by ecancer reporter Clare Sansom
 
The clinical and commercial success of antibody therapeutics is one of the most significant trends in the pharmaceutical industry in the early twenty-first century.

 
More than half the ten top-selling drugs of 2012 were monoclonal antibodies, and of these, three – rituximab, trastuzumab, and bevacizumab – target different types of cancer; the other three target auto-immune disorders such as rheumatoid arthritis.

 
A recent report in Nature Reviews Cancer listed twelve monoclonal antibodies, or products including anthbodies, approved by the FDA for treating solid and haematological malignancies, and many more are in clinical trials.

 
However, these drugs are still more expensive to produce and less convenient to deliver to patients than most of the more conventional “small molecule” drugs, and there is much interest in the pharmaceutical and biotech industries in enhancing the technologies that are used to design and develop them.

 
It was not surprising, therefore, that a recent one-day meeting on the theme of advances in antibody therapeutics organised  by the life sciences networking organisation One Nucleus should draw a large audience from a wide range of companies.

 
This meeting was held at the Babraham Institute, near Cambridge, UK in late January 2013.
 

It was the sixth in One Nucleus’ series of specialist meetings in important therapeutic areas to be held under their “Life Science Leadership” banner, and the fourth of these to feature oncology.

 
Babraham was considered a particularly appropriate location for this meeting as it is very close to the UK headquarters of the established and successful biological therapeutics company Medimmune, and several smaller companies with a similar research focus are located in the immediate area. 
 
 
The focus of the meeting was on recent advances in techniques for the development of antibody therapeutics, rather than their application to any specific therapeutic area.

 
Nevertheless, many of the examples presented to illustrate these were in oncology, and it became clear that this is an area where these technologies are in rapid development.
 
 
Mike Dalrymple, director of business development at MRC Technology, a technology transfer company attached to the UK’s Medical Research Council, began the day with an overview and history of the development of antibody based therapeutic products, starting with the introduction of “antisera” as long ago as the 1890s.
 

He tracked antibody technologies themselves from the earliest rodent antibodies in the 1970s through chimeric antibodies in which only the variable domains are derived from rodents and humanised ones with rodent-based antigen binding sites to the fully human antibodies that are appearing on the market today and that are least likely to lead to a toxic immune response.
 

Trastuzumab, the first and still the most widely known antibody therapy used in oncology is a humanised antibody directed against the ERBB2 or HER2 receptor that is over-expressed in about 20% of breast tumours.
  

Antibodies may be exquisite in their specificity, but they are proteins – large macro-molecules – and so pose more serious challenges for pharmaceutical development than small molecule drugs.
 

David Lowe of Medimmune described the concept of “developability”: how antibodies selected as candidate drugs must not only be potent and specific but have appropriate physical properties and be stable in solution without aggregation.
 

He explained how his company is using in vitro and even in silico screening methods to predict these properties in the earliest stages of antibody development, much as candidate small molecule drugs are now screened for unfavourable ADME properties at a very early stage.
 

Oncology is one of the most important therapeutic areas for Medimmune, with products in clinical trials against a number of antigens including CTLA-4, which is found on the surface of T cells and down-regulates the immune system, thus increasing tumour immune tolerance.
  

Speakers from several companies described novel antibody technologies with potential applications in oncology.
 

F-Star, a biotech company with research facilities at the Babraham Research Campus in Cambridge, specialises in the development of so-called “bispecific” antibodies: essentially, antibodies with two binding sites.

 
John Haurum, Chief Executive Officer at F-star, described how the antibody constant region, can be engineered to recognise an antigen.

 
Monoclonal antibodies formed by combining variable regions with this “Fcab domain” behave in all other ways like normal monoclonal antibodies, but bind two different antigens (which may be separate epitopes on the same protein).

 
The company has developed an Fcab domain that binds to a different epitope on HER2 than trastuzumab and that has improved potency in mouse models of cancer.

 
“We are using this domain to develop new cancer therapies”, said Haurum.

  
Coupling a drug molecule to an antibody can be a particularly effective technique in oncology.
 

An antibody-drug conjugate is, as John Burt from London-based PolyTherics explained, a true “magic bullet” with the antibody playing the part of a guided missile in delivering the toxic payload of the drug compound to the site of the tumour.
 
The cytotoxic drug is only released from its antibody once it is inside a tumour cell, avoiding “off target” toxicity.
 
