Fc-engineered antibodies leverage neutrophils to drive control of Mycobacterium tuberculosis

Novel vaccination and therapeutic strategies are urgently needed to mitigate the tuberculosis (TB) epidemic. While extensive efforts have focused on potentiating cell-mediated immunity to control Mycobacterium tuberculosis ( Mtb ) infection, less effort has been invested in exploiting the humoral immune system to combat Mtb . Emerging data point to a role for antibodies in microbial control of Mtb , however the precise mechanism(s) of this control remain incompletely understood. Here we took an antibody Fc-engineering approach to determine whether Fc-modifications could improve the ability of antibodies to restrict Mtb , and to define Fc-mediated mechanism(s) antibodies leverage for this restriction. Using an antibody specific to the capsular polysaccharide α-glucan, we engineer a panel of Fc variants to augment or dampen select antibody effector functions, rationally building antibodies with enhanced capacity to promote Mtb restriction in a human whole blood model of infection. Surprisingly, restrictive Fc-engineered antibodies drive Mtb control in a neutrophil, not monocyte, dependent manner. Using single cell RNA sequencing, we show that restrictive antibodies promote neutrophil survival and expression of cell intrinsic antimicrobial programs. These data provide a roadmap for exploiting Fc-engineered antibodies as a novel class of TB therapeutics able to harness the protective functions of neutrophils to achieve disease control. ### Competing Interest Statement GA is a founder and equity holder of Seromyx Systems, and an employee and equity holder of Leyden Labs. The interests of GA were reviewed and are managed by Mass General Brigham in accordance with their conflict of interest policies. The remaining authors declare no conflicts of interest.