6T3J

Dual Epitope Targeting by Anti-DR5 Antibodies

Summary for 6T3J

• Entry DOI: 10.2210/pdb6t3j/pdb
• Descriptor: IgG1-hDR5-01-Heavy Chain, IgG1-hDR5-01-Light Chain, IgG1-hDR5-05-Heavy Chain, ... (5 entities in total)
• Functional Keywords: dr5, antibody, apoptosis
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 10
• Total formula weight: 223384.30

Authors

Tauchert, M.J.,Augustin, M.,Krapp, S.,Overdijk, M.B.,Breij, E.C.W.,Hibbert, R.G. (deposition date: 2019-10-11, release date: 2020-09-16, Last modification date: 2024-10-16)

Primary citation

Overdijk, M.B.,Strumane, K.,Beurskens, F.J.,Ortiz Buijsse, A.,Vermot-Desroches, C.,Vuillermoz, B.S.,Kroes, T.,de Jong, B.,Hoevenaars, N.,Hibbert, R.G.,Lingnau, A.,Forssmann, U.,Schuurman, J.,Parren, P.W.H.I.,de Jong, R.N.,Breij, E.C.W.
Dual Epitope Targeting and Enhanced Hexamerization by DR5 Antibodies as a Novel Approach to Induce Potent Antitumor Activity Through DR5 Agonism.
Mol.Cancer Ther., 19:2126-2138, 2020

PubMed Abstract: Higher-order death receptor 5 (DR5) clustering can induce tumor cell death; however, therapeutic compounds targeting DR5 have achieved limited clinical efficacy. We describe HexaBody-DR5/DR5, an equimolar mixture of two DR5-specific IgG1 antibodies with an Fc-domain mutation that augments antibody hexamerization after cell surface target binding. The two antibodies do not compete for binding to DR5 as demonstrated using binding competition studies, and binding to distinct epitopes in the DR5 extracellular domain was confirmed by crystallography. The unique combination of dual epitope targeting and increased IgG hexamerization resulted in potent DR5 agonist activity by inducing efficient DR5 outside-in signaling and caspase-mediated cell death. Preclinical studies and demonstrated that maximal DR5 agonist activity could be achieved independent of Fc gamma receptor-mediated antibody crosslinking. Most optimal agonism was observed in the presence of complement complex C1, although without inducing complement-dependent cytotoxicity. It is hypothesized that C1 may stabilize IgG hexamers that are formed after binding of HexaBody-DR5/DR5 to DR5 on the plasma membrane, thereby strengthening DR5 clustering and subsequent outside-in signaling. We observed potent antitumor activity and in large panels of patient-derived xenograft models representing various solid cancers. The results of our preclinical studies provided the basis for an ongoing clinical trial exploring the activity of HexaBody-DR5/DR5 (GEN1029) in patients with malignant solid tumors.

PubMed: 32847982
DOI: 10.1158/1535-7163.MCT-20-0044

Experimental method

X-RAY DIFFRACTION (3.05 Å)