Application of Antibody Engineering in the Development of Next Generation Antibody-Based Therapeutics

Abstract

The evolution of therapeutic antibodies has encompassed multiple engineering efforts in the hope of improving the efficacy, safety, and duration of effects of antibody-based drugs. Advances in protein engineering technologies afforded investigators the ability to overcome problems associated with introducing foreign antibodies into humans. These efforts included antibody chimerization, humanization, and the more recent development of human antibodies, all of which reduced anti-drug immune responses. Additional efforts have engineered antibody variable regions that encode multiple specificities into a single molecular entity. Apart from optimizing antigen-binding capabilities and reducing immunogenicity, many advances have been made that modulate an antibody's ability to interact with cells and serum components of the immune system. Manipulation of antibody glycosylation or the amino acid sequence has had a significant impact on recruitment of the Fc-dependent effector functions. This chapter presents an overview of V region and Fc modifications and focuses on advances in engineering to tailor an antibody's function relative to the intended therapeutic need.

Challenges in Antibody Development against Tn and Sialyl-Tn Antigens

“…The expansion of therapeutic antibodies is a dynamic field that evolves alongside with technological developments. Advances in antibody engineering allowed to overcome the main problems associated with the immune response developed against foreign antibodies introduced into humans [ 137 ]. Antibody chimerization, humanization and the development of human antibodies were the major strategies adopted to reduce immunogenicity [ 68 ].…”

“…Several approaches can be used to manipulate the variable regions in order to increase the binding affinity for antigens, or tune the binding specificity, namely chain-shuffling, randomization of CDRs and induced mutations in the variable regions [ 138 , 139 ]. On the other hand, modifications in glycosylation or amino acid sequences in the constant region can modulate the Fc effector functions of antibodies, since this region is involved in ADCC and CDC [ 137 , 139 ]. Extension of the IgG half-life in serum is accomplished by engineering the Fc region particularly in modulation of its interaction with the neonatal Fc receptor (FcRn) which is associated with immunoglobulin protection from intracellular degradation [ 140 ].…”

Bioteknologi Teori dan Aplikasi

“…Untuk meminimalkan efek imunogenik murine Mabs dalam terapi manusia, komponen imunogenik murine dihilangkan dengan peningkatan efisiensi melalui berbagai pendekatan (Rodrigues ME, et al, 2010). Imunogenisitas total Mab oleh karena itu berkurang tanpa mempengaruhi kemampuan pengenalan dari antibodi asli (Brezski RJ, Almagro JC, 2012). Antibodi yang dihasilkan dari humanisasi menjadi lebih relevan dalam pengobatan penyakit inflamasi dan kanker, dengan beberapa produk antibodi tersedia di pasaran, dan yang lainnya sedang menjalani uji klinis (O'Brien LM, et al, 2012).…”