The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index.
Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice
Open accessAbstract
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.
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Cites
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Cited by
Bispecific antibodies: a mechanistic review of the pipeline
Labrijn, A. F., Janmaat, M. L., Reichert, J. M., & Parren, P. W. H. I. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0028-1 · Cited by 1,303
TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy
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“To generate recombinant antibody, the heavy chain gBlocks (VH and CH1 mIgG2A; Integrated DNA technologies) was cloned into the pFUSEmIgG2A-Fc1 vector with L234A, L235A, P329G (LALA-PG) mutation (Lo et al., 2017), and the light chain gBlock (VL and Cκ; Integrated DNA technologies) was cloned into the mIgG2Adeficient pF…”
Dejanovic, B., Huntley, M. A., De Mazière, A., Meilandt, W. J., Wu, T., Srinivasan, K., Jiang, Z., Gandham, V., Friedman, B. A., Ngu, H., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.014 · Cited by 517
PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer
Oh, S. A., Wu, D.-C., Cheung, J., Navarro, A., Xiong, H., Cubas, R., Totpal, K., Chiu, H., Wu, Y., Comps-Agrar, L., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-0075-x · Cited by 459
Winkler, E. S., Gilchuk, P., Yu, J., Bailey, A. L., Chen, R. E., Chong, Z., Zost, S. J., Jang, H., Huang, Y., Allen, J. D., et al. (2021) · Cell · doi:10.1016/j.cell.2021.02.026 · Cited by 366
Metadata
- Authors
- Lo, M., Kim, H. S., Tong, R. K., Bainbridge, T. W., Vernes, J.-M., Zhang, Y., Lin, Y. L., Chung, S., Dennis, M. S., Zuchero, Y. J. Y., Watts, R. J., Couch, J. A., Meng, Y. G., Atwal, J. K., Brezski, R. J., Spiess, C., & Ernst, J. A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 292
- Issue
- 9
- Pages
- 3900-3908
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2578585563
- Cited by
- 323
- References
- 43
- FWCI
- 13.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Lo, M., Kim, H. S., Tong, R. K., Bainbridge, T. W., Vernes, J.-M., Zhang, Y., Lin, Y. L., Chung, S., Dennis, M. S., Zuchero, Y. J. Y., Watts, R. J., Couch, J. A., Meng, Y. G., Atwal, J. K., Brezski, R. J., Spiess, C., & Ernst, J. A. (2017). Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m116.767749
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
