Science: The secret of CD20 monoclonal antibodies to treat B-cell malignancies.

CD20 is a complete membrane protein expressed during the development of B lymphocytes and is involved in the conduction of in-cell calcium signals associated with B cells' subjects.
CD20 is also expressed on B-cell malignancies, CD20 is the target of therapeutic antibodies in tumor immunotherapy.
, therapeutic CD20 monoclonal antibodies are divided into Type I and Type II.
type I is more effective than type II in collecting supplements, inducing cytotoxicity (CDC) of strong complement dependence.
type I and some B cells are combined twice as much as type II.
Lytoxi monoantigen (RTX), which clinically treats non-Hodgkin's lymphoma and certain autoimmune diseases, is a type I CD20 monoclonal antibody.
, type I CD20 monoclonal antibody atumumab (OFA) and type II CD20 monoclonal antibody obinutuzumab (OBZ) have been used to treat chronic lymphocytic leukemia (CLL).
been used clinically for more than two decades, the mechanism is still not clear enough.
14, 2020, a paper published in Science reveals the different binding mechanisms of CD20 therapeutic antibodies.
DOI: 10.1126/science.abb8008 This study proves that CD20 oligomer is important for monoclonal antibody binding mechanism, and that the djupolymer is a natural oligomer of CD20: CD20 The structure of -Fab OFA indicates that CD20 binometogens are stabilized by extensive sub-base contact, and that these sub-base conservative contacts do not have extensive Fab-Fab estogeneity interactions, nor do they bind individual Fab molecules to two CD20 sub-base.
study also found that cholesterol-like lipids were arranged in double layers and combined to the outer and inner half of the sub-base interface, suggesting that cellular cholesterol could further stabilize CD20 binary.
the key mechanism difference between type I CD20 monoclonal antibodies (IgG I) and type II (IgG II) is that when combined with CD20, IgG II forms a 1:2 (IgG II:CD20) "end" complex, which prevents the binding of other IgG II.
IgG I to form a 1:2 or 2:1 (IgG I:CD20) "seed" complex, so that IgG or CD20 molecules are then connected in series.
series of IgG I molecules that are combined with CD20 will partially increase the concentration of the Fc domain and promote its oligomerization to recruit C1q.
IgG II end complex (which cannot connect other molecules) will require a higher antigen density for Fc oligomering, which explains why the difference in IgG I and IgG II complement collection capacity is strongly dependent on CD20 expression levels.
why can OFA activate supplements more effectively than RTX? Because both form seed complexes.
Fab OFA's binding angle is sharper than Fab RTX's, suggesting that the series of IgG OFA seed complexes brings their Fc domain closer together, further promoting its oligarchy.
researchers have built a symmetrical hexa-CD20-FAB RTX and hexa-CD20-FABOFA models, which suggest that Fab OFA molecules bind to the CD20 closer to the corresponding Fc domain by about 15 cents, thus possible closer to low-polymerization.
IgG binding chemical metering is a key determinant of mAb's ability to collect supplements, but the Fab molecular angle and flexibility of CD20 in seed complexes also play a role.
summary, after binding to CD20, type II monoclonal antibodies form an end complex, unable to recruit additional monoclonal antibodies and complement components, while type I seed complex can increase the local concentration of monoclonal antibodies to effectively activate the complement.
in type I monoclonal antibodies, the ofatumumab complex shows the best geometry to complement the complement.
the molecular mechanisms revealed in this study help to rationalize the design of a new generation of mAb and biosimilar molecules, fine-tune the treatment of different B-cell malignancies and autoimmune diseases, and better control the effectiveness of treatment.
above are the type I and type II CD20 monoclonal antibody binding mechanism with CD20 and the CD20-IgG hemogenerer model.