With more than 100 therapeutic monoclonal antibodies (mAbs) approved worldwide, therapeutic antibodies have become a major category in the pharmaceutical market and represent the fastest growing area of the biopharmaceutical industry. The targeting of surface antigens expressed on tumor cells by mAbs has revolutionized cancer therapeutics. Due to their properties of strict specificity and strong affinity for target antigens, mAbs have become a powerful tool in the fight against cancer.

Targeted mAbs are a form of cancer immunotherapy treatment that can disrupt cancer cell activity and alert the immune system to target and eliminate cancer cells. Some therapeutic antibody drugs on the market rely on antibody-dependent cell-mediated cytotoxicity (ADCC) as a mechanism of action. Enhancing ADCC is thought to be one of the most promising and practical approaches to make an antibody more efficacious. Therapeutic antibodies with enhanced ADCC have the potential to increase the therapeutic effect and significantly reduce antibody dosage requirements, resulting in fewer side effects and treatment costs.

Due to the scarcity of effective tumor targets and the difficulty in finding new targets, biobetters appear to have recently gained more media attention. Biobetter antibodies are antibodies that target the same validated epitope as marketed antibodies, but have been engineered to have improved properties, such as better safety, enhanced efficacy (e.g., ADCC), and even lower toxicity.

By enhancing the ADCC effect, antibody drugs can exert a stronger tumor-killing function, which is one of the directions for the development of biobetters. Since the natural affinity of antibodies and FcγR is relatively weak, engineering modification has become a common method to enhance the affinity. The main strategy to enhance ADCC functionality has been to modify the Fc portion of the mAb to increase binding affinity for activation of FcγRIIIA through site-directed mutagenesis, alteration of Fc domain glycosylation, and/or removal of Fc domain fucosylation.

※ Fc mutagenesis
Generation of IgG1 variants with stronger binding capacity that can activate FcγR by mutagenesis has been an effective strategy to enhance ADCC efficiency in vitro. In addition to modifying the Fc residues, the Fc part can also be asymmetrically designed to generate heterodimer with different heavy chains, to acquire more stable antibodies with enhanced ADCC function. At present, a variety of mutations at different sites have been found through methods such as alanine scanning, computer structure simulation, and high-throughput methods.

※ Glycoengineering
ADCC enhancement through glycoengineering is becoming the preferred technology platform because it has low immunogenicity potential and has less impact on the overall antibody protein structural stability introduced by altered glycosylation. It is now widely recognized that removal of the core fucose from the Fc N-glycans represents the most effective approach for enhancing ADCC activity.

Various approaches have been utilized to produce nonfucosylated proteins and antibodies, involving manipulation of host biosynthetic pathways by gene knockdown/knockout or overexpression of glycoprocessing enzymes, and/or in vitro chemoenzymatic glycosylation remodeling.

Detailed analysis of the mechanisms of action of mAbs has revealed that amplifying effector functions, in particular ADCC, is a promising approach to increase clinical benefit. Although many of the mAbs have shown stronger efficacy by using ADCC enhancement technology, the impact of various modifications on critical micelle concentration (CMC) and subsequent proprietary drugs need to be evaluated.

https://adcc.creative-biolabs.com/adcc-enhancement-technology.htm
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A big fan of biological science and technology