Currently, FDA-licensed pharmaceuticals used to treat rheumatoid arthritis (RA) focus largely on alleviation of symptoms, either through pain management, general immunosuppression, or by antagonizing cytokines such as TNF-?. Despite recent advances in biologic therapies, these treatments do not address the underlying autoimmune condition. To develop a peptide vaccine-based therapy for RA, we used the human proteoglycan (PG)-induced arthritis (PGIA) and the closely related recombinant human PG G1-domain induced arthritis (GIA) models of RA, two mouse models resembling the human disease in their pathologic and genetic features, female preponderance, production of anti-citrullinated protein antibodies and rheumatoid factor. The ligand epitope antigen presentation system (LEAPS?) is a peptide vaccine platform designed to modulate the immune response in an antigen-specific manner. LEAPS peptides are composed of an immune cell binding ligand (ICBL) conjugated to a disease-related peptide (autoepitope). One of the LEAPS conjugates is CEL-4000, which utilizes the DerG ICBL from the human MHC class II ? chain that has T helper cell 2 (Th2) polarizing activity, potentially dampening Th1- or Th17-driven autoimmune responses characteristic for RA. In the phase I SBIR study, we showed that CEL-4000, a DerG LEAPS conjugate of the immunodominant epitope (PG70) of the G1 domain of the PG molecule, effectively treats arthritis in the PGIA and GIA models of RA. We hypothesized and then demonstrated that the CEL-4000 LEAPS vaccine modulates the underlying immune responses that drive disease progression in PGIA and GIA. Efficacy was demonstrated by suppressive effects of CEL-4000 on arthritis severity, histopathology of peripheral joints, and cytokine responses. The four Aims of the proposed phase II study are:
Aim 1. Determine the in vitro T-cell responses to CEL-4000, the antigen presenting function of CEL-4000-treated dendritic cells (DCs), and whether the conjugate alone and/or conjugate-treated cells alter the differentiation of Th0 cells to distinct Th subsets.
Aim 2. Demonstrate therapeutic efficacy of LEAPS-activated DCs or T cells (or a mixture of both) from mice with GIA after ex vivo treatment of these cells with CEL-4000 and adoptive transfer to immunodeficient mice.
Aim 3. Extend the CEL-4000 binding and activation studies to rat, non-human primate (NHP), and human peripheral blood cells.
Aim 4. Meet with FDA officials, review the CEL-4000 IND-enabling program for in vivo immunogenicity, toxicity and safety, and conduct the relevant and agreed-upon in vivo vaccine treatment studies in NHP. Perform IND-enabling studies using human cells and CEL-4000 in a cytokine release assay as an independent assessment of a potential drug- induced ?cytokine storm?. Completion of these Aims will further elucidate the molecular basis for CEL-4000 efficacy and lay the ground work for an IND submission. The proposed studies will further our understanding of the therapeutic immune response elicited by LEAPS peptide- and cell-based vaccines, and initiate the steps towards human trials.

Public Health Relevance

Rheumatoid arthritis (RA) is an autoimmune disease leading to the inflammatory destruction of the joints; we are evaluating a potential new clinical candidate that provides a novel peptide-based approach to therapeutic intervention in RA. Unlike currently available therapies, the CEL-4000 vaccine, described in this application, is able to suppress RA-promoting immune responses as demonstrated in two animal models of RA. CEL-4000 utilizes the Ligand Epitope Antigen Presentation System (LEAPS) peptide vaccine platform technology that combines an immune cell binding and a disease-related (autoantigenic) peptide. The CEL- 4000 LEAPS likely modulates immune responses in an antigen-specific manner by targeting immune cells that are key players in RA. The proposed phase II studies will further elucidate the mode of action of CEL- 4000 on the target cells, determine whether it is more efficacious when administered in a conventional peptide vaccine format or as a cell therapy following ex vivo treatment of autologous (self) immune cells, and conduct preparatory steps to advance the CEL-4000 vaccine to the clinic.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mao, Su-Yau
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cel-Sci Corporation
United States
Zip Code