Development and validation of panoptic Meso scale discovery assay to quantify total systemic interleukin-6.

AIM: Interleukin-6 (IL-6), a multifunctional cytokine, exists in several forms ranging from a low molecular weight (MW 20-30 kDa) non-complexed form to high MW (200-450 kDa), complexes. Accurate baseline IL-6 assessment is pivotal to understand clinical responses to IL-6-targeted treatments. Existing assays measure only the low MW, non-complexed IL-6 form. The present work aimed to develop a validated assay to measure accurately total IL-6 (complexed and non-complexed) in serum or plasma as matrix in a high throughput and easily standardized format for clinical testing. METHODS: Commercial capture and detection antibodies were screened against humanized IL-6 and evaluated in an enzyme-linked immunosorbent assay format. The best antibody combinations were screened to identify an antibody pair that gave minimum background and maximum recovery of IL-6 in the presence of 100% serum matrix. A plate-based total IL-6 assay was developed and transferred to the Meso Scale Discovery (MSD) platform for large scale clinical testing. RESULTS: The top-performing antibody pair from 36 capture and four detection candidates was validated on the MSD platform. The lower limit of quantification in human serum samples (n = 6) was 9.77 pg l(-1) , recovery ranged from 93.13-113.27%, the overall pooled coefficients of variation were 20.12% (inter-assay) and 8.67% (intra-assay). High MW forms of IL-6, in size fractionated serum samples from myelodysplastic syndrome and rheumatoid arthritis patients, were detected by the assay but not by a commercial kit. CONCLUSION: This novel panoptic (sees all forms) IL-6 MSD assay that measures both high and low MW forms may have clinical utility.

Breakthrough cancer medicine and its impact on novel drug development in China: report of the US Chinese Anti-Cancer Association (USCACA) and Chinese Society of Clinical Oncology (CSCO) Joint Session at the 17th CSCO Annual Meeting.

The US Chinese Anti-Cancer Association (USCACA) teamed up with Chinese Society of Clinical Oncology (CSCO) to host a joint session at the17th CSCO Annual Meeting on September 20th, 2014 in Xiamen, China. With a focus on breakthrough cancer medicines, the session featured innovative approaches to evaluate breakthrough agents and established a platform to interactively share successful experiences from case studies of 6 novel agents from both the United States and China. The goal of the session is to inspire scientific and practical considerations for clinical trial design and strategy to expedite cancer drug development in China. A panel discussion further provided in-depth advice on advancing both early and full development of novel cancer medicines in China.

Pharmacokinetics, efficacy and toxicity of different pegylated liposomal doxorubicin formulations in preclinical models: is a conventional bioequivalence approach sufficient to ensure therapeutic equivalence of pegylated liposomal doxorubicin products?

PURPOSE: To examine whether a conventional bioequivalence approach is sufficient to ensure the therapeutic equivalence of liposomal products, the pharmacokinetics, efficacy and toxicity of different formulation variants of the marketed Doxil(/Caelyx product, pegylated liposomal doxorubicin (PLD), were evaluated in several preclinical models. METHODS: Six different variants of the marketed PLD formulation were prepared by incorporating minor changes in the composition and liposome size of the original formulation. The pharmacokinetics of 5 formulations were evaluated in albino mice following i.v. administration at 6 mg/kg. Selected variants along with Doxil/Caelyx (formulation 1, Doxil-control) were tested for antitumor activity in the MDA-MB-231 xenograft mouse model following 3 repeated administrations at 2 mg/kg or 3 mg/kg (once weekly for 3 weeks) and/or toxicity in Cynomolgus monkeys following 6 repeated administrations at 2.5 or 4.0 mg/kg. Formulations 1-4 were tested for antitumor activity and formulations 1, 2, 6 and 7 were evaluated in a monkey toxicity study. The toxicokinetics of total doxorubicin was determined after the first and last dose in the monkey toxicity study. RESULTS: In the albino mouse, formulations 2 and 3 had plasma pharmacokinetic profiles similar to Doxil-control (formulation 1). Although these three formulations had similar pharmacokinetic profiles, formulation 2 showed significantly (P < 0.05) longer survival time and better efficacy (reduced tumor volume) over other formulations tested for antitumor activity at the 3 mg/kg dose. In monkeys, formulation 2 gave systemic exposure of doxorubicin approximately the same as formulation 1; however, multi-focal degeneration of renal cortical tubules and hypocellularity of the bone marrow were observed with formulation 2 but not with formulation 1 (Doxil-control). Formulations 6 and 7 gave lower exposure to doxorubicin compared to Doxil-control, but were associated with higher severity and frequency of toxic effects (hematological effects, elevated liver enzymes). It was concluded that plasma pharmacokinetics and systemic exposure of doxorubicin did not correlate well with the antitumor activity and toxicity profiles for PLD products. Hence, a conventional bioequivalence approach is not appropriate for establishing therapeutic equivalence of generic PLD products. A carefully designed clinical study evaluating clinical safety, efficacy and pharmacokinetics should be considered for establishing the therapeutic equivalency of generic versions of Doxil.