Cambridge Antibody Technology

Last updated

Cambridge Antibody Technology Group Plc
Type Public limited company
LSE:  CAT Nasdaq:  CATG
IndustryBiopharmaceutical
Founded1989 (Daly Laboratories, Babraham)
Founder David Chiswell, Sir Greg Winter, John McCafferty, Medical Research Council
Defunct2007 (2007)
FateAcquired by AstraZeneca in 2006; combined with MedImmune in 2007
Successor MedImmune
Headquarters Granta Park, Cambridgeshire, England, United Kingdom
Area served
Worldwide
Key people
 David Chiswell (CEO 1996–2002)
Peter Chambré (CEO 2003–2006)
Products Adalimumab, discovery of; belimumab discovery of
ServicesTherapeutic monoclonal antibody discovery and development
Revenue£172.50m (six months ending 31 March 2006*)
£147.25m (six months ending 31 March 2006*)
£25.25m (six months ending 31 March 2006*)
Total assets £215.98m (six months ending 31 March 2006*)
Total equity £180.97m (six months ending 31 March 2006*)
OwnerAstraZeneca
Number of employees
Approximately 300 (2006)
Footnotes /references
*Financials for six-month period prior to acquisition by AstraZeneca were distorted by the settlement for royalties payable on Adalimumab sales

Cambridge Antibody Technology (officially Cambridge Antibody Technology Group Plc, informally CAT) 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.

Contents

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] [4] AstraZeneca subsequently acquired MedImmune LLC, [5] which it combined with CAT to form a global biologics R&D division called MedImmune. [6] CAT was often described as the 'jewel in the crown' of the British biotechnology industry [7] and during the latter years of its existence was the subject of frequent acquisition speculation.

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 miles (16 km) 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 92,000 sq ft (8,500 m2). 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]

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:

  • 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]

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]

Drug Royalty Corporation Inc.

In 1994, CAT signed a royalty deal with Drug Royalty Corporation Inc. (DRC) such that DRC would receive future royalty revenue from CAT's products.

In January 2002, CAT made a share-based offer to buy DRC for £55 million so that it could buy out this royalty obligation. CAT valued DRC at C$3.00 a share, and this offer was initially recommended by the board of directors of DRC. On 8 March 2002 the investment company Inwest made a competing offer valuing DRC at C$3.05 per share. [27] CAT's offer would see DRC shareholders receiving CAT shares whilst Inwest's offer would see the DRC shareholder receiving cash. DRC's board of directors changed their decision and recommended Inwest's offer. After a number of deadline extensions from CAT the offer from Inwest was accepted by the DRC shareholders. Inwest purchased DRC on 2 May 2002, and the company began operating as a private entity that continues operation today as DRI Capital. [28]

As a result of this failure to purchase DRC, CAT's right to buy back royalty interest was triggered at a cost to CAT of C$14 million (£6.2 million) by way of 463,818 CAT shares. [29]

Oxford Glycosciences

On 23 January 2003 CAT made a share-based offer for Oxford Glycosciences (OGS) [30] and at an Extraordinary General Meeting shareholders voted to approve the merger. In March of this year CAT saw a decline in its share price. Discussions regarding the applicability of the royalty offset provisions for HUMIRA with Abbott Laboratories had started, and these had a negative impact on the CAT share price depressing the value of CAT's offer. [31] [32]

On 26 February 2003 the British-based biotechnology group Celltech subsequently made a hostile £101 million cash offer for OGS [33] and began buying OGS shares. Some reported that this activity represented the UK biotechnology industry's first-ever bidding war. [34] Despite this improved offer from Celltech, OGS continued to recommend the CAT offer. [35]

Celltech continued to buy OGS shares and the OGS board pressed CAT to improve the terms of its offer as the Celltech shareholding reached 10.55%. [36] OGS became alarmed that Celltech's share purchase would prompt CAT to walk away because, under takeover rules, it would not be able to forcibly purchase the 10.55 per cent stake Celltech owned. CAT failed to improve the terms of its bid forcing OGS to abandon the agreement. [37]

Celltech continued buying shares and, as their stake reached 25%, so the board of OGS met to reluctantly recommend the Celltech offer. Celltech completed the purchase of OGS in April 2003. [38] Some newspapers reported that the failure of the bid by CAT would means that CAT would have to cut some of its workforce. [39] Celltech was itself purchased by the Belgian drugmaker UCB in mid-2004. [40]

Genencor

On 1 November 2005 CAT announced it was acquiring two anti-CD22 immunotoxin products from Genencor, namely GCR-3888 and GCR-8015. [41] Genencor is the biotechnology division of Danisco [42] and the acquisition meant CAT would hire certain former Genencor key employees to be responsible for the development of the programmes. [43]

GCR-3888 and GCR-8015 were discovered and initially developed by the National Cancer Institute, which is part of the U.S. National Institutes of Health. Genencor licensed the candidates for hematological malignancies and entered into a Cooperative Research and Development Agreement (CRADA) with the NIH, which will now be continued by CAT. Under the original licence agreement with the NIH, CAT gained the rights to a portfolio of intellectual property associated with the programs and would pay future royalties to the NIH.

