Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Characterization of a Potent and Neutralizing Fully Human Anti CD44 Antibody PF 03475952
Runnels1, Herbert A., Weber1, Gregory L., Min1, Jing, Kudlacz2, Elizabeth, Zobel1, James, Donovan2, Carol, Thiede2, Mark
CD44 is a cell adhesion molecule believed to play a critical role in T cell and monocyte infiltration in the inflammatory process. The reduction of CD44 expression or its ability to properly interact with its key ligand hyaluronic acid (HA) inhibits migration and subsequent activation of cells within sites of inflammation such as synovial tissue and is expected to decrease production of pro-inflammatory cytokines such as TNF-a, IL-6, and IL-1b in the synovium. The genetic knock-out of CD44 expression in mice resulted in a decreased incidence and severity of disease in a mouse arthritis model.
We developed PF-03475952 which is a fully human IgG2 anti-CD44 monoclonal antibody (mAb).
Binding of PF-03475952 to CD44 inhibits binding of HA, induces loss of CD44 from the cell surface, and inhibits LPS-induced cytokine release from various leukocytes. PF-03475952 also passed a series of safety pharmacology assays designed to assess the risk of the mAb to bind Fc receptors, activate complement, stimulate cytokine release from human whole blood and stimulate cytokine release from peripheral blood mononuclear cells using platebound stimuli. The latter assay was designed specifically to mitigate the cytokine storm potential as seen with TGN1412 (the immunostimulatory CD28 superagonist mAb) and utilized a TGN1412-like mAb as a positive control. PF-03475952 exhibits high affinity binding to both human and cynomolgus monkey CD44, but does not cross-react with rodent CD44. Thus, supporting the rationale of anti-CD44 therapy, a surrogate, rat anti-mouse CD44 mAb (IM7) was utilized to demonstrate a dose-dependent decrease of disease incidence and severity in a mouse collagen-induced arthritis model. Importantly, efficacy was correlated with >= 50% loss (measured at 24h post final dose) of cell surface CD44 on circulating cells, which provided a pharmcodynamic marker for both monkey studies and human clinical trials. Loss of CD44 expression on CD3+ lymphocytes was monitored following a single dose in cynomolgus monkeys. The recovery of CD44 expression was found to be dose-dependent. PF-03475952 doses of 1, 10 and 100 mg/kg reduced CD44 expression below 50% for 218, 373 and >504 h, respectively.
Targeting of CD44 is a unique mechanism of action in the treatment of inflammatory diseases and is expected to reduce joint damage induced by inflammatory mediators resulting in disease modification in inflammatory diseases such as RA.
To cite this abstract, please use the following information:
Runnels, Herbert A., Weber, Gregory L., Min, Jing, Kudlacz, Elizabeth, Zobel, James, Donovan, Carol, et al; Characterization of a Potent and Neutralizing Fully Human Anti CD44 Antibody PF 03475952 [abstract]. Arthritis Rheum 2009;60 Suppl 10 :405