Cambridge Antibody Technology Group (CAT) became a major player in biotech. Pioneer-technology.com explores the story behind its triumph, revealing the innovative strategies and technologies that led to the discovery of Humira and its acquisition by AstraZeneca. Learn how CAT’s success reshaped the biotechnology landscape with novel antibody therapeutics, phage display, and single-domain antibodies.
1. What Sparked the Creation of Cambridge Antibody Technology Group?
Cambridge Antibody Technology (CAT) emerged from a need to advance antibody technology beyond humanization. Instead of just improving existing methods, the goal was to develop fully human antibodies.
Sir Greg Winter, a Professor of Biochemistry at Cambridge University, didn’t initially plan to start a company. He sought support for his research from established companies but faced resistance. Companies questioned the need for alternatives to humanizing antibodies, a well-established technique. Winter’s motivation to create CAT was fueled by potential competition from Richard Lerner and the Scripps Research Institute, who were exploring similar ideas. Facing limited resources with only six people in his group, Winter recognized the urgency to improve methods for generating V-gene repertoires and isolating antibodies with binding activities. This led him to seek alternative avenues, ultimately resulting in the formation of CAT.
Antibody Technology
Two new opportunities arose. The first was meeting David Chiswell from Amersham, whose antibody humanization program was being shut down. Chiswell saw potential in Winter’s approach and suggested starting a company. The second opportunity came from Geoffrey Grigg, an Australian friend with a small company called Peptide Technology (later Peptech), who offered to invest in the technology. With £750,000 from Peptech, Cambridge Antibody Technology (CAT) was founded, marking the beginning of a significant biotech venture.
2. What Challenges Did Cambridge Antibody Technology Group Face in Its Early Years?
Raising funds and navigating strategic disagreements were significant hurdles for Cambridge Antibody Technology Group (CAT) in its early days.
Securing funding beyond the initial investment from Peptech proved challenging in the early 1990s. Additionally, the Board of Directors had differing views on the company’s direction. Peptech favored collaborations with large pharmaceutical companies rather than raising funds to develop its own products. In 1993-94, Knoll Pharmaceuticals approached CAT with interest in developing an anti-TNF antibody. This collaboration proved beneficial, with CAT’s team gaining valuable experience that ultimately led to the creation of Humira. However, these strategic differences culminated in 1996 when the Board decided to list the company on the London Stock Exchange. Feeling he had contributed as much as he could, Winter resigned from the board to focus on his academic research.
3. How Did Phage Display Technology Originate at Cambridge Antibody Technology Group?
Phage display technology emerged from efforts to improve humanized antibodies and overcome the limitations of traditional hybridoma methods.
While at the Medical Research Council (MRC), Winter aimed to improve methods for making humanized antibodies. The process of cloning mouse variable region (V) genes was slow, so he explored using the polymerase chain reaction (PCR) to speed it up. After comparing mouse V-genes, he realized PCR primers could amplify most of them. Around the same time, Winter had a frustrating experience trying to make hybridomas, where all the cells got infected with mycoplasma. This led him to question the need for hybridomas and consider cloning genes directly from the spleen. Recognizing the challenge of finding the right binding pairs among numerous antibody-coding genes, Winter and his team developed a rapid screening method.
Phage Display Protocol
In collaboration with Cambridge Antibody Technology, they fused V-genes to the coat protein gene of a bacteriophage, displaying antibody fragments on the phage surface. Phages with the desired specificity were isolated by binding to a solid-phase antigen. While initially focused on antibodies from immunized mice, the technology proved powerful enough to create antibodies from unimmunized human peripheral blood lymphocytes. This breakthrough marked the origin of phage display technology.
4. What Role Did Cambridge Antibody Technology Group Play in Developing Humira?
Cambridge Antibody Technology Group (CAT) played a pivotal role in the development of Humira through its collaboration with Knoll Pharmaceuticals.
In the early 1990s, CAT was approached by Knoll Pharmaceuticals, who were keen on developing an anti-TNF antibody. Through this collaboration, CAT’s team gained valuable experience and insights. The work conducted during this partnership directly contributed to the development of Humira, a blockbuster therapeutic antibody. This collaboration highlights CAT’s significant impact on the biopharmaceutical industry, demonstrating their ability to translate innovative research into commercially successful products.
5. What Happened After Cambridge Antibody Technology Group Floated on the Stock Exchange?
After Cambridge Antibody Technology Group (CAT) went public, Greg Winter stepped down from the board, and the company was later acquired by AstraZeneca.