CAT intended to file an Investigational New Drug (IND) application for GCR-8015 in various CD22 positive B-cell malignancies, including Non-Hodgkin lymphoma and chronic lymphocytic leukaemia, following a period of manufacturing development which is expected to be complete by the end of 2006 and to support the NCI's ongoing development of GCR-3888 in Hairy cell leukaemia (HCL) and paediatric acute lymphoblastic leukaemia (pALL). [41]

CAT-8015 exhibited a greater affinity for CD22 than its predecessor, CAT-3888 [44] and CAT's language such as "CAT will support the NCI's ongoing development of CAT-3888..." suggested at the time that their focus was on the second generation candidate. [45]

On 16 May 2013, AstraZeneca announced that CAT-8015, now Moxetumumab, [46] has started Phase III clinical trials. [47]

Collaborations

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

Products and pipeline

CAT had[ when? ] a number of significant products in the pipeline. These included:

CAT developed their display technologies further into several patented antibody discovery/functional genomics tools which were named Proximol [112] and ProAb. ProAb was announced in December 1997 [113] and involved high throughput screening of antibody libraries against diseased and non-diseased tissue, whilst Proximol used a free radical enzymatic reaction to label molecules in proximity to a given protein. [114] [115]

In September 1999, it was announced that CAT's Library product and ProAb would each receive Millennium Products status. [116] Of the 4,000 products submitted to the Design Council for these awards, 1,012 were chosen and, to attain Millennium Product status, products had to: open up new opportunities, challenge existing conventions, be environmentally responsible, demonstrate the application of new or existing technology, solve a key problem and show clear user benefits. [117]

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

Winter IIWinter/Huse/LernerMcCaffertyGriffithsKawasaki
PCT Publication NumberWO90/05144 [119] WO90/14424 [120] WO90/14430 [121] WO92/01047 [122] WO93/11236 [123] WO91/05058 [124]
USUS6,248,516, US6,545,142US6,291,158, US6,291,159US6,291,160, US6,291,161, US6,680,192US5,969,108, US6,172,197, US6,806,079US5,885,793, US6,521,404, US6,544,731, US6,555,313, US6,593,081, US6,582,915US5,643,768, US5,658,754
EuropeEP0368684EP0472638EP0425661, EP1026239 (pending as of July 2009)EP0589877, EP0774511, EP0844306 (pending as of July 2009)EP0616640, EP1024191 (pending as of July 2009)EP0494955
AustraliaAU0634186AU651065AU643948AU0664155AU0665221AU038762
JapanJP02919890JP33211592-508759JP031769175-509967 (pending as of July 2009)JP03127158, 2000-240298 (pending as of July 2009)
Canada2002868 (pending as of July 2009)CA201684120168422086936 (pending as of July 2009)2124460 (pending as of July 2009)CA2067194
South KoreaKR0184860––KR0222326–KR0185192, KR0204359, KR0204360
DenmarkDK175392–––––

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]

Publications

Scientists at CAT pioneered the use of phage display such that variable antibody domains could be expressed on filamentous phage antibodies, as reported in a key Nature publication, "Phage antibodies: filamentous phage displaying antibody variable domains". [127]

Other key CAT publications included:

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] [142]

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. [143] During his time at CAT, Chiswell had established himself as a significant character in the biotechnology business. [144] In 2003, Chiswell became chairman of the BioIndustry Association, [145] and in June 2006 was awarded an OBE for services to the UK Bioscience Industry in the UK and Overseas. [146]

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

Peter Chambré replaced Dave Chiswell as CEO in early 2002. [152] Chambré had been the CEO of Bespak PLC since May 1994 [153] and, in July 2000, became the chief operating officer of the genomics company Celera. [154] A few years after CAT, Chambré went on to hold a number of roles including director positions at BTG [155] and Spectris, [156] followed by an Industrialist in Residence position at 3i. [157] Chambré went on to executive positions at Cancer Research UK, [158] and more recently, Chambré became Chairman of the Board of Directors at Immatics biotechnologies NV, [159] and Member of the Board of Trustees at Our Future Health. [160]

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. [161] 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. [162]

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. [163] In the event it was not possible to procure finance for this activity and, as a result, microarray activity at CAT was terminated. [164] Johnson is currently a partner at medicxi, a venture capital firm focused on life sciences investments based on the asset-centric approach to investing. [165] [166] He was formerly with Index Ventures, having joined the venture capital firm in 2010. [167] [168]

Jane Osbourn OBE joined CAT as a senior scientist in 1993. [169] 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 [170] and, in 2019, was awarded the Order of the British Empire medal for services to "Human Monoclonal Antibody Drug Research and Development and Biotechnology". [171]

Awards

CAT's most significant award was the Prix Galien, [172] awarded for outstanding achievement in product and technology development, in recognition of its creativity in the development of novel human monoclonal antibody therapeutics especially in relation to its product CAT-152, which was used to treat fibrotic scarring in certain ophthalmology conditions. [173]

See also

Related Research Articles

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References

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