Therapeutic Antibodies—Protein Engineering to InfluenceADME,PK, and Efficacy

Abstract This chapter focuses on protein engineering strategies to reduce nonspecific uptake. One of those strategies tries to reduce the isoelectric point (pI) of the antibody by protein engineering, which can be an effective way to reduce nonspecific cellular uptake as well as improve various pharmacokinetic properties of the antibody. The authors have developed a technology to reduce target‐mediated clearance by adding a pH‐dependent antigen binding property to the therapeutic antibody, thereby increasing its chances of being recycled. For antibodies targeting soluble antigens, conventional antibodies still face significant drawbacks even if their pharmacokinetic profile is in the acceptable range. In some cases, higher concentrations of the therapeutic antibody are needed due to this accumulation of antigen, which may require substantially higher dose levels. The authors have also developed a technology to reduce antigen accumulation by optimized pH‐dependent antigen binding and increased affinity to neonatal Fc receptor (FcRn) or Fcγ receptors (FcγRs).