The same degree of increase in CRS was not observed in the trial using an IgG4-CD28 hinge-TM domain configuration (IgG4-28-41BB), further underscoring that the identity and/or combination of hinge-TM structural domains can exert significant influence on manifestation of CRS toxicity even when the scFv, costimulatory and activation domains are the same (Figure 3) [37,38]. Here, CD28 is linked to congenital rubella syndrome.