Antibody Engineering: From Bispecifics to Humanization

Antibody engineering has made remarkable advancements since the invention of hybridoma technology in 1975 by Köhler and Milstein, leading to the creation of therapeutic agents that exhibit high specificity and reduced adverse effects.  

Bispecifics

Immunoglobulin G (IgG), the most common type of antibody found in blood circulation, is monospecific and recognizes only a single antigen, with the exception of IgG4. In contrast, bispecific antibodies are designed to recognize and bind to two different targets. This is useful as a therapeutic as it can be designed to redirect, for instance, immune cells such as T cells, to selectively engage and eliminate target tumor cells. In addition, bispecific antibodies can assist in the delivery of therapeutic payloads, such as toxins or drugs, to specific sites in the body.¹

Fc engineering 

The antibody’s Fc region has been shown to mediate effector functions such as ADCC and CDC, which can significantly affect therapeutic effectiveness. Antibody dependent cell mediated cytotoxicity (ADCC) occurs when antibody-opsonized target cells activate Fc gamma receptors on the surface of macrophages to induce phagocytosis. Complement-dependent cytotoxicity (CDC) results from the C1q protein binding to the Fc region which are in turn bound to a cell surface antigen, thus inducing cell death. These Fc-dependent effector functions are continuously being fine-tuned to increase the potency of antibodies.²

Humanization

The humanization of antibodies is a method to reduce the immunogenicity of antibodies from non-human species. It is typically used to develop monoclonal antibodies for human administration, by modifying protein sequences to increase similarity to antibody variants produced naturally in humans. At first, genetic engineering was used to generate chimeric antibodies, which contained human constant domains and as well as non-human variable domains to retain specificity. Humanized antibodies were then created by grafting antibody complementarity-determining regions from the non-human antibody onto a human variable region framework.³

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References:

1. Yélamos, J. (2022). Current innovative engineered antibodies. International Review of Cell and Molecular Biology, 369, 1-43. https://doi.org/10.1016/bs.ircmb.2022.03.007 

2. Moore, G. L., Chen, H., Karki, S., & A, G. (2010). Engineered Fc variant antibodies with enhanced ability to recruit complement and mediate effector functions. MAbs, 2(2), 181-189. https://doi.org/10.4161/mabs.2.2.11158 

3. Waldmann H. (2019). Human Monoclonal Antibodies: The Benefits of Humanization. Methods in molecular biology (Clifton, N.J.), 1904, 1–10. https://doi.org/10.1007/978-1-4939-8958-4_1