The immunogenicity of humanized and fully human antibodies

By F. Harding, M. Stickler, J. Razo, R. Dubridge. mAbs, 2010

704 citations recorded by the source corpus.

Monoclonal antibodies represent an attractive therapeutic tool as they are highly specific for their targets, convey effector functions and enjoy robust manufacturing procedures. Humanization of murine monoclonal antibodies has vastly improved their in vivo tolerability. Humanization, the replacement of mouse constant regions and V framework regions for human sequences, results in a significantly less immunogenic product. However, some humanized and even fully human sequence-derived antibody molecules still carry immunological risk. To more fully understand the immunologic potential of humanized and human antibodies, we analyzed CD4+ helper T cell epitopes in a set of eight humanized antibodies. The antibodies studied represented a number of different VH and VL family members carrying unique CDR regions. In spite of these differences, CD4+ T cell epitopes were found only in CDR-sequence containing regions. We were able to incorporate up to two amino acid modifications in a single epitope that reduced the immunogenic potential while retaining full biologic function. We propose that immunogenicity will always be present in some antibody molecules due to the nature of the antigen-specific combining sites. A consequence of this result is modifications to reduce immunogenicity will be centered on the affinity-determining regions. Modifications to CDR regions can be designed that reduce the immunogenic potential while maintaining the bioactivity of the antibody molecule.

Subfields: Immunology, Molecular Biology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/8bd3b14b23d181c2e81d86adf634ce8ad44792b4

How researchers see this paper

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In Molecular Biology

1. A. Teplyakov
2. Gary Gilliland
3. Dennis R. Goulet
4. M. Chiu

In Radiology, Nuclear Medicine and Imaging

1. A. Teplyakov
2. Gary Gilliland
3. Dennis R. Goulet
4. M. Chiu

Citations in the corpus

• Antibody Structure and Function: The Basis for Engineering Therapeutics (2019, background): “The idea of incorporating human germline residues into the CDRs is related to the finding that CDRs are likely the only segments in humanized and fully human antibodies to contain CD4+ T-cell epitopes [140].”