Open AccessFc-engineered antibodies with immune effector functions completely abolished
Author(s) -
Ian Wilkinson,
Stephen F. Anderson,
Jeremy Fry,
Louis Julien,
David C. A. Neville,
Omar Qureshi,
Gary Watts,
Geoff Hale
Publication year - 2021
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0260954
Subject(s) - immunogenicity , antibody , receptor , immunoglobulin fc fragments , fusion protein , fragment crystallizable region , immune system , protein engineering , immunoglobulin g , effector , cytokine , microbiology and biotechnology , biology , immunology , chemistry , computational biology , biochemistry , recombinant dna , gene , enzyme
Elimination of the binding of immunoglobulin Fc to Fc gamma receptors (FcγR) is highly desirable for the avoidance of unwanted inflammatory responses to therapeutic antibodies and fusion proteins. Many different approaches have been described in the literature but none of them completely eliminates binding to all of the Fcγ receptors. Here we describe a set of novel variants having specific amino acid substitutions in the Fc region at L234 and L235 combined with the substitution G236R. They show no detectable binding to Fcγ receptors or to C1q, are inactive in functional cell-based assays and do not elicit inflammatory cytokine responses. Meanwhile, binding to FcRn, manufacturability, stability and potential for immunogenicity are unaffected. These variants have the potential to improve the safety and efficacy of therapeutic antibodies and Fc fusion proteins.