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Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice.

ABSTRACT: The antibody Fc region regulates antibody cytotoxic activities and serum half-life. In a therapeutic context, however, the cytotoxic effector function of an antibody is often not desirable and can create safety liabilities by activating native host immune defenses against cells expressing the receptor antigens. Several amino acid changes in the Fc region have been reported to silence or reduce the effector function of antibodies. These earlier studies focused primarily on the interaction of human antibodies with human Fc-γ receptors, and it remains largely unknown how such changes to Fc might translate to the context of a murine antibody. We demonstrate that the commonly used N297G (NG) and D265A, N297G (DANG) variants that are efficacious in attenuating effector function in primates retain potent complement activation capacity in mice, leading to safety liabilities in murine studies. In contrast, we found an L234A, L235A, P329G (LALA-PG) variant that eliminates complement binding and fixation as well as Fc-γ-dependent, antibody-dependent, cell-mediated cytotoxity in both murine IgG2a and human IgG1. These LALA-PG substitutions allow a more accurate translation of results generated with an "effectorless" antibody between mice and primates. Further, we show that both human and murine antibodies containing the LALA-PG variant have typical pharmacokinetics in rodents and retain thermostability, enabling efficient knobs-into-holes bispecific antibody production and a robust path to generating highly effector-attenuated bispecific antibodies for preclinical studies.

SUBMITTER: Lo M

PROVIDER: S-EPMC5339770 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice.

Lo Megan M Kim Hok Seon HS Tong Raymond K RK Bainbridge Travis W TW Vernes Jean-Michel JM Zhang Yin Y Lin Yuwen Linda YL Chung Shan S Dennis Mark S MS Zuchero Y Joy Yu YJ Watts Ryan J RJ Couch Jessica A JA Meng Y Gloria YG Atwal Jasvinder K JK Brezski Randall J RJ Spiess Christoph C Ernst James A JA

The Journal of biological chemistry 20170111 9

The antibody Fc region regulates antibody cytotoxic activities and serum half-life. In a therapeutic context, however, the cytotoxic effector function of an antibody is often not desirable and can create safety liabilities by activating native host immune defenses against cells expressing the receptor antigens. Several amino acid changes in the Fc region have been reported to silence or reduce the effector function of antibodies. These earlier studies focused primarily on the interaction of huma ...[more]

PMID: 28077575

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Dataset Information

Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice.

Publications

Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice.

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