The Fc includes the CH2 and CH3 domains of the heavy chain constant region ( 14). The hinge region can be subdivided into upper, core, and lower hinge regions ( 19). C-terminal to the Fab is the hinge, and the crystallizable fragment (Fc) ( 17, 18). Each heavy and light chain heterodimer includes the antigen binding fragment (Fab) composed of the light chain paired to the variable region of the heavy chain and the CH1 domain of the heavy chain constant region ( 17, 18). The two heterodimers are paired together via disulfide bonds between the heavy chains ( 15, 16). Each heavy chain associates with a light chain through disulfide bonds and non-covalent interactions to form a heterodimer ( 14). An intact full-length antibody consists of two 50 kD heavy chains and two 25 kD light chains resulting in a 150 kD full-length, soluble immunoglobulin ( 13). To optimize an antibody one must understand how the antibody is constructed and the role of each of its parts. While most approved biologics are traditional antibodies, optimized antibodies like Orencia ® (abatacept), Soliris ® (eculizumab), Nplate ® (romiplostim), and Removab ® (catumaxomab) have paved the way for optimized antibodies as treatment options ( 11). This concept is the foundation of antibody optimization efforts in industry laboratories as well as academic research laboratories. How the antibody counteracts the biologic process can be optimized for selectivity and potency by modifying the sequence of the antibody-based molecule to enhance or abrogate its interaction with the host immune system ( 11, 12). Elucidation of these mechanisms fuels the development of antibody-based biologics to counteract the abnormal biologic process that is causing disease. Therefore, many pharmaceutical companies are including antibody-like molecules in their development portfolio due to their high capacity to generate revenue.īasic science continues to discover the underlying mechanisms of genetic disorders, cancer, and infectious diseases ( 9, 10). It is estimated that global sales of antibody-based products approach $60–75 billion in any given year ( 2– 8). Consistent with an expected annual approval rate of six to nine additional antibodies ( 3), the number of approved antibodies and antibody-like biologics in the United States has climbed to more than 70 ( 1, 4). In 2015 there were 44 antibodies approved for human use in the United States and Europe ( 2). Since the approval of the first monoclonal antibody by the FDA in 1986 ( 1), there has been a rapid increase in the number of available monoclonal antibodies or antibody derivatives. This review will describe the concepts being applied to optimize the hinge and crystallizable fragment of antibodies, and it will detail how these interactions can be tuned up or down to mediate a biological function that confers a desired disease outcome. The molecular details of these interactions have led to manipulation of the sequences and glycosylation of hinge and constant domains to enhance or reduce antibody effector functions and circulating half-life. Molecular and structural studies have provided insight into how the hinge and constant domains from antibodies across different species, isotypes, subclasses, and alleles are recognized by host cell receptors and complement protein C1q. It is the hinge and constant domains of the antibody that engage host receptors or complement protein to mediate a myriad of effector functions and regulate antibody circulation. While antibody:antigen engagement is critical for an efficacious antibody biologic, equally as important are the hinge and constant domains of the heavy chain. With the vast capability of antibodies to affect infectious and genetic diseases much effort has been placed on improving and tailoring antibodies for specific functions. In general these biopharmaceuticals can be used for blocking protein:protein interactions, crosslinking host receptors to induce signaling, recruiting effector cells to targets, and fixing complement. Laboratory of Protein Expression, Departments of Surgery, Molecular Genetics and Microbiology, and Immunology, Duke University Medical Center, Duke Human Vaccine Institute, Durham, NC, United StatesĪntibodies and Fc-fusion antibody-like proteins have become successful biologics developed for cancer treatment, passive immunity against infection, addiction, and autoimmune diseases.
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