The interaction of PrP C to PrP Sc is critically dependent on the structural compatibility of the molecules as supported by the existence of a species barrier for prion infection, related to minor differences in the primary sequence of PrP C in different species. Therefore, it is not surprising that antibodies that may alter or mask the critical epitopes on PrP C and/or PrP Sc , involved during the mutual conformational complementarity required in prion propagation, will be inhibitory for prion replication. Although many anti-PrP antibodies targeting different regions of PrP may have some therapeutic effect in vitro, it is not clear how this relates to their efficacy in vivo. On the one hand, it is tempting to speculate that only the antibodies exhibiting near complete inhibition in vitro would be effective in vivo given the obstacle of the blood brain barrier and access to PrP in cells. However, it is also possible that only partial inhibition of conversion is required in vivo allowing the cells to ''recover''. In either case, it would be advantageous for these therapeutic antibodies to have high affinities of binding to PrP C and/or PrP Sc , as well as targeting specific critical PrP domains. One can hypothesize that the simultaneous targeting of more than one critical epitope will lead to greater benefits. However, co-treatment experiments performed with a mixture of two antibodies compatibly binding cell-surface PrP C did not show any benefit with compared to treatment involving a single Mab in our current experiments. In a previous study [58] , we demonstrated synergistic binding with one of our antibody pairs. Synergistic binding of inhibitory Mabs, i.e. reaction with an antibody that increases the binding of the second antibody, would be predicted to enhance the inhibitory effect. Further studies with antibody pairs fitting this description will be required to test this hypothesis. In addition, determining the significance of the Mab's ability to bind both PrP C and PrP Sc may provide further insight into the conversion process.