Modified chimeric polypeptides with improved pharmacokinetic properties
The present invention provides VEGF antagonists with improved pharmacokinetic properties. According to certain embodiments, a fusion polypeptide capable of antagonizing VEGF activity is provided comprising a modified extracellular ligand binding domain of a VEGF receptor fused to a multimerizing component.
1. A chimeric polypeptide capable of antagonizing VEGF activity consisting of a modified extracellular ligand binding domain of a VEGF receptor fused to a multimerizing component,
wherein the modified extracellular ligand binding domain consists of an immunoglobulin-like (Ig) domain of human Flt1 and an Ig domain of human Flk1, wherein the Ig domain of human Flt1 is Ig domain 2, and wherein the Ig domain of human Flk1 is Ig domain 3,
wherein the chimeric polypeptide exhibits improved pharmacokinetic properties as compared to a chimeric polypeptide consisting of only Ig domains of Flt1.
2. The chimeric polypeptide of claim 1 , wherein the Ig domain 2 of Flt1 is located upstream of the Ig domain 3 of Flk1.
3. The chimeric polypeptide of claim 2 , wherein the chimeric polypeptide comprises SEQ ID NO:12.
4. The chimeric polypeptide of claim 2 , wherein the chimeric polypeptide comprises SEQ ID NO:16.
5. The chimeric polypeptide of claim 1 , wherein the Ig domain 2 of Flt1 is located downstream of the Ig domain 3 of Flk1.
6. The chimeric polypeptide of claim 1 , wherein the multimerizing component comprises an immunoglobulin domain.
7. The chimeric polypeptide of claim 6 , wherein the immunoglobulin domain is selected from the group consisting of the Fc domain of IgG, and the heavy chain of IgG.