Cambridge Antibody Technology — BrandWiki

Cambridge Antibody Technology

Overview

Cambridge Antibody Technology Group Plc

type	Private
fate	Acquired by AstraZeneca in 2006; combined with MedImmune in 2007
successor	MedImmune
foundation	1989 (Daly Laboratories, Babraham)
founder	David Chiswell, Sir Greg Winter, John McCafferty, Medical Research Council
defunct	2007
location	Granta Park, Cambridgeshire, England
area served	Worldwide
key people

Cambridge Antibody Technology Group Plc, (commonly referred to as CAT) was a biotechnology company headquartered in Cambridge, England. Its core focus was on antibody therapeutics, primarily using Phage Display and Ribosome Display technology.

Phage Display Technology was used by CAT to create adalimumab, the first fully human antibody blockbuster drug. Humira, the brand name of adalimumab, is an anti-TNF antibody discovered by CAT as D2E7, then developed in the clinic and marketed by Abbvie, formerly Abbott Laboratories. CAT was also behind belimumab, the anti-BlyS antibody drug marketed as Benlysta and the first new approved drug for systemic lupus in more than 50 years.[1] In 2018, the Nobel Prize organisation awarded one quarter of the Nobel Prize in Chemistry to a founding member of CAT, Sir Greg Winter FRS "for the phage display of peptides and antibodies".[2]

Founded in 1989, CAT was acquired by AstraZeneca for £702m in 2006.[3]

industry	Biopharmaceutical

products	Adalimumab, discovery of; belimumab discovery of

services	Therapeutic monoclonal antibody discovery and development

revenue	£172.50m (six months ending 31 March 2006*)

operating income	£147.25m (six months ending 31 March 2006*)

net income	£25.25m (six months ending 31 March 2006*)

assets	£215.98m (six months ending 31 March 2006*)

equity	£180.97m (six months ending 31 March 2006*)

owner	AstraZeneca

num employees	Approximately 300 (2006)

footnotes	*Financials for six-month period prior to acquisition by AstraZeneca were distorted by the settlement for royalties payable on Adalimumab sales

History

CAT was founded in 1989 by Dr. David Chiswell OBE and Sir Greg Winter, with major scientific contributions from Dr. John McCafferty and the Medical Research Council (UK) (MRC). Operations began at the MRC laboratories in Cambridge. In May 1990, operations moved to the Daly Research Laboratories at Babraham Institute, Cambridge.[8]

In 1992, CAT moved to Beech House on the Melbourn Science Park to occupy units B1 and B2. In 1993 the company expanded into unit B3, into B4 into 1995, and in 1998 into units B5, B6, B8 and B9. CAT completed the occupation of Beech House by finally occupying B7 by the late 1990s.

CAT listed on the London Stock Exchange in 1997, raising £43 million, and went through a second round of funding in 2000, raising over £90 million.

In 1999, CAT expanded into a second location in Melbourn called Cambridge House.[9] After leaving Melbourn, CAT sold this location on to housing developers in early 2006.[10]

In 2000, after a succession of deals[11] that focussed on harnessing the exploitation of the human genome, CAT's share price peaked at over £50 per share.

Also in 2000, CAT decided to move out of Melbourn to a science park called Granta Park, roughly 10 mi away.[12][13] Of the buildings on the park, the first to be occupied was the Franklin Building followed, in late 2002, by a move to a new corporate headquarters at the Milstein Building.

The Franklin Building, named after Rosalind Franklin, was formally opened in 2001 by David Sainsbury, Baron Sainsbury of Turville.[14] The Milstein Building was named after César Milstein, and had a modular design with separate laboratory (46,000 sq ft) and administration blocks (21,000 sq ft).[15] In the same year, CAT listed on the NASDAQ.

When AstraZeneca acquired CAT in June 2006, plans were announced to occupy a new building on Granta Park, GP15, offering a further 92000 sqft. Refurbishment of this building took approximately 18 months and the building was officially opened, in November 2008, with the name Aaron Klug Building.[16][17]

Acquisitions

Aptein Inc.

