IBL-America is proud to showcase a few publications where our comprehensive Research Drug Monitoring assay kits were used.

Check out the highlights below and follow the link to view.

Ustekinumab Dosing Individualization in Crohn’s Disease Guided by a Population Pharmacokinetic–Pharmacodynamic Model

Jurij Aguiar Zdovc 1,†, Jurij Hanžel 2,3,† , Tina Kurent 2 , Nejc Sever 2 , Matic Koželj 2 , Nataša Smrekar 2 , Gregor Novak 2 , Borut Štabuc 2,3, Erwin Dreesen 4,5 , Debby Thomas 4 , Tomaž Vovk 1 , Barbara Ostanek 6 , David Drobne 2,3 and Iztok Grabnar 1,*

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571278/

Abstract: Ustekinumab is a monoclonal antibody used in Crohn’s disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic–pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.

VEGF TrapR1R2 Suspended in the Semifluorinated Alkane F6H8 Inhibits Inflammatory Corneal Hem- and Lymphangiogenesis

Viet Nhat Hung Le1,2,* , Deniz Hos1,3,* , Yanhong Hou1,4,5, Madlen Witt6, Mikhail Barkovskiy6, Felix Bock1,†, and Claus Cursiefen1,3,†

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571278/

Purpose: Semifluorinated alkanes (SFAs) are used at the ocular surface as lubricants or vehicles for drugs. The purpose of this study was to test the effect of vascular endothelial growth factor (VEGF) TrapR1R2 suspended in the SFA perfluorohexyloctane (Trap/F6H8) on corneal neovascularization.

Results: Trap/F6H8 was as effective as Trap in inhibiting corneal hemangiogenesis and lymphangiogenesis after 2 weeks of treatment. After 3 days of treatment, Trap/F6H8 was even more effective than Trap in inhibiting corneal hemangiogenesis. Both treatment groups (Trap/F6H8 and Trap) significantly reduced corneal CD45+ cell recruitment. Epithelial closure after debridement was unaffected by Trap/F6H8 or Trap. Conclusions: In this study, we demonstrate that F6H8 is a potential carrier for VEGF TrapR1R2 to topically treat corneal neovascularization. Our findings might open new treatment avenues for local anti-angiogenic therapy at the cornea, as F6H8 is already approved for the usage at the ocular surface. Translational Relevance: With this study we show for the first time that SFAs can serve as carriers for anti-angiogenic drugs at the ocular surface.

Inductively coupled plasma mass spectrometry assay for quantification of free infliximab in serum

Igor Y. Pavlova, Rebecca L. Parkera, Eszter Lazar-Molnara, Frederick G. Strathmannb,

Julio C. Delgado,⁎

https://pubmed.ncbi.nlm.nih.gov/31034880/

TNF antagonists such as infliximab are effective for the treatment of several inflammatory and autoimmune diseases. Recent clinical studies have advocated the importance of measuring trough infliximab levels to guide treatment decisions. We have developed a novel assay for measuring serum free infliximab levels using inductively coupled plasma-mass spectrometry (ICP-MS). The method involves the incubation of patient serum in wells coated with recombinant TNF, followed by detection with lanthanide-labeled monoclonal anti-human IgG1 and ICP-MS analysis. Full method validation was performed and results for clinical samples tested with the new method were compared with those obtained from a capture ELISA and a cell-based assay. Validation of the ICPMS assay revealed a lower limit of detection of 0.4 μg/mL in serum. The linear range of quantitation was 1–50 μg/mL. The within-run and between-run precision had a coefficient of variation (CV) of<10%, and the accuracy of the assay had a CV of<15%. In serum samples, the ICP-MS method was devoid of analytical interferences by high levels of hemoglobin, bilirubin and triglycerides. Serum sample results from 123 drugnaive donors revealed a test cutoff at 0.5 μg/mL. Test results from clinical samples obtained by the ICP-MS method showed strong correlation with both the ELISA and cell-based assay. The ICP-MS methodology presented in this study is a robust method for measuring TNF antagonist serum levels, which makes it well suited for therapeutic drug monitoring in the clinical laboratory.

Peak Concentrations of Ustekinumab After Intravenous Induction Therapy Identify Patients With Crohn’s Disease Likely to Achieve Endoscopic and Biochemical Remission

Hanžel J, Zdovc J, Kurent T, Sever N, Javornik K, Tuta K, Koželj M, Smrekar N, Novak G, Štabuc B, Dreesen E, Thomas D, Vovk T, Grabnar I, Drobne D

https://pubmed.ncbi.nlm.nih.gov/32109630/

Background & aims: Little is known about the relationship between ustekinumab exposure during the first 2 weeks of treatment and outcomes of patients with Crohn's disease (CD). We investigated the relationship between serum concentrations of ustekinumab during the first 2 weeks of treatment and endoscopic and biochemical remission in patients with CD.

Results: Endoscopic remission was achieved in 10 patients (24.4%) at week 24; biochemical remission was achieved in 17 patients (41.5%) at week 8, 17 patients (41.5%) at week 16, and 21 patients (51.2%) at week 24. Peak concentrations associated with endoscopic remission (area under the receiver operating characteristic curve, 0.717; 95% CI, 0.517-0.916); 6 of 13 patients (46%) with peak concentrations above 105 μg/mL (upper tercile) achieved endoscopic remission, compared with only 1 of 14 patients (7%) with peak concentrations below 88 μg/mL (lower tercile). All exposure parameters during the first 2 weeks were associated with biochemical remission. There was no significant difference between the associations of peak concentrations, week-2 concentrations, area under the curve through week 2, or later exposure measures (at weeks 4 and 8) with biochemical or endoscopic remission.

Conclusions: In a prospective study, we found that serum concentrations of ustekinumab as early as 1 hour after intravenous infusion might be used to identify patients with CD most likely to achieve endoscopic remission. This early measurement might be used to optimize treatment of CD.

Cetuximab produced from a goat mammary gland expression system is equally efficacious

as innovator cetuximab in model systems of cancer.

Qian Wang1, William Gavin3, Nick Masiello3, Khanh B. Tran1 , Gotz Laible1, 2,4 and Peter R

Shepherd1,4, *

https://pubmed.ncbi.nlm.nih.gov/33024714/

Abstract: Humanised monoclonal antibodies have proven a very effective mode of therapy for a wide range of conditions. With many of the monoclonal antibody drugs now coming off patent there is an increasing interest in developing biosimilar, or even biobetter, forms of these drugs. With the commercial competition associated with such generic products there is increasing demand for improved production and purification system for biosimilars. Cetuximab, also known as Erbitux, is widely used in cancer therapy, especially in advanced colorecal cancer, metastatic non-small cell lung cancer and head and neck cancer and it will come off patent in the near future. We have previously reported on a genetically engineered goat system to produce cetuximab (gCetuximab) in milk. Herein we now report on the further charactization of the gCetuximab produced utilizing additional and more sophisticated biological assays. There is similar bioactivity of the gCetuximab compared with the commercial product produced in mammalian cell culture. In particular both cetuximab antibodies selectively target EGFR and induce its internalization to down regulate EGFR signaling. Both forms have very similar half life in animals and in a HT29 colorectal cancer xenograft model have similar efficacy. We also show that the toxin MMAE can be conjugated to gCetuximab, that this targets it to cells and that this results in direct cell killing in HT29 cells. This demonstrates that the gCetuximab will also be a viable vehicle for antibody drug conjugate based therapies. Taken together, this shows that the goat milk monoclonal antibody production system is an effective way of producing a biosimilar form of cetuximab.