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18 | SEPTEMBER 1, 2016 | GENengnews.com | Genetic Engineering & Biotechnology News Duncan J. Huston-Paterson, D.Phil., Soma S.R. Banik, Ph.D., and Benjamin J. Doranz, Ph.D. To discover therapeutically relevant anti- bodies efficiently, discovery groups are in- creasingly turning to functional screening strategies that can quickly isolate molecules with desired cellular effects. The challenge of this approach, however, is characterizing antibodies of interest to identify their bind- ing targets. The lack of suitable methods to identify the targets of functional antibodies and ligands, particularly membrane proteins (which are the targets for more than 60% of FDA-approved antibody therapies), has led to freezers full of potential therapeutic can- didates with no known target. The persistence of this problem is exem- plified by alemtuzumab (Campath), the first FDA-approved monoclonal antibody dis- covered using functional screening, which required nearly a decade of biochemical analysis before finally identifying CD52 as its target. The Membrane Proteome Array To address the need for antibody target deconvolution and receptor identification, Integral Molecular has developed the Mem- brane Proteome Array (MPA). The MPA is a high-throughput cell-based platform for identifying the targets of orphan antibodies and other ligands that bind to membrane proteins (Figure 1). Membrane proteins account for roughly a quarter of all the proteins encoded by the hu- man genome and often fold into conforma- tionally complex structures that are difficult to retain outside of the cell. The key feature of the MPA is that human membrane pro- teins are individually expressed and tested in their native state directly within human cells, thereby retaining their structural integrity and native post-translational modifications. The MPA makes use of the largest mem- brane protein library yet assembled, repre- senting over 4,500 unique human membrane proteins. Each membrane protein clone in the MPA includes a C-terminal epitope tag, allowing confirmation of protein expression and the ability to verify the integrity of the membrane protein library. Integral Molecular has leveraged its 15 years of experience working on membrane proteins by including optimized variants of the most recalcitrant membrane proteins, overcoming challenges with their expression and trafficking. The screening process at Integral Molecu- lar has been entirely automated, enabling rapid and reproducible binding profiles to be generated. To provide the highest level of FDA inspected 2011, 2013, 2014 Your clinical development partner manufacturing from Ph I to commercialization. Reliable CMO for biopharmaceuticals since 1994. Making your injectable GMP plasmid DNA manufacturing scalable to kg 150 g Eurogentec is part of KANEKA Corp. www.biologics.eurogentec.com | biologics@eurogentec.com Plasmid DNA Microbial experts Proteins & conjugates A High-Throughput Platform for Identifying Membrane Protein Antibody Targets Screening the Membrane Proteome DRUG DISCOVERY Tutorial Figure 2. (A) Integral Molecular's MPA has been used to profile the specificity of antibodies with known targets, thereby de-risking antibody development by identifying off-target binding that could cause patient side-effects. (B) The MPA has also been used to identify the targets of orphan antibodies, resulting in new intellectual property, novel therapeutic targets, and new disease biomarkers. Figure 1. Integral Molecular's MPA is a high-throughput cell-based platform for identifying the membrane protein targets of antibodies and other ligands. Membrane proteins are expressed in human cells within 384-well microplates, and ligand binding is detected by flow cytometry, allowing sensitive detection of both specific and off-target binding.