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How Chimeric Antibodies Paved the Way for Antibody Engineering Advances
How Chimeric Antibodies Paved the Way for Antibody Engineering Advances
Biointron2024-10-09Read time: 5 mins
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.
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.
Our High-throughput Fully Human Antibody Discovery Platform integrates Cyagen’s HUGO-Ab™ mice with Biointron’s AbDrop™ microdroplet-based single B cell screening. This powerful combination accelerates the discovery and development of fully human antibodies, reducing the time from target identification to therapeutic candidate to just three months. Learn more about the service here.
References:
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://doi.org/10.3389/fimmu.2017.01751
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://doi.org/10.4161/mabs.2.3.11641
Abinvivo offers a range of antibody products for in vivo research, each designed to meet specific research needs and applications in preclinical studies and antibody development.
Complementarity-determining regions (CDRs) are polypeptide sequences within antibodies (Abs) that dictate the specific recognition and binding of antigens. Antibodies are part of the human immune response and are composed of two heavy and two light protein chains. These chains are divided into variable (V) and constant (C) regions, with the V region responsible for binding to unique antigens.
Antigens are molecules or molecular structures that are recognized by the immune system, particularly by antibodies, T cells, and B cells. The immune response to an antigen varies depending on the antigen type and the part of the immune system involved. This interaction underpins immunity by helping the body distinguish between self and non-self molecules.