Specifically targeting angiopoietin-2 inhibits angiogenesis, Tie2-expressing monocyte infiltration, and tumor growth.

Abstract

PURPOSE:

Angiopoietin-1 (Ang1) plays a key role in maintaining stable vasculature, whereas in a tumor Ang2 antagonizes Ang1's function and promotes the initiation of the angiogenic switch. Specifically targeting Ang2 is a promising anticancer strategy. Here we describe the development and characterization of a new class of biotherapeutics referred to as CovX-Bodies, which are created by chemical fusion of a peptide and a carrier antibody scaffold.

EXPERIMENTAL DESIGN:

Various linker tethering sites on peptides were examined for their effect on CovX-Body in vitro potency and pharmacokinetics. Ang2 CovX-Bodies with low nmol/L IC(50)s and significantly improved pharmacokinetics were tested in tumor xenograft studies alone or in combination with standard of care agents. Tumor samples were analyzed for target engagement, via Ang2 protein level, CD31-positive tumor vasculature, and Tie2 expressing monocyte penetration.

RESULTS:

Bivalent Ang2 CovX-Bodies selectively block the Ang2-Tie2 interaction (IC(50) < 1 nmol/L) with dramatically improved pharmacokinetics (T(½) > 100 hours). Using a staged Colo-205 xenograft model, significant tumor growth inhibition (TGI) was observed (40%-63%, P < 0.01). Ang2 protein levels were reduced by approximately 50% inside tumors (P < 0.01), whereas tumor microvessel density (P < 0.01) and intratumor proangiogenic Tie2(+)CD11b(+) cells (P < 0.05) were significantly reduced. When combined with sunitinib, sorafenib, bevacizumab, irinotecan, or docetaxel, Ang2 CovX-Bodies produced even greater efficacy (∼80% TGI, P < 0.01).

CONCLUSION:

CovX-Bodies provide an elegant solution to overcome the pharmacokinetic-pharmacodynamic problems of peptides. Long-acting Ang2 specific CovX-Bodies will be useful as single agents and in combination with standard-of-care agents.

• Authors: Hanhua Huang, Jing-Yu Lai, Janet Do, Dingguo Liu, Lingna Li, Joselyn Del Rosario, Venkata R Doppalapudi, Steven Pirie-Shepherd, Nancy Levin, Curt Bradshaw, Gary Woodnutt, Rodney Lappe, Abhijit Bhat
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 5 Pg. 1001-11 (Mar 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21233403 (Publication Type: Journal Article)
• Copyright: ©2011 AACR.

Chemical References

• Angiogenesis Inhibitors
• Angiopoietin-2
• CD11b Antigen
• Immunoconjugates
• Peptides
• Platelet Endothelial Cell Adhesion Molecule-1
• Receptor Protein-Tyrosine Kinases
• Receptor, TIE-2
• Tek protein, mouse

Topics

• Angiogenesis Inhibitors (pharmacokinetics, pharmacology, therapeutic use)
• Angiopoietin-2 (antagonists & inhibitors, metabolism)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacokinetics, pharmacology, therapeutic use)
• CD11b Antigen (analysis)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression
• Humans
• Immunoconjugates (pharmacokinetics, pharmacology, therapeutic use)
• Macrophages (drug effects)
• Male
• Mice
• Monocytes
• Neoplasms, Experimental (drug therapy, pathology)
• Neovascularization, Pathologic (metabolism)
• Peptides (therapeutic use)
• Platelet Endothelial Cell Adhesion Molecule-1 (analysis)
• Rats
• Rats, Sprague-Dawley
• Receptor Protein-Tyrosine Kinases (genetics, metabolism)
• Receptor, TIE-2
• Xenograft Model Antitumor Assays