Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation

Abstract

Therapeutic antibody technology heavily dominates the biologics market and continues to present as a significant industrial interest in developing novel and improved antibody treatment strategies. Many noteworthy advancements in the last decades have propelled the success of antibody development; however, there are still opportunities for improvement. In considering such interest to develop antibody therapies, this review summarizes the array of challenges and considerations faced in the design, manufacture, and formulation of therapeutic antibodies, such as stability, bioavailability and immunological engagement. We discuss the advancement of technologies that address these challenges, highlighting key antibody engineered formats that have been adapted. Furthermore, we examine the implication of novel formulation technologies such as nanocarrier delivery systems for the potential to formulate for pulmonary delivery. Finally, we comprehensively discuss developments in computational approaches for the strategic design of antibodies with modulated functions.

Keywords: aggregation; formulation; manufacture challenges; stability; therapeutic antibody.

Figure 1

The proportions of therapeutic antibody formats approved for therapeutic use as of December 2018^, IMGT^® depicted through (a) a pie chart and (b) a table format.

Figure 2

Schematic representation of a whole monoclonal antibody (mAb), a fragment mAb, and prominent fusion mAb formats that have been developed for strategic therapeutic uses. Proteins fused to mAb fragments are depicted as blue ovals for a general representation; however, fusion proteins may vary in size and structure. Fragment formats include the crystallizable (Fc), antigen binding (Fab and F(ab)2), and single-chain variable (scFv) fragments. Further whole mAb formats include the antibody–drug conjugate (ADC), triomab, dual variable domain immunoglobulin (DVD-Ig), and immunoglobulin–scFv fusion (IgG-scFv). Multispecific fragment formats include the F(ab)2 bispecific, bispecific T-cell engager (BiTE), dual affinity re-targeting molecule (DART), and tandem diabody (tandAb).

Figure 3

Schematic representation of the concept stages of mAb drug development in which considerations follow on from one process to the next in the design and manufacture of mAb-based therapeutics.