Nowadays, therapeutic monoclonal antibodies have become an important treatment for cancer and autoimmune diseases. The efficacy of a monoclonal antibody not only depends on its antibody binding region (Fab), but its crystallizable region (Fc) also plays an important role. Fab can specifically recognize the tumor-associated antigen (TAA), thereby regulating the downstream signaling pathways related to TAA. Fc can exert a series of effect functions such as ADCC, ADCP and CDC to further enhance the efficacy of monoclonal antibodies. At the same time, Fc can also bind to FcRn to extend the half-life of monoclonal antibodies.
Although most therapeutic IgGs approved to date retain the natural IgG Fc domain, the knowledge gained in the past few decades provide opportunities for the design of tailored and more effective immunotherapies that exhibiting greater performance. The emergence of monoclonal antibodies for the treatment of various pathological conditions has provided more insights into the biology of Fc receptors and proposed new strategies for the development of improved therapies using Fc receptor interactions. Selecting the appropriate IgG subtype and Fc region modification strategies are becoming current a hot spot for therapeutic antibodies research and development.
Creative Biolabs always pays attention to the most cutting-edge research results and is committed to supporting researchers around the world. Keeping pace with the recent advances made in the design of biologics that modulate or exploit Fc receptor-IgG interactions, we provide customers with a variety of innovative Fc modification strategies, which are currently under investigation in clinical trials that have been precisely tuned to achieve a desired therapeutic effect.
The Fc region of IgG molecules can perform a series of biological functions to further enhance the efficacy of monoclonal antibodies. Fc can bind to FcγRs, which is mainly expressed on various types of immune leukocytes. When leukocytes are recruited and activated, they can trigger antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP), thereby eliminating target tumor cells. Fc can also bind to serum complement molecules (C1q), and then form a membrane attack complex (MAC) to eliminate target cells. This process is called complement-dependent cytotoxicity (CDC). The Fc region can also bind to the newly born Fc receptor (FcRn) in a PH-dependent manner to prevent the antibody from being degraded by endosomes, thereby prolonging the half-life of the monoclonal antibody.
Fig.1 Schematic diagram of Fc region function: ADCC, ADCP, CDC.
Fc modification achieves the enhancement of antibody function through directional design to meet the needs of different monoclonal antibodies. For example, increase the affinity of Fc and FcγRIIa/IIIa to enhance ADCC effect or increase the affinity of Fc and C1q to enhance CDC effect, thereby more effectively clearing target tumor cells; increase the affinity of Fc and FcγRIIb to enhance immunosuppressive effect, so it can be used for autoimmunity as well as the elimination of allergens; for simple antagonist antibodies, knocking out the binding of Fc and FcγRs can avoid side effects such as ADCC; enhancing the binding of Fc and FcRn can prolong the half-life of the monoclonal antibody in vivo.
Fig.2 Fc region modification strategies. (Sondermann, 2016)
Glycosylation modification accounts for more than 50% of all PTMs (Post-translational Modification). For therapeutic protein drugs (such as recombinant protein drugs and antibody drugs), glycosylation modification plays an important role in the safety and effectiveness of therapeutic antibody drugs by affecting immunogenicity, half-life, and effector factors.
The glycosylation form of antibody drugs is mainly N-glycosylation, and the main monosaccharides involved are glucose, galactose, mannose, N-acetylglucosamine, N-acetylgalactosamine, fucose, sialic acid (NANA, NGNA). We provide a variety of Fc-based glycosylation modification services.
Through the modification of the Fc region, the binding of Fc to FcγRIIa on macrophages and FcγRIIIa on NK cells can be enhanced, and these cells can be recruited more effectively, thereby killing tumor cells. All of our antibodies modified by Fc-directed mutagenesis showed stronger ADCC and ADCP activity.
FcγRIIb is the only Fc receptor with inhibitory function. It is usually expressed on the same cells as other activating FcγRs, and plays a negative feedback regulation effect on the signals of FcγRIIa and FcγRIIIa. Therefore, FcγRIIb can be applied to the treatment of autoimmune diseases and allergic diseases. Our Fc modification strategy can significantly enhances the affinity for FcγRIIb.
The interaction between Fc and C1q is a key step in triggering the CDC effect. Since the affinity between Fc and C1q is weak, more efficient antibodies can be obtained through Fc modification. Our Fc-engineered antibody has been verified to increase C1q binding capacity by 47 times and CDC activity by approximately 6 times.
IgG molecules can bind to FcRn in a PH-dependent manner to avoid degradation by endosomes, thereby prolonging the half-life of monoclonal antibodies. Therefore, enhancing its affinity with FcRn through Fc modification and extending its half-life are of great significance for improving the frequency of dosing, patient compliance and cost. Our Fc engineering strategy can enhance the affinity of Fc and FcRn while maintaining its PH selectivity, thereby effectively extending the half-life of anti-antibody.
For more details about our ADCC enhancement Therapeutic Fc Engineering Technology service, please do not hesitate to contact us.
Creative Biolabs provides luciferase-based ADCC assay. This Jurkat cell based assay is pioneered by Creative Biolabs, and the methodology is very well accepted by the field. See attached ADCC Reporter Assay Protocol for further details.
All products and services are for Research Use Only. Do Not use in humans.
ADCC Assay WT vs AfucoTM Mabs Visit
Antibody Fc Engineering: Towards Better Therapeutics Visit