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Crystal Antibodies Are Powered By Evolution

Since immune responses are regulated through self-tolerance, a host will generally only develop antibodies against portions (epitopes) of the target that are different from its own version (orthologue) of that same target. The extent to which orthologues diverge is simply a function of the genetic drift that occurs over time. Mice and humans last shared a common ancestor ~95 million years ago, whereas chickens and humans last shared a common ancestor over 300 million years ago. The result is that for any given human target protein, the murine orthologue will be more homologous than the chicken orthologue, and therefore a chicken host will have a greater opportunity to “see foreign epitopes” upon immunization. This translates to a more robust and diverse immune response. We like to say that the advantage of our system is powered by evolution.

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Her2 Model

The animation below illustrates the impact of sequence divergence using a structural model of human HER2 extracellular domain. Murine-divergent residues are highlighted in red and chicken-divergent residues highlighted in green (deletions in yellow). Regions of HER2 which are shaded green but not red may be uniquely recognized by the chicken immune system.

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To see a homology comparison for your protein of interest, try our homology tool…

Examples of enhancing epitope coverage on human targets by using chicken immunization.

Sequence comparisons underscore the advantage of using Crystal Bioscience's antibody discovery platform. We have assembled a library of 18,000 proteins that are shared by humans, mice and chickens. We invite you to use this algorithm to compare the sequence of your target protein. In more than 95% of cases, the chicken sequence has lower homology to human than the mouse orthologue. In practical terms, this translates to a greater epitope coverage and isolation of unique antibodies that are unavailable from any other antibody discovery platform. But don't take our word for it - plug in your target and see for yourself.

Crystal Antibodies Reveal Novel Epitopes

In a direct comparison of two panels of mAbs, one from mouse immunization and one from chicken immunization, raised against the same target (human progranulin), both overlapping and non-overlapping epitope bins were observed. Some epitopes were defined by both antibody panels while others were defined by only the chicken panel. The “chicken only” epitopes often corresponded with species cross-reactivity. For more information, see this article by Abdiche, et al. 2015.

Node plot showing overlapping and non-overlapping epitope bins between panels of mAbs from mouse (purple) or chicken (green).

The ability to generate antibodies to novel epitopes is important for discovering antibodies with rare biological activities, and can lead to a strong IP position for certain therapeutic targets.

Crystal Antibodies Are Species-cross Reactive

Chickens often generate antibodies that are cross-reactive to human and murine orthologues. Such antibodies are rarely obtained from mice because it requires the breaking of self-tolerance. Species cross-reactive antibodies can be selectively recovered from immunized chickens using the GEM assay. They are especially useful when rodent models of disease are anticipated because they obviate the need for developing a second “surrogate antibody” for that purpose.

Species cross-reactivity profiles of a panel of transgenic chicken mAbs raised against human progranulin.

Crystal Antibodies Can Bind Highly Conserved Targets

Chickens have been the “go to” host animal for many years for raising (polyclonal) antibodies to highly conserved targets that are non-immunogenic in mouse. Crystal’s GEM technology now makes recovering mAbs from chicken facile, and thus opens up this class of targets for new therapeutic approaches. For an example see our Case Study on BDNF.