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Review
. 2015 Mar 30:6:135.
doi: 10.3389/fimmu.2015.00135. eCollection 2015.

Modulation of CD44 Activity by A6-Peptide

Malcolm Finlayson  1
Affiliations
Review

Modulation of CD44 Activity by A6-Peptide

Malcolm Finlayson. Front Immunol. .

Abstract

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.

Keywords: A6; CD44; CLL; HA; metastasis; ocular; recurrence; resistant.

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Figures

Figure 1
Figure 1
Schematic representation of urokinase plasminogen activator (uPA) domains illustrating the location of A6.
Figure 2
Figure 2
Serine 138 of uPA is included in the A6-peptide sequence.
Figure 3
Figure 3
A comparison of the sequence homology between A6 and amino acid residues 120–127 of the CD44 link domain.
See this image and copyright information in PMC

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