Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange

Antibodies play a central role in immunity by forming an interface with the innate immune system and, typically, mediate proinflammatory activity. We describe a novel posttranslational modification that leads to anti-inflammatory activity of antibodies of immunoglobulin G, isotype 4 (IgG4). IgG4 antibodies are dynamic molecules that exchange Fab arms by swapping a heavy chain and attached light chain (half-molecule) with a heavy-light chain pair from another molecule, which results in bispecific antibodies. Mutagenesis studies revealed that the third constant domain is critical for this activity. The impact of IgG4 Fab arm exchange was confirmed in vivo in a rhesus monkey model with experimental autoimmune myasthenia gravis. IgG4 Fab arm exchange is suggested to be an important biological mechanism that provides the basis for the anti-inflammatory activity attributed to IgG4 antibodie

Switching time and parameter optimization in nonlinear switched systems with multiple time-delays

Abstract In this paper, we consider a dynamic optimization problem involving a general switched system that evolves by switching between several subsystems of nonlinear delay-differential equations. The optimization variables in this system consist of: (1) the times at which the subsystem switches occur; and (2) a set of system parameters that influence the subsystem dynamics. We first establish the existence of the partial derivatives of the system state with respect to both the switching times and the system parameters. Then, on the basis of this result, we show that the gradient of the cost function can be computed by solving the state system forward in timefollowed by a costate system backward in time. This gradient computation procedure can be combined with any gradient-based optimization method to determine the optimal switching times and parameters. We propose an effective optimization algorithm based on this idea. Finally, we consider three numerical examples, one involving the 1,3-propanediol fed-batch production process, to illustrate the effectiveness and applicability of the proposed algorithm