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Crystal Bioscience Technology. Scientific image.

In vivo Molecular Evolution

There are two fundamental choices when selecting a system to generate novel antibodies: in vivo or in vitro. Historically, antibodies have been raised experimentally in animals, but with the advent of phage display in the 1990’s antibody discovery could be done entirely in vitro, which offers a number of advantages. Theoretically, antibodies can be quickly identified. Practically, there is no need to immunize animals. Furthermore, the antibodies have immediate therapeutic application because libraries can be derived from human sequences. With these attributes one might expect that an in vitro system would quickly make other approaches obsolete. However, the reality is that more than 90% of the FDA approved antibodies originated in an in vivo system. (See Table 1).


Table 1 » Therapeutic monoclonal antibodies approved by the FDA. Antibodies generated by in vivo affinity maturation are shown in purple. Antibodies derived in vitro by phage displayed in green.


This outcome implies that on balance, drug developers have been able to identify therapeutic antibody candidates more effectively by accessing an in vivo immune response. Naturally arising antibodies benefit from the breadth and depth of a large host repertoire that is leveraged by an adaptive immune response. The iterative process of diversification (mutation) and antigen-driven selection that occurs during affinity maturation in a live animal allows for the sampling of an immense amount of sequence space – a repertoire orders of magnitude greater than even the largest in vitro library.

Scientific imageSplenic germinal centers containing fluorescent antigen (One hour post injection).

The complex molecular and cellular interactions occurring in germinal centers as antigens are processed and presented to B cells yield high affinity and highly specific antibodies. To date no in vitro system has been developed for antibody discovery that can replicate the level of sophistication exemplified by the native immune system present in all vertebrate animals. At Crystal, our philosophy is not to rebuild an artificial (and less effective) version of this exquisite (and only partially understood) system when the real thing can be easily accessed using our GEM technology. Rather, we aim to harness the power of a natural immune response to create novel, best-of-class, molecules that will be beneficial for the management of human disease. Our pragmatic approach is supported by the overwhelming presence of affinity matured antibodies in the marketplace.