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Novel Maturation Process for Generating High-Affinity Antibodies

PEGS Boston, Boston, MA, USA
April 8, 2019

For certain therapeutic and diagnostic applications, antibodies with affinities in the low picomolar range are required. The affinities of antiprotein antibodies derived directly from Morphosys’ Ylanthia® library are typically in the nanomolar range, but also clones with sub-nanomolar affinities are selected from this library. Here, we present a new, systematic affinity maturation process to generate optimized antigen-binding clones with affinities in the picomolar range, based on Morphosys’ Ylanthia® and arYla library technologies. In a first step, in vivo, primary antibodies (generally of the IgM isotype), which have a very low affinity to their target molecule, are generated. In a later stage, high-affinity antibodies of the IgG isotype are produced by class switching and introduction of point mutations in the V region genes, a process called ‘hypermutation’. In the course of the immune response, the cells that produce antibodies of the highest affinity to the target are selected. However, it has been observed that during this in vivo maturation process, the B cell response is limited by an apparent affinity ceiling near a KD of > 100 pM (Batista and Neuberger, 1998). Furthermore, the mutations introduced during the natural maturation affect not only the CDRs, but also, albeit to a lesser extent, the framework regions of the antibody. Affinity maturation using the Ylanthia® CDR modules mimics this natural process of variation and selection with very important exceptions: During the Ylanthia® maturation process, point mutations are not randomly introduced in the V region genes as this might lead to amino acid exchanges in the framework regions and thus to deviations from the antibody germline sequences. Instead, only the CDR regions are changed.

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