Increment in Drug Loading on an Antibody-Drug Conjugate Increases Its Binding to the Human Neonatal Fc Receptor in Vitro

Molecular Pharmaceutics
Guillaume BrachetValérie Gouilleux-Gruart

Abstract

Antibody-drug conjugates, such as brentuximab vedotin (BTXv), are an innovative category of monoclonal antibodies. BTXv is bioconjugated via the chemical reduction of cysteine residues involved in disulfide bonds. Species of BTXv containing zero, two, four, six, or eight vedotin molecules per antibody coexist in the stock solution. We investigated the influence of drug loading on the binding of the antibody to FcRn, a major determinant of antibody pharmacokinetics in humans. We developed a hydrophobic interaction chromatography (HIC) method for separating the different species present in the stock solution of BTXv, and we purified and characterized the collected species before use. We assessed the binding of these different species to FcRn in a cellular assay based on flow cytometry and surface plasmon resonance. HIC separated the different species of BTXv and allowed their collection at adequate levels of purity. Physicochemical characterization showed that species with higher levels of drug loading tended to form more aggregates. FcRn binding assays showed that the most conjugated species, particularly those with saturated loading, interacted more strongly than unconjugated BTXv with the FcRn.

References

Jul 1, 1984·The Journal of Cell Biology·R Rodewald, J P Kraehenbuhl
Sep 1, 1995·American Journal of Obstetrics and Gynecology·A MalekH Schneider
Jan 5, 2002·Current Pharmaceutical Biotechnology·A J Grillo-LópezC A White
Jul 10, 2003·Vaccine·Neil E Simister
Sep 10, 2003·Seminars in Oncology Nursing·Kristi V Schmidt, Barbara A Wood
Sep 26, 1964·Nature·F W BRAMBELLI G MORRIS
Oct 27, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kevin J HamblettJoseph A Francisco
Jun 1, 2005·Journal of Cell Science·Estelle E NewtonNeil E Simister
Jun 10, 2005·Rapid Communications in Mass Spectrometry : RCM·Alexandru C LazarWei Zhang
Apr 12, 2006·Biochemistry·Chaity ChaudhuryClark L Anderson
Aug 19, 2007·Nature Reviews. Immunology·Derry C Roopenian, Shreeram Akilesh
Nov 13, 2007·Bioconjugate Chemistry·Irwin HollanderPhilip R Hamann
Dec 29, 2007·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Wei WangD Q Wang
Mar 5, 2008·Bioconjugate Chemistry·Stephen C AlleyPeter D Senter
Jan 21, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Nicole M OkeleyStephen C Alley
Apr 29, 2010·Journal of Pharmacokinetics and Pharmacodynamics·Nelson L JumbeJay Tibbitts
May 26, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Weirong WangThomayant Prueksaritanont
Sep 11, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·R Angelo de ClaroRichard Pazdur
Jun 12, 2013·MAbs·Christophe PassotValérie Gouilleux-Gruart
Feb 19, 2014·Bioconjugate Chemistry·Qun ZhouClark Q Pan
Feb 25, 2014·Bioconjugate Chemistry·Yilma T AdemOsigwe Esue
Feb 20, 2015·Protein Science : a Publication of the Protein Society·Julien MarcouxSarah Cianférani
Mar 15, 2015·Molecular Immunology·E Sally WardRaimund J Ober

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Citations

Jan 7, 2017·Bioconjugate Chemistry·Brian A MendelsohnJulien Dugal-Tessier
Sep 20, 2017·Pharmaceutical Research·Paul MalikJonathan Blay
Mar 3, 2020·Chemical & Pharmaceutical Bulletin·Michinori AkaiwaBrian A Mendelsohn
Jan 7, 2020·Médecine sciences : M/S·Alain BeckNicolas Joubert
Jan 7, 2020·Médecine sciences : M/S·Alain BeckRenaud Respaud
Jul 4, 2018·Analytical and Bioanalytical Chemistry·Xiaoshuang HeSicen Wang
Sep 18, 2020·Pharmaceuticals·Nicolas JoubertCaroline Denevault-Sabourin
Jun 25, 2018·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Alexandre GoyonDavy Guillarme

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