugate vaccines were prepared using epitopes from PG that elicit immune responses in RA patients: epitope PG70 (DerG-PG70, also designated CEL-4000) and the citrullinated form of another epitope (PG275Cit).

Why Don't We Have a Vaccine Against Autoimmune Diseases? - A Review.

This review examines some of the reasons why we don't have a vaccine against autoimmune diseases and highlights the progress that has been made. Many autoimmune diseases, such as rheumatoid arthritis (RA), multiple sclerosis (MS) and type 1 diabetes (T1D), are driven by autoimmune T cell responses. Unlike vaccines for most infectious diseases, which elicit antibody responses, are intended for immuno-naive individuals and considered preventative, a vaccine for an autoimmune disease must be therapeutic and resolve or control the on-going autoimmune response and condition in the diseased host.

Lessons from next generation influenza vaccines for inflammatory disease therapies.

Lessons can be learned for treating inflammatory diseases such as rheumatoid arthritis (RA) from next generation approaches for development of universal influenza vaccines. Immunomodulation of inflammatory diseases, rather than ablation of cytokine or cellular responses, can address the root cause of the disease and provide potential cure. Like influenza, there are different antigenic 'strains' and inflammatory T cell responses, Th1 or Th17, that drive each person's disease.

An epitope-specific DerG-PG70 LEAPS vaccine modulates T cell responses and suppresses arthritis progression in two related murine models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune joint disease maintained by aberrant immune responses involving CD4+ T helper (Th)1 and Th17 cells. In this study, we tested the therapeutic efficacy of Ligand Epitope Antigen Presentation System (LEAPS™) vaccines in two Th1 cell-driven mouse models of RA, cartilage proteoglycan (PG)-induced arthritis (PGIA) and PG G1-domain-induced arthritis (GIA). The immunodominant PG peptide PG70 was attached to a DerG or J immune cell binding peptide, and the DerG-PG70 and J-PG70 LEAPS vaccines were administered to the mice after the onset of PGIA or GIA symptoms.

LEAPS Vaccine Incorporating HER-2/neu Epitope Elicits Protection That Prevents and Limits Tumor Growth and Spread of Breast Cancer in a Mouse Model.

The prototype J-LEAPS T cell vaccine for HER-2/neu breast cancer (J-HER) consists of the murine HER-2/neu H-2 CD8 T cell epitope covalently attached through a triglycine linker to the J-immune cell binding ligand (ICBL) (human 2 microglobulin peptide). The J-ICBL was chosen for its potential to promote Th1/Tc1 responses. In this proof-of-concept study, the ability of J-HER to prevent or treat cancer was tested in the TUBO cell-challenged BALB/c mouse model for HER-2/neu-expressing tumors.

Rheumatoid arthritis vaccine therapies: perspectives and lessons from therapeutic ligand epitope antigen presentation system vaccines for models of rheumatoid arthritis.

The current status of therapeutic vaccines for autoimmune diseases is reviewed with rheumatoid arthritis as the focus. Therapeutic vaccines for autoimmune diseases must regulate or subdue responses to common self-antigens. Ideally, such a vaccine would initiate an antigen-specific modulation of the T-cell immune response that drives the inflammatory disease.

LEAPS therapeutic vaccines as antigen specific suppressors of inflammation in infectious and autoimmune diseases.

The L.E.A.

J-LEAPS peptide and LEAPS dendritic cell vaccines.

The J-LEAPS vaccines contain a peptide from β-2-microglobulin covalently attached to disease-related peptides of 8-30 amino acids which contain a T cell epitope. The J-LEAPS vaccines can initiate a protective Th1 immune response or modulate an ongoing Th17 autoimmune response to the peptide. J-LEAPS vaccines activate and direct the nature of the subsequent immune response by promoting the maturation of precursor cells into a unique type of dendritic cell that produces interleukin 12, but not IL-1 or tumour necrosis factor, and presents the antigenic peptide to T cells.

