Antibodies or immunoglobulins (Ig) are a group of structurally & functionally related glycoproteins that confer humoral immunity in humans and animals. The antibody backbone typically consists of two identical heavy chains and two identical light chains. Five antibody classes or isotypes (IgG, IgA, IgM, IgD, IgE) are recognized in mice and humans on the basis of different constant regions in the heavy chains. Over the last few decades, the industry has concentrated on developing new technologies for antibody production and engineering with the aims to optimize or enhance its manufacturability and therapeutic efficacy. The clinical outcome of a therapeutic antibody is driven by a more complex interplay between the antibody, the cognate antigen that for example is expressed on stromal or tumor cells, and our immune system. There are many approaches to improving the clinical performance for antibody-based therapeutics, including antibody humanization, antibody-drug conjugate (ADC) and bispecific antibody.
The first attempt to engineer mouse antibodies to facilitate therapeutic use was chimerization. This involves genetically replacing mouse constant regions with the corresponding human constant regions, while retaining the mouse variable regions responsible for antigen binding. Antibody humanization (also known as CDR-grafting or reshaping) was invented as a more elegant solution to the immunogenicity problem of murine antibodies. Antibody humanization involves the design and synthesis of composite variable regions, which contain the amino acids of mouse CDRs integrated into the FWRs of a human antibody variant. The resulting antibody retains both the specificity and binding affinity of the original mouse antibody, and is sufficiently human to deceive the patient’s immune system. Both chimerization and humanization strategies have been proven successful in clinic.
It is possible to exploit human immune response in the discovery of truly and fully human antibodies for therapeutic applications. Human immune response works essentially in the same way as that in a mouse or transgenic animal genetically engineered to express human antibodies. Therefore, persons experiencing a challenge to their immune system, such as an infectious virus, a passive vaccination, or abnormal tumor cells are a potential source of discovering antibodies directed against that challenge. This approach seems especially useful for the development of anti-viral and anti-cancer (of particular types) therapies that exploit the principles of passive immunity. Variants of this approach have been demonstrated with proof-of-principle in preclinical studies and several are finding way into clinical development.
There are more than 300 monoclonal antibodies currently in clinic and on market for various therapeutic, diagnostic, and preventive applications. Among them, about 45% are humanized antibodies, 35% are fully human antibodies, and 10% are chimeric antibodies.
- Examples of approved chimeric antibodies:
- Basiliximab(Simulect®)
- Cetuximab(Erbitux®)
- Infliximab (Remicade®)
- Rituximab (Rituxan®)
- Examples of approved humanized antibodies:
- Alemtuzumab (Campath®)
- Atlizumab (Actemra®)
- Bevacizumab (Avastin®)
- Daclizumab (Zanapax®)
- Natalizumab (Tysabri®)
- Omalizumab (Xolair®)
- Palivizumab (Synagis®)
- Pertuzumab (Omnitarg®)
- Pembrolizumab (Keytruda®)
- Trastuzumab (Herceptin®)
- Examples of approved fully human antibodies:
- Adalimumab (Humira®)
- Belimumab (Benlysta®)
- Denosumab (Prolia®)
- Ipilimumab (Yervoy®)
- Nivolumab (Opdivo®)
- Ofatumumab (Arzerra®)
- Panitumumab(Vectibix®)
- Ustekinumab (Stelara®)