The immunogenicity of human-origin therapeutic antibodies are associated with V gene usage

Abstract

Therapeutic antibodies can elicit unwanted immune responses in a subset of patients, which leads to the production of anti-drug antibodies (ADA). Some of these ADAs have been reported to effect the pharmacokinetics, efficacy and/or safety of the therapeutic antibodies. The sequence diversity of antibodies are generated by VDJ recombination and mutagenesis. While the antibody generation process can create a large candidate pool for identifying high-affinity antibodies, it also could produce sequences that are foreign to the human immune system. However, it is not clear how VDJ recombination and mutagenesis impact the clinical ADA rate of therapeutic antibodies. In this study, we identified a positive correlation between the clinical ADA rate and the number of introduced mutations in the antibody sequences. We also found that the use of rare V alleles in human-origin antibody therapeutics is associated with higher risk of immunogenicity. The results suggest that antibody engineering projects should start with frameworks that contain commonly used V alleles and prioritize antibody candidates with low number of mutations to reduce the risk of immunogenicity.

Humanization of pan-HLA-DR mAb 44H10 Hinges on Critical Residues in the Antibody Framework

“…Indeed, Fabs using either an IGHV2-26 heavy chain or an engineered IGHV4-59 heavy chain (with FW back-mutations) paired with nearly identical light chains (differing only by two amino acids) had melting temperatures differing by ~5.5°C (Figure 3E,H), illustrating the superior thermostability of the IGHV4-59 framework. Another consideration is the frequency of chosen framework regions in various human populations, as V and J genes are polymorphic [52][53][54], and the use of rare V alleles in antibody therapeutics has been associated with a higher risk of immunogenicity [55]. Thus, commonly used V alleles serve as a good starting point for the engineering of humanized antibodies as they are likely to be recognized evenly in all human populations.…”

Humanization of Pan-HLA-DR mAb 44H10 Hinges on Critical Residues in the Antibody Framework

“…Indeed, Fabs using either an IGHV2-26 heavy chain or an engineered IGHV4-59 heavy chain (with FW back-mutations) paired with nearly identical light chains (differing only by two amino acids) had melting temperatures differing by ~5.5 °C ( Figure 3 E,H), illustrating the superior thermostability of the IGHV4-59 framework. Another consideration is the frequency of chosen framework regions in various human populations, as V and J genes are polymorphic [ 52 , 53 , 54 ], and the use of rare V alleles in antibody therapeutics has been associated with a higher risk of immunogenicity [ 55 ]. Thus, commonly used V alleles serve as a good starting point for the engineering of humanized antibodies as they are likely to be recognized evenly in all human populations.…”