Hyaluronan (HA) is a non-
sulfated glycosaminoglycan distributed throughout the extracellular matrix that plays a major role in cell adhesion, migration, and proliferation. CD44, a multifunctional
cell surface glycoprotein, is a receptor for HA. In addition, CD44 is known to interact with other receptors and
ligands, and to mediate a number of cellular functions as well as
disease progression. Studies have shown that binding of HA to CD44 in
cancer cells activates survival pathways resulting in
cancer cell survival. This effect can be blocked by anti-CD44
monoclonal antibodies. A6 is a capped, eight l-
amino acid peptide (Ac-KPSSPPEE-NH2) derived from the biologically active
connecting peptide domain of the
serine protease, human
urokinase plasminogen activator (uPA). A6 neither binds to the uPA
receptor (uPAR) nor interferes with uPA/uPAR binding. A6 binds to CD44 resulting in the inhibition of migration, invasion, and
metastasis of
tumor cells, and the modulation of CD44-mediated cell signaling. A6 has been shown to have no dose-limiting toxicity in animal studies. A6 has demonstrated efficacy and an excellent safety profile in Phase 1a, 1b, and 2 clinical trials. In animal models, A6 has also exhibited promising results for the treatment of
diabetic retinopathy and wet
age-related macular degeneration through the reduction of
retinal vascular permeability and inhibition of
choroidal neovascularization, respectively. Recently, A6 has been shown to be directly cytotoxic for B-lymphocytes obtained from patients with
chronic lymphocytic leukemia expressing the
kinase, ZAP-70. This review will discuss the activity of A6, A6 modulation of HA and CD44, and a novel strategy for therapeutic intervention in disease.