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Linking Antibody Fc Domain to Endostatin Significantly Improves Endostatin Half-life and Efficacy

2008; American Association for Cancer Research; Volume: 14; Issue: 5 Linguagem: Inglês

10.1158/1078-0432.ccr-07-1530

1557-3265

Tong-Young Lee, Robert M. Tjin Tham Sjin, Shahla Movahedi, Bissan Ahmed, Elke Pravda, Kin-Ming Lo, Stephen D. Gillies, Judah Folkman, Kashi Javaherian,

Cell Adhesion Molecules Research

Abstract Purpose: The half-life of the antiangiogenic molecule endostatin that has been used in clinical trial is short (∼2 h). In addition, ∼50% of the clinical grade endostatin molecules lack four amino acids at their NH2 termini. Lack of these amino acids gives rise to a molecule that is devoid of zinc, resulting in no antitumor activity. Our goal was to develop a new version of endostatin that does not show such deficiency. Experimental Design: A recombinant human endostatin conjugated to the Fc domain of IgG was constructed and expressed in mammalian cell culture. The presence of Fc has been shown by previous investigators to play a major role in increasing the half-life of the molecule. Fc-endostatin was tested in tumor-bearing mice, and its half-life was compared with the clinical grade endostatin. Results: The antitumor dose of Fc-endostatin was found to be ∼100 times less than the clinical grade endostatin. The half-life of Fc-endostatin in the circulation was found to be weeks rather than hours, as observed for endostatin alone. In addition, a U-shaped curve was observed for antitumor activity of endostatin as a function of endostatin concentration delivered to the animals. Conclusion: Fc-endostatin is a superior molecule to the original clinical endostatin. Due to its long half-life, the amount of protein required is substantially reduced compared with the clinically tested endostatin. Furthermore, in view of the U-shaped curve of efficacy observed for endostatin, we estimate that the requirement for Fc-endostatin is ∼700-fold less than endostatin alone. The half-life of endostatin is similar to that of vascular endothelial growth factor–Trap and Avastin, two other antiangiogenic reagents. We conclude that a new clinical trial of endostatin, incorporating Fc, may benefit cancer patients.