Research into the mechanisms of intravenous immunoglobulin is often challenging due to the complexity of polyclonal preparations, including diversity, repertoires, blocking, or anti-idiotypic antibodies.
Intravenous immunoglobulin (IVIG) has the potential to induce multiple biologic responses for targeting heterogenous disorders due to its anti-inflammatory mechanisms of actions, serving as a source for novel therapeutics, according to the results of a study published in Frontiers in Immunology. However, investigators noted that research into these mechanisms is often challenging due to the complexity of polyclonal preparations, including diversity, repertoires, blocking, or anti-idiotypic antibodies.
IVIG has been used as a replacement therapy for immunodeficiencies, as well as the treatment of some autoimmune or inflammatory disorders. The study authors noted that IVIG “contains antibodies to host attachment sites of viruses, bacteria, and bacterial toxins, which might prevent adhesion or limit sequelae of infectious disease.”
Previous studies have identified both canonical and non-canonical mechanisms for the therapeutic effects in infectious and autoimmune diseases. Data on the mechanisms have helped the development of novel therapeutics from IVIG. Investigators reviewed the recent developments of IVIG and determined the current challenges and risks of using the therapy, specifically with polyclonal immunoglobulin preparations.
In the review, investigators discussed the canonical functions, which are the more conventional functions of IVIG, including the fragment antigen binding (Fab) and the constant fragment crystallizable (Fc) domain. According to the study authors, the Fab fragment is associated with specific molecular recognition and binding antigens whereas Fc-mediated effector functions can activate or regulate immune cells.
Non-canonical functions have been interpreted as alternative antibody activities, which can include antibody-mediated catalysis and proteolytic activities, direct pathogen inactivation, modification of gene expression and metabolism, and reactive oxygen species. Investigators added that T cell epitopes, known as Tregitopes, contain the framework for Fab and Fc. The study authors noted that in research, this is thought to “expand and activate regulatory T cells subsequent to their processing and presentation on human class II major histocompatibility complex molecules by antigen-presenting cells.”
In the review, investigators did observe low IgG reactivities for tumor-associated carbohydrates antigens, which were expressed on common variable immunodeficiency-associated malignancies. They said that IVIG replacement therapy may not only help infectious diseases but could contribute to protection from malignancies that are tumor-specific antibodies in immunodeficient patients.
Another use, as detailed by the study authors, includes the use of individualized treatments with specific immunoglobulin preparations. They said that preparing IVIG consisting of IgG from those with selective IgA deficiency, rather than from healthy individuals, could be more beneficial for some patients because it would naturally enrich IgG.
As for novel immunotherapeutic agents, investigators found that polyclonal immunoglobulin preparations have helped the development of treatments for autoimmune and chronic inflammatory disorders, such as a recombinant IgG1 Fc hexamer, which had an anti-inflammatory effect on rheumatoid arthritis.
However, investigators did identify challenges due to the complexity of the preparations. This included the availability of suitable disease models and species differences of xenogeneic models. They said these could affect treatment responses, including neutrophils. Additionally, the treatment responses could vary due to patient characteristics and diseases states.
The authors wrote, “the identification of suitable biomarkers and individual antibody ‘barcodes,’ may be needed for more personalized applications and immunoglobulin products.”
Although there are challenges to the therapeutics, the study authors added that a better understanding of the diversity of the antibodies is needed for drug discovery and clinical applications, which could be essential to novel antibody immunotherapies.
von Gunten S, Schneider C, Imamovic L, Gorochov G. Antibody diversity in IVIG: therapeutic opportunities for novel immunotherapeutic drugs. Front Immunol. 2023;14:1166821. doi:10.3389/fimmu.2023.1166821