Humira’s creation begins with mice but ends with a medication considered fully human, a process made possible by advances in antibody engineering. While the initial blueprint for the drug was discovered using a mouse, the final product administered to patients does not contain mouse proteins.
The Original Mouse-Derived Antibody
The development of the drug that would become Humira, also known by its scientific name adalimumab, required finding an antibody that could effectively neutralize a specific protein in the human body called Tumor Necrosis Factor-alpha (TNF-alpha). In many autoimmune diseases, the body overproduces TNF-alpha, leading to chronic inflammation and tissue damage.
To generate an effective countermeasure, researchers immunized a mouse with human TNF-alpha. This process triggered the mouse’s immune system to recognize the human protein as foreign and produce antibodies against it. From this response, scientists isolated a particularly effective murine (mouse) antibody that bound tightly to human TNF-alpha, successfully blocking its inflammatory activity. This antibody, D2E7, was the first step.
However, using a pure mouse antibody directly in humans presents a challenge. The human immune system can recognize the mouse protein as an invader. This recognition can lead to the production of anti-drug antibodies, which can neutralize the medication, reduce its effectiveness over time, and potentially cause adverse reactions. The goal was to retain the mouse antibody’s targeting function while making the molecule itself appear human.
Creating a “Fully Human” Monoclonal Antibody
To overcome the limitations of a murine antibody, scientists turned to a technology known as phage display. This technique allows researchers to create and screen vast libraries containing billions of different human antibody fragments. These fragments are genetically inserted into bacteriophages, which are viruses that infect bacteria. The phages then “display” these human antibody pieces on their outer surfaces.
Using the original mouse antibody as a guide, researchers used phage display to find a human antibody that could do the same job. They sifted through these libraries to identify human antibody fragments that bound to the exact same target on TNF-alpha with high affinity. This process, known as guided selection, used the mouse antibody’s unique targeting ability as a template to find a human equivalent.
Once the ideal human antibody fragments were identified, their genetic codes were isolated. These codes were then used to construct a complete, full-size antibody molecule made entirely from human protein sequences. The resulting drug, adalimumab, is referred to as a “fully human” monoclonal antibody because its amino acid sequence is human, even though the discovery work involved a mouse. This innovation marked a departure from earlier “chimeric” antibodies, which were fusions of mouse and human parts.
Clinical Significance of a “Fully Human” Drug
The primary advantage of a fully human antibody relates to a concept called immunogenicity, which is the tendency of a substance to provoke an immune response. Because the structure of adalimumab is entirely human, the patient’s immune system is less likely to identify it as a foreign threat.
This reduced immunogenicity can lead to better long-term outcomes. When the body does not create anti-drug antibodies, the medication is more likely to remain effective over its course of treatment. Patients are less prone to developing resistance. This stability allows for more consistent management of chronic inflammatory conditions like rheumatoid arthritis, Crohn’s disease, and psoriasis.
A lower risk of an immune reaction can translate to a better safety profile. While all medications have potential side effects, minimizing the foreign nature of the drug reduces the chances of certain types of infusion or injection-site reactions. The “fully human” design of Humira was a factor in its approval as the first antibody of its kind by the U.S. Food and Drug Administration (FDA) and set a new standard for biologic therapies.