Antibodies are specialized proteins produced by the immune system, designed to identify and neutralize foreign invaders like viruses or bacteria. When used as medicines, these biological molecules can be engineered to precisely target disease-causing cells or harmful proteins within the body. This targeted approach minimizes impact on healthy cells, offering a focused way to address various illnesses.
Methods for Finding Therapeutic Antibodies
The journey to discover a therapeutic antibody often begins with exposing an immune system to a specific disease target, such as a cancer cell protein or a bacterial component. Hybridoma technology, a classic method, involves immunizing a mouse with the desired antigen. After the mouse develops an immune response, its antibody-producing B cells are harvested from the spleen. These B cells are then fused with immortal myeloma cells, creating hybridoma cells that continuously produce large quantities of a single type of antibody, known as a monoclonal antibody.
Another laboratory technique for antibody discovery is phage display. This method involves creating vast libraries of antibody fragments displayed on the surface of bacteriophages, which are viruses that infect bacteria. Scientists then “pan” this library, exposing the phages to the target antigen, allowing only the phages displaying antibodies that bind to the target to be selected. The genes encoding these binding antibody fragments are then isolated and used to produce the full antibody.
Modern approaches have advanced antibody discovery. Single B-cell technologies, for instance, involve isolating individual B cells from immunized animals or even human patients. Techniques enable the high-throughput isolation of single B cells that produce antibodies against a specific antigen. The antibody genes from these individual cells are then directly amplified and sequenced, allowing for rapid identification of promising candidates.
Another method utilizes transgenic animals that have been genetically engineered to carry human immunoglobulin genes. These mice have their own mouse antibody genes silenced, allowing them to produce fully human antibodies upon immunization with a target antigen. This approach bypasses the need for humanization later in the development process. These platforms accelerate the initial discovery phase.
Engineering Antibodies for Therapy
Once a promising antibody candidate is discovered, it often requires further modification to be suitable for human therapeutic use. Antibodies derived from non-human sources, such as mice, can trigger an immune response in humans, leading to rejection or reduced effectiveness. To address this, a process called humanization or chimerization is performed. Chimerization involves replacing most of the mouse antibody’s structure with human antibody parts, keeping only the antigen-binding regions from the mouse.
A more refined process, humanization, genetically engineers the mouse antibody to replace nearly all of its structure with human components, leaving only the specific loops that directly bind to the target antigen. This modification reduces the likelihood of the human immune system recognizing the antibody as foreign, improving its safety and longevity. After humanization, scientists may further refine the antibody’s ability to bind to its target through a process known as affinity maturation. This involves making small, targeted changes to the antibody’s binding tips and then selecting variants that bind more strongly or effectively.
Beyond enhancing binding, antibodies can be engineered into advanced formats to improve their therapeutic function. Antibody-drug conjugates (ADCs) link a potent chemotherapy drug precisely to an antibody. The antibody acts as a guided missile, delivering the toxic payload directly to disease-causing cells that express a specific target protein, such as cancer cells, thereby minimizing damage to healthy tissues. Another format is bispecific antibodies, which are engineered to bind to two different targets simultaneously. This dual targeting capability can be used to bring immune cells into close proximity with cancer cells, or to block two different disease pathways at once.
Preclinical and Clinical Evaluation
Before an engineered antibody can be tested in humans, it undergoes a preclinical evaluation phase. This stage involves laboratory-based in vitro studies to confirm the antibody’s specific binding, potency, and intended mechanism of action on target cells. Following this, animal studies are conducted to assess the drug’s safety profile, potential toxicity, and pharmacokinetics. These animal models also help evaluate the antibody’s effectiveness in a living system, providing preliminary data on its therapeutic potential before human trials begin.
The transition to human testing involves a series of clinical trial phases, each with distinct objectives. Phase I trials involve a small group of healthy volunteers or patients, focusing on assessing the drug’s safety, identifying a safe dosage range, and understanding its pharmacokinetics in humans. This initial phase helps determine how the human body processes the antibody and if any unexpected side effects occur.
Building on Phase I data, Phase II trials enroll a larger cohort of patients with the target disease. This phase evaluates the drug’s effectiveness, safety, and optimal dosing regimen for the target patient population. If the antibody shows promising results in Phase II, it progresses to Phase III trials. These large-scale studies compare the new antibody drug to existing standard treatments or a placebo, confirming its benefits, monitoring for less common side effects, and providing the comprehensive data required for regulatory approval.
Therapeutic Applications of Antibody Drugs
Antibody drugs are used across various medical fields, offering targeted solutions for complex diseases. In oncology, these drugs combat cancer. Some antibodies, like trastuzumab, target proteins such as HER2, blocking growth signals and marking these cells for destruction by the immune system. Other antibodies, known as immune checkpoint inhibitors like pembrolizumab, work by blocking proteins that cancer cells use to hide from the immune system, allowing T cells to attack tumors. Antibody-drug conjugates (ADCs) also enhance cancer treatment.
Beyond cancer, antibody drugs have made significant strides in managing autoimmune diseases, where the immune system mistakenly attacks the body’s own tissues. For instance, adalimumab targets and neutralizes tumor necrosis factor-alpha (TNF-α), a protein that drives inflammation in conditions such as rheumatoid arthritis, Crohn’s disease, and psoriasis, helping to reduce inflammation and alleviate symptoms. By precisely interfering with specific components of the immune response, these antibodies can restore balance and prevent tissue damage.
The utility of antibody drugs extends to other diverse areas of medicine. In infectious diseases, antibodies like palivizumab are used to prevent severe respiratory syncytial virus (RSV) infections by targeting a viral protein and inhibiting its ability to infect cells. Antibodies also play a role in cardiovascular health, with drugs such as evolocumab targeting PCSK9, a protein that regulates cholesterol levels, leading to a reduction in harmful LDL cholesterol. These examples highlight the impact of antibody-based therapies in improving patient outcomes.