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Highly reduced binding to high and low affinity mouse Fc gamma receptors by L234A/L235A and N297A Fc mutations engineered into mouse IgG2a

Arduin, Elodie and Arora, Seguinde and Bamert, Paulo Roky and Kuiper, Torsten and Popp, Simone and Geisse, Sabine and Grau, Roger and Calzascia, Thomas and Zenke, Gerhard and Kovarik, Jiri (2015) Highly reduced binding to high and low affinity mouse Fc gamma receptors by L234A/L235A and N297A Fc mutations engineered into mouse IgG2a. Molecular Immunology, 63 (2). pp. 456-463.

Abstract

The effects of the Fc silencing mutations such as Leucine (L) to Alanine (A) substitution at the position 234 and 235 (LALA) and the Alanine (A) to Asparagine (N) substitution at position 297 (N297A) are well investigated for human IgG. However, the effects of the same two silencing Fc mutations in a mouse IgG backbone are not yet well investigated in respect to binding to mouse Fc gamma receptors (FcgR) and complement and subsequent effector functions. By using a mouse IgG2a tool antibody directed against mouse OX40L, we demonstrate a highly reduced binding to high and low affinity recombinant and cell expressed mouse FcgRs, when compared to the mouse IgG2a with the wild type backbone. Reduced FcgR binding by the two investigated Fc mutants could further be confirmed on primary mouse macrophages expressing their native FcgRs, where the high affinity mouse FcgRI was identified as major Fc interaction partner. In addition, we reveal that the LALA and N297A mutations in the mIgG2 also reduced binding to C1q of human origin. Thus, here we provide experimental evidence that the two investigated Fc mutations in the mouse IgG backbone lead to similar “silencing” properties as previously demonstrated for the human IgG and thus represent a useful method to alter effector functions in tool antibodies to be used in mouse models

Item Type: Article
Keywords: Fc mutations mouse IgG2a mouse Fc gamma receptors C1q binding
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22913

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