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Antibody Optimization

Biointron 2024-01-20 Read time: 3 mins
Optimize.jpg
Image credit: DOI: 10.1161/CIRCULATIONAHA.113.002033

Antibody optimization encompasses several strategies which improve the safety and efficacy of antibodies, which is extremely important for therapeutic use. Before entering clinical trials, therapeutic antibody candidates typically undergo several phases of research and development, which include antibody discovery and screening based on antigen binding, lead selection based on biological function, and antibody optimization. Safety methods include antibody humanization and deimmunization, and efficacy methods include affinity maturation and Fc effector function engineering.


Safety

Antibody humanization is a method to reduce the immunogenicity of antibodies from non-human species. It is often used to develop monoclonal antibodies for human administration by modifying protein sequences to increase similarity to antibody variants produced naturally in humans. Typically, this is done by grafting antibody complementarity-determining regions (CDRs) from the non-human antibody onto a human variable region framework, depending on if a human residue would affect binding affinity. If the non-human residue is maintained, this is called ‘back mutation’.1

Deimmunization and tolerization are processes which can be used when fully humanized mAbs are still displaying immunogenicity due to epitope sequences in the antibody. Human T-cell epitopes may activate helper T-cells, causing the sustained production of antibodies and neutralization of the therapeutic effect. Deimmunization allows for the identification and removal of these epitopes using unspecific shielding approaches or site-directed mutagenesis, through either experimental or computational approaches.2,3


Efficacy

Affinity maturation refers to the process of improving antibody affinity and binding interactions to target antigens. This is performed in the lab in vitro by random mutagenesis, targeted mutagenesis, chain shuffling or in silico approaches, with subsequent selection. This directed evolution process is similar to the somatic hypermutation that naturally occurs in mammalian B cells in vivo.4

Fc effector function improvement is useful for therapeutic effectiveness as the antibody’s Fc region mediates effector functions such as antibody dependent cell-mediated cytotoxicity (ADCC), antibody induced complement dependent cytotoxicity (CDC), and antibody dependent cell-mediated phagocytosis (ADCP), which all lead to phagocytosis or cell death. Approaches to improve the affinity of Fc regions include glycosyl modifications, computational designing, and high-throughput screening.1


At Biointron, we are dedicated to accelerating antibody discovery, optimization, and production. Our team of experts can provide customized solutions that meet your specific research needs. Contact us to learn more about our services and how we can help accelerate your research and drug development projects. 


References:

  1. Wang, B., Kankanamalage, S. G., Dong, J., & Liu, Y. (2021). Optimization of therapeutic antibodies. Antibody Therapeutics, 4(1), 45-54. https://doi.org/10.1093/abt/tbab003

  2. Jones, T.D., Crompton, L.J., Carr, F.J., Baker, M.P. (2009). Deimmunization of Monoclonal Antibodies. In: Dimitrov, A. (eds) Therapeutic Antibodies. Methods in Molecular Biology™, vol 525. Humana Press. https://doi.org/10.1007/978-1-59745-554-1_21

  3. Zinsli, L. V., Stierlin, N., Loessner, M. J., & Schmelcher, M. (2021). Deimmunization of protein therapeutics – Recent advances in experimental and computational epitope prediction and deletion. Computational and Structural Biotechnology Journal, 19, 315-329. https://doi.org/10.1016/j.csbj.2020.12.024

  4. Denice T.Y. Chan, Maria A.T. Groves; Affinity maturation: highlights in the application of in vitro strategies for the directed evolution of antibodies. Emerg Top Life Sci 12 November 2021; 5 (5): 601–608. doi: https://doi.org/10.1042/ETLS20200331;


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