An antibody is a Y-shaped protein produced by the immune system to identify and neutralize foreign substances, known as antigens, such as bacteria and viruses. These protective proteins circulate in the blood and bind specifically to unwanted substances, marking them for removal from the body. Scientists have leveraged this natural defense mechanism to create therapeutic antibodies, which are engineered versions used in medicine to treat various diseases. Humanized antibodies represent a significant advancement in this field of therapeutic agents.
Understanding Therapeutic Antibodies
Antibodies are proteins made by B cells, a type of white blood cell, to recognize and fight off foreign substances like viruses or bacteria. This natural defense mechanism has been harnessed by scientists to create therapeutic antibodies for medical treatment.
Early therapeutic antibodies, derived entirely from non-human sources like mice, often triggered an undesirable immune response in humans, known as immunogenicity. The human immune system recognized these foreign mouse antibodies as invaders, leading to the production of anti-drug antibodies (ADAs). This response could reduce the therapeutic antibody’s effectiveness by neutralizing it or accelerating its clearance from the body, and also caused adverse side effects.
The Evolution of Humanized Antibodies
To address the immunogenicity of murine antibodies, chimeric antibodies were developed as an intermediate step. These hybrid molecules are engineered by fusing the variable (antigen-binding) regions of a mouse antibody with the constant regions of a human antibody. This design typically consists of approximately 70% human and 30% murine sequences, which helped reduce the human immune response.
Building on chimeric antibodies, humanized antibodies were developed to be even more human-like, minimizing mouse-derived sequences to about 5% to 10% of the total antibody. This engineering involves grafting only the minimal necessary parts of the mouse antibody, specifically the Complementarity-Determining Regions (CDRs), into a human antibody framework. CDRs are the small, hypervariable loops within the variable regions that directly bind to the antigen, determining the antibody’s specificity.
The humanization process reduces immunogenicity compared to murine or chimeric antibodies, making them safer and more effective for human use. This genetic engineering preserves the antigen-binding specificity of the original mouse antibody while largely replacing foreign sequences with human ones. While fully human antibodies, which contain no mouse sequences, offer even lower immunogenicity, humanized antibodies continue to be widely used and comprise a majority of approved therapeutic antibodies due to their balance of efficacy and reduced immune response.
Applications in Medicine
Humanized antibodies have diverse applications in medicine, treating various medical conditions by targeting specific molecules or cells involved in disease processes. Their engineered compatibility with the human immune system makes them valuable therapeutic tools.
In cancer treatment, humanized antibodies can target specific markers on cancer cells, block growth signals, or deliver cytotoxic agents. For example, trastuzumab is a humanized antibody used for HER2-positive breast cancer, where it targets the HER2 receptor. Rituximab, a chimeric antibody, is also used for lymphoma, targeting the CD20 protein on B cells.
For autoimmune diseases, humanized antibodies can block inflammatory pathways or deplete specific immune cells. Adalimumab, a fully human antibody, is used for rheumatoid arthritis and Crohn’s disease by targeting TNF-alpha. Natalizumab, a humanized antibody, targets alpha-4 integrin in multiple sclerosis and Crohn’s disease to reduce inflammation and tissue damage.
Humanized antibodies are also employed in infectious diseases to neutralize viruses or bacteria, or for prophylaxis. While early therapeutic antibodies for infectious diseases carried immunological risks, modern humanized antibodies offer improved safety. They can directly neutralize pathogens or recruit immune cells to eliminate infected cells, as seen in developments against influenza viruses and Staphylococcus aureus.