Introduction

Immunoglobulin G (IgG) is the most abundant antibody isotype in human serum, accounting for about 70-80% of total immunoglobulins. It plays a crucial role in the adaptive immune system by neutralizing pathogens, facilitating opsonization, and activating the complement cascade. IgG molecules are monomeric antibodies with two identical antigen-binding sites, making them highly specific and versatile. Standard IgG is widely studied and used as a therapeutic and diagnostic tool due to its robust immune functions, long half-life, and well-characterized structure.

IgG is also the basis for many therapeutic antibodies, including monoclonal antibodies (mAbs), which are produced using recombinant technologies. These properties make IgG a cornerstone of antibody-based research, diagnostics, and therapies.

Structure of Standard IgG

IgG molecules have a Y-shaped structure composed of:

• Two Heavy Chains
  Each heavy chain contains a variable region (V_H) responsible for antigen binding and constant regions (CH1, CH2, CH3).
• Two Light Chains
  The light chains are also divided into variable (V_L) and constant regions (C_L), which pair with the heavy chains to form antigen-binding domains.
• Fab Region (Fragment Antigen-Binding)
  The Fab region contains the V_H and V_L domains, forming two identical antigen-binding sites. The antigen-binding specificity is determined by complementarity-determining regions (CDRs) within the variable domains.
• Fc Region (Fragment Crystallizable)
  The Fc region, composed of CH2 and CH3 domains, interacts with Fc receptors (FcγRs) on immune cells and the complement system, mediating effector functions such as ADCC and CDC. The Fc region also binds to neonatal Fc receptors (FcRn), extending the IgG’s half-life in circulation.

Subclasses of IgG

Human IgG is divided into four subclasses, each with distinct biological properties:

• IgG1
  Most abundant subclass; highly effective in neutralization and ADCC. Used in many therapeutic monoclonal antibodies.
• IgG2
  Primarily involved in responses to carbohydrate antigens. Less efficient at FcγR binding and immune activation.
• IgG3
  Highly potent in complement activation but has a shorter half-life compared to other subclasses.
• IgG4
  Has unique anti-inflammatory properties and does not trigger ADCC or CDC. Often found in chronic inflammatory conditions.

Mechanisms of Action

• Antigen Neutralization
  IgG antibodies bind to toxins or viral particles, preventing them from interacting with host cells.
• Opsonization
  IgG coats pathogens, marking them for phagocytosis by macrophages and neutrophils through interaction with Fcγ receptors (FcγRs).
• Antibody-Dependent Cellular Cytotoxicity (ADCC)
  IgG triggers the killing of infected or cancerous cells by engaging natural killer (NK) cells through FcγRs.
• Complement Activation (CDC)
  IgG molecules activate the classical complement pathway, resulting in membrane attack complex (MAC) formation and target cell lysis.
• Half-Life Extension via FcRn Recycling
  Binding to neonatal Fc receptors (FcRn) prevents degradation and recycles IgG, giving it a half-life of about 21 days in humans.

Applications of Standard IgG

• Therapeutic Monoclonal Antibodies
  IgG is the backbone of monoclonal antibody therapeutics used in cancer immunotherapy (e.g., trastuzumab), autoimmune disease treatment (e.g., infliximab), and infectious disease management.
• Passive Immunization
  IgG-based therapies, such as intravenous immunoglobulin (IVIG), provide passive immunity by delivering a broad range of antibodies to patients with immune deficiencies or autoimmune diseases.
• Diagnostics and Research Tools
  IgG is widely used in ELISA assays, immunohistochemistry (IHC), Western blotting, and biosensors to detect specific antigens or proteins.
• Vaccine Development
  IgG responses serve as the primary indicator of immunity in vaccine studies, including vaccines for viral infections like COVID-19 and influenza.

Advantages of IgG

• Long Half-Life: The FcRn-mediated recycling pathway extends IgG’s half-life, ensuring sustained immune responses and prolonged therapeutic effects.
• Effector Functions: IgG can trigger ADCC, CDC, and phagocytosis, enhancing immune clearance of pathogens or cancer cells.
• Versatility and Scalability: Recombinant IgG antibodies are easily produced in mammalian cell lines (e.g., CHO or HEK293 cells), ensuring scalability for research and therapeutic use.
• Reduced Immunogenicity: Humanized and fully human IgG antibodies minimize the risk of immune reactions in patients, improving safety.

Challenges and Limitations

• Production Costs: Producing therapeutic-grade IgG in mammalian systems (e.g., CHO cells) can be expensive due to the need for complex media and long culture periods.
• Glycosylation Variability: Inconsistent glycosylation on the Fc region can affect antibody function and therapeutic efficacy.
• Immunogenicity: Although humanized IgG antibodies reduce immunogenicity, some patients may still develop anti-drug antibodies (ADAs), reducing treatment effectiveness.
• Limited Tissue Penetration: The large size of IgG (~150 kDa) restricts its penetration into certain tissues, limiting its effectiveness in some therapeutic applications.

GenScript Services and Solutions

GenScript provides a wide range of services for IgG development and production:

• Custom Antibody Production: High-quality production of monoclonal and polyclonal IgG antibodies using mammalian expression systems.
• Humanization and Fc Engineering: GenScript offers antibody humanization and Fc optimization to enhance effector functions and reduce immunogenicity.
• Antibody Purification and Analytics: Advanced purification methods and analytical tools ensure high purity and functional integrity.
• Stable Cell Pool & Cell Line Platform: GenScript provides high expression levels for high-quality antibodies with fast turnaround times.

Conclusion

Standard IgG is a critical component of the immune system and serves as the foundation for many diagnostic and therapeutic applications. Its well-defined structure, effector functions, and extended half-life make it an ideal candidate for monoclonal antibody development and passive immunization therapies. Despite challenges related to production costs, glycosylation variability, and tissue penetration, advances in antibody engineering, bioprocessing, and AI-based design are driving the next generation of IgG-based biologics. As these innovations continue, IgG antibodies will remain at the forefront of immunotherapy and biomedical research.

Related Article

What are the Different Bispecific Antibody Formats?
The Structure and Function of Antibodies | GenScript