The role of antibodies in the host response against Mycobacterium tuberculosis ( M. tb ) bacteria is still poorly understood. We previously isolated two monoclonal antibodies (mAbs), p4-36 and p4-163, from an M. tb infected donor that target two non-overlapping epitopes on PstS1, a subunit of the M. tb phosphate transporter. Although these antibodies reduced lung bacterial burden in mice (30–40% reduction in CFU), their efficacy remained modest for therapeutic application. Here, we employed a rational antibody engineering approach to further enhance their anti- M. tb potency. Affinity maturation of p4-163 yielded p4-163LR, a variant with superior binding to PstS1 and improved recognition of live, attenuated M. tb . Surprisingly, p4-163LR alone did not confer enhanced protection against virulent M. tb in vivo . However, the generation of a bispecific antibody combining p4-36 and p4-163LR (Bi-S 36/163LR) significantly improved bacterial binding and antibody-dependent cellular phagocytosis (ADCP). Notably, prophylactic administration of Bi-S 36/163LR led to a ~ 1 log reduction in lung bacterial burden compared to control animals treated with isotype control. These findings define a novel, structure-guided strategy to amplify the functional capacity of natural anti- M. tb antibodies and highlight bispecific antibody platforms as promising candidates for host-directed tuberculosis immunotherapy.
Akanksha et al. (Wed,) studied this question.