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.
Highlights
Though any genetic variant of a protein could be called an allotype, in immunology, the term is commonly used for hereditary antigenic determinants expressed on immunoglobulin (Ig) polypeptide chains
With the exception of allelic GM3 and GM17 determinants expressed in the Fd region, all other GM alleles are expressed in the Fc region of γ chains
genome-wide association studies (GWAS) are assumed to be able to detect/tag all share any haplotypes. Nucleotide substitutions (SNPs) in the genome whose frequency is at least 5% or less
Summary
Though any genetic variant of a protein could be called an allotype, in immunology, the term is commonly used for hereditary antigenic determinants expressed on immunoglobulin (Ig) polypeptide chains. Using an ADCC inhibition assay, we have shown that IgG1 expressing the GM 3+,1-,2- allotypes was effective in inhibiting cetuximab- and trastuzumab-mediated ADCC of respective target cells, in the presence of NK cells expressing either valine or phenylalanine allele of FcγRIIIa [51] These findings have important implications for engineering antibodies with human γ1 C region. No data are available on the prevalence of anti-allotype antibodies in patients treated with mAbs. In summary, inclusion of polymorphic GM, KM, and FcγR alleles in cancer immunology investigations could identify novel immune pathways to tumor immunity.
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