TY - JOUR
T1 - “Redirecting an anti-IL-1β antibody to bind a new, unrelated and computationally predicted epitope on hIL-17A”
AU - Fischman, Sharon
AU - Levin, Itay
AU - Rondeau, Jean Michel
AU - Štrajbl, Marek
AU - Lehmann, Sylvie
AU - Huber, Thomas
AU - Nimrod, Guy
AU - Cebe, Régis
AU - Omer, Dotan
AU - Kovarik, Jiri
AU - Bernstein, Shmuel
AU - Sasson, Yehezkel
AU - Demishtein, Alik
AU - Shlamkovich, Tomer
AU - Bluvshtein, Olga
AU - Grossman, Noam
AU - Barak-Fuchs, Reut
AU - Zhenin, Michael
AU - Fastman, Yair
AU - Twito, Shir
AU - Vana, Tal
AU - Zur, Nevet
AU - Ofran, Yanay
N1 - Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/9/29
Y1 - 2023/9/29
N2 - Antibody engineering technology is at the forefront of therapeutic antibody development. The primary goal for engineering a therapeutic antibody is the generation of an antibody with a desired specificity, affinity, function, and developability profile. Mature antibodies are considered antigen specific, which may preclude their use as a starting point for antibody engineering. Here, we explore the plasticity of mature antibodies by engineering novel specificity and function to a pre-selected antibody template. Using a small, focused library, we engineered AAL160, an anti-IL-1β antibody, to bind the unrelated antigen IL-17A, with the introduction of seven mutations. The final redesigned antibody, 11.003, retains favorable biophysical properties, binds IL-17A with sub-nanomolar affinity, inhibits IL-17A binding to its cognate receptor and is functional in a cell-based assay. The epitope of the engineered antibody can be computationally predicted based on the sequence of the template antibody, as is confirmed by the crystal structure of the 11.003/IL-17A complex. The structures of the 11.003/IL-17A and the AAL160/IL-1β complexes highlight the contribution of germline residues to the paratopes of both the template and re-designed antibody. This case study suggests that the inherent plasticity of antibodies allows for re-engineering of mature antibodies to new targets, while maintaining desirable developability profiles.
AB - Antibody engineering technology is at the forefront of therapeutic antibody development. The primary goal for engineering a therapeutic antibody is the generation of an antibody with a desired specificity, affinity, function, and developability profile. Mature antibodies are considered antigen specific, which may preclude their use as a starting point for antibody engineering. Here, we explore the plasticity of mature antibodies by engineering novel specificity and function to a pre-selected antibody template. Using a small, focused library, we engineered AAL160, an anti-IL-1β antibody, to bind the unrelated antigen IL-17A, with the introduction of seven mutations. The final redesigned antibody, 11.003, retains favorable biophysical properties, binds IL-17A with sub-nanomolar affinity, inhibits IL-17A binding to its cognate receptor and is functional in a cell-based assay. The epitope of the engineered antibody can be computationally predicted based on the sequence of the template antibody, as is confirmed by the crystal structure of the 11.003/IL-17A complex. The structures of the 11.003/IL-17A and the AAL160/IL-1β complexes highlight the contribution of germline residues to the paratopes of both the template and re-designed antibody. This case study suggests that the inherent plasticity of antibodies allows for re-engineering of mature antibodies to new targets, while maintaining desirable developability profiles.
UR - http://www.scopus.com/inward/record.url?scp=85172826753&partnerID=8YFLogxK
U2 - 10.1038/s42003-023-05369-x
DO - 10.1038/s42003-023-05369-x
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 37773269
AN - SCOPUS:85172826753
SN - 2399-3642
VL - 6
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 997
ER -