On 15 July 1998, CAT completed the acquisition of Aptein Inc.[9] This acquisition "...further strengthened its world leading position in antibody display technology...giving CAT controlling patents in the field of polysome display. Polysome display involves the use of polysomes, a type of molecule responsible for protein synthesis within the human body, to display functional antibody proteins in vitro.". Three years later David Glover, CAT's Chief Medical Officer at the time, summarised the acquisition as one which essentially acquired Aptein's patent estate[18]

"Under the terms of the agreement CAT purchased the issued share capital and outstanding share options and warrants of Aptein for a total consideration of up to $11 million satisfied by the issue of up to 2.366 million CAT shares (an implied CAT share price of 278p.) $6 million of the consideration was satisfied by the issue of 1.290 million CAT shares on closing. The balance of the consideration of up to $5 million will be satisfied by the issue of up to 1.076 million CAT shares after Aptein's European patents have been sustained through opposition or appeal. In accordance with accounting standards the cost of acquiring this new technology has been capitalised and will be written off over the lives of the patents concerned.".[19]

Patents

CAT pioneered the application of Phage Display and Ribosome Display technology for the design and development of human monoclonal antibody therapeutics and which was reflected in the breadth of the company's patent portfolio. The Cambridge patent portfolio includes about 40 families of patents, covering both technologies and products.

Three main families of major patents cover Cambridge antibody library and Phage Display technology:

'Winter II' and 'Winter/Huse/Lerner' patents cover Medimmune's processes for generating the collections of human antibody genes that comprise MedImmune Cambridge libraries. MedImmune has patents issued in Europe, South Korea, Japan, Australia and the US and a patent application is pending in Canada. These patents are co-owned by the MRC, The Scripps Research Institute and Stratagene and MedImmune currently has exclusive commercial exploitation rights, subject to certain rights held by the Medical Research Council (MRC), Scripps and Stratagene and their pre-existing licensees.

'McCafferty' covers the process by which human antibodies are displayed on phage (Phage Display) and methods of selecting antibodies to desired targets from libraries. MedImmune has patents issued in Europe, Australia, South Korea and Japan and a patent application is pending in Canada. These patents are co-owned by MedImmune and the MRC.

'Griffiths' covers the use of Phage Display technology to isolate human anti-self' antibodies that specifically bind to molecules found in the human body. CAT has patents issued in Australia, Europe and the US and patent applications are pending in Canada and Japan. This patent is co-owned by MedImmune Cambridge and the MRC.

In 2011 "The High Court of England and Wales has ruled that two patents (EP 0774511 and EP 2055777) owned by MedImmune that describe methods of phage display are invalid because of obviousness."[118]

List of Patents

Patent Dispute with MorphoSys

The German biotechnology company MorphoSys generates human antibodies using its phage display-based 'HuCal' (Human Combinatorial Antibody Library) technology.[125] In the late 1990s both companies found themselves jockeying for strong IP position in the area of therapeutic human antibody generation by way of a specific dispute (details on MorphoSys page).

The long, and protracted, dispute resulted which was eventually settled in late 2002 when some argued the settlement was enforced by an industry cash crunch. The 'delighted' CEO at the time, Peter Chambré, reflected that the deal put an end to the distraction to both parties caused by the litigation.[126]

Management and notable people

CAT was founded by David Chiswell MBE and Sir Greg Winter, with major scientific contributions from John McCafferty.

Sir Greg Winter FRS is credited with invented techniques to both humanise (1986) and, later, to fully humanise using phage display, antibodies for therapeutic uses.[128][129][130][131][132][133][134] Previously, antibodies had been derived from mice, which made them difficult to use in human therapeutics because the human immune system had anti-mouse reactions to them.[135][136][137][138][139] For these developments Winter was awarded the 2018 Nobel Prize in Chemistry along with George Smith and Frances Arnold.[140][141][2]

Dave Chiswell OBE was responsible for operational management of CAT from 1990 to 2002, including time as chief executive officer from 1996 to 2002. Chiswell announced he was standing down from CAT on 26 November 2001.[142] During his time at CAT, Chiswell had established himself as a significant character in the biotechnology business.[143] In 2003, Chiswell became chairman of the BioIndustry Association,[144] and in June 2006 was awarded an OBE for services to the UK Bioscience Industry in the UK and Overseas.[145]

CAT was governed by a board and, latterly, a Scientific Advisory Board. Members included:

Peter Chambré replaced Dave Chiswell as CEO in early 2002.[151] Chambré had been the CEO of Bespak PLC since May 1994[152] and, in July 2000, became the chief operating officer of the genomics company Celera.[153] A few years after CAT, Chambré went on to hold a number of roles including director positions at BTG[154] and Spectris,[154] followed by an Industrialist in Residence position at 3i.[155] Chambré went on to executive positions at Cancer Research UK,[156] and more recently, Chambré became Chairman of the Board of Directors at Immatics biotechnologies NV,[157]

