CellSpot and Monoclonal Antibody Therapeutics
The Discovery Challenge — Finding Best in Class Antibodies
Monoclonal antibodies are one of the most exciting classes of drugs today, generating a significant market opportunity for the treatment of unmet medical needs. Antibodies are used to treat broad disease indications and have a number of advantages over small molecules, including specificity, wider safety margins and higher approval rates.
What makes a good antibody?
- High epitope specificity. An epitope is the part of a macromolecule antigen or target that is recognized by the antibodies, B cells or T cells that comprise the immune system. An antibody must specifically bind to the correct epitope to neutralize a medically important target that suppresses the clinical pathology.
- High affinity. Affinity relates to the strength with which an antibody molecule binds an epitope, with very high affinity sometimes required to achieve an efficacious antibody. If ultra-high affinity is not required, higher affinity is still important for reducing the cost of manufacturing by reducing the dose required to neutralize the antigenic target.
- Low cross-reactivity. The toxicity potential of an antibody is tied in part to the specificity with which it binds to its target antigen. The optimal monoclonal antibody (mAb) is selected from a large pool of MAbs that discriminate among closely related antigens and do not bind to millions of irrelevant antigens present in the human body. Reliance solely on epitope specificity and affinity as selection criteria reduces the likelihood of finding antibodies with very low cross-reactivity against the broader array of antigens.
- Low immunogenicity. Antibodies in development today are either humanized or fully human in contrast to the preceding generation chimeric --part human, part mouse – antibodies. The distinction among these classes lies in the percentage of the antibody’s amino acids derived from non-human sources. The more non-human sequences included, the more likely the body will reject the antibody. It has long been believed that the best antibody would come directly from man. Compared to hyper-immunized mice, antigen-exposed humans typically have a relatively low frequency of B cells making antibodies against a particular epitope and it has proven difficult to generate therapeutic antibodies from human blood cells.
CellSpot™ technology can find good antibodies
Trellis’ technology, CellSpot™, was invented to overcome the deficiencies of current screening methods for high performance antibodies: limited throughput and number of screening parameters. CellSpot can isolate superior antibodies by directly screening for 10 different parameters simultaneously such as specificity, affinity, and cross-reactivity with other antigens. The combination of selection criteria leads to a low frequency of candidate antibodies that meet all the criteria. Because of CellSpot’s ability to screen up to 1,000,000 cells in several days, 3 to 4 orders of magnitude greater than other methods, it is possible to find the best antibodies that would have otherwise escaped detection. The qualitative increase in throughput further enables discovery of antibodies directly from human blood cells with the result that safer, non-immunogenic antibodies can be found.
Many target antigens have traditionally been difficult to neutralize using antibodies. Well-known difficult targets include highly conserved proteins, ion channels and other transmembrane proteins. An example of the latter class is G Protein-Coupled Receptors (GPCRs). Although difficult targets for antibodies, they are among the most attractive drug targets available. They are implicated in many diseases and are the most validated class of druggable targets, representing about half of modern drugs.
Trellis is using CellSpot to discover antibodies for its own pipeline, incorporating the full set of characteristics needed to optimize their potential success as therapeutics. CellSpot can find very rare antibodies that have been identified and recovered from human blood cells.