In 1996, the decision to float CAT on the London Stock Exchange brought underlying differences among the Board of Directors to the forefront. Greg Winter, feeling that the scientific team was thriving and that he could no longer significantly contribute, resigned from the board. He chose to immerse himself back into his academic laboratory. Later, in 2006, CAT was acquired by AstraZeneca for £702 million, marking a major milestone in UK biotech history.
Antibody Research
6. What Was Greg Winter’s Second Biotech Venture After Cambridge Antibody Technology Group?
Greg Winter’s second biotech venture was Domantis, which focused on developing antibody single domains.
Before CAT, Winter had discovered antibody heavy chains with binding activities. Although early attempts to develop these were unsuccessful due to poor biophysical properties and lack of interest from potential partners, Winter revisited the idea. These single domains offered the potential to shrink antibodies for better tumor penetration and provided a simple module for building new antibodies. When CAT went public, the Medical Research Council (MRC) agreed that CAT would not exclusively develop antibody single domains, allowing the MRC to use phage display technology for this purpose. Ian Tomlinson at the MRC then seriously pursued this concept, successfully isolating human single domains with good biophysical properties. To commercialize these domains, Winter, Tomlinson, and others founded Diversys, which was later renamed Domantis. Peptech, along with MVM, invested in Domantis, with Peptech contributing $20 million for a 40% stake, making the financial aspect smoother than with CAT.
7. How Did Cambridge Antibody Technology Group Contribute to Antibody Engineering?
Cambridge Antibody Technology Group (CAT) made significant contributions to antibody engineering through its pioneering work in phage display technology and the development of fully human antibodies.
CAT revolutionized antibody engineering by creating methods for generating and screening large libraries of human antibodies using phage display. This approach allowed for the rapid identification of antibodies with high affinity and specificity, bypassing the need for traditional hybridoma technology. CAT’s success in developing fully human antibodies, such as Humira, demonstrated the potential of phage display for therapeutic antibody discovery. These advancements not only transformed the field of antibody engineering but also paved the way for new treatments for various diseases.
8. What Is the Significance of Cambridge Antibody Technology Group’s Success in the Biotech Industry?
Cambridge Antibody Technology Group’s (CAT) success is significant for several reasons:
- Pioneering Technology: CAT’s development and application of phage display technology revolutionized antibody discovery, providing a powerful tool for generating fully human antibodies.
- Commercial Success: The discovery and development of Humira, a blockbuster drug, validated CAT’s technology and demonstrated the potential of therapeutic antibodies.
- Industry Impact: CAT’s success inspired and paved the way for numerous other biotech companies focused on antibody therapeutics, driving innovation in the field.
- Financial Return: The acquisition of CAT by AstraZeneca for £702 million marked one of the largest biotech acquisitions in the UK, providing substantial returns to investors and highlighting the value of innovative biotech companies.
9. How Did Cambridge Antibody Technology Group Overcome Technical Challenges in Antibody Development?
Cambridge Antibody Technology Group (CAT) addressed several technical challenges in antibody development through innovative approaches and strategic collaborations.
- Generating Human Antibodies: CAT utilized phage display technology to create large libraries of human antibodies, overcoming the limitations of traditional methods that relied on animal immunization.
- Improving Antibody Affinity: CAT developed methods for affinity maturation, allowing them to enhance the binding strength of antibodies to their targets.
- Optimizing Antibody Properties: CAT worked on improving the biophysical properties of antibodies, such as stability and solubility, to ensure their suitability for therapeutic applications.
- Collaborative Approach: CAT collaborated with pharmaceutical companies like Knoll to leverage their expertise in drug development and commercialization, accelerating the development process.
10. What Lessons Can Be Learned From Cambridge Antibody Technology Group’s Journey?
Several key lessons can be learned from Cambridge Antibody Technology Group’s (CAT) journey:
- Innovation is Key: CAT’s success was built on its pioneering work in phage display technology, which revolutionized antibody discovery.
- Strategic Partnerships Matter: Collaborations with companies like Knoll Pharmaceuticals were crucial for the development and commercialization of Humira.
- Adaptability is Essential: CAT’s ability to adapt to changing market conditions and technological advancements allowed it to remain competitive.
- Visionary Leadership is Important: Greg Winter’s vision and leadership were instrumental in guiding CAT through its early challenges and setting it on the path to success.
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