Summary
VHH nanobodies can sometimes elicit immunogenic reactions even after humanization. However, this rarely occurs with clinical VHHs.
Details
Rossotti et al. outline four reasons for immunogenicity among humanized VHHs: (1)
- Exposure of VH/VL interface, a surface that is foreign to the human immune system
- Loop conformation of CDR3, owing to its longer length relative to human antibodies
- Sequence profile of CDR3, which is unusual relative to human CDRH3 sequences
- Noncanonical disulfides
This does not explain why the C-terminus attracts so much attention from the immune system specifically.
1.
Rossotti MA, Bélanger K, Henry KA, Tanha J. Immunogenicity and humanization of single‐domain antibodies. The FEBS Journal. 2021;289(14):4304–27. Available from: https://doi.org/10.1111/febs.15809