AMG-386, a selective angiopoietin-1/-2-neutralizing peptibody for the potential treatment of cancer.
The VEGF/VEGFR and angiopoietin/Tie-2 signaling pathways are important in the process of vascular endothelial growth (angiogenesis) and in the maintenance of tumor-associated blood vessels. While there are several agents targeting the VEGF/VEGFR signaling pathway, there are none available that target the angiopoietin/Tie-2 signaling pathway. The first such agent to reach clinical trials is AMG-386 (2xCon4C), being developed by Amgen Inc and licensed in Japan to Takeda Bio Development Center Ltd. AMG-386 is an anti-angiopoietin peptibody comprising a peptide with angiopoietin-binding properties that is fused to the Fc (crystallizable fragment) region of an antibody and inhibits the interaction between the ligands angiopoietin-1 and angiopoietin-2 with the Tie-2 receptor. AMG-386 significantly inhibited the growth of tumors in a variety of mouse xenograft models. In phase I trials of AMG-386 as a monotherapy or in combination with chemotherapy in patients with advanced solid tumors, AMG-386 demonstrated only mild toxicities, and one complete response and several partial responses were achieved in patients. Phase II trials of AMG-386 in combination with chemotherapy were ongoing in a variety of solid tumors, including breast, ovarian, colorectal, gastric and renal cell cancers. If safe and effective, AMG-386 could be an exciting addition to other antiangiogenic therapies in solid tumors.
Neal
Joel
J
Stanford University Cancer Center, 875 Blake Wilbur Drive, Stanford, CA 94305-5826, USA.
Wakelee
Heather
H
D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors*; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000075202:Contraindications; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D010330:Patents as Topic; D010455:Peptides / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D010455:Peptides; D011993:Recombinant Fusion Proteins; C551398:trebananib