Revisiting the Antigen 85 Complex as a Target for Functional Antibody-Based Strategies Against Mycobacterium...

The antigen 85 (Ag85) complex of Mycobacterium tuberculosis comprises secreted mycolyltransferases essential for cell wall biosynthesis and envelope integrity. Although extensively studied as immunodominant antigens and targets of small-molecule inhibitors, their potential for antibody-mediated functional modulation remains underexplored. In this review, we re-evaluate the Ag85 complex from a mechanistic and therapeutic perspective, focusing on its accessibility, structural organization, and functional vulnerabilities within the mycobacterial cell envelope. We highlight the distinction between antigen recognition and functional modulation, noting that conventional antibody responses often target immunodominant but functionally irrelevant epitopes. We propose that nanobodies represent a promising platform for targeting conformationally or spatially restricted regions of Ag85 enzymes that are not readily accessible to conventional antibodies. Based on structural and biochemical insights, we outline a framework in which Ag85-targeting nanobodies act as sensitizing agents that perturb cell wall biosynthesis and enhance susceptibility to antibiotics or cell wall-degrading enzymes. We further discuss key challenges, including antigen accessibility under physiological conditions, intracellular localization, and nanobody stability, which may influence the feasibility of this approach.