5VEB

Crystal structure of a Fab binding to extracellular domain 5 of Cadherin-6

5VEB の概要

• エントリーDOI: 10.2210/pdb5veb/pdb
• 分子名称: anti-CDH6 Fab heavy chain, anti-CDH6 Fab light chain, Cadherin-6, ... (6 entities in total)
• 機能のキーワード: antibody, cell adhesion, antibody-drug conjugate, cancer, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 123009.37

構造登録者

Zhu, X.,Bialucha, C.U.,London, A.,Clark, K.,Hu, T. (登録日: 2017-04-04, 公開日: 2017-06-07, 最終更新日: 2024-04-24)

主引用文献

Bialucha, C.U.,Collins, S.D.,Li, X.,Saxena, P.,Zhang, X.,Durr, C.,Lafont, B.,Prieur, P.,Shim, Y.,Mosher, R.,Lee, D.,Ostrom, L.,Hu, T.,Bilic, S.,Rajlic, I.L.,Capka, V.,Jiang, W.,Wagner, J.P.,Elliott, G.,Veloso, A.,Piel, J.C.,Flaherty, M.M.,Mansfield, K.G.,Meseck, E.K.,Rubic-Schneider, T.,London, A.S.,Tschantz, W.R.,Kurz, M.,Nguyen, D.,Bourret, A.,Meyer, M.J.,Faris, J.E.,Janatpour, M.J.,Chan, V.W.,Yoder, N.C.,Catcott, K.C.,McShea, M.A.,Sun, X.,Gao, H.,Williams, J.,Hofmann, F.,Engelman, J.A.,Ettenberg, S.A.,Sellers, W.R.,Lees, E.
Discovery and Optimization of HKT288, a Cadherin-6-Targeting ADC for the Treatment of Ovarian and Renal Cancers.
Cancer Discov, 7:1030-1045, 2017

PubMed Abstract: Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell-cell adhesion molecule cadherin-6 () as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody-drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models-a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models , including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation. We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. .

PubMed: 28526733
DOI: 10.1158/2159-8290.CD-16-1414

実験手法

X-RAY DIFFRACTION (2.34 Å)