Affinity Maturation for Antibody

Duration: 3 min

Jeffery Shi

Protein and Antibody Product Marketing

Jeffrey Shi, Head of Protein and Antibody Product Marketing Team of Marketing Department. He and his team are responsible for customer-centric development of full product life cycle management for Protein and Antibody, and drive the sustainable development of the protein antibody business.

Talk to Author

Affinity maturation is a critical step in optimizing the binding strength of an antibody to its target. Naturally, antibodies produced by the immune system undergo a sophisticated process known as somatic hypermutation ^[1]. This process occurs in B cells, where the DNA encoding the antibody's variable regions undergoes mutations at a high rate. These mutations result in a diverse pool of antibody variants, each with potentially different affinities for the target antigen. Through a selection process known as clonal selection, B cells expressing antibodies with higher affinity for the antigen are preferentially selected for survival and proliferation. This natural evolutionary process enables the immune system to produce antibodies with significantly improved binding properties, thereby enhancing the body's ability to effectively combat infections and diseases.

Figure 1 The process of affinity maturation ^[2]

In the laboratory, scientists have developed advanced techniques to mimic this natural process and induce affinity maturation in antibodies. One common method is site-directed mutagenesis, where specific changes are introduced into the DNA sequence of the antibody's variable regions. This targeted approach allows researchers to precisely alter particular amino acids that are crucial for antigen binding ^[3]. Another widely used technique is error-prone PCR, which introduces random mutations throughout the variable regions ^[4]. This method generates a broad spectrum of antibody variants, from which those with enhanced affinity can be identified through rigorous screening processes, such as phage display or yeast display.

Traditional affinity maturation is a tedious and time-consuming process. Recently, scientists from Stanford University have been leveraging AI to guide mutations for affinity maturation. Their study shows that AI models can predict evolutionarily plausible mutations without requiring prior knowledge of the target antigen, binding specificity, or protein structure. By using language-model-guided evolution on seven antibodies, they significantly enhanced binding affinities—up to 160-fold in unmatured antibodies—within just two rounds of laboratory evolution. Additionally, these AI-designed antibodies exhibited favorable thermostability and viral neutralization against Ebola and SARS-CoV-2 pseudoviruses, demonstrating the potential of this approach for efficient and versatile protein evolution.

The ultimate goal of these laboratory techniques is to produce an antibody that binds with high specificity and affinity to its target antigen. High-affinity antibodies are invaluable in the field of therapeutics, as they can be used to treat a wide range of diseases, including cancers, autoimmune disorders, and infectious diseases. By optimizing the binding properties of antibodies, researchers aim to maximize their effectiveness and minimize potential side effects, thereby creating highly potent and specific therapeutic agents. This process of affinity maturation not only enhances the therapeutic potential of antibodies but also contributes to the development of more effective diagnostic tools and research reagents, advancing the overall field of biomedicine.

References

[1] Muecksch F, Weisblum Y, Barnes C O, et al.. Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations. Immunity. 2021 Aug 10;54(8):1853-1868.e7. doi: 10.1016/j.immuni.2021.07.008.

[2]Marks C, Deane CM. How repertoire data are changing antibody science. J Biol Chem. 2020 Jul 17;295(29):9823-9837. doi: 10.1074/jbc.REV120.010181.

[3] Bezie Y, Tilahun T, Atnaf M, et al. The potential applications of site-directed mutagenesis for crop improvement: A review. J Crop Sci Biotechnol. 2020 Dec;24:229-244. doi: 10.1007/s12892-020-000.

[4] Lee S O, Fried S D. An error prone PCR method for small amplicons. Anal Biochem. 2021 Sep 1;628:114266. doi: 10.1016/j.ab.2021.114266.