2018 Nobel Prize in Chemistry(2)
Reason for Award
for the phage display of peptides and antibodies
Laureates
United Kingdom of Great Britain and Northern Ireland
United States of America
Explanation
Phages are tiny viruses that infect bacteria. Scientists learned to decorate a phage’s surface with many different “sticky hands.” They then fish out the phages whose hands stick tightly to the desired target. Those sticky hands can be special antibodies that stop disease and become medicines. Thanks to Winter and Smith, such antibodies now treat arthritis and cancer. It’s like quickly finding the perfect key in a box full of thousands of keys.
Related Keywords
phage display
A molecular evolution technique that displays peptides or antibodies on bacteriophage coat proteins and selects variants based on target binding. The physical linkage between phenotype and gene allows immediate recovery of coding DNA. Libraries of >10^9 variants are routine, a key strength. It revolutionized therapeutic antibody discovery and is spreading to diagnostics and enzyme evolution. NGS now permits dynamic tracking of selection trajectories.
bacteriophage
Viruses that infect bacteria; M13, T7, and λ are common display scaffolds. Their small genomes are easily engineered and high replication rates enable large libraries. Design must balance infectivity and display density. Recombinant phages are typically handled at biosafety level 1, an operational advantage.
therapeutic antibody
Antibodies that bind specific targets to treat disease; they dominate pharmaceutical sales since the late 1990s. Fully human antibodies from phage display show low immunogenicity and fewer side effects. Indications span cancer immunotherapy, autoimmune diseases, and viral infections. Production typically uses CHO cells followed by purification.
peptide library
A large collection of random or semi-designed peptide sequences. Phage display readily builds libraries of 10^9 variants for inhibitor or ligand discovery. Diversity exceeds that of synthetic peptide libraries, and post-selection gene sequencing is rapid. Cyclization or D-amino-acid substitution often enhances affinity and protease resistance.
TNF-alpha
A pro-inflammatory cytokine implicated in many autoimmune diseases. Anti-TNF antibodies such as adalimumab and infliximab neutralize it therapeutically. Reducing excess TNF-α alleviates rheumatoid arthritis and ulcerative colitis. Treatment increases infection risk, requiring clinical monitoring. Phage-derived antibodies are fully human, minimizing immunogenicity.
adalimumab
The first fully human therapeutic antibody, approved in 2002, targeting TNF-α. Developed using Winter’s phage display and sold as Humira. Treats rheumatoid arthritis, psoriasis, Crohn’s disease, and more. Annual revenue exceeds US$10 billion. Biosimilars are reshaping the market landscape.
humanized antibody
Antibodies in which mouse CDRs are grafted onto human frameworks to reduce immunogenicity. Once dominant but now partially replaced by fully human antibodies. Still used for IP navigation or when binding properties must be preserved. In silico optimization and de-immunization are advancing, alongside glyco-engineering to enhance function.
molecular evolution
The study and exploitation of evolutionary change at molecular scale, experimentally or computationally. Techniques include phage display, directed evolution, and SELEX. It transfers evolutionary principles to chemistry, materials, and medicine to create novel functional molecules. Adaptive landscape topology and epistasis analysis are hot topics. Predictability of evolution is intensely debated.
autoimmune disease
Diseases in which the immune system attacks self tissues, e.g., rheumatoid arthritis, type 1 diabetes, SLE. Antibody drugs targeting cytokines or co-stimulatory molecules are becoming standard therapy. Phage-derived antibodies offer high specificity and fewer side effects. Biomarker discovery and personalized medicine are advancing.
cancer immunotherapy
Therapies that harness a patient’s immune system to attack tumors. Checkpoint antibodies against PD-1/PD-L1 or CTLA-4 are emblematic. Phage display supplies high-affinity scFvs for CAR-T cells and bispecific antibodies. Resistance mechanisms and adverse events like cytokine storm remain challenges. Understanding the tumor microenvironment and combination regimens are central to progress.