Features and protective efficacy of human mAbs targeting Mycobacterium tuberculosis arabinomannan

Abstract

A better understanding of the epitopes most relevant for antibody-mediated protection against tuberculosis (TB) remains a major knowledge gap. We have shown that human polyclonal IgG against the Mycobacterium tuberculosis ( M . tuberculosis ) surface glycan arabinomannan (AM) and related lipoarabinomannan (LAM) is protective against TB. To investigate the impact of AM epitope recognition and Fcγ receptor (FcγR) binding on antibody functions against M . tuberculosis , we isolated a high-affinity human monoclonal antibody (mAb; P1AM25) against AM and showed its binding to oligosaccharide (OS) motifs we previously found to be associated with in vitro functions of human polyclonal anti-AM IgG. Human IgG1 P1AM25, but not 2 other high-affinity human IgG1 anti-AM mAbs reactive with different AM OS motifs, enhanced M . tuberculosis phagocytosis by macrophages and reduced intracellular growth in an FcγR-dependent manner. P1AM25 in murine IgG2a, but neither murine IgG1 nor a non–FcγR-binding IgG, given intraperitoneally prior to and after aerosolized M . tuberculosis infection, was protective in C57BL/6 mice. Moreover, we demonstrated the protective efficacy of human IgG1 P1AM25 in passive transfer with M . tuberculosis –infected FcγR-humanized mice. These data enhance our knowledge of the important interplay between both antibody epitope specificity and Fc effector functions in the defense against M . tuberculosis and could inform development of vaccines against TB.

Antigen specificity shapes antibody functions in tuberculosis

“…Monoclonal IgG1 targeting the bacterial surface exposed heparin binding hemagglutinin (HBHA) enhance bacterial entry into epithelial cells and subsequent Mtb burden through FcRn (27). Monoclonal IgG targeting Mtb cell wall proteins (PstS1, HspX, and LpqH) (26,76,77) and monoclonal and polyclonal IgG targeting the bacterial glycan arabinomannan inhibit Mtb through Fc dependent and independent mechanisms (25,61,62,65). Thus, while the overall mixture of Mtb cell wall proteins enhances disease in this study, it is likely that within the cell wall fraction, some individual antigens induce protective and others disease enhancing antibodies.…”

“…To evaluate how antigen specificity alters antibody modulation of Mtb, we used in vitro macrophage models of infection. This quintessential immune cell niche has the capacity to restrict and also permit bacterial replication (20,25,26,55,(59)(60)(61)(62)(63)(64). Monoclonal and polyclonal antibodies have been shown to mediate differential uptake of extracellular Mtb into the macrophage (25,26,61,62,65).…”

“…This quintessential immune cell niche has the capacity to restrict and also permit bacterial replication (20,25,26,55,(59)(60)(61)(62)(63)(64). Monoclonal and polyclonal antibodies have been shown to mediate differential uptake of extracellular Mtb into the macrophage (25,26,61,62,65). In this cohort, to measure the impact of polyclonal IgG on Mtb burden resulting from opsonophagocytosis of extracellular bacteria into the macrophage, we used a virulent Mtb H37Rv reporter strain (Mtb-276) where luminescence correlates with bacterial burden (Supplemental Figure 4A) (66,67).…”

Recognition and control of Mycobacterium tuberculosis-infected cells: from basics to the clinic: a NIAID/WGNV workshop report 2023

“…The last speaker of this session was Jacqueline Achkar (Albert Einstein College of Medicine) who spoke on protective antigen specificity of antibodies and B cells in TB. Several studies have provided clear evidence for antibody-mediated immunity against TB, including FcγR-mediated effects but knowledge on protective B cell antigens remains limited (50)(51)(52)(53)(54)(55)(56). Recent mucosal and intravenous BCG vaccine studies with NHPs showed associations of airway IgA, IgG, and IgM with protection against TB disease (9,57,58), highlighting the potential protective role of antibodies and B cells in the lung during initial Mtb exposure and infection [reviewed in Boom et al ( 59)].…”