The development of chimeric antibodies was a significant turning point in antibody engineering. To engineer more human-like antibodies, researchers combined the variable regions of antibodies from one species with the constant regions of another, resulting in increased antigen specificity with reduced immunogenicity. This was a key advance in making antibodies more suitable for therapeutic applications in humans.
Initially, antibodies derived from mice were common in early research, but their therapeutic use in humans was limited due to the high risk of immune responses against these foreign proteins. Chimeric antibodies, which typically consist of murine variable regions and human constant regions, addressed this issue. The human component of the chimeric antibody reduces the risk of being identified as a foreign body, while the murine portion retains its high affinity for specific antigens.1
Impact on Therapeutic Monoclonal Antibodies
Chimeric antibodies represented the first major improvement in monoclonal antibody design for clinical use. The first FDA-approved chimeric antibody was rituximab, a therapeutic antibody targeting CD20 on B-cells, used to treat non-Hodgkin’s lymphoma. The success of rituximab opened doors for more therapeutic chimeric antibodies, including infliximab for autoimmune diseases and cetuximab for cancer. These chimeric antibodies became the foundation upon which the antibody-based therapeutics market grew, with multiple applications across oncology, autoimmune diseases, and infectious diseases.
One of the advantages of using chimeric antibodies is their ability to retain the antigen-binding properties of murine antibodies, which are often highly specific and bind with high affinity to their targets. The move from murine to chimeric antibodies significantly improved the safety profile of antibody therapeutics, making them more feasible for long-term treatment in humans. This not only increased patient tolerance but also expanded the potential for antibody use in chronic diseases.
Related: The Future of Therapeutics: Fully Human Antibodies
Impact on Antibody Discovery
Chimeric antibodies provided an intermediate step between mouse monoclonals and fully human antibodies. The next logical step beyond chimerization was humanization, which involved not only replacing the constant regions but also modifying the variable regions to more closely resemble those found in human antibodies. This process typically involved grafting the antigen-binding loops from a mouse antibody onto a human antibody framework.
While humanization improved the safety and efficacy of therapeutic antibodies, developing fully human antibodies carried a lower risk for inducing immune responses in humans than mouse or chimeric antibodies.2 Two key technologies enabled this leap:
Phage Display: This technology allowed the creation of large libraries of fully human antibodies that could be screened for high-affinity binding to specific antigens. Phage display does not rely on an immune response for antibody generation, meaning that human antibodies can be directly selected based on their antigen-binding capabilities. This approach allows for the generation of highly specific antibodies without introducing any foreign components, completely avoiding the immunogenicity issues seen with mouse-derived antibodies.
Transgenic Mice: Another breakthrough was the development of transgenic mice that had been genetically engineered to produce fully human antibodies. These mice possess human immunoglobulin genes, and when immunized, they produce antibodies that are indistinguishable from those made by the human immune system. These antibodies can then be harvested and used as therapeutic agents with minimal risk of immune reactions in patients.
Both technologies built upon the success of chimeric antibodies, which had demonstrated the potential of antibodies with human constant regions. Chimeric antibodies proved the concept that retaining the binding specificity of non-human antibodies while introducing human elements could result in more effective and safer therapeutics. As a result, phage display and transgenic mice provided the tools to go beyond chimerization and humanization to produce fully human antibodies, which are now widely used in modern drug development.
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Almagro, J. C., R., T., Mayra, S., & Penichet, M. L. (2018). Progress and Challenges in the Design and Clinical Development of Antibodies for Cancer Therapy. Frontiers in Immunology, 8, 309477. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01751/full
Harding, F. A., Stickler, M. M., Razo, J., & DuBridge, R. B. (2010). The immunogenicity of humanized and fully human antibodies: Residual immunogenicity resides in the CDR regions. MAbs, 2(3), 256-265. https://www.tandfonline.com/doi/full/10.4161/mabs.2.3.11641
Antibody specificity refers to an antibody's ability to selectively bind to a unique epitope on a target antigen while avoiding interactions with unrelated antigens. This property arises from the highly specialized antigen-binding site located in the variable region of the antibody, which determines its unique binding characteristics.
Antibody affinity refers to the strength of the binding interaction between a single antigen epitope and the paratope (binding site) of an antibody. This interaction is a fundamental measure of how well an antibody recognizes its specific antigen target.
Recombinant antibodies are produced using genetic engineering techniques, unlike traditional antibody production, where the immune system generates antibodies without direct control over their sequence. By introducing genes encoding antibody fragments into host cells, such as bacteria or mammalian cells, recombinant antibodies can be expressed, purified, and deployed for applications including research, diagnostics, and therapeutics.
Recombinant antibody expression is a biotechnological process that involves engineering and producing antibodies outside their natural context using recombinant DNA technology.
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