A therapeutic anti-Streptococcus mutans monoclonal antibody used in human passive protection trials influences the adaptive immune response

Abstract

The adhesin known as Antigen I/II, P1 or PAc of the cariogenic dental pathogen Streptococcus mutans is a target of protective immunity and candidate vaccine antigen. Previously we demonstrated that immunization of mice with S. mutans complexed with anti-AgI/II monoclonal antibodies (MAbs) resulted in changes in the specificity, isotype and functionality of elicited anti-AgI/II antibodies in the serum of immunized mice compared to administration of bacteria alone. In the current study, an anti-AgI/II MAb reported in the literature to confer unexplained long term protection against S. mutans re-colonization following passive immunization in human clinical trials (MAb Guy’s 13), and expressed in tobacco plants (MAb Guy’s 13 plantibody), was evaluated for its potential immunomodulatory properties. Immunization of BALB/c mice with immune complexes of Guy’s 13 plantibody bound to S. mutans whole cells resulted in a similar change in specificity, isotype, and functionality of elicited anti-AgI/II antibodies as had been observed for other immunomodulatory MAbs. This new information, coupled with the recently solved crystal structure of the adhesin, now provides a rational explanation and plausible mechanism of action of passively administered Guy’s 13/Guy’s 13 plantibody in human clinical trials, and how long-term prevention of S. mutans carriage well past the application period of the therapeutic antibody could have been achieved.

Immunogenicity and In Vitro and In Vivo Protective Effects of Antibodies Targeting a Recombinant Form of the Streptococcus mutans P1 Surface Protein

“…Expression and purification of full-length P1 (CG14), truncated P1 fragments (P1 39 -512 ) (NR21, LT1, and MA41), and the adjuvant proteins (LTK4R and FliC) in E. coli or B. subtilis strains were performed according to previously described protocols (36)(37)(38). The LT derivative LTK4R shows reduced toxicity compared to the reference LT form (38), while recombinant FliC represents the phase 1 flagellin type (named FliCi) originally expressed by S. Typhimurium LT2 (39).…”

YidC1 and YidC2 are functionally distinct proteins involved in protein secretion, biofilm formation and cariogenicity of Streptococcus mutans

“…4a). P1 has a highly unusual tertiary structure (Larson et al, 2010) and the binding sites of the mAbs, several of which recognize complex conformational epitopes (McArthur et al, 2007), have now been mapped on the 3D model (Robinette et al, 2011). While there was an overall decrease in immunoreactivity of all anti-P1 antibodies tested in the absence of YidC2, the binding of some antibodies was affected more than others.…”

Potent In Vitro and In Vivo Activity of Plantibody Specific for Porphyromonas gingivalis FimA

“…In some human trials, passive immunization using the plantibodies exhibited long-term effects on S. mutans recolonization, lasting up to 2 years (20). Recently, Robinette et al (47) proposed that the long-term effect of passively administered Guy's 13 plantibody may be due to the immunomodulatory property of the antibody. In the study, immune complexes of Guy's 13 plantibody bound to S. mutans whole cells induced change in specificity, isotype, and functionality of the elicited anti-AgI/II antibodies.…”

“…simple monovalent adhesive interaction but may act by a higherorder structural mechanism through which immune complexes of the plantibody bound to S. mutans whole cells increase the immunogenicity of relevant target epitopes. In fact, long-term effects of passively administered antibody are not uncommon and may stem from the deliberate or inadvertent formation of immune complexes in situ (47,48).…”

“…Similarly, anti-FimA plantibody may be used as a mouthwash or topically applied into the subgingival area of teeth after periodontal scaling and root planing and intervention for periodontal disease. Before applying such a strategy, further study is needed to determine whether anti-FimA plantibody has any modulatory effect on the host immune response to P. gingivalis in vivo and to define an optimal antigen/antibody ratio for eliciting the beneficial immunomodulatory effect, as observed in Guy's 13 plantibody (47). Further studies employing P. gingivalis strains with different types of fimbriae are also required to investigate the inhibitory effects of anti-FimA plantibody and its usefulness for passive immunization to control P. gingivalis-induced periodontal disease.…”