Krishna, M. & Nadler, S. G. Immunogenicity to biotherapeutics—the role of anti-drug immune complexes. Front. Immunol. 7, 21. https://doi.org/10.3389/fimmu.2016.00021 (2016).
Google Scholar
Dingman, R. & Balu-Iyer, S. V. Immunogenicity of protein pharmaceuticals. J. Pharm. Sci. 108, 1637–1654. https://doi.org/10.1016/j.xphs.2018.12.014 (2019).
Google Scholar
Hermeling, S., Crommelin, D. J., Schellekens, H. & Jiskoot, W. Structure-immunogenicity relationships of therapeutic proteins. Pharm. Res. 21, 897–903. https://doi.org/10.1023/b:pham.0000029275.41323.a6 (2004).
Google Scholar
Lumizyme [Package Insert]. (Genzyme Corporation CM, 2011).
Myozyme [Package Insert]. (Genzyme Corporation CM, 2017).
Banugaria, S. G. et al. Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic protein: Lessons learned from Pompe disease. Genet. Med. 15, 123–131. https://doi.org/10.1038/gim.2012.110 (2013).
Google Scholar
Hay, C. R. et al. Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK haemophilia centre directors organisation. Thromb. Haemost. 79, 762–766 (1998).
Google Scholar
Lusher, J. M., Arkin, S., Abildgaard, C. F. & Schwartz, R. S. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate Previously Untreated Patient Study Group. N. Engl. J. Med. 328, 453–459. https://doi.org/10.1056/NEJM199302183280701 (1993).
Google Scholar
Lollar, P., Healey, J. F., Barrow, R. T. & Parker, E. T. Factor VIII inhibitors. Adv. Exp. Med. Biol. 489, 65–73. https://doi.org/10.1007/978-1-4615-1277-6_6 (2001).
Google Scholar
Zhou, Z. Y. et al. Burden of illness: Direct and indirect costs among persons with hemophilia A in the United States. J. Med. Econ. 18, 457–465. https://doi.org/10.3111/13696998.2015.1016228 (2015).
Google Scholar
Gaitonde, P. et al. Exposure to factor VIII protein in the presence of phosphatidylserine induces hypo-responsiveness toward factor VIII challenge in hemophilia A mice. J. Biol. Chem. 288, 17051–17056. https://doi.org/10.1074/jbc.C112.396325 (2013).
Google Scholar
Ramakrishnan, R., Davidowitz, A. & Balu-Iyer, S. V. Exposure of FVIII in the presence of phosphatidyl serine reduces generation of memory B-cells and induces regulatory T-cell-mediated hyporesponsiveness in hemophilia A mice. J. Pharm. Sci. 104, 2451–2456. https://doi.org/10.1002/jps.24513 (2015).
Google Scholar
Schneider, J. L. & Balu-Iyer, S. V. Phosphatidylserine converts immunogenic recombinant human acid alpha-glucosidase to a tolerogenic form in a mouse model of pompe disease. J. Pharm. Sci. 105, 3097–3104. https://doi.org/10.1016/j.xphs.2016.06.018 (2016).
Google Scholar
Glassman, F. Y. et al. Phosphatidylserine is not just a cleanup crew but also a well-meaning teacher. J. Pharm. Sci. 107, 2048–2054. https://doi.org/10.1016/j.xphs.2018.03.027 (2018).
Google Scholar
Gaitonde, P., Peng, A., Straubinger, R. M., Bankert, R. B. & Balu-Iyer, S. V. Phosphatidylserine reduces immune response against human recombinant Factor VIII in Hemophilia A mice by regulation of dendritic cell function. Clin. Immunol. 138, 135–145. https://doi.org/10.1016/j.clim.2010.10.006 (2011).
Google Scholar
Kerr, D. et al. Sensitivity of peripheral membrane proteins to the membrane context: A case study of phosphatidylserine and the TIM proteins. Biochim. Biophys. Acta Biomembr. 2126–2133, 2018. https://doi.org/10.1016/j.bbamem.2018.06.010 (1860).
Google Scholar
Tietjen, G. T. et al. Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4. Proc. Natl. Acad. Sci. USA 111, E1463-1472. https://doi.org/10.1073/pnas.1320174111 (2014).
Google Scholar
Verbrugghe, P. et al. Murine M cells express annexin V specifically. J. Pathol. 209, 240–249. https://doi.org/10.1002/path.1970 (2006).
Google Scholar
Cunin, P. et al. Clusterin facilitates apoptotic cell clearance and prevents apoptotic cell-induced autoimmune responses. Cell Death Dis. 7, e2215. https://doi.org/10.1038/cddis.2016.113 (2016).
Google Scholar
Futter, C. E. & White, I. J. Annexins and endocytosis. Traffic 8, 951–958. https://doi.org/10.1111/j.1600-0854.2007.00590.x (2007).
