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Publication Abstract from PubMed

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-1beta 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-1beta 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.

"Redirecting an anti-IL-1beta antibody to bind a new, unrelated and computationally predicted epitope on hIL-17A".,Fischman S, Levin I, Rondeau JM, Strajbl M, Lehmann S, Huber T, Nimrod G, Cebe R, Omer D, Kovarik J, Bernstein S, Sasson Y, Demishtein A, Shlamkovich T, Bluvshtein O, Grossman N, Barak-Fuchs R, Zhenin M, Fastman Y, Twito S, Vana T, Zur N, Ofran Y Commun Biol. 2023 Sep 29;6(1):997. doi: 10.1038/s42003-023-05369-x. PMID:37773269^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.