An antibody-drug conjugate actually consists of three parts – the antibody, a chemical linker, and the drug – with the linker, according to Burt, “arguably the most important part of the conjugate”.
 
 
Most such conjugates in development use anti-tubulin cytotoxic drugs, although DNA-targeted payloads are generating increasing interest.
 
The first compound to enter the clinic, gemtuzumab ozagamicin (Mylotarg™), combines calicheamicin, a DNA-binding, glycosidic antibiotic, with an antibody against CD33 which is over-expressed in some cases of acute myeloid leukaemia.
 
The withdrawal of this drug from the market due to toxicity in 2010 indicates that there are some ongoing problems with this drug class, although it is now back in clinical trials.
 
Some of these problems undoubtedly arise from the heterogeneous nature of many conjugates, with widely varying numbers and locations of drug linkage sites.
 
Burt described technology developed at PolyTherics for conjugating drugs to the disulphide bonds around the junction between the antibody variable and constant domains.
 
Attaching a drug molecule across a disulphide that occurs in the native antibody uses simple chemistry and maintains the structure, stability and specificity of that antibody.
 
These conjugates are already proving effective in mouse xenograft models of solid tumours. 
  
Jan Alfheim from a Norwegian biotech company, Nordic Nanovector, described the development of radioimmunoconjugates to treat non-Hodgkin’s lymphoma.

 
This name is given to a diverse range of B-cell and T-cell malignancies, with approximately 80-85% of all cases being derived from B cells.

 
Most patients respond well to initial therapy, generally with rituximab and a combination of chemotherapy drugs known as CHOP, but they often relapse.

 
Reasons for this relapse include the heterogeneity of lymphoma cells and the development of resistance, so it is becomes difficult to target all the tumour cells with a single drug.

 
Radioimmunotherapy overcomes this with a “multi-cell kill approach” in which tumour cells neighbouring a cell targeted by the antibody are destroyed by radiation once the antibody reaches its target.

 
The first drug of this type, ibritumomab tiuxetan (Zevalin™), entered the clinic in 2002 but is still undergoing trials in different lymphoma types.
 

Alfheim quoted trial co-investigator Anton Hagenbeek, presenting results from a study in follicular lymphoma in 2011, as saying “"A single infusion of Zevalin matched roughly 16 infusions of rituximab in terms of achieving the same increase in progression free survival… in conclusion, [it] represents the most effective single drug in the treatment of follicular non-Hodgkin’s lymphoma.”

 
Nordic Nanovector’s lead product, Betalutin™, is a second-generation radio-immunotherapy agent that takes the same approach using a different target antigen: CD37, which is found on the surface of lymphoma cells.

 
This candidate drug has been predicted to have a better efficacy and safety profile in lymphoma patients who do not respond to rituximab, and has shown promising results in animal models.
 
The first patient was enrolled into a Betalutin phase I clinical trial in December 2012.
 
Another of the promising technologies discussed at the meeting was the development of antibody fragments with similar properties to full-size antibodies.

 
Hilde Revets from Ablynx, based in Ghent, Belgium, described how antibody-derived proteins that contain the unique structural and functional properties of naturally-occurring heavy-chain antibodies are being harnessed for therapeutic use.

 
These single domain molecules, termed “Nanobodies®”,harbour the full antigen-binding capacity of the original heavy-chain antibody.  

 
The unique, well characterised properties of Nanobodies enable them to outperform conventional therapeutic antibodies in several critical areas including recognition of hidden epitopes; cavity binding; flexibility in drug format; and tailoring the half-life.
 

Moreover these therapeutic proteins are very stable and manufacturable, which allows for alternative routes of administration. 

 
Clinical proof-of-concept has already been achieved with two Nanobodies in treating the autoimmune condition, rheumatoid arthritis.
 

Kevin Matthews, CEO of Isogenica, based in Chelmsford, UK, explained the relevance of this work to oncology: “As Nanobodies are so much smaller than standard antibodies, they penetrate tumour tissue better.”
 
 
The meeting ended with an inspiring keynote lecture by Professor Yajun Guo of the Chinese Engineering Research Centre for Antibody Medicine in Shanghai who described the enormous progress that Chinese scientists have made in this research field in recent years and invited European scientists to collaborate with him and his colleagues.
 

It is clear that China is already a major player in antibody therapeutics and that its importance is bound to increase, not least in oncology.

References

AM Scott, JD Wolchok & Old, LJ (2012). Nature Reviews Cancer 12, 278-287