Balancing charge in the complementarity-determining regions of humanized mAbs without affecting pI reduces non-specific binding and improves the pharmacokinetics

• Published in: mAbs Vol. 7; no. 3; pp. 483 - 493
• Main Authors: Datta-Mannan, Amita, Thangaraju, Arunkumar, Leung, Donmienne, Tang, Ying, Witcher, Derrick R, Lu, Jirong, Wroblewski, Victor J
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 04.05.2015
• Subjects: Animals; Antibodies, Monoclonal, Humanized - chemistry; Antibodies, Monoclonal, Humanized - genetics; Antibodies, Monoclonal, Humanized - immunology; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antibodies, Monoclonal, Humanized - pharmacology; antibody pharmacokinetics; Antibody Specificity - genetics; CDR modification; charge interactions of IgGs; Complementarity Determining Regions - chemistry; Complementarity Determining Regions - genetics; Complementarity Determining Regions - immunology; Complementarity Determining Regions - pharmacology; FcRn recycling; HEK293 Cells; Humans; Immunoglobulin G - chemistry; Immunoglobulin G - genetics; Immunoglobulin G - immunology; Immunoglobulin G - pharmacology; in vitro degradation; Isoelectric Point; Mice; Models, Molecular; non-specific binding; radiolabel antibody biodistribution; antibody pharmacokinetics; AUC, area under the curve; IgGs, immunoglobulins; IV, intravenous; FcRn, neonatal Fc receptor; FcRn recycling; charge interactions of IgGs; ELISA, enzyme-linked immunosorbent assay; CDR, complementarity-determining region; radiolabel antibody biodistribution; HBSS, Hank's balanced salt saline solution; HEK293 cells; PK, pharmacokinetics; CDR modification; KD, equilibrium dissociation constant; SD, standard deviation; TCA, trichloroacetic acid; TMDD, target-mediated drug disposition; KDa, kilodalton; non-specific binding; pI, isoelectric point; SPR, surface plasmon resonance; in vitro degradation; 125I, Iodine 125

Lowering the isoelectric point (pI) through engineering the variable region or framework of an IgG can improve its exposure and half-life via a reduction in clearance mediated through non-specific interactions. As such, net charge is a potentially important property to consider in developing therape...