Some Thoughts on the Use of Intravenous Immune Globulins
               This is another note coming from material gathered for my in progress book on plasma proteins.  Intravenous immune globulin (IVIG) is approved for use in primary immune deficiency (1).  While there are efforts to develop recombinant polyclonal antibodies (2,3) , it is not clear as to whether the recombinant polyclonal product will be truly competitive with the plasma-derived product.   The existing polyclonal IVIG product is a safe product with few adverse reactions. There is some interest in gene therapy for immune deficiency (4) but such therapy is in the distant future considering the slow progress in this therapeutic approach.   The use of IVIG for primary immune deficiency  is secure; however, the bulk of the use of IVIG is for "off-label" indications such chronic inflammatory demyelinating polyneuropathy (5-7).  Here there are several major issues with the off-label use of IVIG.  First, the molecular mechanism of IVIG is, at best, poorly understood.  Second, it is clear that a only a very small portion of the commercial IVIG product is required for the therapeutic effect  (8-11).   Elucidation of the molecular mechanism of action will allow the identification of the IVIG fraction required for the therapeutic effect.  This should allow the development of a monoclonal antibody for many of the current and proposed off-label indications of IVIG.  That said, I may be overlooking the power of polyclonality in some of these applications but that likely needs to be determined to justify continued use of IVIG (12,13).  I don't want to leave the impression that IVIG is in any way an eclipsed product but rather is considerable opportunity in the area of infectious disease (14).
References
1. Cunningham-Rundles, C., Key aspects for successful immunoglobulin therapy of primary immunodeficiencies, Clin.Exp.Immunol. 164 (Suppl. 2), 16-19, 2011.
2.  Tolstrup, A.B., Frandsen, T.P., and Bregenhot,S., Development of recombinant human polyclonal antibodies for the treatment of complex human diseases, Expt.Opinion Biol.Ther. 6, 905-912, 2006
3.  Stasi, R., Rozrolimupab, symphobodies against rhesus D, for the potential prevention of hemolytic disease of the newborn and the treatment of idiopathic thrombocytopenic purpura, Curr.Opin.Mol.Ther. 12, 734-740, 2010.
4.  Fischer, A., Hacein-Bey-Abina, S., and Cavazzano-Calvo, M., Gene therapy for primary adaptive immune deficiencies, J.Allergy Clin.Immunol. 127, 1356-1359, 2011.
5. Darabi, K., Abdel-Wahab, O., and Dzik, W.H., Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature, Transfusion 46, 741-751, 2006.
6.  Foster, R., Suri, A., Filate, W., et al., Use of intravenous immune globulin in the ICU: a retrospective review of prescribing practices and patient outcomes, Transfus.Med. 20, 403-408, 2010.
7. Simoens, S., The use of intravenous immunoglobulins in Belgium, Int.Arch.Allergy Immunol. 154, 173-176, 2011
8. Fuchs, S., Feferman, T., Meidler, R., et al., A disease-specific fraction isolated from IVIG is essential for the immunosuppressive effect of IVIG in experimental autoimmune myasthenia gravis, J.Neuroimmunol. 194, 89-96, 2008.
9.  Mimouni, D., Blank, M., Payne, A.S., et al., Efficacy of intravenous immunoglobulin (IVIG) affinity-purified anti-desmoglein anti-idiotypic antibodies in the treatment of an experimental model of pemphigus,  Clin.Exptl.Immunol. 162, 543-549, 2010.
10.  Stadlmann, J., Weber, A., Pabst, M., et al., A close look at human IgG sialylation and subclass distribution after lectin fractionation, Proteomics  9, 4143-4153, 2009.
11.  Séïté, J.F., Cornec, D., Renaudineau, Y., et al., IVIg modulates BCR signaling through CD22 and promotes apoptosis in mature B lymphocytes, Blood 116, 1698-1704, 2010.
12.  Lemieux, R., Bazin, R., and Néron, S., Therapeutic intravenous immunoglobulins, Mol.Immunol. 42, 839-848, 2005.
13.  Hartung, H.-P., Mouthon, L.,  Ahmed, R., et al., Clinical applications of intravenous immunoglobulins (IVIg) - beyond immunodeficiencies and neurology, Clin.Exptl.Immunol. 153 (Suppl 1), 23-33, 2009.
14.  Luke, T.C., Cadadevall,A., Watowich, S.J., et al., Hark back: passive immunotherapy for influenza other infections, Crit.Care.Med. 38 (4 Suppl), e66-73, 2010.