Current strategies in antibody engineering: Fc engineering and pH‐dependent antigen binding, bispecific antibodies and antibody drug conjugates

Abstract

Antibody engineering technologies are constantly advancing to improve the clinical effectiveness of monoclonal antibodies (mAbs). Effector functions may be modified by engineering the Fc region, for example to improve or reduce binding to Fc gamma receptors (FcγRs) or complement factors. Other examples for Fc engineering include modification of the half-life of immunoglobulin G (IgG); various studies have shown that half-life can be prolonged by increasing the affinity of Fc for the Fc neonatal receptor (FcRn). Furthermore, engineered pH-dependent antigen binding can be applied to enhance the recycling of IgG via FcRn, enabling binding to additional target molecules. Since bispecific approaches may elicit desired effects on disease targets, a variety of bispecific formats have been developed, including variants that structurally mimic IgG. Finally, antibody-drug conjugates (ADCs) create new opportunities for treatment of certain diseases. Advances in antibody generation, selection of highly cytotoxic molecules and production of stable linkers have paved the way to the development of many ADCs that can be tested in clinical trials. This review covers current antibody engineering strategies for the modification of therapeutic antibodies in the areas of Fc engineering and pH-dependent antigen binding, bispecific antibodies and ADCs.