The mechanism of action of monoclonal antibody blends in the potential replacement of anti-D in HDFN

Although polyclonal anti-D has been highly successful at preventing hemolytic disease of the fetus and newborn, a recombinant alternative is long overdue. To design a successful monoclonal antibody (mAb) therapy to replace plasma-derived anti-D, it is important to determine the antibody–mediated immune suppression (AMIS) mechanism. Recently, blends of mAbs targeting different epitopes recapitulated the ‘complete’ AMIS induced by anti-RBC polyclonal antibodies, but the exact mechanism remains unknown. Potential mechanisms for AMIS induced by mAb blends: 1) Steric-hindrance 2) The presence of IgG-Fc regions on the red blood cell (RBC) surface 3) Several antibodies on the RBC surface induce antigen loss on the erythrocyte 4) Deviation of the immune response from the RBC toward the AMIS antibody The aim of this project is to determine if AMIS induced by mAb blends is due to one of these mechanisms. We will use the HOD mouse model of RBC immunization, with RBCs expressing a well-characterized antigen, in combination with a panel of mAbs that recognize different epitopes of the antigen. This work will provide critical knowledge of the mechanism of action of AMIS antibodies to provide a much-needed biological understanding of AMIS mechanisms that will inform the development of a recombinant anti-D therapeutic.

LAZARUS, Alan

St. Michael's Hospital

Postdoctoral Fellowship Program

Ontario

$165,000