First-in-human dose-escalation safety and PK trial of a novel intravenous humanized monoclonal CovX body inhibiting angiopoietin 2.

Rosen, Lee S.; Mendelson, David S.; Cohen, Richard B.; Gordon, Michael S.; Goldman, J. W.; Bear, I. K.; Byrnes, B.; Perea, Rachelle; Schoenfeld, Steven; Gollerkeri, Ashwin

doi:10.1200/jco.2010.28.15_suppl.2524

Cited by 17 publications

(14 citation statements)

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“…Sequestering both Ang1 and Ang2 can inhibit tumor growth, and there were no significant side effects associated with pharmacologic reduction of Ang1 and Ang2 in mice (18). In a phase I studies of AMG-386, a peptibody trapping both Ang1 and Ang2, and CVX-060, a CovX-Body selectively trapping Ang2, significant tumor blood flow reduction was observed with dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) and early clinical benefit were observed as well (19,38). The common side effects of these agents are mild and include fatigue, proteinuria, and peripheral edema for AMG-386 (19) and fatigue and proteinuria for CVX-060 (38).…”

Section: Discussionmentioning

confidence: 99%

“…In a phase I studies of AMG-386, a peptibody trapping both Ang1 and Ang2, and CVX-060, a CovX-Body selectively trapping Ang2, significant tumor blood flow reduction was observed with dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) and early clinical benefit were observed as well (19,38). The common side effects of these agents are mild and include fatigue, proteinuria, and peripheral edema for AMG-386 (19) and fatigue and proteinuria for CVX-060 (38). If the mild adverse event profile observed in the early clinical trials persists through advanced clinical development, these agents will be very attractive partners in combination with other antiangiogenic or chemotherapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

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Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Huang

Lai²,

Do³

et al. 2011

Clinical Cancer Research

132

123

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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 CovXBody 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 CD11bþ 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Huang

Lai²,

Do³

et al. 2011

Clinical Cancer Research

132

123

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“…Different approaches have been described to target the angiopoetin/ Tie axis in early clinical trials (20,21). The most common side effects reported in patients with cancer include fatigue, A n t i -A n g -1 A n t i -A n g -2 A n t i -A n g -2 A n t i -V E G F -A A n t i -A n g -1 A n t i -A n g -2 A n t i -V E G F -A C o n t r o l A n t i -A n g -2 A n t i -V E G decreased appetite, nausea, upper abdominal pain, back pain, and dyspnea (20). Peripheral edema has only been associated with dual inhibition of Ang-1 and Ang-2 (21).…”

Section: Discussionmentioning

confidence: 99%

“…Recent data also demonstrated that Ang-2 inhibitors, both as single agents or in combination with anti-VEGF therapy mediate antitumor effects (16)(17)(18) and interfere with metastasis formation (19). Recently, different approaches have been described to target the angiopoietin/ Tie axis in clinical trials (20,21).…”

Section: Introductionmentioning

confidence: 99%

Ang-2-VEGF-A CrossMab, a Novel Bispecific Human IgG1 Antibody Blocking VEGF-A and Ang-2 Functions Simultaneously, Mediates Potent Antitumor, Antiangiogenic, and Antimetastatic Efficacy

