Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys.
Bispecific antibodies (BsAbs) can affect multiple disease pathways, thus these types of constructs potentially provide promising approaches to improve efficacy in complex disease indications. The specific and non-specific clearance mechanisms/biology that affect monoclonal antibody (mAb) pharmacokinetics are likely involved in the disposition of BsAbs. Despite these similarities, there are a paucity of studies on the in vivo biology that influences the biodistribution and pharmacokinetics of BsAbs. The present case study evaluated the in vivo disposition of 2 IgG-fusion BsAb formats deemed IgG-ECD (extracellular domain) and IgG-scFv (single-chain Fv) in cynomolgus monkeys. These BsAb molecules displayed inferior in vivo pharmacokinetic properties, including a rapid clearance (> 0.5 mL/hr/kg) and short half-life relative to their mAb counterparts. The current work evaluated factors in vivo that result in the aberrant clearance of these BsAb constructs. Results showed the rapid clearance of the BsAbs that was not attributable to target binding, reduced neonatal Fc receptor (FcRn) interactions or poor molecular/biochemical properties. Evaluation of the cellular distribution of the constructs suggested that the major clearance mechanism was linked to binding/association with liver sinusoidal endothelial cells (LSECs) versus liver macrophages. The role of LSECs in facilitating the clearance of the IgG-ECD and IgG-scFv BsAb constructs described in these studies was consistent with the minimal influence of clodronate-mediated macrophage depletion on the pharmacokinetics of the constructs in cynomolgus monkeys The findings in this report are an important demonstration that the elucidation of clearance mechanisms for some IgG-ECD and IgG-scFv BsAb molecules can be unique and complicated, and may require increased attention due to the proliferation of these more complex mAb-like structures.
a Department of Drug Disposition, Development/ Commercialization , Lilly Research Laboratories, Lilly Corporate Center , Indianapolis , Indiana , USA.
Amita
A
Datta-Mannan
b Department of Biotechnology Discovery Research , Lilly Research Laboratories, Lilly Corporate Center , Indianapolis , Indiana , USA.
Johnny E
JE
Croy
a Department of Drug Disposition, Development/ Commercialization , Lilly Research Laboratories, Lilly Corporate Center , Indianapolis , Indiana , USA.
Linda
L
Schirtzinger
a Department of Drug Disposition, Development/ Commercialization , Lilly Research Laboratories, Lilly Corporate Center , Indianapolis , Indiana , USA.
Stacy
S
Torgerson
b Department of Biotechnology Discovery Research , Lilly Research Laboratories, Lilly Corporate Center , Indianapolis , Indiana , USA.
Matthew
M
Breyer
a Department of Drug Disposition, Development/ Commercialization , Lilly Research Laboratories, Lilly Corporate Center , Indianapolis , Indiana , USA.
Victor J
VJ
Wroblewski
D000818:Animals; D018033:Antibodies, Bispecific / Q000493:pharmacokinetics*; D002196:Capillaries / Q000378:metabolism*; D006207:Half-Life; D015395:Histocompatibility Antigens Class I; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D011961:Receptors, Fc
D018033:Antibodies, Bispecific; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; C100688:Fc receptor, neonatal
Antibody pharmacokinetics; bifunctional antibodies; bispecific antibodies; clodronate; liver sinusoidal endothelial cells; non-specific binding