Multi-mechanistic monoclonal antibodies targeting S. aureus {alpha}-toxin and clumping factor A: Activity and efficacy comparisons of a mAb combination and an engineered bispecific antibody approach [PublishAheadOfPrint]

Secreted α-toxin (AT) and surface-localized clumping factor A (ClfA) are key virulence determinants in S. aureus bloodstream infections. We previously demonstrated that prophylaxis with a multi-mechanistic monoclonal antibody (mAb) combination against AT (MEDI4893*) and ClfA (11H10) provided greater strain coverage and improved efficacy in a S. aureus lethal bacteremia model. Subsequently, 11H10 was found to exhibit reduced affinity and impaired inhibition of fibrinogen binding to ClfA002 expressed by members of a predominant hospital associated MRSA clone, ST5. Consequently, we identified another anti-ClfA mAb (SAR114) from human tonsillar B-cells with >100-fold increased affinity for three prominent ClfA variants, including ClfA002, and potent inhibition of bacterial agglutination by 112 diverse clinical isolates. We next constructed bispecific (BiS) Abs comprised of 11H10 or SAR114 as IgG scaffold and grafted anti-AT (MEDI4893*) scFv to the amino or carboxy-terminus of the anti-ClfA heavy chains. Although the BiSAbs exhibited in vitro potencies similar to the parental mAbs, only 11H10-BiSAb, but not SAR114-BiSAb showed protective activity in murine infection models comparable to the respective mAb combination. In vivo activity with SAR114-BiSAb was observed in infection models with S. aureus lacking ClfA. Our data suggest that high affinity binding to ClfA sequesters the SAR114-BiSAb to the bacterial surface, thereby reducing both AT neutralization and protection in vivo. These results indicate that a mAb combination targeting ClfA and AT is more promising for future development than the corresponding BiSAb.

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