Current therapeutic approaches to rheumatoid arthritis ("RA") (corticosteroids, methotrexate, neutralization of TNF-?) rely upon broad-spectrum immunosuppression, an approach that is not uniformly effective and is frequently associated with significant side-effects. To address this market gap, Radikal Therapeutics (RTX) is developing a novel soluble receptor decoy receptor fusion protein (hR-421) that induces immune tolerance in antigen (Ag)-specific activated T-cells. Constructed from Ig-Fc and the second ecto domain of the CCR5 receptor, hR-421 binds and neutralizes al 3 CCR5-binding chemokine ligands (MIP-?, MIP-?, RANTES) and prevents their binding and activation of the CCR1, CCR3, and CCR5 membrane receptors. In contrast to CCR5 inhibitors, mR-421 (the murine homologue of hR-421) blocks CCR5-independent pro-inflammatory pathways and is effective in CCR5 knock-out mice. Therapy with mR- 421 profoundly suppresses experimental allergic encephalomyelitis (EAE), a classic autoimmune model system, even when treatment is initiated after disease onset. Moreover, Ag-specific effector Th1 cells isolated from EAE donors treated in vivo with mR-421 produce substantially less pro-inflammatory cytokines and suppress EAE in adoptive transfer experiments. This latter effect is driven by the ability of mR-421 to prevent the co-stimulatory signal on Th1 CD4+ T cells. Based on these findings, we hypothesize that R-421 will prevent co-stimulation and thus the downstream proliferation and activation of Th1 CD4+ cells in RA. We now propose to extend the protective effects of the R-421 technology beyond the published findings in neuroinflammation and establish its potential benefit in a clinically-relevant model of RA. Male DBA mice inoculated with collagen in CFA and rechallenged on Day 21 to induce autoimmune arthritis, will be treated with mR-421 (2, 4, 8 mg/kg), an irrelevant IgG1 control, or etanercept (6.25 mg/kg) beginning at the time of significant disease (Day 21), as characterized by an arthritic score of 2 (scale of 0-16). Additionally, we will include a sham control group not exposed to collagen/CFA or treatment. Animals will be monitored for clinical evidence of arthritis over a period of 6 weeks, a timepoint characterized in controls by erythema and edema of the entire paw including digits (score=12). Plasma m-R421 concentrations will be related to clinical outcome, so as to construct a pharmacodynamic profile that will guide future clinical dosing. We expect mR-421 to reduce joint injury, in a dose and plasma concentration dependent fashion, as defined by a reduction in the mean arthritic score that is equivalent or superior to the treatment effect elicited by the gold-standard clinically-approved agent etanercept. These findings are expected to parallel the effects of mR-421 on synovial lipid peroxidation, neutrophil infiltration, pro-inflammatory gene expression peroxynitrite production, poly(ADP-ribose)polymerase formation, and gross and histologic injury scores, and on draining lymph node populations of Th1 and Treg lymphocytes.

Public Health Relevance

Rheumatoid arthritis is a devastating autoimmune disease characterized by lifelong disability and inexorable progression. Currently approved agents are partially effective and nearly one-third of patients do not obtain adequate relief. We are developing a novel drug that specifically blocks the specific immune disturbance that underlies this condition. We will test this agent in a clinically-relevant small animal model and determine the most effective dose, in anticipation of definitive large animal studies to confirm its efficacy and safety.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43AR062372-01A1
Application #
8370466
Study Section
Special Emphasis Panel (ZRG1-IMM-G (10))
Program Officer
Mao, Su-Yau
Project Start
2012-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$298,327
Indirect Cost
Name
Radikal Therapeutics, Inc.
Department
Type
DUNS #
833130045
City
West Tisbury
State
MA
Country
United States
Zip Code
02575