Proteins are synthesized as linear chains of amino acids, but their true functional complexity emerges after translation. Post-translational modifications (PTMs) introduce chemical changes to proteins, profoundly influencing their structure, function, and interactions. For antibodies, these modifications play a critical role in their diversity, specificity, and therapeutic potential.
Types of Post-Translational Modifications
1. Chain Additions
Glycosylation: Antibodies frequently undergo N-linked glycosylation at the Fc domain. This process regulates effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement activation.
O-linked glycosylation and glycation, while less common, can influence antigen binding and serum half-life.
Sulfation and Cysteinylation: These modifications occur in the variable domain and affect antigen binding and immune signaling.
2. Chain Trimming
C-terminal Lysine Clipping: A process that occurs during antibody manufacturing, lysine clipping can impact antibody charge heterogeneity, affecting stability and function.
3. Amino Acid Modifications
Cyclization: Conversion of the N-terminal glutamine to pyroglutamic acid can enhance antibody stability and resistance to degradation.
Deamidation and Isomerization: These age-related changes can reduce antigen-binding affinity and functional efficacy.
Oxidation: Commonly affects methionine and tryptophan residues, potentially impairing Fc receptor binding.
Carbamylation: Alters the charge and structural integrity of antibodies, influencing their activity.
4. Disulfide Bond Alterations
Disulfide Scrambling: Disruption of hinge-region disulfide bonds can weaken antibody structural stability, reducing functional potency.
The Role of PTMs in Antibody Function
Enhancing Antigen Recognition
PTMs in antibody variable domains modulate binding affinity and specificity. For example, glycosylation in the Fab region can either enhance or hinder antigen binding, depending on the modification's context.
Regulating Effector Functions
Fc-mediated activities, such as ADCC and complement-dependent cytotoxicity (CDC), are highly sensitive to PTMs. Controlled glycosylation patterns in the Fc region, such as the absence of fucose, can significantly increase ADCC activity.
Microheterogeneity and Functional Diversity
Each antibody molecule can exist as a population of variants due to PTMs, creating microheterogeneity. This diversity introduces differences in potency, stability, and activity, which are particularly relevant in therapeutic antibody development.
PTMs in Antibody Therapeutics
Manufacturing Challenges and Opportunities: Initially considered a manufacturing nuisance, PTMs are now leveraged to enhance antibody properties. Strategies include controlled glycosylation to optimize therapeutic efficacy and engineering stable disulfide bonds to improve antibody durability.
Tailored Therapeutics: PTMs are being intentionally manipulated to create next-generation antibodies with enhanced or novel functionalities, such as bispecific antibodies and antibody-drug conjugates (ADCs).
Related: Recombinant Protein Expression in Mammalian Cells & E.coli
DOI: 10.3389/fbioe.2022.856049Antibodies have become essential tools for the diagnosis and treatment of numerous human diseases. However, non-human antibodies, such as those derived from murine sources, often provoke human anti-mouse antibody (HAMA) responses. This immunogenicity leads to rapid clea
In therapeutic antibody development, achieving high-affinity antigen binding is central to improving drug efficacy, durability, and safety.Biointron’s High-Throughput Fully Human Antibody Discovery service is designed to meet this need by integrating advanced screening and engineering technol
I. Introduction to Hybridoma TechnologyHybridoma technology, developed by Köhler and Milstein in 1975, is a foundational method for producing monoclonal antibodies (mAbs). The approach involves fusing antibody-producing B lymphocytes with immortal myeloma cells to form hybridoma cells. These hybrid
Introduction to Monoclonal Antibody Discovery Monoclonal antibodies (mAbs) are one of the most successful classes of biologic drugs on the global pharmaceutical market. Since the approval of Orthoclone OKT3 in 1986, over 100 mAbs have been approved by the U.S. FDA for indications incl
ScientistとScience Exchangeとのご利用可能です。
