DOTA-functionalized polylysine

• Verfasst von: Grünberg, Jürgen [VerfasserIn]
• Verfasst von: Sarko, Dikran [VerfasserIn]
• Verfasst von: Mier, Walter [VerfasserIn]
• Titel: DOTA-functionalized polylysine
• Titelzusatz: a high number of DOTA chelates positively influences the biodistribution of enzymatic conjugated anti-tumor antibody chCE7agl
• Verf.angabe: Jürgen Grünberg, Simone Jeger, Dikran Sarko, Patrick Dennler, Kurt Zimmermann, Walter Mier, Roger Schibli
• E-Jahr: 2013
• Jahr: April 2, 2013
• Fussnoten: Gesehen am 16.02.2021
• Titel Quelle: Enthalten in: PLOS ONE
• Ort Quelle: San Francisco, California, US : PLOS, 2006
• Jahr Quelle: 2013
• Band/Heft Quelle: 8(2013,4) Artikel-Nummer e60350, 10 Seiten
• ISSN Quelle: 1932-6203
• DOI: doi:10.1371/journal.pone.0060350
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Blood
• Sach-SW: Cancers and neoplasms
• Sach-SW: Enzymes
• Sach-SW: Glutamine
• Sach-SW: Hepatocellular carcinoma
• Sach-SW: Lysine
• Sach-SW: Ovarian cancer
• Sach-SW: Radiolabeling
• K10plus-PPN: 1745989803

Abstract

Site-specific enzymatic reactions with microbial transglutaminase (mTGase) lead to a homogenous species of immunoconjugates with a defined ligand/antibody ratio. In the present study, we have investigated the influence of different numbers of 1,4,7,10-tetraazacyclododecane-N-N′-N′′-N′′′-tetraacetic acid (DOTA) chelats coupled to a decalysine backbone on the in vivo behavior of the chimeric monoclonal anti-L1CAM antibody chCE7agl. The enzymatic conjugation of (DOTA)1-decalysine, (DOTA)3-decalysine or (DOTA)5-decalysine to the antibody heavy chain (via Gln295/297) gave rise to immunoconjugates containing two, six or ten DOTA moieties respectively. Radiolabeling of the immunoconjugates with 177Lu yielded specific activities of approximately 70 MBq/mg, 400 MBq/mg and 700 MBq/mg with increasing numbers of DOTA chelates. Biodistribution experiments in SKOV3ip human ovarian cancer cell xenografts demonstrated a high and specific accumulation of radioactivity at the tumor site for all antibody derivatives with a maximal tumor accumulation of 43.6±4.3% ID/g at 24 h for chCE7agl-[(DOTA)-decalysine]2, 30.6±12.0% ID/g at 24 h for chCE7agl-[(DOTA)3-decalysine]2 and 49.9±3.1% ID/g at 48 h for chCE7agl-[(DOTA)5-decalysine)]2. The rapid elimination from the blood of chCE7agl-[(DOTA)-decalysine]2 (1.0±0.1% ID/g at 24 h) is associated with a high liver accumulation (23.2±4.6% ID/g at 24 h). This behavior changed depending on the numbers of DOTA moieties coupled to the decalysine peptide with a slower blood clearance (5.1±1.0 (DOTA)3 versus 11.7±1.4% ID/g (DOTA)5, p<0.005 at 24 h) and lower radioactivity levels in the liver (21.4±3.4 (DOTA)3 versus 5.8±0.7 (DOTA)5, p<0.005 at 24 h). We conclude that the site-specific and stoichiometric uniform conjugation of the highly DOTA-substituted decalysine ((DOTA)5-decalysine) to an anti-tumor antibody leads to the formation of immunoconjugates with high specific activity and excellent in vivo behavior and is a valuable option for radioimmunotherapy and potentially antibody-drug conjugates (ADCs).