Affinity maturation of TCR-like antibodies using phage display guided by structural modeling

Rahel Frick; Lene S Høydahl; Ina Hodnebrug; Erik S Vik; Bjørn Dalhus; Ludvig M Sollid; Jeffrey J Gray; Inger Sandlie; Geir Åge Løset

doi:10.1093/protein/gzac005

Affinity maturation of TCR-like antibodies using phage display guided by structural modeling

Protein Eng Des Sel. 2022 Feb 17:35:gzac005. doi: 10.1093/protein/gzac005.

Authors

Rahel Frick^{1

2

3}, Lene S Høydahl^{1

2

4}, Ina Hodnebrug^{1

2}, Erik S Vik⁵, Bjørn Dalhus^{6

7}, Ludvig M Sollid^{1

4}, Jeffrey J Gray^{8

9

10}, Inger Sandlie^{1

2}, Geir Åge Løset^{1

2

5}

Affiliations

¹ Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway.
² Centre for Immune Regulation and Department of Biosciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway.
³ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA.
⁴ KG Jebsen Coeliac Disease Research Centre, University of Oslo, Sognsvannsveien 20, 0372 Oslo, Norway.
⁵ Nextera AS, Gaustadalléen 21, 0349 Oslo, Norway.
⁶ Department for Medical Biochemistry, Institute for Clinical Medicine, University of Oslo, Sognsvannsveien 20, 0372 Oslo, Norway.
⁷ Department for Microbiology, Clinic for Laboratory Medicine, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway.
⁸ Program in Molecular Biophysics, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA.
⁹ Department of Chemical and Biomolecular Engineering and Institute of NanoBioTechnology, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA.
¹⁰ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA.

Abstract

TCR-like antibodies represent a unique type of engineered antibodies with specificity toward pHLA, a ligand normally restricted to the sensitive recognition by T cells. Here, we report a phage display-based sequential development path of such antibodies. The strategy goes from initial lead identification through in silico informed CDR engineering in combination with framework engineering for affinity and thermostability optimization, respectively. The strategy allowed the identification of HLA-DQ2.5 gluten peptide-specific TCR-like antibodies with low picomolar affinity. Our method outlines an efficient and general method for development of this promising class of antibodies, which should facilitate their utility including translation to human therapy.

Keywords: antibody; celiac disease; phage display.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antibodies*
Bacteriophages*
Humans
Peptides / genetics
Receptors, Antigen, T-Cell / genetics
T-Lymphocytes

Substances

Antibodies
Peptides
Receptors, Antigen, T-Cell

Grants and funding

R01 GM078221/GM/NIGMS NIH HHS/United States