There are four subtypes of IgG antibodies: IgG1, IgG2, IgG3, IgG4. Although the positions and numbers of disulfide bonds are different, the spatial structures of the four subtype antibodies are very similar. This paper combs the differences in the structure and physiological activities of four IgG antibody subtypes, and then discusses its application in the development of recombinant antibody drugs.
IgG1 is the most abundant in plasma and is the most subtype of recombinant antibody. The FcRn affinity of IgG3 is weak and the half-life is only 9 days. Considering that pharmacokinetics requires more frequent administration, it is rarely used to develop antibody drugs. In addition, various subtypes of antibodies will change during development, and children's IgG1 levels will reach adulthood at 5 years of age, while other subtypes of antibodies will slowly increase.
In recent years, with the expansion of new indications and the discovery of new therapeutic mechanisms, the application of IgG2 and IgG4 subtypes has gradually increased.
Taking an immunological checkpoint inhibitor as an example, the PD-1/PD-L1 pathway theoretically blocks the pathway with a PD-1 antibody or a PD-L1 antibody, thereby suppressing inhibition of T cells and the like, thereby killing the cells. This mechanism of action is different from previous mechanisms such as anti-cancer antibodies relying on ADCC activity to kill cells. Therefore, PD-1 antibodies Opdivo and Keytruda are designed to use the IgG4 subtype with weak ADCC activity, and the PD-L1 antibody Tecentriq uses IgG1 subclass. Type but using antibody engineering to remove glycosylation and no ADCC activity.
Of course, the various mechanisms of action of antibody drugs interact and are very complex. In theory, ADCC activity can also synergize with the PD-1/PD-L1 pathway to kill cancer cells. More is the balance between safety and effectiveness, which is waiting to accumulate more clinical experience and further understand its network of mechanisms of action. For example, the IgG1 subtype of strong ADCC activity used by the Pfizer PD-L1 antibody Avelumab, and the PD-1 antibody of Baekje Shenzhou also undergo antibody engineering of Fc (the modification of Fc is mostly the modification of glycosylation modification). The comparison of these attempts with accumulated clinical data has helped us to gain a deeper understanding of the more detailed mechanism of action of PD-1/PD-L1 antibody drugs.
As mentioned above, antibody subtype selection and antibody engineering are all specific attempts in the development of antibody drugs. Taking antibody engineering as an example: Roche's third-generation CD20 antibody is transformed into a cell line with no salt-to-alkali carbonylation by cell line (glycosylation-related enzyme), thereby expressing antibodies with high ADCC activity, which is the transformation of cell line level.
A more mature technique is protein-level modification. For example, the Roche PD-L1 antibody Tecentriq achieves deglycosylation by mutating the Asn-298 glycosylation site, and the Korean-American LAPS long-acting protein technology is modified by E. coli expression without aglycosylation. Fc, chemically coupled to protein drugs in vitro (using only its long-acting mechanism); Genexine's HyFc long-acting fusion protein technology, through hybrid Fc, combines the flexibility of the IgD hinge region with the low ADCC/CDC activity of IgG4 , get long-acting, safe protein drugs.
With the development of new antibody drugs such as bispecific antibodies and ADCs, the application range of antibody engineering has been greatly expanded. If the subtypes of bispecific antibodies have been found to be different, the ADCC activity can be significantly affected.
Related services:
No comments:
Post a Comment