Modeling Strategy to Inform Antibody Binding Affinity for Soluble Targets

Here we present a modeling strategy to design an antibody drug with appropriate binding affinity that saturates a soluble antigen (A) to prevent its high affinity binding with another soluble antigen (B) in target tissue. A three-compartment TMDD model was developed using typical monoclonal antibody PK parameters and antigen-specific literature parameters to capture antibody-soluble antigen (A) interaction and antigen-antigen (A-B) interaction, respectively. The modeling goal was to establish antibody affinity-dose relationship (Q3W dosing frequency) to achieve desired target occupancy with conservative drug partitioning to the target tissue. Our modeling suggests that sub-nanomolar antibody affinity would be required to achieve desired target occupancy of soluble antigen (A) under a range of target turnover rates (minutes to hours) and in the presence of soluble antigen (B). In future, this preliminary three-compartment TMDD model will be calibrated for specific soluble antigens to guide the development of antibodies against soluble targets.