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February 16, 2021 no comments

The history – and the future – of antibody discovery technologies

Monoclonal antibodies are now well-established as a mainstay of the therapeutic armoury.   More than a hundred antibodies have now been approved as drugs, making up around a third of all approvals over the last three years.  This reflects a number of inherent advantages of antibodies over “conventional” small-molecule drugs: their inherent specificity allows off-target toxicities to be eliminated; their long-life makes them suitable for infrequent dosing, in some cases as little as twice in a year; and, perhaps most importantly, antibodies can be found against essentially any extracellular target.

Small molecules are well-suited to inhibiting enzymes, such as kinases or proteases, but they struggle to block protein:protein interactions.  Antibodies, by contrast, excel at blocking peptide and protein ligands binding to receptors, and, through antibody-mediating clearance, removing circulating proteins from the plasma altogether.

But antibodies can play even smarter tricks.  They can exploit their exquisite specificity to carry toxic payloads to specific locations, they can mimic the binding of natural ligands to act as agonists and they can even be engineered into bispecific (or multispecific) formats to hit several targets at once. Indeed, sophisticated multispecific antibodies are now fulfilling their potential in the clinic, achieving outcomes that are not possible with other modalities.

Delivering these undoubted advantages of antibodies as therapeutics has been dependent on advances in technology.  Four milestones stand out, all with strong links to Cambridge – where it all began in the mid-1970s.

The first technological leap was the invention of hybridoma technology, by César Milstein together with his post-doc Georges Köhler working at the world-famous Laboratory of Molecular Biology in Cambridge.  By fusing individual B cells to immortal cancer cells, they were able to create cell lines that could make essentially infinite amounts of a single antibody.  Recognised with a Nobel Prize for Physiology or Medicine in 1984, the ability to make monoclonal antibodies at scale laid the foundation for antibodies as therapeutics.

But creating a monoclonal antibody against a target of interest was still laborious, depending on immunising mice and letting nature create the antibody that the scientists eventually cloned out and immortalised.  That changed in the late 1980s, with the invention of phage-display libraries by Greg Winter and John McCafferty, also in the Cambridge-based Laboratory of Molecular Biology.  Recombinant library technology solved two problems in one: it allowed researchers to create human antibodies directly …

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