The development of monoclonal antibodies (mAbs) production technology enabled their application in the clinic for the treatment of a wide range of diseases, especially cancer. As the long-term pioneer as well as market leader in the field of therapeutic antibody development, Creative Biolabs has successfully established the fucose knockout technology platform to modulate antibody-dependent cell-mediated cytotoxicity (ADCC).
Along with the clinical success of recombinant humanized therapeutic antibodies against various human malignancies, such as colon, breast, and hematological cancer, the antibody drugs present a major new class in therapeutic agents. However, the improvement of antibody in vivo efficacy continues to be a challenge. There are two independent mechanisms for the in vivo physiological activity mediation, which are target neutralization or apoptosis and biological activities, antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The importance of ADCC for antibody clinical efficacy has been clear from genetic analyses of leukocyte receptor (FcγR) polymorphisms. It has been proved that compared with fucosylated counterparts, the antibodies lacking core fucose residues from the Fc N-glycans always show stronger ADCC even at lower concentrations. Unfortunately, the existing market therapeutic antibodies are heavily fucosylated as they are produced in mammalian cell lines with intrinsic enzyme activity responsible for the core-fucosylation of the Fc N-glycans of the products. In this case, scientists at Creative Biolabs has established the novel fucose knockout technology platform to improve the antibody ADCC activity.
Fig.1 The impact of fucose and sialic acid on the pharmacokinetic and pharmacodynamic properties of pertuzumab. (Luo, 2017)
Based on years of research, Creative Biolabs has built several methods for the successful production of highly non-fucosylated therapeutics.
Research has reported that the deletion of the FUT8 gene could enhance the FcγRIIIa binding affinity and lead to an increased ADCC activity. FUT8 protein is the only α-1,6 fucosyltransferase that catalyzes the transfer of fucose residues from GDP-fucose to the innermost GlcNAc of the tri-mannosyl core structure via the α-1,6 linkage in the medial Golgi cisternae. Consequently, cell lines that are genetically engineered are incapable of adding fucose to the oligosaccharide chain. The FUT8 knockout has the essential characteristics of host cells for robust manufacturing of fucose-negative therapeutic antibodies with enhanced ADCC, making it an ideal technology to produce ADCC-enhanced antibodies.
As a pioneer and the undisputed global leader in the field of antibody functional assays, Creative Biolabs offers a series of services and platforms to strengthen your understanding of your candidate antibodies and to facilitate their transformation from preclinic to the clinic. If you are interested in our technologies and services, please do not hesitate to contact us for more detailed information.
Reference
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