PMID- 24101228 OWN - NLM STAT- MEDLINE DCOM- 20140804 LR - 20201222 IS - 1538-8514 (Electronic) IS - 1535-7163 (Linking) VI - 12 IP - 12 DP - 2013 Dec TI - APG350 induces superior clustering of TRAIL receptors and shows therapeutic antitumor efficacy independent of cross-linking via Fcgamma receptors. PG - 2735-47 LID - 10.1158/1535-7163.MCT-13-0323 [doi] AB - Cancer cells can be specifically driven into apoptosis by activating Death-receptor-4 (DR4; TRAIL-R1) and/or Death-receptor-5 (DR5; TRAIL-R2). Albeit showing promising preclinical efficacy, first-generation protein therapeutics addressing this pathway, especially agonistic anti-DR4/DR5-monoclonal antibodies, have not been clinically successful to date. Due to their bivalent binding mode, effective apoptosis induction by agonistic TRAIL-R antibodies is achieved only upon additional events leading to antibody-multimer formation. The binding of these multimers to their target subsequently leads to effective receptor-clustering on cancer cells. The research results presented here report on a new class of TRAIL-receptor agonists overcoming this intrinsic limitation observed for antibodies in general. The main feature of these agonists is a TRAIL-mimic consisting of three TRAIL-protomer subsequences combined in one polypeptide chain, termed the single-chain TRAIL-receptor-binding domain (scTRAIL-RBD). In the active compounds, two scTRAIL-RBDs with three receptor binding sites each are brought molecularly in close proximity resulting in a fusion protein with a hexavalent binding mode. In the case of APG350-the prototype of this engineering concept-this is achieved by fusing the Fc-part of a human immunoglobulin G1 (IgG1)-mutein C-terminally to the scTRAIL-RBD polypeptide, thereby creating six receptor binding sites per drug molecule. In vitro, APG350 is a potent inducer of apoptosis on human tumor cell lines and primary tumor cells. In vivo, treatment of mice bearing Colo205-xenograft tumors with APG350 showed a dose-dependent antitumor efficacy. By dedicated muteins, we confirmed that the observed in vivo efficacy of the hexavalent scTRAIL-RBD fusion proteins is-in contrast to agonistic antibodies-independent of FcgammaR-based cross-linking events. CI - (c)2013 AACR. FAU - Gieffers, Christian AU - Gieffers C AD - Corresponding Author: Oliver Hill, Apogenix GmbH, Im Neuenheimer Feld 584, Heidelberg 69120, Germany. Phone: 49-6221-58608-18; Fax: 49-6221-58608-10; E-Mail: oliver.hill@apogenix.com. FAU - Kluge, Michael AU - Kluge M FAU - Merz, Christian AU - Merz C FAU - Sykora, Jaromir AU - Sykora J FAU - Thiemann, Meinolf AU - Thiemann M FAU - Schaal, Rene AU - Schaal R FAU - Fischer, Carmen AU - Fischer C FAU - Branschadel, Marcus AU - Branschadel M FAU - Abhari, Behnaz Ahangarian AU - Abhari BA FAU - Hohenberger, Peter AU - Hohenberger P FAU - Fulda, Simone AU - Fulda S FAU - Fricke, Harald AU - Fricke H FAU - Hill, Oliver AU - Hill O LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20131007 PL - United States TA - Mol Cancer Ther JT - Molecular cancer therapeutics JID - 101132535 RN - 0 (APG350) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (Peptide Fragments) RN - 0 (Receptors, IgG) RN - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand) RN - 0 (Recombinant Fusion Proteins) RN - SQ67484MA7 (drozitumab) SB - IM MH - Animals MH - Antibodies, Monoclonal/pharmacology MH - Antibodies, Monoclonal, Humanized MH - Antineoplastic Agents/administration & dosage/chemistry/*pharmacology MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Mice MH - Models, Biological MH - Peptide Fragments/administration & dosage/chemistry/*pharmacology MH - Receptors, IgG/*metabolism MH - Receptors, TNF-Related Apoptosis-Inducing Ligand/agonists/antagonists & inhibitors/*metabolism MH - Recombinant Fusion Proteins/administration & dosage/chemistry/*pharmacology MH - Xenograft Model Antitumor Assays EDAT- 2013/10/09 06:00 MHDA- 2014/08/05 06:00 CRDT- 2013/10/09 06:00 PHST- 2013/10/09 06:00 [entrez] PHST- 2013/10/09 06:00 [pubmed] PHST- 2014/08/05 06:00 [medline] AID - 1535-7163.MCT-13-0323 [pii] AID - 10.1158/1535-7163.MCT-13-0323 [doi] PST - ppublish SO - Mol Cancer Ther. 2013 Dec;12(12):2735-47. doi: 10.1158/1535-7163.MCT-13-0323. Epub 2013 Oct 7.