CEL-SCI Corporation (NYSE CVM) and their scientific collaborators announced today that the Company's CEL-2000 vaccine demonstrated that it is able to block the progression of rheumatoid arthritis (RA) in a mouse model.
The results were published in the scientific peer-reviewed Journal of International Immunopharmacology (online edition) in an article titled "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" with lead author Dr. Daniel Zimmerman. The study was co-authored by scientists from CEL-SCI, Washington Biotech, Northeastern Ohio Universities Colleges of Medicine and Pharmacy (NEOUCOMP) and Boulder BioPath.
CEL-2000, administered after disease (RA) symptoms had started, prevented, in a statistically significant manner, the further development of arthritic conditions, including joint swelling and deformation, bone and cartilage changes and was accompanied by serum cytokine alterations over the CEL-2000 treatment period with comparable or better activity than the well accepted etanercept (Enbrel®) therapy. The mode of action is very consistent with the findings of induction of IL-12 followed by interferon gamma and an inhibition of TNF-alpha and IL-17 production. TNF-alpha and IL-17 are both key cytokines for induction of the pathology seen in rheumatoid arthritis and TNF-alpha is the target of many current RA therapies such as Enbrel, Remicaid, and Humaria. The protection effect mediated by CEL-2000 treatment against RA was also demonstrated histologically with significant reductions in: 1) inflammation, 2) cartilage destruction, 3) bone resorption, and 4) pannus membrane formation in the synovial space compared to untreated controls.
Geert Kersten, Chief Executive Officer of CEL-SCI said, "These experimental results were achieved through a reduction of the inflammatory response that is known to attack the patients' joints. The mode of action of CEL-2000 in RA appears to be similar to our new investigational therapy for H1N1 hospitalized patients, as it attempts to avoid the excess TNF-alpha and other pro-inflammatory cytokines. We feel that this new data is encouraging both for this rheumatoid arthritis vaccine as well as in support of our H1N1 treatment currently under development."
In these studies, mice were injected with collagen to induce the autoimmune (RA) disease. Therapy with Enbrel or CEL-2000 was initiated after disease (RA) symptoms have been established and treatment continued for 28 days after the initiation of a significant, uniform, and measurable level of arthritic disease in groups of mice. CEL-2000 was administered only twice, however Enbrel had to be administered every other day for the 28 day study period (as indicated for Enbrel use). The extent of disease, as measured by deformation of foot joints (Arthritic Index (AI) score), of untreated animals and any improvements resulting from CEL-2000 and Enbrel treated animal were then compared. In another study, CEL-2000 was administered 5 times over a 70 day period and the animals were monitored for a total study period of 90 days. In each case, CEL-2000 treatment proved effective in blocking progression of disease (RA) with statistically significant reduction in AI score compared to controls. The CEL-2000 treatment was deemed safe and well tolerated without any reported adverse effects related to treatment.
The CEL-2000 treatment appeared to change the course of the immune response in the diseased (RA) animals, limiting the development of the destructive action of Th17 and tumor necrosis factor alpha (TNF-alpha). Analysis of serum levels of 21 cytokines/chemokines after 10 days of CEL-2000 treatment indicated reductions in the characteristic cytokine markers of rheumatoid arthritis, TNF-alpha and IL-17, as well as IL-6, and MCP-1. A number of cytokine changes were also seen with Enbrel treatment, but to a lesser degree than that seen with CEL-2000 treatment.
CEL-2000 may also offer a number of potential advantages over existing rheumatoid arthritis treatments, such as Enbrel. Data collected in the animal studies conducted with CEL-2000 demonstrated that CEL-2000 is an effective treatment against rheumatoid arthritis even with administration of many fewer treatments than for example Enbrel. CEL-2000 is also potentially a more disease-type specific therapy, should be significantly less expensive to manufacture, and finally, CEL-2000 could also be useful for patients who are not able to take or who may be unresponsive to other existing anti-arthritis therapies.
This research featured the multidisciplinary team of collaborators bringing to the project expertise of several different animal models of arthritis (Washington Biotech), long time association with modern molecular therapies and evaluation for RA (Bolder Biopath), experience with other LEAPS immunogens, and experience and expertise studying cytokines and with mechanistic studies of the LEAPS technology (NEOUCOMP), and peptide technologies (21st Century Biochemicals) to complement the expertise of the CEL-SCI researchers.
Rheumatoid arthritis treatments comprise an approximately $13 billion market. Enbrel, a leading rheumatoid arthritis treatment sold by Amgen and Wyeth, reported US sales in 2007 of about $3.2 billion. Enbrel is a soluble recombinant protein of a human TNF-alpha receptor linked to human IgG Fc. In some cases, human or humanized monoclonal antibodies specific against TNF-alpha have also been used for therapy in rheumatoid arthritis. These therapies remove or inactivate TNF-alpha, a natural human cytokine required in many immune functions for normal defenses.
CEL-SCI's rheumatoid arthritis vaccine CEL-2000 was discovered as part of work with the Company's ongoing research and development activities with its L.E.A.P.S.™ (Ligand Epitope Antigen Presentation System) technology. L.E.A.P.S. is a novel T-cell modulation platform technology that enables CEL-SCI to design and synthesize proprietary immunogens. Any disease for which an antigenic sequence has been identified, such as infectious, parasitic, malignant or autoimmune diseases and allergies, are potential therapeutic or preventive sites for the application of L.E.A.P.S. technology.
The concept behind the L.E.A.P.S. technology is to directly mimic cell-cell interactions and activate immune cells with synthetic peptides. The L.E.A.P.S. constructs containing the antigenic disease epitope linked to a immune-cell binding ligand (ICBL) can be manufactured by peptide synthesis or by covalently linking the two peptides. Depending upon the type of L.E.A.P.S. construct and ICBL used, CEL-SCI is able to direct the outcome of the immune response towards the development of T-cell function with primarily effector T-cell functions (T Lymphocyte; helper/effector T lymphocyte, type 1 or 2 [Th1 or Th2], cytotoxic [Tc] or suppressor [Ts]). Therefore, it would appear that the L.E.A.P.S. construct represents a chimeric peptide with bi-functional behavior.