Kienast

Klein

Scheuer

et al. 2013

Clinical Cancer Research

182

158

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Purpose: VEGF-A blockade has been clinically validated as a treatment for human cancers. Angiopoietin-2 (Ang-2) expression has been shown to function as a key regulator of tumor angiogenesis and metastasis. Experimental Design: We have applied the recently developed CrossMab technology for the generation of a bispecific antibody recognizing VEGF-A with one arm based on bevacizumab (Avastin), and the other arm recognizing Ang-2 based on LC06, an Ang-2 selective human IgG1 antibody. The potency of Ang-2-VEGF CrossMab was evaluated alone and in combination with chemotherapy using orthotopic and subcutaneous xenotransplantations, along with metastasis analysis by quantitative real-time Alu-PCR and ex vivo evaluation of vessels, hypoxia, proliferation, and apoptosis. The mechanism of action was further elucidated using Western blotting and ELISA assays. Results: Ang-2-VEGF-A CrossMab showed potent tumor growth inhibition in a panel of orthotopic and subcutaneous syngeneic mouse tumors and patient or cell line-derived human tumor xenografts, especially at later stages of tumor development. Ang-2-VEGF-A CrossMab treatment led to a strong inhibition of angiogenesis and an enhanced vessel maturation phenotype. Neoadjuvant combination with chemotherapy resulted in complete tumor regression in primary tumor-bearing Ang-2-VEGF-A CrossMab-treated mice. In contrast to Ang-1 inhibition, anti-Ang-2-VEGF-A treatment did not aggravate the adverse effect of anti-VEGF treatment on physiologic vessels. Moreover, treatment with Ang-2-VEGF-A CrossMab resulted in inhibition of hematogenous spread of tumor cells to other organs and reduced micrometastatic growth in the adjuvant setting. Conclusion: These data establish Ang-2-VEGF-A CrossMab as a promising antitumor, antiangiogenic, and antimetastatic agent for the treatment of cancer. Clin Cancer Res; 19(24); 6730–40. ©2013 AACR.

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“…The maximum tolerated dose (MTD) was not defined and the most common adverse event was fatigue. PK/PD analysis has recommended 15 mg/kg once weekly dosing (41). It is unclear whether increased serum Ang2 levels in this study are due to peptibody binding and accumulation of stabilized complexes in the circulation as opposed to a pharmacodynamics induction of de novo Ang2 The second type of biologic therapeutics are antibodies.…”

Section: Current Therapeutics Targeting the Angiopoietin And Tie2 Patmentioning

confidence: 99%

Angiopoietin-2: An Attractive Target for Improved Antiangiogenic Tumor Therapy

Gerald¹,

Chintharlapalli²,

Augustin³

et al. 2013

Cancer Research

179

167

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Anti-VEGF pathway therapies primarily target immature blood vessels in tumors. However, emerging approaches to combine with targeted therapies impacting the later stages of remodeling and vessel maturation are expected to improve clinical efficacy by expanding the target vessel population. The angiopoietin/Tie ligand/ receptor system is a prototypic regulator of vessel remodeling and maturation. Angiopoietin-2 (Ang2) appears to be a particularly attractive therapeutic target. In fact, the experimental proof-of-concept showing improved efficacy when VEGF and Ang2-targeting therapies are combined has been solidly established in preclinical models, and several Ang2-targeting drugs are in clinical trials. However, rational development of these secondgeneration combination therapies is hampered by a limited understanding of the biological complexity that is generated from agonistic and antagonistic Ang/Tie signaling. This review discusses recent mechanistic advances in angiopoietin signaling, particularly in light of the recent study published on REGN910 and summarizes the status quo of Ang2-targeting therapies. In light of the clarified partial agonist function of Ang2, we propose that clarity on the expression profile of the angiopoietin ligands and Tie1 and Tie2 receptors in subsets of cancer vessels and cancer cells will provide clearer hypotheses for more focused rational clinical trials to exploit this seminal pathway and improve current antiangiogenic therapies. Cancer Res; 73(6); 1649-57. Ó2013 AACR.

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First-in-human dose-escalation safety and PK trial of a novel intravenous humanized monoclonal CovX body inhibiting angiopoietin 2.

Cited by 17 publications

References 0 publications

Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Specifically Targeting Angiopoietin-2 Inhibits Angiogenesis, Tie2-Expressing Monocyte Infiltration, and Tumor Growth

Ang-2-VEGF-A CrossMab, a Novel Bispecific Human IgG1 Antibody Blocking VEGF-A and Ang-2 Functions Simultaneously, Mediates Potent Antitumor, Antiangiogenic, and Antimetastatic Efficacy

Angiopoietin-2: An Attractive Target for Improved Antiangiogenic Tumor Therapy

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