ABSTRACT
Unlike small-molecular drugs with clearly and well-defined composition and structure, biologic drugs have much more complex ingredients, which are usually biomacromolecules including proteins, nucleic acids (DNA, RNA, antisense oligonucleotides), or living microorganisms like virulenceattenuated viruses and bacteria. Among them, recombinant-protein drugs have been the most common biopharmaceuticals so far. Classes of approved recombinant-protein drugs include hormones, cytokines, clotting factors, monoclonal antibodies, vaccine products, enzymes, and novel conjugates. As indicated earlier, biological products have many fundamental differences from chemical compounds. For example, chemical drugs are usually lowmolecular-weight organic compounds (<1000 Da) with simple and definite chemical structures, while biological products have larger sizes and more complex structures. The average molecular weight of biologics ranges from 4,000 Da for nonglycosylated proteins to more than 140,000 Da for monoclonal antibodies (Lanthier et al., 2008). Recombinant-protein drugs fold into threedimensional structures, which have four distinct levels. Amino acids are polymerized into a linear chain by the formation of an amide linkage between the α-carboxyl group of one amino acid and the α-amino group of the next, which is referred to as the primary structure of proteins. The polypeptide then folds into highly regular local substructures such as an alpha helix and beta strand, forming the secondary structures. The spatial relationship of the secondary structures to one another is referred to as tertiary structure, which is stabilized by nonlocal interactions like the hydrophobic core, salt bridges, hydrogen bonds, disulfide bonds, and posttranslational modifications. Many proteins consist of two or more polypeptide chains, and the manner of these associated protein subunits is called the quaternary structure.
