Linking antibody Fc domain to endostatin significantly improves endostatin half-life and efficacy.
OBJECTIVE
The half-life of the antiangiogenic molecule endostatin that has been used in clinical trial is short ( approximately 2 h). In addition, approximately 50% of the clinical grade endostatin molecules lack four amino acids at their NH(2) 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.


METHODS
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 approximately 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.


CONCLUSIONS
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 approximately 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.
Lee
Tong-Young
TY
Vascular Biology Program, Department of Surgery, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.
Tjin Tham Sjin
Robert M
RM
Movahedi
Shahla
S
Ahmed
Bissan
B
Pravda
Elke A
EA
Lo
Kin-Ming
KM
Gillies
Stephen D
SD
Folkman
Judah
J
Javaherian
Kashi
K
D000818:Animals; D017209:Apoptosis; D043169:Endostatins / Q000276:immunology* / Q000493:pharmacokinetics*; D004797:Enzyme-Linked Immunosorbent Assay; D006207:Half-Life; D006801:Humans; D007124:Immunoenzyme Techniques; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D020287:In Situ Nick-End Labeling; D008297:Male; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D043169:Endostatins; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins