Design, creation and in vitro testing of a reduced immunogenicity humanized anti-CD25 monoclonal antibody that retains functional activity

Author:

Stickler Marcia1,Reddy Anita1,Xiong Joanna M1,Wong Melanie H2,Akamatsu Yoshiko1,Hinton Paul R23,Harding Fiona A2

Affiliation:

1. AbbVie, Redwood City, CA, USA

2. Formerly of AbbVie, Redwood City, CA, USA

3. IGM Biosciences, Mountain View, CA, USA

Abstract

Abstract Humanized and fully human sequence-derived therapeutic antibodies retain the capacity to induce anti-drug antibodies. Daclizumab (humanized version of the murine anti-Tac antibody; E.HAT) was selected for a proof of concept application of engineering approaches to reduce potential immunogenicity due to its demonstrated immunogenicity in the clinic. Reduced immunogenicity variants of E.HAT were created by identifying and modifying a CD4+ T cell epitope region in the VH region. Variant epitope region peptides were selected for their reduced capacity to induce CD4+ T cell proliferative responses in vitro. Variant antibody molecules were created, and CD25 affinity and potency were similar to the unmodified parent antibody. Fab fragments from the variant antibodies induced a lower frequency and magnitude of responses in human peripheral blood mononuclear cells proliferation tests. By the empirical selection of two amino acid mutations, fully functional humanized E.HAT antibodies with reduced potential to induce immune responses in vitro were created.

Publisher

Oxford University Press (OUP)

Subject

Molecular Biology,Biochemistry,Bioengineering,Biotechnology

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