This article is based on a poster originally authored by Peter Hsueh, Lili Qin, Jane Liu and Wenlin Ren.
Target proteins are central to the antibody discovery process. These reagents play a critical role in the generation and characterization of therapeutic antibodies. Target proteins are most commonly used for immunization, triggering an immune response that leads to the production of highly target-specific antibodies.
Target proteins are utilized in screening assays to identify and select antibodies that can bind to the target with high affinity. These proteins also serve as useful tools in determining drug candidates’ binding affinity and specificity, enabling antibody candidate optimization during the drug discovery process.
In later stages, purified target proteins are used to validate antibody candidates’ function via techniques designed to assess the kinetics and strength of antibody-target interactions, such as enzyme-linked immunosorbent assays (ELISA) or surface plasmon resonance (SPR).
The ability to maintain target proteins’ native structure is essential because this ensures the accurate presentation of epitopes for effective antibody binding.
Target protein development, therefore, requires careful attention to structural integrity and quality control if issues such as aggregation or conformational changes are to be minimized. This is especially important, because these issues can adversely affect antibody performance.
This article explores a range of target protein design, development, and characterization strategies, highlighting their central role in the discovery of highly specific monoclonal antibodies with excellent therapeutic potential.
Figure 1. Whole picture of design and development strategies for target proteins based on structural analysis and application scenarios. Image Credit: ACROBiosystems
Figure 2. Platforms for the development of high-quality target proteins for specific applications. Image Credit: ACROBiosystems
Case study 1: Structure-oriented protein design
Image Credit: ACROBiosystems
Case study 2: Protein aggregates
Single-chain expression for BAFF trimer production
The single-chain method results in a more homogenous and accurate trimeric protein structure versus conventional methods such as direct expression or expressing the protein trimerically using three elements. This results in improved bioactivity.
Image Credit: ACROBiosystems
Case study 3: Affinity and ‘native’
Optimization of CTLA-4 dimers
CTLA-4 dimer affinity increases by over 10 times versus that of the monomer, making it far more useful in screening and drug validation. This is due to CTLA-4 being expressed as a dimer under native conditions.
SPR - CTLA4 binding to Ipilimumab
Image Credit: ACROBiosystems
Case study 4: Platform-specific QC
Claudin 18.2 virus-like particle (VLP)
Due to the number of different technology platforms used with full-length proteins, quality control of protein reagents for different formats and carriers is necessary. For example, ACROBiosystems’ quality control specifically employs electron microscopy and dynamic light scattering to ensure particle size and uniformity.
Image Credit: ACROBiosystems
Case study 5: Protein conformation
RSV fusion glycoprotein
The identification of pre- and post-fusion conformations for the RSV antigen represented a breakthrough in RSV vaccine development. Ensuring proper protein conformation during therapy development is key to leveraging the potential of this breakthrough, whether it is related to cell therapies, antibodies, or novel, innovative platforms.
Image Credit: ACROBiosystems
Conclusions
The successful discovery of therapeutic antibodies relies on the development of high-quality target proteins with appropriate structural integrity and functional activity.
Target proteins exhibit accurate epitope presentation when they maintain their native conformation – a key factor in generating antibodies with high specificity and affinity.
The proper structure and activity of target proteins are also key to the therapeutic potential and potency of resulting antibodies.
Minimization of structural issues such as conformational changes or aggregation allows researchers to improve the effectiveness of antibody candidates, ultimately facilitating the development of more powerful and precise biologic therapies.
Acknowledgments
Produced from materials originally authored by Peter Hsueh, Lili Qin, Jane Liu, and Wenlin Ren from ACROBiosystems.
About ACROBiosystems
ACROBiosystems is a cornerstone enterprise of the pharmaceutical and biotechnology industries. Their mission is to help overcome challenges with innovative tools and solutions from discovery to the clinic. They supply life science tools designed to be used in discovery research and scalable to the clinical phase and beyond. By consistently adapting to new regulatory challenges and guidelines, ACROBiosystems delivers solutions, whether it comes through recombinant proteins, antibodies, assay kits, GMP-grade reagents, or custom services. ACROBiosystems empower scientists and engineers dedicated towards innovation to simplify and accelerate the development of new, better, and more affordable medicine.
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