Population pharmacokinetics analysis of camidanlumab tesirine in patients with relapsed or refractory Hodgkin lymphoma and non-Hodgkin lymphoma.

PURPOSE: The objective of this analysis was to develop a population pharmacokinetic (PPK) model to characterize camidanlumab tesirine (Cami) pharmacokinetics based on the phase 1 study in relapsed/refractory lymphoma (NCT02432235). METHODS: An initial PPK model was developed based on a two-compartment model with parallel linear and nonlinear elimination pathways. Pharmacokinetic parameters were evaluated for correlation with potential demographic covariates; significant covariates were retained in the final model. RESULTS: In the final PPK model, baseline weight effects were included on clearance (CL), intercompartmental clearance (Q), and the volumes of distribution in the central (V1) and peripheral (V2) compartments. The baseline soluble CD25 (sCD25) effect was included on CL and maximum velocity of saturable clearance (Vmax); sex effect was included on CL and V1; and ethnicity effect was included on deconjugation clearance (CLdec). For a typical patient, CL and CLdec were 0.516 and 0.21 L/day, respectively (tAb elimination half-life: 18.72 days); V1 and V2 were 4.41 and 2.67 L, respectively; Vmax was 0.49 mg/day; the Michaelis-Menten constant (Km) was 0.409 µg/mL; and the first-order rate for decrease of Vmax (KDES) was 0.0197/day. Cami exposure was higher for patients with low baseline sCD25, higher body weight, and females. CONCLUSIONS: The final model described the observed data well, estimates of PK parameters were obtained, and covariates with significant effects on Cami exposure were identified. Altogether, this final PPK model provides a robust basis for analysis of Cami exposure-response relationships and further supports identification of the optimal Cami dosing schedule for patients with relapsed/refractory lymphoma.

Fab-dsFv: A bispecific antibody format with extended serum half-life through albumin binding.

An antibody format, termed Fab-dsFv, has been designed for clinical indications that require monovalent target binding in the absence of direct Fc receptor (FcR) binding while retaining substantial serum presence. The variable fragment (Fv) domain of a humanized albumin-binding antibody was fused to the C-termini of Fab constant domains, such that the VL and VH domains were individually connected to the Cκ and CH1 domains by peptide linkers, respectively. The anti-albumin Fv was selected for properties thought to be desirable to ensure a durable serum half-life mediated via FcRn. The Fv domain was further stabilized by an inter-domain disulfide bond. The bispecific format was shown to be thermodynamically and biophysically stable, and retained good affinity and efficacy to both antigens simultaneously. In in vivo studies, the serum half-life of Fab-dsFv, 2.6 d in mice and 7.9 d in cynomolgus monkeys, was equivalent to Fab'-PEG.

Certolizumab pegol does not bind the neonatal Fc receptor (FcRn): Consequences for FcRn-mediated in vitro transcytosis and ex vivo human placental transfer.

Antibodies to tumor necrosis factor (anti-TNF) are used to treat inflammatory diseases, which often affect women of childbearing age. The active transfer of these antibodies across the placenta by binding of the Fc-region to the neonatal Fc receptor (FcRn) may result in adverse fetal or neonatal effects. In contrast to other anti-TNFs, certolizumab pegol lacks an Fc-region. The objective of this study was to determine whether the structure of certolizumab pegol limits active placental transfer. Binding affinities of certolizumab pegol, infliximab, adalimumab and etanercept to human FcRn and FcRn-mediated transcytosis were determined using in vitro assays. Human placentas were perfused ex vivo to measure transfer of certolizumab pegol and positive control anti-D IgG from the maternal to fetal circulation. FcRn binding affinity (KD) was 132nM, 225nM and 1500nM for infliximab, adalimumab and etanercept, respectively. There was no measurable certolizumab pegol binding affinity, similar to that of the negative control. FcRn-mediated transcytosis across a cell layer (mean±SD; n=3) was 249.6±25.0 (infliximab), 159.0±20.2 (adalimumab) and 81.3±13.1ng/mL (etanercept). Certolizumab pegol transcytosis (3.2±3.4ng/mL) was less than the negative control antibody (5.9±4.6ng/mL). No measurable transfer of certolizumab pegol from the maternal to the fetal circulation was observed in 5 out of 6 placentas that demonstrated positive-control IgG transport in the ex vivo perfusion model. Together these results support the hypothesis that the unique structure of certolizumab pegol limits its transfer through the placenta to the fetus and may be responsible for previously reported differences in transfer of other anti-TNFs from mother to fetus.