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Antibody sequence and structure analysis assists biologic drug design
12 December 2014
Research by UCL's Dr Andrew Martin has led to a series of antibody-related tools being made available for free use online. One of these, the Abysis antibody database, has been visited over 360,000 times by over 8,000 users and is also sold commercially for internal use by companies.
A group led by Dr Martin (UCL Structural & Molecular Biology) is one of the only laboratories specialising in computational analysis and prediction related to antibodies. Since the invention of monoclonal antibodies that bind to a specific substance and so can be used to detect or purify that substance, their potential as 'magic bullet' drugs has been clear. However, it is only relatively recently that problems in their use have been overcome, and antibodies now represent approximately a third of all drugs in development. So-called 'fully human' antibodies have had mixed success in the clinic and the research at the Martin Lab is a valuable contribution to developing antibodies as drugs.
In 2007, Dr Martin developed a new automated method for applying standard numbering schemes to antibody sequences. Various such schemes have been devised, the most popular being the Kabat and Chothia schemes, but there had been no tools that applied these schemes automatically. Applying standard numbering to antibody sequences and structures, as allowed by Dr Martin's research, is fundamental to analysing their properties. In addition, Dr Martin developed a machine learning method to predict the packing angle between the antibody variable domains - again allowing improved prediction and modelling of antibody structure. He developed methods for assessing the 'humanness' of antibodies by evaluating how similar they are to the expressed human repertoire. Combining a number of these tools and resources, he developed the Abysis antibody database, an integrated resource based around a relational database of sequence and structure data together with a set of tools for analysing new sequences.
Dr Martin has been making antibody-related tools available for free use online since 1996, when KabatMan made the Kabat antibody sequence available in a manner that let people perform automated global analyses of antibody sequences for the first time. The initial development of Abysis (2006-2009) was funded by biopharmaceutical company UCB, in return for which they received a version for in-house use. This is now their primary resource for analysis of antibody sequence and structure and is used as a repository for their own in-house antibody sequence data.
Abysis has been made freely accessible online since 2009. Between 2009 and 2012, Dr Martin's antibody-related pages (including Abysis) have been visited more than 570,000 times by nearly 43,000 distinct users. This represents an average of more than 14,600 visits per month from more than 1,100 distinct users.
Abysis has also been released under a commercial license since the end of 2009 through UCL Business for in-house use by commercial customers. It has been purchased by companies ranging from small biotechs to large pharma for use in their antibody therapeutic development pipelines.
Using Abysis, for example, it was shown that Humira, the first 'fully human' antibody (produced by phage display), did not appear especially human in nature. Recent results have shown that almost 30% of patients develop anti-antibody responses within three years. This also suggested that this humanness measure may well be a useful tool to help predict the ability of a substance to provoke an immune response, and it is being used within Abysis for this purpose.
Dr Martin's group has collaborated across and beyond UCL in drug development. In addition, over 800 patents in 2008-2013 alone cited the group's key publications. A recent collaboration with the Centre de Recherche du Service de Santé des Armées (CRSSA) led to Biogen Idec no longer maintaining a patent restricting the use of macaque antibodies as therapeutics. Martin's measure of humanness, available within Abysis, has shown that, contrary to claims in the Idec patent, macaque antibodies can be distinguished from human antibodies. This has therefore given freedom to operate, in the use of macaque antibodies as therapeutics, to all commercial companies as well as for development by the CRSSA.
His expertise in antibodies (and in bioinformatics in general) has led to him being called as an expert witness in patent disputes related to antibodies and gene patenting.