John McCafferty

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John McCafferty is a British scientist, one of the founders of Cambridge Antibody Technology alongside Sir Gregory Winter and David Chiswell. He is well known as one of the inventors of scFv antibody fragment phage display, [1] a technology that revolutionised the monoclonal antibody drug discovery. McCafferty and his team developed this process following failures previously generating antibodies by immunizing mice. [2] Later improvements of antibody phage display technology enables the display of millions of different antibody fragments on the surface of filamentous phage (better known as antibody phage library) and subsequent selection of highly specific recombinant antibodies to any given target. This technology is widely exploited in pharmaceutical industry for the discovery and development of therapeutic monoclonal antibodies to treat mainly cancer, inflammatory and infectious diseases. One of the most successful was HUMIRA (adalimumab), discovered by Cambridge Antibody Technology as D2E7 and developed and marketed by Abbott Laboratories. HUMIRA, an antibody to TNF alpha, was the world's first phage display derived fully human antibody, [3] which achieved annual sales exceeding $1bn [4] therefore achieving blockbuster status. Humira went on to dominate the best-selling drugs lists - in 2016: The best selling drugs list researched by Genetic Engineering & Biotechnology News, published in March 2017, details that Humira occupied the number 1 position for 2015 ($14.012 billion) and 2016 ($16.078 billion). [5] Whilst for 2017, Abbvie reports that Humira achieved $18.427billion of sales in 2017 [6]

In 2002, after 12 years in Cambridge Antibody Technology (now MedImmune, a fully owned subsidiary of pharmaceutical giant AstraZeneca), McCafferty set up a group at the Sanger Institute developing and utilising methods for protein generation and recombinant antibody isolation in high throughput for proteomic applications. McCafferty has been involved in developing large human antibody repertoires both at CAT and at the Sanger Institute from which antibodies of high affinity and specificity to any antigen can be derived. He ran a laboratory at the Biochemistry Dept at University of Cambridge capitalising on the above technologies with a focus on the study of protein:protein interactions driving direct cell:cell communication [7] [8] [9] [10] [11] [12] and has recently founded a new therapeutic antibody discovery biotechnology company, IONTAS Ltd.

In 2018, McCafferty's 1990 phage research paper was cited by the Nobel committee when awarding the chemistry prize to Sir Gregory Winter and George Smith. [13]

Related Research Articles

<span class="mw-page-title-main">Monoclonal antibody</span> Antibodies from clones of the same blood cell

A monoclonal antibody is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.

A phagemid or phasmid is a DNA-based cloning vector, which has both bacteriophage and plasmid properties. These vectors carry, in addition to the origin of plasmid replication, an origin of replication derived from bacteriophage. Unlike commonly used plasmids, phagemid vectors differ by having the ability to be packaged into the capsid of a bacteriophage, due to their having a genetic sequence that signals for packaging. Phagemids are used in a variety of biotechnology applications; for example, they can be used in a molecular biology technique called "phage display".

<span class="mw-page-title-main">Recombinant DNA</span> DNA molecules formed by human agency at a molecular level generating novel DNA sequences

Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination that bring together genetic material from multiple sources, creating sequences that would not otherwise be found in the genome.

<span class="mw-page-title-main">Phage display</span> Biological technique to evolve proteins using bacteriophages

Phage display is a laboratory technique for the study of protein–protein, protein–peptide, and protein–DNA interactions that uses bacteriophages to connect proteins with the genetic information that encodes them. In this technique, a gene encoding a protein of interest is inserted into a phage coat protein gene, causing the phage to "display" the protein on its outside while containing the gene for the protein on its inside, resulting in a connection between genotype and phenotype. The proteins that the phages are displaying can then be screened against other proteins, peptides or DNA sequences, in order to detect interaction between the displayed protein and those of other molecules. In this way, large libraries of proteins can be screened and amplified in a process called in vitro selection, which is analogous to natural selection.

Adalimumab, sold under the brand name Humira and others, is a disease-modifying antirheumatic drug and monoclonal antibody used to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, and uveitis. It is administered by subcutaneous injection. It works by inactivating tumor necrosis factor-alpha (TNFα).

