Transgenic animals are organisms genetically modified to contain one or more foreign genes, known as transgenes, inserted into their genome. These transgenes can be introduced using various genetic engineering techniques, with the goal of conferring specific traits or characteristics onto the animal. In the context of antibody discovery and therapeutic development, transgenic animals can be engineered to express human antibody genes, enabling them to produce fully human antibodies for research and therapeutic purposes. These animals serve as valuable tools for studying gene function, modeling human diseases, and producing biopharmaceuticals, contributing significantly to biomedical research and drug development efforts.
An increasing number of therapeutic antibodies derived from transgenic animals are fully human, offering significant clinical benefits. Techniques such as gene targeting and the integration of human gene loci via bacterial or yeast artificial chromosomes into rodents, or human chromosome fragments into large animals like cattle, have been instrumental. Although these animals can produce specific human immunoglobulins in serum after immunization, the interaction of human constant regions with the endogenous signaling components in these transgenic animals has been less efficient compared to wild-type immunoglobulins. Advances in genetic engineering, like linking human V-region genes to endogenous C-region genes, have led to improvements in antibody yield and immune response, mimicking those of non-modified animals.1
The Rise of Transgenic Animal Models in Antibody Discovery
Innovations in genetic engineering have enabled the integration of human immunoglobulin genes into the genomes of mice, rats, rabbits, chickens, and even cows, thus equipping them with the ability to produce human antibodies through their natural biological processes. This in vivo antibody generation provides many benefits, such as recovering molecules that bind to the target antigen with high specificity and affinity. Further in vivo sequence diversification, somatic hypermutation, and tests for quality control allow for the non-random selection and enrichment of B cells that yield antibodies possessing therapeutically favorable attributes.2
This technological leap has resulted in the creation of platforms like XenoMouse and HuMab-Mouse that have been instrumental in the development of numerous therapeutic antibodies. The technology mimic essential elements of the human antibody repertoire, including usage patterns of V-, D-, and J-segments. The capacity to integrate mouse biology with human antibody sequence data granted researchers access to a diverse source of fully human antibodies, which has since been extended to other species.3
Advantages of Humanized Transgenic Animals
Humanized transgenic animals offer a valuable tool for antibody discovery and development. The use of antibodies with fully human idiotypes can reduce the risk of immune rejection in patients often associated with non-human antibodies. Humanized transgenic animals can also provide a more accurate model of human immune response compared to traditional animal models, allowing for better evaluation of potential antibody therapies before human trials. Moreover, these platforms enable rapid and efficient antibody discovery and development, broadening the scope of treatable diseases with biologics that exhibit high specificity and affinity.
Brüggemann, M., Osborn, M. J., Ma, B., Hayre, J., Avis, S., Lundstrom, B., & Buelow, R. (2015). Human antibody production in transgenic animals. Archivum immunologiae et therapiae experimentalis, 63(2), 101–108. https://doi.org/10.1007/s00005-014-0322-x
Chen, W. C., & Murawsky, C. M. (2018). Strategies for Generating Diverse Antibody Repertoires Using Transgenic Animals Expressing Human Antibodies. Frontiers in Immunology, 9. https://doi.org/10.3389/fimmu.2018.00460
Akkina R. (2014). Humanized Mice for Studying Human Immune Responses and Generating Human Monoclonal Antibodies. Microbiology spectrum, 2(2), 10.1128/microbiolspec.AID-0003-2012. https://doi.org/10.1128/microbiolspec.AID-0003-2012
The therapeutic efficacy of antibodies is closely related to their ability to recognize and bind specific epitopes on target antigens. Epitopes, or antigenic determinants, are a group of amino acids or other chemical groups that are part of a molecule to which an antibody attaches itself. Epitope characterization can help reveal the mechanism of antibody binding and apply intellectual property (patent) protection for novel antibodies, in addition to designing antibodies with high specificity and minimal cross-reactivity.
Understanding the differences between antibody specificity and selectivity is essential for designing and interpreting antibody-based assays in research for experimental accuracy and data interpretation. Antibody specificity refers to an antibody's ability to recognize and bind to a particular epitope—a unique part of an antigen that elicits an immune response.
Antibody-based assays are essential tools in biomedical research, providing the means to detect, quantify, and visualize specific proteins or antigens within complex biological samples. These assays' efficacy hinges on the antibodies' precise properties. While affinity, avidity, specificity, and selectivity are fundamental to antibody performance, the ultimate impact of these properties is heavily influenced by the experimental context in which the antibody is employed.
Biologics, particularly antibodies, have become indispensable in biomedical research and therapeutic development. Research-use-only (RUO) biologics play a pivotal role in preclinical studies, providing researchers with the necessary tools to explore antibody functions and therapeutic potential in vivo.
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