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European Biopharmaceutical Review

Hard to Resist

Antibodies occur naturally in the blood and bind to other – usually foreign – proteins to direct their removal from the body. They play an important role in drug discovery and can also serve as therapeutic treatments themselves – for example, in immune diseases such as rheumatoid arthritis and Crohn’s disease, as well as in infectious conditions and cancer. Many established antibody therapies for cancer – like Herceptin – direct a specific attack on cancer cells, which inhibit their growth or mediate their destruction. However, a new generation of drugs lead their assault by stimulating the body’s own immune system – the immunotherapy approach.

Cancer cells generate a range of unnatural proteins, and immunotherapy works by stimulating the body to attack the diseased cells, rather than relying on drugs. Recent results reported from clinical trials have excited oncologists at top international cancer meetings. Scientists have discovered that some cancer cells can evade the immune system by locking into the programmed cell death 1 (PD-1) pathway.

Antibody Development

T cells are immune system cells that defend the body against pathogens. They have a surface receptor, PD-1, which is activated by binding to another protein called PD-L1. Cells that express the PD-L1 protein can avoid detection by sending a signal that tones down the ‘attack’ message. Therefore, an antibody that blocks the PD-1 pathway should prevent this from happening, allowing the immune system to seek and destroy the cancerous cells.

In 1975, Kohler and Milstein published a method for creating clonally pure mouse antibody preparations (1). These monoclonal antibodies (mAbs) are specific for their target and can be manufactured in huge quantities. Equivalent methods for generating clonal fully human molecules have been less successful, so mouse antibodies are frequently used as a starting point within antibody drug development.

However, these antibodies can illicit a human anti-mouse antibody (HAMA) response when used in humans and they are quickly eradicated. To avoid this, the antibody needs to be ‘humanised’ to prevent its destruction. The first approach to solving this problem focused on creating chimaeric antibodies where the mouse fragment crystallisable (Fc) region is replaced with a human Fc region. It is this area that ensures the antibody binds to a specific receptor, thereby triggering the appropriate immune response. Although these still create a HAMA response, it is less severe, and under conditions where the immune system is already suppressed, they can be very effective.

Grafting Technology

In 1986, Sir Greg Winter at the UK’s Medical Research Council’s Laboratory of Molecular Biology invented CDR grafting, a method for humanising mouse mAbs. This works by transplanting the CDRs – sequences that interact with the target protein or antigen – from mouse antibody genes into an equivalent human framework. The resultant genetically engineered antibodies are effectively seen as ‘self-produced’ and the HAMA response is considerably reduced, if not eliminated. Today, this approach is the technology behind almost all the earliest therapeutic antibodies and some of the biggest blockbuster drugs.

The original CDR grafting technology has been improved over the years, but the basic principles remain the same. In the wake of the success, a raft of competing technologies have been invented, ranging from what might be regarded as crude variants of CDR grafting, to dramatically new ways of producing near or fully human antibodies. Major competitors have also emerged, including methods utilising bacteriophage display of fully human antibody fragments, and transgenic mice where the mouse antibody gene repertoire is replaced by a human one.

In addition, there have been significant advances in the use of antibody fragments, and various natural and artificial proteins with potent building properties. However, the tried and tested CDR grafting approach is still delivering antibody therapeutics almost 30 years after it was first patented; 1986 also saw the approval of the first therapeutic antibody (Orthoclone OKT3) and, after a short gap, it has been followed by a steady stream of new treatments over the ensuing 29 years. Of the top 10 bestselling drugs in 2013-2014, two were antibodies.

On the Market

In total, there are 49 therapeutic mAbs approved or in review in both the EU and US (2). Of the antibody treatments in Phase 3 clinical trials, 33% have been humanised by CDR grafting. This includes new drug Pembrolizumab – now Keytruda® – which is an anti-PD-1 antibody with tremendous potential in a new area of cancer immunotherapy.

The global market for therapeutic antibodies was nearly $70.4 billion in 2014, and is expected to grow at a compound annual growth rate of 12.2% to reach $122.6 billion in 2019 (3). Pharmaceutical and biotechnology companies in the US, Europe and Asia are increasingly developing antibody therapies. Fully human antibody technologies – particularly those derived from transgenic mice – are gradually beginning to dominate over older methods, largely thanks to the widespread investment in competing approaches over the last 15-20 years.


1. Köhler G and Milstein C, Continuous cultures of fused cells secreting antibody of predefined specificity, Nature 256 (5,517): pp495-497, 1975
2. Visit: approved_mabs.php
3. Visit: product/801344/antibody-drugstechnologies-and-global-markets.html

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Michael Dalrymple is Director of Business Development at MRC Technology. After a career in academic research, Mike’s first job was at Inveresk Research. He then moved to PPL Therapeutics, where he rose from Molecular Biology Team Leader to Head of New Product Discovery. After a period of rapid company growth, Michael left to join the MRC Collaborative Centre – later subsumed into MRC Technology. He has been involved in creating MRC’s Development Gap Fund, the Centre for Therapeutics Discovery, and leading a number of major licensing deals.
Michael Dalrymple
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