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European Biopharmaceutical Review

Targeted Treatment

The goal of therapy is to treat infected/diseased tissues and leave healthy tissues unharmed. Unfortunately, therapeutics often have side effects due to off-target interactions, as is evident with chemotherapeutics used to treat cancer. In conditions with high mortality rates (such as cancer), patients are often willing to accept side effects to maximise the effect of treatment on the cancer. However, these off-target effects could be reduced if the drug can be more effectively delivered to the diseased tissues. Examples of this targeting have been achieved through the use of antibody-drug conjugates (ADCs) (see Figure 1).

With the obvious benefits of this targeting approach, it may be surprising to learn that, to date, only four ADCs have received FDA approval – the first of which (Gemtuzumab ozogamicin) was approved in 2001 for the treatment of acute myelognous leukaemia. Several factors have limited ADC progress, which largely revolve around issues with the antibody component. Firstly, antibodies themselves are part of the immune system, and even minimised fragments used in more recent ADC developments are still potentially immunogenic. This can lead to immune-related side effects. Another issue with ADCs is their relatively poor tissue penetration in solid tumours, although this is less problematic for smaller, recombinant antibody fragments. This problem can also be compensated for by linking highly potent drugs, however, this can lead to elevated risk of vascular leak syndrome (2-3).

Isolating targeting antibodies requires painstaking research to identify and produce a suitable cell surface antigen. This antigen should be uniquely expressed in the diseased tissue or at least expressed in significantly elevated levels, relative to healthy tissue. One example is HER2 − a cell surface receptor, present in approximately 15-30% of breast cancers and targeted with the ADC Trastuzumab emtansine. Once the target protein is identified and produced, a meticulous process of antibody generation and screening is required to isolate the best performing monoclonal antibodies. As these antibodies are typically isolated from rodents, ‘humanising’ the antibody is necessary to limit recognition of the ADC by the patient’s immune system and subsequent clearance from the blood stream (4).

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Edward Barnes is the Laboratory Manager at Aptamer Group and has a BSc in biochemistry from the University of Leeds, UK. In his final year, Edward undertook an aptamer-based project under the guidance of Dr David Bunka, allowing him to refine his aptamer selection skills. He completed an MSc in bioscience technology at the University of York, UK. Edward has recently completed his PhD experimental work, jointly managed between Aptamer Group and the University of Manchester, UK. His thesis is now submitted and is expected to be complete by the end of the summer 2018.

Dr David Bunka is the Chief Technical Officer at Aptamer Group and holds a PhD in molecular biology from the University of Leeds, UK. He spent 12 years developing high throughput automated aptamer selection methods at the university and built up a sold international reputation in the field. Since 2003, David has isolated >300 aptamers against a wide variety of targets including: small molecule antibiotics, food contaminants, disease-associated proteins, several cancer-associated cell lines, viruses, and patient tissue samples. Since joining the group officially in 2012, David has authored several aptamer papers in peer reviewed journals, including invited review articles and a book chapter in 2012 for the Royal Society of Chemistry entitled "Therapeutic Uses of Nucleic Acid Aptamer Conjugates".

Dr Arron Tolley is the Chief Executive Officer of Aptamer Group and holds a PhD in molecular biology and biophysics from the University of Leeds, UK, and a BSc in molecular medicine. Arron has several years' experience raising aptamers against complex cellular targets and model disease systems. He has developed several aptamer panels against model cell lines associated with oesophageal adenocarcinoma. Arron still plays an active role in the R&D side of the group and is credited with the invention and development of a new aptamer based biomarker discovery platform (Aptasort) to be offered to the life sciences industry through the aptamer group.
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Edward Barnes
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Dr David Bunka
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Dr Arron Tolley
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