The crosslinking requirement is also important to their in vivo activity, and Fcγ receptors on tumor-associated leukocytes are thought to provide a crosslinking scaffold that promotes antibody-dependent, TRAILR2-mediated apoptosis of cancer cells ( 10). Relative to soluble TRAIL, agonistic antibodies against TRAILR2 are less potent in inducing cell death and require higher-order crosslinking to enhance their in vitro activity ( 7–9). As with other members of the TNF-family, TRAIL is a homotrimeric ligand that is initially produced as a membrane-bound protein, but can be released in soluble form following proteolytic processing. For this reason, agonists of TRAILR2 are being developed as anticancer therapeutics, including TRAIL, the natural ligand for this receptor, as well as agonistic monoclonal antibodies ( 3–6). TNF-related apoptosis inducing ligand receptor 2 (TRAILR2) is a member of the TNF receptor superfamily that, when activated, induces apoptosis in a broad range of cancer cells, but not normal cells ( 1, 2). The TRAILR2 superagonists described here have the potential for superior clinical activity in settings insensitive to the current therapeutic agonists that target this pathway. Enhanced potency was also observed in vivo in a tumor xenograft setting. An optimized multivalent agonist consisting of 8 tandem Tn3 repeats was highly potent in triggering cell death in TRAIL-sensitive cell lines and was 1 to 2 orders of magnitude more potent than TRAIL. Optimization of binding affinity, molecular format, and valency contributed to cumulative enhancements of agonistic activity. Multivalent presentation of this basic unit induced cell death in TRAILR2-expressing cell lines. The monomer Tn3 unit was a fibronectin type III domain engineered for high-affinity TRAILR2 binding. Toward addressing that possibility, we have developed multivalent forms of a new binding scaffold (Tn3) that are superagonists of TRAILR2 and can induce apoptosis in tumor cell lines at subpicomolar concentrations.
The reasons for discrepant preclinical and clinical observations are not understood, but one possibility is that the current TRAILR2 agonists lack sufficient potency to achieve a meaningful response in patients.
#Small protein scaffold better than antibody trial#
Unfortunately, this optimism has been tempered by trial data that, thus far, are not showing clear signs of efficacy in cancer patients. The natural ligand and agonistic antibodies show antitumor activity in preclinical models of cancer, and this had led to significant excitement in the clinical potential of these agents. Activation of TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) can induce apoptosis in a variety of human cancer cell lines and xenografts, while lacking toxicity in normal cells.
0 kommentar(er)
