Monoclonal antibodies (mAbs) are useful therapeutics for targeted treatments in oncology, autoimmune disorders, and infectious diseases. Among the key distinctions in therapeutic mAbs are those labeled “fully human” and “humanized.” Both rely heavily on animal models—primarily mice—and genetic engineering techniques to achieve their therapeutic properties.
Fully Human mAbs: Genetic Engineering at Work
Fully human mAbs are derived from transgenic mice that carry human immunoglobulin genes. The process begins by immunizing these transgenic mice with the target antigen, which might be a protein related to a disease pathway. After the mice’s immune system produces antibodies against the antigen, the genetic sequences responsible for the antibodies are isolated and engineered for therapeutic use. The Chinese hamster ovary (CHO) cells are then used to produce large quantities of these antibodies.
Transgenic mice offer a unique advantage by providing a humanized immune system context. This allows antibodies to undergo natural immune diversification and selection, akin to that in the human body, resulting in highly efficacious antibodies suitable for therapeutic use due to their high affinity and low immunogenicity.
Humanized mAbs: Mouse and Human Components
On the other hand, humanized mAbs start with a wild-type mouse, which carries its natural mouse immunoglobulin genes. These mice are immunized similarly, but the resulting antibodies are not immediately suitable for human use because they are fully mouse-derived. To create a humanized mAb, the complementarity determining regions (CDRs)—the parts of the antibody that bind to the target—are transplanted onto a human antibody scaffold. The resulting hybrid antibody contains human framework regions but retains mouse-derived regions responsible for antigen binding.
Anti-Drug Antibodies (ADAs) and Their Impact
One of the critical concerns with both fully human and humanized mAbs is the potential for patients to develop ADAs. ADAs can neutralize the therapeutic mAbs, reducing their efficacy or causing adverse reactions. Factors like the overall sequence of the antibody, glycosylation patterns, and patient-specific immune responses all play a role in eliciting ADAs.
Engineering Beyond Affinity: Optimizing Biophysical Properties
While much of the focus in mAb development has historically been on antigen-binding affinity, other molecular traits are now receiving attention. Modern molecular engineering allows for optimization beyond just the binding strength of the antibody. For example, developers can improve the stability of mAbs, extending their shelf life and making them more resilient to the manufacturing process. Similarly, efforts are made to reduce immunogenicity by fine-tuning the antibody’s interaction with the immune system, often targeting regions outside of the CDRs, such as the constant (Fc) region.
The Fc region, responsible for mediating interactions with immune cells and other components of the immune system, can also be engineered for improved therapeutic outcomes. Altering glycosylation patterns in this region, for instance, can enhance the antibody’s half-life or modulate its effector functions, such as antibody-dependent cellular cytotoxicity (ADCC). These functional improvements are vital in creating mAbs that not only bind effectively but also exhibit optimal therapeutic activity with minimal side effects.
References:
- Lotus Mallbris, Davies, J., Glasebrook, A., Tang, Y., Wolfgang Glaesner, & Nickoloff, B. J. (2016). Molecular Insights into Fully Human and Humanized Monoclonal Antibodies: What are the Differences and Should Dermatologists Care? The Journal of Clinical and Aesthetic Dermatology, 9(7), 13. https://pmc.ncbi.nlm.nih.gov/articles/PMC5022998/