John McCafferty developed much of the phage display technology used by CAT. McCafferty left CAT to start a group at the Wellcome Trust Sanger Institute where, as part of the ATLAS project, his group demonstrated the potential for large-scale high-throughput generation and validation of monoclonal antibodies.[159] This work built on CAT's ProAb technology. McCafferty 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, George Smith and Frances Arnold.[160]

Kevin Johnson joined CAT in 1990, contributed to the discovery of D2E7, played a key role in CAT's initial public offering (IPO) and, by July 1997, was appointed to the Board as Research Director. In 2000, Johnson became Chief Technology Officer responsible for exploitation and development of CAT's technology platforms. In November 2002, CAT announced its intention to seek independent financing for its development of the application of antibodies on microarrays for personalised medicine, as this fell outside CAT's focus on therapeutic antibodies and Johnson positively spearheaded this push.[161] In the event it was not possible to procure finance for this activity and, as a result, microarray activity at CAT was terminated.[162] Johnson is currently a partner at medicxi, a venture capital firm focused on life sciences investments based on the asset-centric approach to investing.[163][164] He was formerly with Index Ventures, having joined the venture capital firm in 2010.[165][166]

Jane Osbourn OBE joined CAT as a senior scientist in 1993.[167] Osbourn was a co-author of several, high-impact publications to come out of CAT. When merged with MedImmune, after the acquisition by AstraZeneca, Osbourn became the site leader of MedImmune Cambridge. Osbourn went on to chair the UK's BioIndustry Association in 2015[168] and, in 2019, was awarded the Order of the British Empire medal for services to "Human Monoclonal Antibody Drug Research and Development and Biotechnology".[169]

César Milstein CH FRS, a Nobel Prize-winning biochemist in the field of antibody research. Milstein shared the Nobel Prize in Physiology and Medicine in 1984 with Niels Jerne and Georges Köhler.[146]
Sir Aaron Klug OM FRS FMedSci HonFRMS, a Nobel Prize-winning laureate, was a British chemist and biophysicist, and winner of the 1982 Nobel Prize in Chemistry for his development of crystallographic electron microscopy. He sat on both the board and the scientific advisory board.[147]
Professor Peter Garland – appointed as a non-executive director in 1990, then became non-executive chairman of the board in 1995. Garland has been the Chief Executive of Institute of Cancer Research, 1989–99 and was a fellow of University College London.[148]
Dr Paul Nicholson – replaced Peter Garland as chairman in 2003.[149] Nicholson was chairman when AstraZeneca bought CAT.

Aptein Inc.

Aptein was founded by Glenn Kawasaki, who is currently, amongst other positions, CEO at Accium BioSciences.[20]

According to an article published in Nature in 2002, that focused on the automation of proteomics,..."Normally, an mRNA molecule passes through the ribosome-like ticker-tape and is released, along with the newly synthesised protein molecule, when a sequence of three bases known as a 'stop codon' is reached. In Aptein's technology, stop codons are eliminated so that the completed antibody and its mRNA remain bound together on the ribosome. The system, which CAT is now optimising, is entirely cell-free and so is more amenable to automation. This should make it possible to construct libraries that are orders of magnitude larger than those created using phage display."[21]

CAT published on their optimisation work with Ribosome Display, including:

CAT used extensive data sets from ribosome display to patent protect their anti-IL-13 monoclonal antibody, CAT-354, in a world-first of sequence-activity-relationship claims.[26]

The discovery of tralokinumab, a therapeutic antibody against IL-13.[22]
An improved method for eukaryotic ribosome display[23]
A comparison of phage and ribosome display approaches for improving antibody affinity and stability showing the advantages of ribosome display[24]
The use of ribosome display to optimise pharmacology and "developability" of therapeutic proteins[25]

Collaborations

CAT entered into many collaborations with technology and pharmaceutical companies, including:

