­An in vivo method for diversifying the functions of therapeutic antibodies

Background

Antibodies are one of the fastest growing drug classes with a major impact particularly in oncology, autoimmunity and chronic inflammatory diseases. These products must meet stringent criteria of target specificity and affinity for their clinical application. Thus, there is a need for reliable methods to either modify or diversify therapeutic antibodies and allow selection for the most optimal properties.

Technology Overview

Dr. Frederick Alt’s lab at Boston Children’s Hospital has developed an in vivo method for antibody optimization or discovery that exploits the normal diversification mechanism that occurs naturally during B cell development and activation in mice, namely V(D)J recombination in progenitor B cells and somatic hypermutation (SHM) in B cells that have encountered antigen. Repeated cycles of mutation and selection lead to mature antibodies with enhanced specificity and affinity.

Technology Proof of Concept

• Two mouse models that predominantly assemble heavy chain immunoglobulin (IgH) of an existing therapeutic anti-PD1 antibody (17D8, Nivolumab) were generated by an intricate engineering of the mouse IgH locus.
• Both models led to antibody rearrangements (i.e., new antibodies) in 33 – 40% of the cells analyzed.
• Immunization with human PD1 induced robust anti-PD1-binding IgG in plasma of both mouse models. Many of these antibodies represented novel, high affinity anti-PD1 antibodies that, like 17DI, block that interaction of PD1 with its ligands.  However, other new high affinity anti-PD1 antibodies had acquired the opposite activity of enhancing PD1/ligand interaction.  These latter antibodies might suppress deleterious T cell activities in autoimmune diseases.
• This general class of models, with certain genetic modifications, has been used in proof-of-concept studies to discover novel human therapeutic antibodies following immunization with and antigen of interest.

Benefits

• Exploits the natural in vivo B cell maturation process to derive novel antibodies
• Modularity of the models can readily accommodate additional antibodies beyond anti-PD-1 for antibody diversification,
• Additional modifications of the model allow the platform to be robustly used as a novel approach for discovery of potentially therapeutic human antibodies

Applications

• Development of variant antibodies from a prototype with new binding modes and/or improved specificity
• Diversification of binding antibody repertoire
• The approach should be generally applicable for diversifying many other therapeutic antibodies.
• The approach should be generally applicable for discovering new therapeutic human antibodies