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Ref Type Journal Article
PMID (21233403)
Authors Huang H, Lai JY, Do J, Liu D, Li L, Del Rosario J, Doppalapudi VR, Pirie-Shepherd S, Levin N, Bradshaw C, Woodnutt G, Lappe R, Bhat A
Title Specifically targeting angiopoietin-2 inhibits angiogenesis, Tie2-expressing monocyte infiltration, and tumor growth.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 17
Issue 5
Date 2011 Mar 01
URL
Abstract Text 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.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.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).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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CVX-060 CVX-060 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CVX-060 PF-04856884 CVX-060 (PF-04856884) is a peptide-antibody fusion protein that targets Angiopoeitin-2 (Ang2), resulting in decreased angiogenesis, and potentially leading to decreased tumor growth (PMID: 21233403, PMID: 27651308).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colon cancer not applicable CVX-060 + Sorafenib Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of CVX-060 and Nexavar (sorafenib) resulted in increased tumor growth inhibition compared to either agent alone in a colon cancer cell line xenograft model (PMID: 21233403). 21233403
Unknown unknown colon cancer not applicable CVX-060 + Sunitinib Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of CVX-060 and Sutent (suntinib) resulted in increased tumor growth inhibition compared to either agent alone in a colon cancer cell line xenograft model (PMID: 21233403). 21233403
Unknown unknown colon cancer not applicable Bevacizumab + CVX-060 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of CVX-060 and Avastin (bevacizumab) resulted in increased tumor growth inhibition compared to either agent alone in a colon cancer cell line xenograft model (PMID: 21233403). 21233403
Unknown unknown colon cancer not applicable CVX-060 Preclinical - Cell line xenograft Actionable In a preclinical study, CVX-060 inhibited tumor growth in a colon cancer cell line xenograft model (PMID: 21233403). 21233403