Google Scholar
Kawasaki, Y., Nakagawa, A., Nagaosa, K., Shiratsuchi, A. & Nakanishi, Y. Phosphatidylserine binding of class B scavenger receptor type I, a phagocytosis receptor of testicular sertoli cells. J. Biol. Chem. 277, 27559–27566. https://doi.org/10.1074/jbc.M202879200 (2002).
Google Scholar
Rigotti, A., Acton, S. L. & Krieger, M. The class B scavenger receptors SR-BI and CD36 are receptors for anionic phospholipids. J. Biol. Chem. 270, 16221–16224. https://doi.org/10.1074/jbc.270.27.16221 (1995).
Google Scholar
Weiner, H. L. Oral tolerance, an active immunologic process mediated by multiple mechanisms. J. Clin. Investig. 106, 935–937. https://doi.org/10.1172/JCI11348 (2000).
Google Scholar
Weiner, H. L., da Cunha, A. P., Quintana, F. & Wu, H. Oral tolerance. Immunol. Rev. 241, 241–259. https://doi.org/10.1111/j.1600-065X.2011.01017.x (2011).
Google Scholar
Fadok, V. A. et al. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 148, 2207–2216 (1992).
Google Scholar
Bar, P. R. Apoptosis–the cell’s silent exit. Life Sci. 59, 369–378. https://doi.org/10.1016/0024-3205(96)00315-3 (1996).
Google Scholar
Munoz, L. E., Lauber, K., Schiller, M., Manfredi, A. A. & Herrmann, M. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat. Rev. Rheumatol. 6, 280–289. https://doi.org/10.1038/nrrheum.2010.46 (2010).
Google Scholar
Miyanishi, M. et al. Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435–439. https://doi.org/10.1038/nature06307 (2007).
Google Scholar
Santiago, C. et al. Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds. Immunity 27, 941–951. https://doi.org/10.1016/j.immuni.2007.11.008 (2007).
Google Scholar
Kobayashi, N. et al. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27, 927–940. https://doi.org/10.1016/j.immuni.2007.11.011 (2007).
Google Scholar
Yang, P. C. et al. TIM-4 expressed by mucosal dendritic cells plays a critical role in food antigen-specific Th2 differentiation and intestinal allergy. Gastroenterology 133, 1522–1533. https://doi.org/10.1053/j.gastro.2007.08.006 (2007).
Google Scholar
Juliano, R. L. & Stamp, D. The effect of particle size and charge on the clearance rates of liposomes and liposome encapsulated drugs. Biochem. Biophys. Res. Commun. 63, 651–658. https://doi.org/10.1016/s0006-291x(75)80433-5 (1975).
Google Scholar
Frasch, S. C. et al. Neutrophils regulate tissue Neutrophilia in inflammation via the oxidant-modified lipid lysophosphatidylserine. J. Biol. Chem. 288, 4583–4593. https://doi.org/10.1074/jbc.M112.438507 (2013).
Google Scholar
Rice, D. R., Clear, K. J. & Smith, B. D. Imaging and therapeutic applications of zinc(II)-dipicolylamine molecular probes for anionic biomembranes. Chem. Commun. 52, 8787–8801. https://doi.org/10.1039/c6cc03669d (2016).
Google Scholar
Andree, H. A. et al. Binding of vascular anticoagulant alpha (VAC alpha) to planar phospholipid bilayers. J. Biol. Chem. 265, 4923–4928 (1990).
Google Scholar
Weiner, H. L. Oral tolerance: Immune mechanisms and treatment of autoimmune diseases. Immunol. Today 18, 335–343 (1997).
Google Scholar
Weiner, H. L. et al. Oral tolerance: Immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu. Rev. Immunol. 12, 809–837. https://doi.org/10.1146/annurev.iy.12.040194.004113 (1994).
Google Scholar
Bjornsson, O. G., Murphy, R. & Chadwick, V. S. Physiochemical studies of indocyanine green (ICG): Absorbance/concentration relationship, pH tolerance and assay precision in various solvents. Experientia 38, 1441–1442. https://doi.org/10.1007/BF01955757 (1982).
Google Scholar
Kraft, J. C. & Ho, R. J. Interactions of indocyanine green and lipid in enhancing near-infrared fluorescence properties: The basis for near-infrared imaging in vivo. Biochemistry 53, 1275–1283. https://doi.org/10.1021/bi500021j (2014).
Google Scholar
Yoon, H. J., Lee, H. S., Lim, J. Y. & Park, J. H. Liposomal indocyanine green for enhanced photothermal therapy. ACS Appl. Mater Interfaces 9, 5683–5691. https://doi.org/10.1021/acsami.6b16801 (2017).
Google Scholar
Wang, X., Terhorst, C. & Herzog, R. W. In vivo induction of regulatory T cells for immune tolerance in hemophilia. Cell Immunol. 301, 18–29. https://doi.org/10.1016/j.cellimm.2015.10.001 (2016).
Google Scholar
Oida, T. et al. CD4+CD25− T cells that express latency-associated peptide on the surface suppress CD4+CD45RBhigh-induced colitis by a TGF-beta-dependent mechanism. J. Immunol. 170, 2516–2522. https://doi.org/10.4049/jimmunol.170.5.2516 (2003).
