Modified antibodies comprising modified IgG2 domains that induce agonistic or antagonistic properties and uses thereof

摘要

The inventors have shown that human IgG2 (h2) is directed against anti-CD40 antibodies and antibodies with specificity for other immunostimulatory receptors, such as 4-1BB and CD28, through a combination of in vitro and in vivo approaches. It exhibits a unique FcyR-independent agonist activity. Studies of LOB7.4, an anti-human CD40 mAb, revealed that the unique activity of h2 depends on the exact sequence of the hinge and CH1 disulfide bonds. Chemical “shuffling” or mutagenicity to “lock” LOB7.4 to either the more flexible “h2A” or the more confluent “h2B” conformation provides antagonistic and agonistic properties, respectively. Granted. Manipulation of h2 in this manner allows the development of reagents with either immunostimulatory or immunosuppressive properties that are directly involved in the design of therapeutic mAb drugs and fusion proteins. [Selection] Figure 1