complexes [46]. If the antigens were exogenous antibodies (immunoglobulins),
those antibodies are also recognized by Kupffer cells using this receptor FccR too.
In contrast, FcRn (neonatal Fc receptor) resides in hepatocytes, most of the
epithelial and endothelial cells as well as macrophages, which act to protect IgG
from degradation, by recycling the endocytosed IgG to the circulation [46, 47].
Once nanomaterials reach liver via systemic circulation, they will be contacted
by macrophages or non-professional phagocytic cells or dendritic cells (in liver,
mDC, pDC) and these cells examine whether these nanomaterials have the patterns
of pathogens or damaged cells. Nanomaterials would be taken up by Kupffer cells,
escape via fenestrae to space of Disse to reach hepatocytes and/or pDC, or circulate
back to the systemic veins (hepatic vein and inferior vena cava) via the heart to
come back again to the sinusoids [26]. It is known that the surface characteristics of
nanomaterials influence their fates in biodistribution and the innate immune
responses to systemic-injected nanomaterials had better be understood according to
the composition of the modified surfaces of these nanomaterials.
Nanomaterials are usually PEGylated and have the ligands such as antibodies on
their surface. PEGylated nanomaterials circulate longer and have been stealthy in
that they hide from immune responses [44]. PEGylated surface, either brush or
mushroom [48], should not have induced immune responses either innate or
adaptive. Interestingly, it caused IgM responses on the second injection, which
raised concern [49]. Kupffer cells would have either engulfed PEGylated nanomaterials removing completely them from the circulation very rapidly, not presenting them to the lymphocytes of adaptive immunity, or would have digested and
presented them to the cells in charge of adaptive immunity. Or the cells in charge of
this latter endeavor of antigen presenting would have been rather mDC cells or
other myeloid cells than Kupffer cells [50].
Elimination of biologics or specifically of therapeutic monoclonal antibodies
have come to be understood in very much detail during the last two decades [51–53].
As we can decorate the surfaces of nanomaterials with human, humanized, chimeric
or murine monoclonal antibodies or their engineered fragments, our knowledge of
the disposal of biomacromolecules are now be cited to predict the fate of engineered
antibody-bound nanomaterials. When the therapeutic monoclonal antibodies were to
be approved from regulatory agencies, humoral immune responses were routinely
examined and we know that ‘immunogenicity’ of these antibodies range from 0 to
99% [54, 55]. Murine antibodies tended to elicit higher anti-antibody responses,
however, human antibodies were not without antibody responses and this antibody
was supposed to be against complementarity-determining region (CDR) among
variable domains of the light and heavy chains [55]. Investigators have tried to avoid
this antibody response to the therapeutic antibodies by removing such problematic
non-human glycosylation as galactose-a1,3-galactose, N-glycolylneuraminic acid,
b1,2-xylose and a1,3 fucose during their manufacturing or by adding carbohydrate
residues to improve biodistribution [55].
Summarizing the current understanding, IgG types of therapeutic antibodies are
supposed to be cleared via FccR after uptake by expert phagocytic cells such as
Kupffer cells or recycled via FcRn after endocytosis by non-professional phagocytic
400
D. S. Lee and Y. K. Shin
those antibodies are also recognized by Kupffer cells using this receptor FccR too.
In contrast, FcRn (neonatal Fc receptor) resides in hepatocytes, most of the
epithelial and endothelial cells as well as macrophages, which act to protect IgG
from degradation, by recycling the endocytosed IgG to the circulation [46, 47].
Once nanomaterials reach liver via systemic circulation, they will be contacted
by macrophages or non-professional phagocytic cells or dendritic cells (in liver,
mDC, pDC) and these cells examine whether these nanomaterials have the patterns
of pathogens or damaged cells. Nanomaterials would be taken up by Kupffer cells,
escape via fenestrae to space of Disse to reach hepatocytes and/or pDC, or circulate
back to the systemic veins (hepatic vein and inferior vena cava) via the heart to
come back again to the sinusoids [26]. It is known that the surface characteristics of
nanomaterials influence their fates in biodistribution and the innate immune
responses to systemic-injected nanomaterials had better be understood according to
the composition of the modified surfaces of these nanomaterials.
Nanomaterials are usually PEGylated and have the ligands such as antibodies on
their surface. PEGylated nanomaterials circulate longer and have been stealthy in
that they hide from immune responses [44]. PEGylated surface, either brush or
mushroom [48], should not have induced immune responses either innate or
adaptive. Interestingly, it caused IgM responses on the second injection, which
raised concern [49]. Kupffer cells would have either engulfed PEGylated nanomaterials removing completely them from the circulation very rapidly, not presenting them to the lymphocytes of adaptive immunity, or would have digested and
presented them to the cells in charge of adaptive immunity. Or the cells in charge of
this latter endeavor of antigen presenting would have been rather mDC cells or
other myeloid cells than Kupffer cells [50].
Elimination of biologics or specifically of therapeutic monoclonal antibodies
have come to be understood in very much detail during the last two decades [51–53].
As we can decorate the surfaces of nanomaterials with human, humanized, chimeric
or murine monoclonal antibodies or their engineered fragments, our knowledge of
the disposal of biomacromolecules are now be cited to predict the fate of engineered
antibody-bound nanomaterials. When the therapeutic monoclonal antibodies were to
be approved from regulatory agencies, humoral immune responses were routinely
examined and we know that ‘immunogenicity’ of these antibodies range from 0 to
99% [54, 55]. Murine antibodies tended to elicit higher anti-antibody responses,
however, human antibodies were not without antibody responses and this antibody
was supposed to be against complementarity-determining region (CDR) among
variable domains of the light and heavy chains [55]. Investigators have tried to avoid
this antibody response to the therapeutic antibodies by removing such problematic
non-human glycosylation as galactose-a1,3-galactose, N-glycolylneuraminic acid,
b1,2-xylose and a1,3 fucose during their manufacturing or by adding carbohydrate
residues to improve biodistribution [55].
Summarizing the current understanding, IgG types of therapeutic antibodies are
supposed to be cleared via FccR after uptake by expert phagocytic cells such as
Kupffer cells or recycled via FcRn after endocytosis by non-professional phagocytic
400
D. S. Lee and Y. K. Shin