Immunogenicity in Antibody Therapeutics

Monoclonal antibodies (mAbs) are attractive therapeutic tools, being highly specific for their targets. However, immunogenicity—the potential of a therapeutic antibody to provoke an immune response—remains a risk.

What is Immunogenicity?

Immunogenicity refers to the immune system’s recognition of a therapeutic antibody as foreign, leading to the production of anti-drug antibodies (ADAs). These ADAs can neutralize the therapeutic efficacy, alter pharmacokinetics, and even cause adverse immune responses. Factors influencing immunogenicity are categorized as:

• Extrinsic Factors: Aggregates, contaminants, or co-administered medications that trigger immune responses. 

• Intrinsic Factors: The molecular structure of the antibody, including variable (V) regions and glycosylation patterns, which can harbor immunogenic epitopes. 

Humanization and Fully Human Antibodies

Therapeutic antibodies have evolved through several generations: 

• Murine Antibodies: Derived from mice, these showed efficacy but caused significant immunogenic responses in humans due to their foreign origin. 

• Chimeric Antibodies: Featuring human constant regions combined with murine variable regions, these were less immunogenic but not without risk. 

• Humanized Antibodies: Retaining murine CDRs within human frameworks, these reduced immunogenicity further while maintaining specificity. 

• Fully Human Antibodies: Developed through phage display or transgenic mice, these antibodies have entirely human amino acid sequences, drastically lowering immunogenicity.  

The Root Cause of Immunogenicity

The immunogenicity of therapeutic antibodies often arises from their CDR (complementarity-determining regions)—the regions responsible for antigen binding. These CDRs can harbor CD4+ T cell epitopes, which are linear peptide fragments recognized by the patient’s immune system. When presented by HLA class II molecules, these epitopes activate CD4+ T cells, initiating a cascade that produces ADAs. 

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References:

1. Harding, F. A., Stickler, M. M., Razo, J., & DuBridge, R. B. (2010). The immunogenicity of humanized and fully human antibodies: Residual immunogenicity resides in the CDR regions. MAbs, 2(3), 256. https://doi.org/10.4161/mabs.2.3.11641