Antibodies, a key element of the immune system, play dual roles through two distinct structural regions: the antigen-binding fragment (Fab) and the crystallizable fragment (Fc). These regions not only bind antigens but also trigger immune responses that facilitate antigen clearance. The Fab region, responsible for antigen recognition, binds with high specificity, while the Fc region engages immune system components such as phagocytes or proteins from the complement pathway to promote antigen removal. This combination allows antibodies to both recognize pathogens and coordinate their elimination.
Understanding the division of labor within the antibody structure provides essential insights for the development of therapeutic antibodies, as manipulating these regions can tailor antibody-based treatments to trigger specific immune responses. For instance, some therapeutic antibodies are engineered to enhance Fc-mediated effector functions, improving their ability to recruit immune cells for cancer immunotherapy or autoimmune disease interventions.
The Basic Structure of Antibodies
Antibodies all share a common Y-shaped structure composed of two identical heavy chains and two identical light chains. This structure is divided into two Fab arms and an Fc stem. The Fab regions contain both constant and variable domains, with the variable domains forming the antigen-binding site. The heavy and light chains fold into a series of immunoglobulin folds, characterized by anti-parallel β-sheets. The Fab domain’s two variable regions, together called the variable fragment (Fv), confer antigen specificity.
Within the Fv, the specificity of antigen binding is provided by three hypervariable loops, known as complementarity determining regions (CDRs), surrounded by more conserved framework regions (FRs). The hypervariability of these CDRs allows antibodies to recognize a vast array of antigens, making them incredibly versatile in immune defense.
These structural elements—particularly the CDRs—are essential targets for antibody engineering in therapeutic applications. By modifying the CDRs, researchers can develop antibodies with higher affinity for specific targets or those that can recognize novel antigens, broadening the therapeutic utility of monoclonal antibodies in cancer, infectious diseases, and inflammatory conditions.
DOI: 10.1074/jbc.REV120.010181
Glycosylation of Antibodies: Key to Functionality and Stability
Antibodies are glycosylated proteins, meaning that sugar chains are attached to specific amino acid residues within the antibody structure. Glycosylation is particularly critical in the Fc region, where it modulates both the stability and function of the antibody. In human IgG, the Fc region consists of two paired CH3 domains and two CH2 domains, the latter of which are separated and hold oligosaccharide chains. These sugar chains shield the hydrophobic faces of the CH2 domains, preventing them from pairing and affecting the overall structure.
The glycosylation pattern can greatly influence an antibody’s biological activity, especially in Fc receptor binding and activation of the complement system. For example, the presence of terminal sugars such as sialic acid, fucose, or mannose can alter the antibody’s effector functions, such as its ability to mediate antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). Altering glycosylation patterns through engineering techniques has become a powerful strategy in designing therapeutic antibodies with enhanced efficacy or reduced immunogenicity.
The detailed understanding of antibody structure, particularly the Fab and Fc regions, has paved the way for advanced therapeutic antibody design. Modifying the Fab region, such as optimizing CDR sequences, allows for increased specificity and affinity for target antigens. This is crucial in developing therapeutic antibodies that must precisely target specific cancer cells or pathogens without cross-reacting with healthy tissues.
The Fc region offers opportunities to enhance or diminish immune effector functions depending on the therapeutic goal. For example, in certain cancers, increasing Fc-mediated ADCC can boost the immune system’s ability to recognize and destroy cancer cells. On the other hand, reducing effector functions may be beneficial in autoimmune diseases, where dampening the immune response can prevent further tissue damage.
Additionally, engineering antibody glycosylation can tailor these molecules for better clinical outcomes. Glycoengineering is used to optimize antibody-dependent effector functions or to reduce the risk of adverse immune responses. These strategies are transforming the therapeutic landscape, especially in oncology and chronic inflammatory diseases, where antibodies are frontline treatments.
