The forgotten tale of immunoglobulin allotypes in cancer risk and treatment

Abstract

Monoclonal antibody (mAb) has fulfilled the promise of being the “Magic Bullet” in oncology with the clinical success of mAbs against CD20, Her-2/neu, epidermal growth factor receptor, vascular endothelial cell growth factor and others in a variety of cancers. Most manufacturers of mouse-human chimeric antibodies (and most immunologists) have treated the constant region of human immunoglobulin (Ig) as if it were naturally monomorphic and therefore not immunogenic in humans. In fact, the constant region of Ig heavy and light chain is highly polymorphic, and yet Ig haplotypes are usually not defined by genome-wide association studies nor are they considered to be important for optimizing mAb therapy. We hereby summarize evidence that Ig allotypes are important and biologically relevant in that they contribute to the etiopathogenesis of many malignant, infectious, and autoimmune diseases. Because Ig allotypes differ from each other in engaging Fc receptor, we argue that future development of effective mAb therapy for cancer should take a patient-specific approach by using the correct allotype for each patient to maximize the efficacy of this therapy.

Immunoglobulin genes implicated in glioma risk

“…Several genes, including some belonging to the immune system, have been implicated in glioma pathogenesis 1 - 10 . But the putative role of γ marker (GM) allotypes, encoded by three highly polymorphic IGHG loci 11 on chromosome 14, has not been evaluated. There is a strong immunogenetic rationale for investigating the role of GM allotypes in the etiopathogenesis of glioma considering that these determinants modulate an immunoevasion strategy of human cytomegalovirus (HCMV), a common herpes virus that is thought to be an active promoter or oncological modulator of gliomagenesis 12 - 16 .…”

NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation

“…IgG allotypes, determined by polymorphic residues on the constant region of H and L chains, also modulate avidity of the FcgR-IgG interaction and could influence, through additional mechanisms, the efficacy of a humoral response (24). Indeed, several of these genetic markers were associated with autoimmunity, malignant diseases, and susceptibility to infection (24)(25)(26) and could modulate the immune response to HSV-1.…”

“…Indeed, several of these genetic markers were associated with autoimmunity, malignant diseases, and susceptibility to infection (24)(25)(26) and could modulate the immune response to HSV-1. Twenty-six Ig allotypes have been identified in humans; these include 20 Gm allotypes, determined by polymorphisms in the gamma H chain locus (IGHG), and another 3 found on the kappa L chain (Km1, Km2, and Km3) (27).…”

Endogenous antibody responses to mucin 1 in a large multiethnic cohort of patients with breast cancer and healthy controls: Role of immunoglobulin and Fcγ receptor genes

“…One contributory factor could be the divergent allele frequencies at GM, KM, and FcγR loci among the racial groups examined in this investigation. Additionally, linkage disequilibrium between GM alleles in the Japanese is different from that in whites or blacks, resulting in distinct arrays of GM haplotypes in these groups (Oxelius and Pandey, 2013; Pandey and Li, 2013). It follows that linkage disequilibrium between any putative immune response genes for the MUC1 epitopes might also be different in these groups, contributing to the ethnic differences in genetic associations with antibody responses.…”