Somatic Hypermutation

Somatic hypermutation (SHM) is a critical enzymatic process utilized by B cells to generate antibodies. Our immune system is highly adapted to generate antibodies toward a variety of different infectious agents using a limited set of genes within our genomes. To accomplish this many millions of different antibodies can be generated through the processes of gene recombination and SHM. Antibodies are encoded within the human genome as disparate genes, named the variable (V), diversity (D) and joining (J) genes, which are joined together through the process of recombination, and displayed on the surface of specialist cells, called B cells. On encountering an infectious disease, antigen B cells displaying the recombined antibodies  are stimulated to  initiate the process of SHM which results in an enormous number of variants of the recombined antibodies thereby transforming the initially weak-binding antibodies into high specificity, high affinity variants.

The biochemistry responsible for SHM was poorly understood until recently. Seminal work by two key antibody experts, Dr. Matthew Scharff and Dr. Michael Neuberger, was the first to demonstrate that the process of SHM is catalyzed through an enzyme called activation-induced cytidine deaminase, also known as AID, acting directly on antibody DNA. It was discovered that AID regulates SHM by becoming activated immediately following B cell antigen stimulus and targets specific DNA motifs present specifically within antibody VDJ sequences. Hence, SHM is a non-random process that is exquisitely evolved to generate disease-fighting antibodies. SHM and the role of AID is identical across a variety of species.  The human immune system has also evolved to tolerate the specific non-random mutations mediated by AID, such that SHM-derived antibodies appear more natural to the human body as compared to randomly mutated sequences.  This property is important in using SHM to generate therapeutic antibodies.

AnaptysBio is the first company to  successfully replicate SHM in vitro as a platform technology for the generation of therapeutic antibodies.  Leveraging the breakthrough biochemical understanding of the role of AID, AnaptysBio’s proprietary SHM-XEL™ platform overcomes key limitations associated with historical antibody platform technologies and provides a novel approach for the discovery, maturation and optimization of therapeutic antibodies.  Key aspects of SHM-XEL are described in the following section.