TABLE 1.

Clinical challenges associated with hepatic clearance of biological therapies and strategies to mitigate risk during drug development.

Clinical challenge	Explanation	Mitigating strategy
Impact of LSEC Fc receptors on antibody PK	Accelerated or delayed clearance of circulating antibody	Modify Fc portion to enhance interaction with FcRn and improve half life Modify Fc portion to minimize interaction with FcγRIIb
Localized hepatotoxicity or DILI in reponse to antibody therapy in humans	Enhanced deposition and clearance by LSEC leading to vasculotoxicity	Analysis of Fc portion and specific testing of clearance by human FcR to minimize crosslinking and activation in sinusoid
Complement mediated toxicity/Sinusoidal obstruction syndrome associated with antibody therapy	Immune complex binding to LSEC and cell apoptosis leading to exposure of basal lamina	Careful screening for binding to Fc receptors on LSEC
Altered antibody PK in older patients or patients with underlying liver disease	LSEC capillarization, reduction in hepatic albumin production	Careful screening for pre-existing disease in patient populations. Age-dependent pharmacokinetic assessment at Phase 1 testing
Complications due to autoantibody production in hepatic autoimmunity	LSEC capillarization or autoantibody occupancy of FcRs impacting on PK	Use of FcRn blockers to enhance IgG degradation
Desire to improve half life of therapeutic antibody	Accelerated clearance by hepatic FcγRIIb	Engineering of Fc portion to minimize interaction or delay internalization of receptor
Lack of clinical efficacy upon testing in human subjects	Reduced abilities of rodent or primate models to recreate human hepatic antibody clearance	Inclusion of human cell based or tissue array screens in pre-trail development stages