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

Authors' Affiliations: ¹ Vascular Biology Program, Department of Surgery, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts and ² EMD Lexigen Research Center, Billerica, Massachusetts

Requests for reprints: Kashi Javaherian, Karp Family Research Laboratories, Room 11.213, 1 Blackfan Circle, Boston, MA 02115. Phone: 617-919-2392; Fax: 617-730-0231; E-mail: kashi.javaherian{at}childrens.harvard.edu.

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.