John McCafferty has been a co-founder of 3 biotechnology companies focussed on the development of therapeutic antibodies (Cambridge Antibody Technology, IONTAS and Maxion Therapeutics). He is currently Affiliated professor at the Department of Medicine bringing the advances of recombinant antibody technology to bear on the scourge of snakebite envenomation in the developing world.
Biography
John McCafferty was one of the founders of Cambridge Antibody Technology (CAT) where he was a co-inventor of antibody phage display, the subject of the 2018 Nobel Prize in Chemistry awarded to his co-inventor Sir Gregory Winter. Phage display technology is used worldwide and has yielded at least fifteen approved therapeutic antibodies. This includes Humira which is the world’s biggest selling drug on a cumulative basis, which was created at CAT.
In 2012 he formed IONTAS, a company which has generated multiple drug leads currently in clinical trial by partner companies. At IONTAS John and colleagues developed a novel antibody fusion technology (KnotBody technology) which enables generation of ion channel-modulating antibodies. Ion channels are an important target class for which there are currently no antibody drugs. He has founded Maxion Therapeutics to take bring this technology to the clinic. Maxion’s lead programme addresses auto-immunity by targeting a voltage-gated channel (Kv1.3) used by a subset of auto-reactive T cells.
Interspersed with company formation John has held academic positions at the Wellcome Trust Sanger Institute and is currently an Affiliated professor at the Department of Medicine. There he seeks to bring his long experience in recombinant antibody technology to bear on the problems of the developing world and in particular the scourge of snakebite envenomation.
Research
Snakebite envenomation kills 100,000 people/year and causes debilitating injury to 100,000's more victims. The main therapeutic intervention for snakebite envenomation relies on the century-old approach of injecting victims with animal-derived polyclonal antiserum. Animal immunisation generates high affinity antibodies and undoubtedly saves lives, but the use of immune antiserum has a number of limitations around consistency, redundancy and immunogenicity.
Working in collaboration with Institut Clomido Picado, Costa Rica (a producer of equine anti-venom antibodies) the group are using recombinant antibody technology towards the capture, sequencing and characterisation of the immune repertoire arising from venom immunisation to create a defined, oligoclonal chimeric antibody cocktail.
John has an additional interest in creating antibody modulators of ion channels. Despite much effort by biotechnologists over the last 3 decades, creation of ion channel modulators has proven difficult. In order to overcome these challenges, Dr McCafferty and colleagues at Maxion Therapeutics have developed a novel molecular format (a KnotBodyTM) wherein a surface loop of an antibody is replaced by naturally occurring small peptides with ion channel modulating activity (“knottins”). This results in a fusion molecule (A KnotBody) combining the best of both worlds with the ion channel blockade of the knottin and the benefits of an antibody (i.e. long half-life, standard manufacturing and potential for engineering improved specificity and potency using phage display and mammalian display technologies).
Publications
Ledsgaard L, Wade J, Jenkins TP, Boddum K, Oganesyan I, Harrison JA, Villar P, Leah RA, Zenobi R, Schoffelen S, Voldborg B, Ljungars A, McCafferty J, Lomonte B, Gutiérrez JM , Laustsen AH, Karatt-Vellatt A (2023) Discovery and optimization of a broadly- neutralizing human monoclonal antibody against long-chain α-neurotoxins from snakes. Nature Comm. 14:682 https://doi.org/10.1038/s41467-023-36393-4
Michael R. Dyson, Edward Masters, Deividas Pazeraitis, Rajika L. Perera, Johanna L. Syrjanen, Sachin Surade, Nels Thorsteinson, Kothai Parthiban, Philip C. Jones, Maheen Sattar, Gordana Wozniak-Knopp, Florian Rueker, Rachael Leah, John McCafferty (2020) Beyond affinity: selection of antibody variants with optimal biophysical properties and reduced immunogenicity from mammalian display libraries mAbs 12(1):1829335, DOI: 10.1080/19420862.2020.1829335
Kothai Parthiban, Rajika L. Perera, Maheen Sattar, Yanchao Huang, Sophie Mayle, Edward Masters, Daniel Griffiths, Sachin Surade, Rachael Leah, Michael R. Dyson, John McCafferty (2019) A comprehensive search of functional sequence space using large mammalian display libraries created by gene editing mAbs 11:5, 884-898 https://doi.org/10.1080/19420862.2019.1618673
Laustsen AH, Karatt-Vellatt A, Masters EW, Arias AS, Pus U, Knudsen C, Oscoz S, Slavny P, Griffiths D, Luther A, Leah R, Lindholm M, Lomonte B, Gutierrez JM, McCafferty J (2018) In vivo neutralization of dendrotoxin-mediated neurotoxicity of black mamba venom by oligoclonal human IgG antibodies Nature Communications 9 p3928 DOI:10.1038/s41467-018-06086-4
Biffi G, Tannahill D, McCafferty J, Balasubramanian S (2013) Quantitative visualization of DNA G quadruplex structures in human cells Nature Chemistry 5 182-186 https://doi.org/10.1038/nchem.1548
Bradbury A, Duebel S, Sidhu D, McCafferty J. (2011) Beyond natural antibodies: the power of in vitro display technologies. Nature Biotechnology 29 245-254 https://doi.org/10.1038/nbt.1791
Schofield DJ, Pope A, …… McCafferty J (2007) Application of phage display to high throughput antibody generation and characterisation. Genome Biology 8 R254 DOI:10.1186/gb-2007-8-11-r254
Vaughan, T., Williams, A.J., Pritchard, K., Osbourn, J.K., Pope, AP, Earnshaw, J.C., Wilton, J., McCafferty J., Johnson K.S. (1996) Human antibodies with sub-nanomolar affinities isolated from a large non-immunised phage display library. Nature Biotechnology 14 p309-314 DOI:10.1038/nbt0396-309
McCafferty, J., Griffiths, A. D., Winter, G., Chiswell, D. J. (1990) Phage antibodies: filamentous phage displaying antibody variable domains. Nature 348 p552-4 DOI:10.1038/348552a0
