Target identification in Antibody Drug Discovery is the process of identifying the molecular target of an Antibody - usually target cell surface molecules such as receptors or antigens expressed on tumor cells or other host cells. Steps involve identifying druggable targets (defined as the likelihood of being able to modulate a target with a therapeutic). Target identification can be approached by direct biochemical methods, genetic interactions or computational inference. In many cases, however, combinations of approaches may be required to fully characterize on-target and off-target effects and to understand mechanisms of Ab-binding to the target antigen.
But how is a target selected?
- Based on published data: Literature target, patents etc.
- "Omic" studies: Transcriptional profiling and proteomics data that lead to the discovery of genes and proteins with aberrant expression patterns in disease states.
What are some of the considerations that go into target selection?
- Target accessibility: It should reside in physiological location accessible to Ab. Brain targets are notoriously difficult to treat using Ab therapeutics because the blood-brain barrier prevents their entry into brain. Single domain Abs/nanobodies can help in such cases owing to their small size (~13kDa).
- Expression: Should be expressed in pathological tissue.
- Concentration: Should be present at level that is detectable and can be stoichiometrically bound by Ab therapeutic.
What happens after a target is identified?
- Therapeutic strategy is defined: For example, a common molecular mechanism for an antibody-based therapeutic is the blockade of a ligand-receptor interaction, for which there are three conceivable targeting strategies: an anti-ligand antibody, an anti-receptor antibody, and a receptor-Fc fusion protein1.
Target Assessment & Validation
The first step after a target has been identified is to validate it. Validation is simply defined as having gathered adequate scientific evidence for the target's disease association and its therapeutic potential. This is achievable through animal model studies, including mouse genetics. Examples listed below:
- Deletion of the mouse ortholog and/or overexpression of mouse protein should mimic human pathology1.
- Ab-based intervention of target in an animal mimicking human disease should yield the desired therapeutic outcome1.
Typically a monoclonal antibody (mAb) recognizing the mouse ortholog of the intended human protein is obtained as a surrogate Ab to facilitate target validation. Research materials/reagents at this stage typically include surrogate antibodies, transgenic animals and cell lines. Biological experiments also include knockout, transgenic animals or RNAi techniques. Majority of targets meet some but not all criteria and additional validation efforts are often conducted.
The previous section in this series is "Antibody Drug Discovery Overview". To review, click 建立责权一致的工作机制.
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1Shih, H. H. in Development of Antibody-Based Therapeutics (ed M.A; Bornstein Tabrizi, G.G.; Klakamp, S.L.) Ch. 2, 9-32 (Springer, 2012).