Google Scholar
Huang, W., Solouki, S., Carter, C., Zheng, S. G. & August, A. Beyond type 1 regulatory T cells: Co-expression of LAG3 and CD49b in IL-10-producing T cell lineages. Front. Immunol. 9, 2625. https://doi.org/10.3389/fimmu.2018.02625 (2018).
Google Scholar
Gagliani, N. et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat. Med. 19, 739–746. https://doi.org/10.1038/nm.3179 (2013).
Google Scholar
Schmidt, A., Oberle, N. & Krammer, P. H. Molecular mechanisms of treg-mediated T cell suppression. Front. Immunol. 3, 51. https://doi.org/10.3389/fimmu.2012.00051 (2012).
Google Scholar
Romano, M., Fanelli, G., Albany, C. J., Giganti, G. & Lombardi, G. Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity. Front. Immunol. 10, 43. https://doi.org/10.3389/fimmu.2019.00043 (2019).
Google Scholar
Sakaguchi, S., Wing, K., Onishi, Y., Prieto-Martin, P. & Yamaguchi, T. Regulatory T cells: How do they suppress immune responses?. Int. Immunol. 21, 1105–1111. https://doi.org/10.1093/intimm/dxp095 (2009).
Google Scholar
Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787. https://doi.org/10.1016/j.cell.2008.05.009 (2008).
Google Scholar
Lim, H. W., Hillsamer, P., Banham, A. H. & Kim, C. H. Cutting edge: Direct suppression of B cells by CD4+ CD25+ regulatory T cells. J. Immunol. 175, 4180–4183. https://doi.org/10.4049/jimmunol.175.7.4180 (2005).
Google Scholar
Neutra, M. R., Pringault, E. & Kraehenbuhl, J. P. Antigen sampling across epithelial barriers and induction of mucosal immune responses. Annu. Rev. Immunol. 14, 275–300. https://doi.org/10.1146/annurev.immunol.14.1.275 (1996).
Google Scholar
Mabbott, N. A., Donaldson, D. S., Ohno, H., Williams, I. R. & Mahajan, A. Microfold (M) cells: Important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 6, 666–677. https://doi.org/10.1038/mi.2013.30 (2013).
Google Scholar
Hilligan, K. L., Connor, L. M., Schmidt, A. J. & Ronchese, F. Activation-induced TIM-4 expression identifies differential responsiveness of intestinal CD103+ CD11b+ dendritic cells to a mucosal adjuvant. PLoS ONE 11, e0158775. https://doi.org/10.1371/journal.pone.0158775 (2016).
Google Scholar
Shaw, T. N. et al. Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression. J. Exp. Med. 215, 1507–1518. https://doi.org/10.1084/jem.20180019 (2018).
Google Scholar
Mazzini, E., Massimiliano, L., Penna, G. & Rescigno, M. Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1(+) macrophages to CD103(+) dendritic cells. Immunity 40, 248–261. https://doi.org/10.1016/j.immuni.2013.12.012 (2014).
Google Scholar
van den Berg, H. M. et al. Timing of inhibitor development in more than 1000 previously untreated patients with severe hemophilia A. Blood 134, 317–320. https://doi.org/10.1182/blood.2019000658 (2019).
Google Scholar
Graca, L. & Waldmann, H. Inducing immune tolearnce to therapeutic protein, cells and tissues. Front. Immunol. https://doi.org/10.3389/fimmu.2017.00560 (2018).
Google Scholar
Raben, N. et al. Enzyme replacement therapy in the mouse model of Pompe disease. Mol. Genet. Metab. 80, 159–169. https://doi.org/10.1016/j.ymgme.2003.08.022 (2003).
Google Scholar
Ramani, K. et al. Phosphatidylserine containing liposomes reduce immunogenicity of recombinant human factor VIII (rFVIII) in a murine model of hemophilia A. J. Pharm. Sci. 97, 1386–1398. https://doi.org/10.1002/jps.21102 (2008).
Google Scholar
Bartlett, G. R. Phosphorus assay in column chromatography. J. Biol. Chem. 234, 466–468 (1959).
Google Scholar
Balu-Iyer, S. V., Ramani, K. & Straubinger, R. M. Method of complexing a protein by the use of a dispersed system and proteins thereof. U.S Patent No. 7625584 (U.S. Patent and Trademark Office, 2009).
Ramani, K., Purohit, V. S., Miclea, R. D., Middaugh, C. R. & Balasubramanian, S. V. Lipid binding region (2303–2332) is involved in aggregation of recombinant human FVIII (rFVIII). J. Pharm. Sci. 94, 1288–1299 (2005).
Google Scholar
Verbruggen, B. et al. The Nijmegen modification of the Bethesda assay for factor VIII: C inhibitors: Improved specificity and reliability. Thromb. Haemost. 73, 247–251 (1995).
Google Scholar

