IgG and FcR Characterization in Small Animal Models of RespiratoryDisease

ABSTRACT
The central hypothesis of this proposal is that the development of effective vaccines and therapeutic antibodies
will benefit from careful evaluation of the full range of potentially protective or harmful antiviral antibody
responses throughout all stages of preclinical testing. Small animal models are often used to assess antibody-
based interventions to provide sterilizing immunity, but these models may also hold value for studying
pathology and mechanisms of protection beyond neutralization. At present, ferrets (Mustela putorius furo) and
Syrian hamsters (Mesocricetus auratus) are thought to be good small-animal models for diverse respiratory
pathogens as both support infection, manifest disease, and transmit virus. To optimally use these models,
there is a critical need to understand the suitability and/or shortfalls of ferrets and hamsters in recapitulating
antibody effector functions that affect human clinical outcomes—requiring basic research into the genetic
diversity, expression patterns, and functional profiles of both antibodies as well as Fc receptors in these
animals. The goal of this project is to perform initial biophysical and functional Fc and FcR profiling in ferrets
and Syrian hamsters to elucidate key variables that impact species-specific Fc-FcR-dependent effector
functions. Achieving this goal is a prerequisite for optimal translation of insights gained from emerging
protective and therapeutic small-animal studies to the clinic and to best prioritize strategies for human clinical
trials. Guided by strong preliminary data, and using a combination of gold-standard and state-of-the art
approaches, the project goal will be achieved though completion of two Specific Aims: 1) Define the
biophysical interactions between FcR and IgG that determine effector functions in ferrets and Syrian
hamsters, 2) Develop novel cell lines and assays for evaluating ferret and hamster Fc-mediated antibody
effector functions in vitro. The data and results obtained by completing the aims of this proposal will be
significant and innovative because they will generate knowledge that will identify the antibody and FcR
interactions capable of tuning immune response towards potent antiviral activity versus promoting pathological
inflammation in ferrets and hamsters. This knowledge will provide a roadmap for effective translation of studies
performed in these small animals, often used to model respiratory pathogens, to outcomes in human trials.

Grant Number: 5R21AI176640-02
NIH Institute/Center: NIH
Principal Investigator: Margaret Ackerman