Maturation of dendritic cell precursors into IL12-producing DCs by J-LEAPS immunogens.

LEAPS (ligand epitope antigen presentation system) vaccines consist of a peptide containing a major histocompatibility antigen binding peptide conjugated to an immune cell binding ligand (ICBL) such as the 'J' peptide from beta-2-microglobulin. Treatment of monocytes, monocytes plus GMCSF, or monocytes plus GMCSF and IL4 with JgD (containing a peptide from gD of herpes simplex virus type 1) or JH (with a peptide from HIV p17 gag protein) was sufficient to promote their maturation into Interleukin 12 producing dendritic cells. JgD-dendritic cells supported allotypic activation of T cells to produce Th1-related cytokines.

CEL-2000: A therapeutic vaccine for rheumatoid arthritis arrests disease development and alters serum cytokine/chemokine patterns in the bovine collagen type II induced arthritis in the DBA mouse model.

The mouse model of collagen induced arthritis (CIA) effectively mimics human disease and thus is useful for testing and development of rheumatoid arthritis (RA) therapies. We developed a Ligand Epitope Antigen Presentation System (LEAPS) peptide hetero-conjugate vaccine containing an epitope of human collagen type II (CEL-2000) that acted as a therapeutic vaccine in the collagen induced arthritis (CIA) mouse model. LEAPS technology converts a small peptide containing a disease specific epitope into an immunogen by attaching it to an immune or T cell binding peptide (I/TCBL).

L.E.A.P.S. heteroconjugate is able to prevent and treat experimental autoimmune myocarditis by altering trafficking of autoaggressive cells to the heart.

We evaluated the efficacy of the Ligand Epitope Antigen Presentation System (L.E.A.

Ligand epitope antigen presentation system vaccines against herpes simplex virus.

The Ligand Epitope Antigen Presentation System (L.E.A.

The L.E.A.P.S. approach to vaccine development.

The Ligand Epitope Antigen Presentation System (L.E.A.

A small peptide (CEL-1000) derived from the beta-chain of the human major histocompatibility complex class II molecule induces complete protection against malaria in an antigen-independent manner.

CEL-1000 (DGQEEKAGVVSTGLIGGG) is a novel potential preventative and therapeutic agent. We report that CEL-1000 confers a high degree of protection against Plasmodium sporozoite challenge in a murine model of malaria, as shown by the total absence of blood stage infection following challenge with 100 sporozoites (100% protection) and by a substantial reduction (400-fold) of liver stage parasite RNA following challenge with 50,000 sporozoites. CEL-1000 protection was demonstrated in A/J (H-2(a)) and C3H/HeJ (H-2(k)) mice but not in BALB/c (H-2(d)) or CAF1 (A/J x BALB/c F(1) hybrid) mice.

CEL-1000--a peptide with adjuvant activity for Th1 immune responses.

CEL-1000 (derG, DGQEEKAGVVSTGLIGGG) is a small immunomodulatory peptide which delivers demonstrated protective activity in two infectious disease challenge models (HSV and malaria) and an allogenic tumor vaccine model. CEL-1000 and other activators (defensin-beta, CpG ODN, and imiquimod) of the innate immune system promote IFN-gamma-associated protective responses. CEL-1000 is an improved form of peptide G (a peptide from human MHC II beta chain second domain, aa 135-149) known to enhance immune responses of other immunogenic peptides.

A modification of the epidermal scarification model of herpes simplex virus infection to achieve a reproducible and uniform progression of disease.

A slight modification in the method used to remove the top keratinized layer of skin in the epidermal scarification model of HSV infection results in an easier, less painful, more uniform and reproducible means of infection. The back of mice was depilated and the top skin layer was removed either by scratching with the side of a 26 gauge needle, or by abrading with sand paper or a hand held motorized pedicure/manicure instrument. The virus was then applied on the scarified or abraded skin and the mice were observed for lesion development from day 3 to 10 post-infection.