Optimization of monoclonal anti-erythrocyte antibodies for improved immunoprophylaxis in a murine model

Donor-derived anti-D prevents hemolytic disease of the fetus and newborn by a process known as antibody-mediated immune suppression (AMIS). It is highly desirable to replace donor-derived anti-D with a monoclonal antibody, however the mechanism(s) of AMIS remains unclear. In this application we propose to examine mechanisms of AMIS induction in a full murine model. We have preliminary data indicating that the Fc region of the AMIS IgG drives AMIS activity and objective 1 will therefore determine and substantiate if AMIS-induction is dependent upon the Fc region of IgG. The IgG Fc region has a single glycosylation site which controls IgG immune functions and can fine-tune IgG immune activities. Objective 2 will first examine if absolute Fc glycosylation is important for AMIS activity. Then we shall generate IgG Fc glycan isoforms (each known to be optimal for different activating/inhibitory functions) to determine if selected major glycan isoforms can be used to optimize IgG AMIS activity. Finally, some monoclonal AMIS antibodies can suppress while others enhance the immune response. Objective 3 is focused on understanding which attributes of an AMIS antibody contribute to “suppression” versus “enhancement” to avoid enhancement which has unfortunately occurred in some patients treated with monoclonal anti-D antibodies.

LAZARUS, Alan

St. Michael's Hospital

Intramural Research Grant Program

Ontario

$400,000