MHC Genetics and Immunogenicity of Therapeutic Proteins

The MHC locus is diverse and redundant in humans, with multiple genes from ancient duplication events. The genes themselves are highly polymorphic. Thus, carriage of several alleles benefits the immune system, as amino acid substitutions in the binding groove of MHC molecules can alter the repertoire of antigens presented to the adaptive immune system.

Because of the highly repetitive nature of the MHC region, high-throughput genotyping methods have not been widely applied to the study of MHC polymorphisms. Specialized SNP chips that target the sequences of MHC

alleles with a rich representation are in development. However, at present, genotyping for HLA type uses long-range PCR reactions that can identify different alleles on the basis of primer design and length of the amplicon. These tests are available through clinical laboratories at blood centers and have been used in many disease association studies; however, application of these tests to Pgx investigations has been less widespread.

Association of specific MHC alleles with development of anti-drug antibody responses has been demonstrated for both small-molecule and protein therapeutics. For example, treatment with IFN-b1b for MS leads to generation of binding or neutralizing antibodies in about 10% to 20% of the population. A study of MHC genes showed that MS patients carrying the HLA-DRB1*0701 allele had higher chances (eight out of nine) of generating antibodies against IFN-b1b (124). The HLA-B*5701 allele has been associated with severe drug hypersensitivity reactions to the antiretroviral drug abacavir (125). Further study of anti-drug antibody responses in association with MHC alleles should enhance our ability to predict which patients are prone to developing such responses.

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