Clinical Use and Therapeutic Potential of IVIG/SCIG, Plasma-Derived IgA or IgM, and Other Alternative Immunoglobulin Preparations

Abstract

Intravenous and subcutaneous immunoglobulin preparations, consisting of IgG class antibodies, are increasingly used to treat a broad range of pathological conditions, including humoral immune deficiencies, as well as acute and chronic inflammatory or autoimmune disorders. A plethora of Fab- or Fc-mediated immune regulatory mechanisms has been described that might act separately or in concert, depending on pathogenesis or stage of clinical condition. Attempts have been undertaken to improve the efficacy of polyclonal IgG preparations, including the identification of relevant subfractions, mild chemical modification of molecules, or modification of carbohydrate side chains. Furthermore, plasma-derived IgA or IgM preparations may exhibit characteristics that might be exploited therapeutically. The need for improved treatment strategies without increase in plasma demand is a goal and might be achieved by more optimal use of plasma-derived proteins, including the IgA and the IgM fractions. This article provides an overview on the current knowledge and future strategies to improve the efficacy of regular IgG preparations and discusses the potential of human plasma-derived IgA, IgM, and preparations composed of mixtures of IgG, IgA, and IgM.

Enhanced Pro-apoptotic Effects of Fe(II)-Modified IVIG on Human Neutrophils

“…As a consequence, IVIG exhibits an immense repertoire of antibodies with specificities toward a magnitude of antigens (1). Its inherent polyspecificity may provide the basis of its pluripotent anti-inflammatory effects if used as a high-dose therapy (2), whereby a broad range of different mechanisms may act in concert, also depending on the pathogenesis of the targeted disease (3)(4)(5). Accordingly, IVIG is successfully used for the treatment of a broad range of heterogenous diseases, including neutrophil-associated disorders such as Kawasaki disease, an acute febrile vasculitis syndrome (6).…”

High dose IVIG successfully reduces high rhGAA IgG antibody titers in a CRIM-negative infantile Pompe disease patient

“…This combination of HSAT with further clinical decline presented a need for a safe intervention, in this case achieved by high dose IVIG therapy, 1 g/kg to reduce antibody titers. IVIG is known for its anti-inflammatory and immunomodulatory effects with a wide clinical use in numerous autoimmune and inflammatory conditions like antiphospholipid-antibody syndrome, chronic inflammatory demyelinating polyneuropathy, Kawasaki disease, and Crohn’s disease [22–24]. Our rationale for using high dose IVIG in this patient was the potential binding of IVIG to the neonatal Fc receptors (FcRn) [23,25] which are responsible for recycling of antibodies, including pathological antibodies such as anti-rhGAA thus blocking rhGAA antibodies from being recycled and leading to their destruction.…”

“…Saturating the FcRn receptor with high dose IVIG may prevent such recycling so that anti-rhGAA IgG antibody titers decrease over time as they are directed towards the degradation pathway [26]. IVIG in lower doses, used as part of the ITI protocol with rituximab and methotrexate in CRIM-negative cases, is primarily added as a source of passive immunity as the pooled IVIG has disease specific IgG antibodies to prevent inter-current infections [7,16,22,17]. The effectiveness of high dose IVIG in this case with significant morbidity represents an alternative approach to reducing antibody titers.…”

Immunoglobulin replacement therapy targeting the BCR in chronic lymphocytic leukemia

“…Thus, in addition to the proposed cytokine profile in the manuscript, unresponsiveness by some CLL samples could be due to the low density of the FcγR or to other factors that still need to be unraveled. In addition to the direct effect on the BCR signaling, several immunomodulatory effects of antibodies in the IgRT have been described that could also contribute to the effect observed in vivo [ 6 ], and that should be considered in future mechanistic experiments.…”

“…However, IgRT only provides IgG, and since CLL patients are often also deficient in other immunoglobulin isotypes [ 1 , 2 ], introduction of IgM and IgA might boost efficacy leading to control of a broader set of infections. Unfortunately, convenient access to these isotypes has not been achieved, although groups are working in optimizing the formulation and chemistry [ 6 ]. Finally, although the etiology of the hypogammaglobulinaemia is not completely understood, it is known that several factors important for the promotion of plasma cells and Ig production are altered in CLL patients, including reduced T-cell function and increased levels of TGF-β [ 2 , 3 ].…”