Understanding mechanistic relationships between IgG titers and Fc effector functions: a computational framework to assess polyfunctionality

Suzanne Shoffner-Beck¹Robert M. Theisen²Kade E Wong¹Supachai Rerks-Ngarm³Punnee Pitisuttithum⁴Sorachai Nitayaphan⁵Stephen Kent^6,7Amy W Chung⁶Kelly B. Arnold^1,8*

• ¹Department of Biomedical Engineering, University of Michigan, Ann Arbor, Indiana, United States
• ²University of Michigan, Michigan, United States
• ³Department of Disease Control, Ministry of Public Health, Bangkok, Thailand
• ⁴Vaccine Trial Centre, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
• ⁵Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
• ⁶Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity at the University of Melbourne, Victoria, Australia
• ⁷Melbourne Sexual Health Centre, Alfred Hospital, Monash University Central Clinical School, Victoria, Australia
• ⁸University of Michigan, Ann Arbor, United States

Recent vaccine and infectious disease studies have highlighted the importance of antibodies that activate cellular Fc functions, including antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC), which are mediated by different Fc gamma Receptors (FcgR). Activation of these functions requires complex overlapping interactions between IgG antibodies, FcgRs, and antigens. Here we created an ordinary differential equation model that simultaneously predicts FcgRIIIa immune complexes upstream of ADCC and FcgRIIa immune complexes upstream of ADCP as a function of antigen, IgG, and FcgR concentration and binding properties. Model results suggested that the maximum formation of immune complexes would not occur at highest total IgG titers. Instead, higher IgG titers have the potential to decrease FcgRIIIa (ADCC) and/or FcgRIIa (ADCP) immune complexes, due to competition between antibody subclasses for antigen and FcgR binding. We used the model to simulate vaccine boosts of IgG1 or IgG3 in 105 participants in an HIV vaccine trial and found that boosting IgG1 and IgG3 in combination was not predicted to result in significant changes in either FcgRIIIa (ADCC) and/or FcgRIIa (ADCP) immune complexes. Surprisingly, boosting IgG3 alone had the potential to significantly decrease ADCP (p<0.00001), though ithowever would increase ADCC responses. We also illustrated how the model could be used to assess how variability in viral load, FcgR expression, FcgR polymorphisms, and IgG titers across different tissue compartments can lead to differences in FcgRIIIa and FcgRIIa complexes.Altogether, these results illustrate how a computational framework provides new quantitative insights into activation of Fc effector functions that could be used to guide future rational design of therapeutic and prophylactic interventions.