Fc engineering for Antibodies?Towards Better Therapeutics

Since the first antibody drug OKT-3 was launched in 1986, more and more therapeutic monoclonal antibodies (mAbs) have entered clinical studies and been approved for marketing, and targeted therapy using therapeutic mAbs has become an effective tool in the fight against cancers, viral infections and immune diseases. With the advancement of cell engineering and genetic engineering technologies, researchers have conducted numerous studies to explore the link between the structural properties of antibodies and their functions in order to better exploit the therapeutic effects of mAbs, and one of the key areas is the modulation of antibody-immune system interactions through Fc engineering.

Targeted therapy using therapeutic mAbs has emerged as an effective tool in the fight against cancer, viral infections, and immune diseases. The therapeutic mAbs can induce death of tumor cells through direct or indirect mechanisms. The direct mechanism relies on the antibody-binding fragment (Fab); the indirect mechanism relies on the crystallizable region (Fc region), which binds to the Fc gamma receptor (Fc?R) expressed on the surface of immune cells, thus performing a series of biological functions to enhance the efficacy of therapeutic mAbs.

In addition to traditional mAbs, advances in antibody engineering technology coupled with a better understanding of antibody Fc function and the establishment of high-throughput screening systems have opened up new avenues for Fc engineered variants. These Fc variants have higher serum stability, as well as antigen binding properties, and there are now multiple approaches to develop Fc variants tailored specifically to achieve a particular function.

1. Glycan engineering

Due to the high relevance of Fc glycans for therapeutic efficacy, optimization of the composition of Fc glycans can enhance the binding and effector functions of Fc?R. It was shown that removal of fucose significantly enhanced Fc?RIIIa affinity and Adcc(antibody-dependent cellular cytotoxicity) activity. In addition to fucose, galactose and sialic acid, to a large extent, affect the immune role of IgGs in the human immune system.

2. Protein engineering approaches

In the past 20 years, with the development of bioinformatics and computer technology, computer simulation has been increasingly applied to protein engineering, leading to the derivation of new tools such as semi-rational design and rational design. Based on structural information, computer design, yeast display, asymmetric engineering, and targeted mutation techniques, many Fc variants have been generated to alter the binding ability to their receptors.

Anti-CD19 antibodies and anti-CD40 antibodies containing double-mutated (S239D/I332E) Fc have been reported to be approximately way more cytotoxic to B-cell lymphoma and leukemia cells than their wild-type Fc-containing counterparts.

In addition to the use of Fc variants to improve binding to their receptors, the binding of Fc to C1q is also a key factor in triggering the CDC (complement-dependent cytotoxicity) response, and therefore many studies have been performed to improve the binding affinity of Fc to C1q. Furthermore, modulating the interaction with FcRn by protein engineering mutations in the Fc region is an approach to improve the pharmacokinetics of therapeutic mAbs.

"To date, several efforts have been reported for therapeutic Fc engineering in improving therapeutic mAbs or fusion proteins. These modified antibodies have shown clinically significant therapeutic efficacy and are considered to be among the most effective drugs for the effective treatment of cancers, autoimmune diseases, inflammations and infections," said a scientist from Creative Biolabs, a biotech company focusing on research-based ADCC/CDC-enhanced therapeutic antibody discovery and development services, "therefore, it is imperative to differentiate through engineering modifications to show their advantages, and it is believed that there will be increasingly fierce competition in the development of therapeutic mAbs in the future, which will also provide a new means for the treatment of human diseases."

Candy Swift: Focus on the cutting edge biological information around the world.