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PLoS One. 2016 Jun 20;11(6):e0157788. doi: 10.1371/journal.pone.0157788. eCollection 2016.

Enhancement of Immune Effector Functions by Modulating IgG's Intrinsic Affinity for Target Antigen.

Author information

1
Department of Antibody Discovery and Protein Engineering, MedImmune, Gaithersburg, Maryland, United States of America.
2
Department of Biopharmaceutical Development, MedImmune, Gaithersburg, Maryland, United States of America.

Abstract

Antibody-mediated immune effector functions play an essential role in the anti-tumor efficacy of many therapeutic mAbs. While much of the effort to improve effector potency has focused on augmenting the interaction between the antibody-Fc and activating Fc-receptors expressed on immune cells, the role of antibody binding interactions with the target antigen remains poorly understood. We show that antibody intrinsic affinity to the target antigen clearly influences the extent and efficiency of Fc-mediated effector mechanisms, and report the pivotal role of antibody binding valence on the ability to regulate effector functions. More particularly, we used an array of affinity modulated variants of three different mAbs, anti-CD4, anti-EGFR and anti-HER2 against a panel of target cell lines expressing disparate levels of the target antigen. We found that at saturating antibody concentrations, IgG variants with moderate intrinsic affinities, similar to those generated by the natural humoral immune response, promoted superior effector functions compared to higher affinity antibodies. We hypothesize that at saturating concentrations, effector function correlates most directly with the amount of Fc bound to the cell surface. Thus, high affinity antibodies exhibiting slow off-rates are more likely to interact bivalently with the target cell, occupying two antigen sites with a single Fc. In contrast, antibodies with faster off-rates are likely to dissociate each binding arm more rapidly, resulting in a higher likelihood of monovalent binding. Monovalent binding may in turn increase target cell opsonization and lead to improved recruitment of effector cells. This unpredicted relationship between target affinity and effector function potency suggests a careful examination of antibody design and engineering for the development of next-generation immunotherapeutics.

PMID:
27322177
PMCID:
PMC4913924
DOI:
10.1371/journal.pone.0157788
[Indexed for MEDLINE]
Free PMC Article

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