<span class="mw-page-title-main">Gregory Winter</span> English biochemist (born 1951)

Sir Gregory Paul Winter is a Nobel Prize-winning English molecular biologist best known for his work on the therapeutic use of monoclonal antibodies. His research career has been based almost entirely at the MRC Laboratory of Molecular Biology and the MRC Centre for Protein Engineering, in Cambridge, England.

Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal antibodies developed for administration to humans. Humanization can be necessary when the process of developing a specific antibody involves generation in a non-human immune system. The protein sequences of antibodies produced in this way are partially distinct from homologous antibodies occurring naturally in humans, and are therefore potentially immunogenic when administered to human patients. The International Nonproprietary Names of humanized antibodies end in -zumab, as in omalizumab.

<span class="mw-page-title-main">Monoclonal antibody therapy</span> Form of immunotherapy

Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective, to induce a specific cell signal, to cause the immune system to attack specific cells, or to bring a drug to a specific cell type.

Bertilimumab is a human monoclonal antibody that binds to eotaxin-1, an important regulator of overall eosinophil function.

<span class="mw-page-title-main">Fusion protein</span> Protein created by joining other proteins into a single polypeptide

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<span class="mw-page-title-main">Cambridge Antibody Technology</span> Defunct British biotechnology company

Cambridge Antibody Technology Group Plc, was a biotechnology company headquartered in Cambridge, England, United Kingdom. Its core focus was on antibody therapeutics, primarily using Phage Display and Ribosome Display technology.

Avimers are artificial proteins that are able to specifically bind to certain antigens via multiple binding sites. Since they are not structurally related to antibodies, they are classified as a type of antibody mimetic. Avimers have been developed by the biotechnology company Avidia, now part of Amgen, as potential new pharmaceutical drugs.

<span class="mw-page-title-main">Ff phages</span> Group of viruses

Ff phages is a group of almost identical filamentous phage including phages f1, fd, M13 and ZJ/2, which infect bacteria bearing the F fertility factor. The virion is a flexible filament measuring about 6 by 900 nm, comprising a cylindrical protein tube protecting a single-stranded circular DNA molecule at its core. The phage codes for only 11 gene products, and is one of the simplest viruses known. It has been widely used to study fundamental aspects of molecular biology. George Smith and Greg Winter used f1 and fd for their work on phage display for which they were awarded a share of the 2018 Nobel Prize in Chemistry. Early experiments on Ff phages used M13 to identify gene functions, and M13 was also developed as a cloning vehicle, so the name M13 is sometimes used as an informal synonym for the whole group of Ff phages.

Synthetic antibodies are affinity reagents generated entirely in vitro, thus completely eliminating animals from the production process. Synthetic antibodies include recombinant antibodies, nucleic acid aptamers and non-immunoglobulin protein scaffolds. As a consequence of their in vitro manufacturing method the antigen recognition site of synthetic antibodies can be engineered to any desired target and may extend beyond the typical immune repertoire offered by natural antibodies. Synthetic antibodies are being developed for use in research, diagnostic and therapeutic applications. Synthetic antibodies can be used in all applications where traditional monoclonal or polyclonal antibodies are used and offer many inherent advantages over animal-derived antibodies, including comparatively low production costs, reagent reproducibility and increased affinity, specificity and stability across a range of experimental conditions.

Creative Biolabs, Inc. is a life-science company which produces and supplies biotech products and services for early drug discovery and development, including various phage display libraries such as pre-made libraries, phage display services, antibody sequencing, and antibody humanization. Customers include pharmaceutical companies, academic institutions, government agencies, clinical research organizations and biotechnology companies.

Recombinant antibodies are antibody fragments produced by using recombinant antibody coding genes. They mostly consist of a heavy and light chain of the variable region of immunoglobulin. Recombinant antibodies have many advantages in both medical and research applications, which make them a popular subject of exploration and new production against specific targets. The most commonly used form is the single chain variable fragment (scFv), which has shown the most promising traits exploitable in human medicine and research. In contrast to monoclonal antibodies produced by hybridoma technology, which may lose the capacity to produce the desired antibody over time or the antibody may undergo unwanted changes, which affect its functionality, recombinant antibodies produced in phage display maintain high standard of specificity and low immunogenicity.