Searle, 1999 – CAT signed, what was at the time, their biggest deal with Searle, the pharmaceutical arm of Monsanto.[47] In 2000, Pharmacia & Upjohn merged with Monsanto and Searle[48] to create Pharmacia Corporation. In 2003, Pfizer acquired Pharmacia.[49] It is unsure as to whether the deal with Searle generated any clinical candidates.
Human Genome Sciences, 2000.[50][51] GlaxoSmithKline purchased HGSI in 2012.[52] The deal with Cambridge Antibody Technology generated, amongst others;
An anti-BLyS antibody – registered by HGSI as LymphoStat-B, also known as belimumab, and subsequently branded as Benlysta.[53] On 16 November 2010 HGSI and GlaxoSmithKline announced the vote of the FDA advisory committee to recommend approval of belimumab for systemic lupus erythematosus.[54] On 9 March 2011 the FDA voted 11 to 2 in favour of approving Benlysta "to treat patients with active, autoantibody-positive lupus who are receiving standard therapy, including corticosteroids, antimalarials, immunosuppressives, and nonsteroidal anti-inflammatory drugs".[55]
An anthrax therapeutic antibody – registered by HGSI as ABthrax, also known as raxibacumab.[56] At the 2 November 2012 meeting of the Anti-Infective Drugs Advisory Committee to the US Food and Drug Administration (FDA) members "voted 16 to 1 in support of the clinical benefit of raxibacumab for the treatment of inhalational anthrax, with one abstention. In addition, the committee voted 18 – 0 in favour of the risk-benefit profile of raxibacumab".[57]
Two anti-TRAIL receptor antibodies – mapatumumab (HGS-ETR1) and lexatumumab (HGS-ETR2).[58] Early work by CAT and HGS scientists showed that HGS-ETR1 induces cell death in certain tumour types.[59] Following this data, HGS exercised an option to enter into an exclusive development partnership for the antibody.[60]
Genzyme, 2000.[61] CAT held significant strength in the area of TGF beta with two products already – lerdelimumab (CAT-152) and metelimumab (CAT-192). The deal with Genzyme was "a broad strategic alliance to develop and commercialise human monoclonal antibodies directed against TGF-beta." All clinical indications, with the exception of ophthalmic uses, were covered by the agreement.[62][63]
The deal resulted in fresolimumab (GC1008), a pan-neutralizing IgG4 human antibody directed against all three isoforms of TGF beta,[64] which had the "potential for treating a variety of diseases".[65] In particular Genzyme are currently using fresolimumab in trials involving immunogenic tumours.
The takeover of CAT by AstraZeneca initiated a change of control clause in the 2008 agreement that gives Genzyme the right to buy out rights to a jointly developed experimental lung drug.[66]
In February 2011, Sanofi-Aventis purchased Genzyme for approximately US$20bn.[67]
Immunex Corp, 2000.[68] CAT's proprietary antibody phage display library for the discovery, development and potential commercialisation of human monoclonal antibodies was licensed to Immunex, in return for a licence fee. This deal was expanded in May 2001 where CAT shared more of the risk of drug development – a so-called "profit-sharing" deal.[69][70] In 2002 Immunex was acquired by Amgen [71] and in December 2003 CAT entered into a new, restructured agreement with Amgen, reportedly focussing in skin disease.[72] It was also reported that, under the terms of the agreement, Amgen had taken responsibility for the further development and marketing of the therapeutic antibody candidates isolated by CAT against two targets on which the parties agreed to collaborate and would bear all the associated costs. In return, CAT received from Amgen an initial fee and potential milestone payments and royalties on future sales. As of February 2004, one candidate had been delivered by CAT to Amgen. A second candidate was the subject of a continuing research program funded by Amgen and conducted by CAT and was to be delivered to Amgen in due course.[73]
Amgen acquired the transgenic mouse company Abgenix[74] meaning that they had access to two different methods of human monoclonal antibody production. As of July 2009, it is not known from which technology any of their monoclonal antibody products in clinical trials have been derived.[75]
AMRAD, 2001. AMRAD subsequently changed its name to Zenyth Therapeutics[76] and, in mid-2006, Zenyth was acquired by CSL Limited.[77] CAT and AMRAD had gone 50:50 with the original deal over the development of an anti-GMCSF-R antibody, which became CAM-3001. After all this corporate manoeuvring, "CSL decided to license its 50% share in the project to MedImmune...MedImmune commenced Phase I clinical trials in December 2007".[78]

Cambridge Antibody Technology

History

Acquisitions

Aptein Inc.

Products and pipeline

Patents

List of Patents

Patent Dispute with MorphoSys

Publications

Management and notable people

Awards

See also

References

Drug Royalty Corporation Inc.

Oxford Glycosciences

Genencor

Aptein Inc.

Drug Royalty Corporation Inc.

Oxford Glycosciences

Genencor

Collaborations