Deciphering Fc-mediated Antiviral Antibody Functions in Animal Models

Schmaljohn, Alan L.; Orlandi, Chiara; Lewis, George K.

Allosteric change in Fc is a phenomenon that remains incompletely resolved in terms of biological significance. However, improved tools in structural analysis restore the possibility that allostery is among the factors that may contribute additively or synergistically to Ab function. Thus, in a subset of MAbs and presumably in a subset of natural polyclonal Abs, the binding of Fab to its cognate epitope results in allosteric FIGURE 4 | Concepts represented as building blocks for effectiveness of cell-targeting Abs in immunity to viral infections. See text for details. Many factors-each with its own quantitative or qualitative dimension-contribute additively or synergistically to reaching a threshold of antiviral activity that meets a standard of protective efficacy (as defined in Box 1). The threshold is not a constant, but varies by individual, host species, virus biotype, dose and route of infection, etc. In short, the figure is intended to illustrate that Fc-mediated aspects of Ab-mediated immunity are interrelated parts of a complex adaptive system that arose during co-evolution of host and virus. To adequately exploit these concepts with vaccines or therapeutic Abs requires either empirical good fortune (the key to almost all licensed vaccines) or understandings that allow rational improvements in design. In the search for statistical or mechanistic correlates of protection, assays that combine several of these factors may be favored. change in Fc, which in turn promotes higher affinity between Fc and FcR than is observed in the absence of Ag (61, 62) . The implication is that, depending upon the assay, in vitro results may be an inadequate predictor of Fc-mediated functional activity of Ab. A different kind of allostery is seen when two MAbs synergize on the basis of how Fab binding to one part of an Ag molecule promotes binding of a second MAb recognizing a different epitope on the same Ag (63) . Newer animal models may add clarity to the functional importance of such allosteric interactions in Ab-mediated protection against viruses.