Isolation of antigen-specific, disulphide-rich knob domain peptides from bovine antibodies

Alex Macpherson, Anthony Scott-Tucker, Anastasios Spiliotopoulos, Catherine Simpson, Justin Staniforth, Adam Hold, James Snowden, Leah Manning, Jean Van Den Elsen, Alastair Lawson

Research output: Contribution to journalArticlepeer-review

Abstract

As a novel alternative to established surface display or combinatorial chemistry approaches for the discovery of therapeutic peptides, we present a method for the isolation of small, cysteine-rich domains from bovine antibody ultralong complementarity-determining regions (CDRs). We show for the first time that isolated bovine antibody knob domains can function as autonomous entities by binding antigen outside the confines of the antibody scaffold. This yields antibody fragments so small as to be considered peptides, each stabilised by an intricate, bespoke arrangement of disulphide bonds. For drug discovery, cow immunisations harness the immune system to generate knob domains with affinities in the picomolar to low nanomolar range, orders of magnitude higher than unoptimized peptides from naïve library screening. Using this approach, knob domain peptides that tightly bound Complement component C5 were obtained, at scale, using conventional antibody discovery and peptide purification techniques.
Original languageEnglish
Article numbere30000821
JournalPLOS Biology
Volume18
Issue number9
DOIs
Publication statusPublished - 4 Sep 2020

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