A Novel Approach to Enhance Specific Immunity by Constraining Antibodies on Nanoparticles

Antibodies have exquisite specificity for their antigen.  Thus antibodies have great therapeutic potential in terms of selectively targeting receptors to either promote or inhibit receptor activity.  Likewise, antibodies can target infected or tumor cells by recognizing their antigen on the cell of interest.  However, the exquisite specificity imparted by the antibody-antigen interaction can be abrogated by the expression of the target receptor on off target cells.  For example soluble anti-CD3 will activate all T cells not just the T cells of interest but on all T cells.  Likewise, anti-CTLA-4 and anti-PD-1 will block these molecules on all T cells not just the T cells of interest.  This concept of the dichotomy of selective target specificity in the absence of cellular specificity can be extended generically to receptor-ligand interactions.  That is the administration of a ligand might have great specificity for a receptor but if the receptor is found both on cells of interest AND normal cells this specificity is in part negated.  
We observed that in T cells upon activation by antigen TCR and PD-1 cluster when compared to nave cells.  We hypothesized that the differences in receptor clustering could be exploited to impart cellular specificity with regard to anti-CD3 activating and anti-PD-1 blocking and agonistic antibodies.  We demonstrate that by constraining anti-CD3 or anti-PD-1 on the surface of a nanoparticle of a specific size we can specifically activate or inhibit antigen-specific T cells of interest without affecting the activation status of antigen-irrelevant cells.  Thus constraining anti-CD3, anti-PD-1 or potentially any blocking, cytotoxic or agonistic antibody can promote the selective activation of preventative and therapeutic vaccines and immunotherapy for infectious diseases or cancer.  Conversely, such an approach might be used to selectively inhibit immune responses in autoimmune diseases and transplantation.  Furthermore, we believe that this approach (constraining a ligand on the surface of a nanoparticle to gain cellular selectivity) might be applied to a vast array of ligand receptor combinations.

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