Summary
The process of humanization can cause Antibodies to become less stable (1). Humanization can also destabilize specific CDRs, leading to failure during humanization (2).
Details
Bahrami (3) give an example of a nanobody that had its framework changed such that its CDR3 conformation changed from kinked to extended. In the process its thermostability dropped by 10°C.
Figures
Figure 6 from (2)
See also
- Stability-activity trade-off during enzyme design and evolution is highly local and not global
- CabBCII-10 is a universal nanobody framework capable of accepting diverse CDRs
1.
Tennenhouse A, Khmelnitsky L, Khalaila R, Yeshaya N, Noronha A, Lindzen M, et al. Computational optimization of antibody humanness and stability by systematic energy-based ranking. Nature Biomedical Engineering. 2023;8(1):30–44. Available from: https://doi.org/10.1038/s41551-023-01079-1
2.
Fernández-Quintero ML, Heiss MC, Liedl KR. Antibody humanization—the Influence of the antibody framework on the CDR-H3 loop ensemble in solution. Protein Engineering, Design and Selection. 2019;32(9):411–22. Available from: https://doi.org/10.1093/protein/gzaa004
3.
Bahrami Dizicheh Z, Chen I-L, Koenig P. VHH CDR-H3 conformation is determined by VH germline usage. Communications Biology. 2023;6(1). Available from: https://doi.org/10.1038/s42003-023-05241-y