<span class="mw-page-title-main">George Smith (chemist)</span> American biologist, Nobel laureate

George Pearson Smith is an American biologist and Nobel laureate. He is a Curators' Distinguished Professor Emeritus of Biological Sciences at the University of Missouri in Columbia, Missouri, US.

Jane Osbourn, OBE, is a scientist and former chair of the UK BioIndustry Association.

Stefan Dübel is a German biologist. Since October 2002, he has been a full professor at the University of Braunschweig and head of the Biotechnology Department of the Institute of Biochemistry, Biotechnology and Bioinformatics. His work is centred around protein engineering, phage display and recombinant antibodies.

James Allen Wells is a Professor of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology at the University of California, San Francisco (UCSF) and a member of the National Academy of Sciences. He received his B.A. degrees in biochemistry and psychology from University of California, Berkeley in 1973 and a PhD in biochemistry from Washington State University with Ralph Yount, PhD in 1979. He completed his postdoctoral studies at Stanford University School of Medicine with George Stark in 1982. He is a pioneer in protein engineering, phage display, fragment-based lead discovery, cellular apoptosis, and the cell surface proteome.

References

  1. ↑ McCafferty J; Griffiths A.D; Winter G; Chiswell D.J (1990). "Phage antibodies: filamentous phage displaying antibody variable domains". Nature. 348 (63017): 552–554. Bibcode:1990Natur.348..552M. doi:10.1038/348552a0. PMID   2247164. S2CID   4258014.
  2. ↑ "Dr John McCafferty on how his antibody phage display work contributed to a Nobel Prize". Next Generation Therapeutics.
  3. ↑ Lawrence, Stacy (2007). "Billion dollar babies—biotech drugs as blockbusters". Nature Biotechnology. 25 (4): 380–382. doi:10.1038/nbt0407-380. PMID   17420735. S2CID   205266758.
  4. ↑ "Cambridge Antibody: Sales update | Company Announcements | Telegraph". Archived from the original on 2011-07-17. Retrieved 2009-07-27.
  5. ↑ "The Top 15 Best-Selling Drugs of 2016". 6 March 2017.
  6. ↑ "AbbVie Reports Full-Year and Fourth-Quarter 2017 Financial Results | AbbVie News Center". Archived from the original on 2018-04-12. Retrieved 2018-03-08.
  7. ↑ "Research in the Department of Biochemistry". Archived from the original on 2009-12-08. Retrieved 2009-12-23.
  8. ↑ http://www.repairingthebody.com/jmccafferty.html%5B‍%5D
  9. ↑ Schofield DJ, Pope A, Clementel V, Buckell J, Chapple SDJ,, Clarke KF, Conquer JS, Crofts AM, Crowther SRE, Dyson MR, Flack G, Griffin GJ, Hooks Y, Howat WJ, Kolb-Kokocinski A,, Kunze S, Martin CD, Maslen GL,, Mitchell JM, OÕSullivan M, Perera RL, Roake W, Shadbolt SP, Vincent KJ, Warford A, Wilson WE, Xie J, Young JL, McCafferty J (2007) Application of phage display to high throughput antibody generation and characterisation. Genome Biology. 8 (11) R254
  10. ↑ Dyson MR, Perera RL, Shadbolt SP, Biderman L, Bromek K, Murzina NV, McCafferty J (2008) Identification of soluble protein fragments by gene fragmentation and genetic selection. Nucl Acid Research 36 e51 http://nar.oxfordjournals.org/cgi/reprint/36/9/e51
  11. ↑ Teng MS, Shadbolt P, Fraser AG, Jansen G, and McCafferty J. (2008) Control of feeding behaviour in C. elegans by human G protein coupled receptors permits screening for agonist-expressing bacteria. Proc Natl Acad Sci, 105 (39) 14826-14831
  12. ↑ Chapple SDJ, Crofts AM, Shadbolt SP, McCafferty J, Dyson MR (2006) Multiplexed expression and screening for recombinant protein production in mammalian cells. BMC Biotechnology 6:49 http://www.biomedcentral.com/1472-6750/6/49
  13. ↑ "Dr John McCafferty on how his antibody phage display work contributed to a Nobel Prize". Next Generation Therapeutics.
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