Atacicept in relapsed/refractory multiple myeloma or active Waldenström's macroglobulinemia: a phase I study.

Background: Advanced multiple myeloma (MM) and Waldenström's macroglobulinemia (WM) are incurable B-cell malignancies. This is the first full clinical report of atacicept, a fusion protein that binds to and neutralises the B-cell survival factors, B-lymphocyte stimulator (BLyS) and A proliferation-inducing ligand (APRIL), in MM and WM.

Methods: In this open-label phase-I study, 16 patients with advanced disease (12 MM, 4 WM) received one cycle of five once-weekly subcutaneous injections of atacicept (2, 4, 7 or 10 mg kg(-1)).

APRIL and TACI interact with syndecan-1 on the surface of multiple myeloma cells to form an essential survival loop.

BLyS and APRIL share two receptors - transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA) - and BLyS binds to a third receptor, BAFF-R. We previously reported that TACI gene expression is a good indicator of a BLyS-binding receptor in human multiple myeloma cell lines (HMCLs), unlike BCMA, which is expressed by all HMCLs or BAFF-R which is typically not expressed by late-stage B cells. We hypothesised a link between APRIL and TACI through syndecan-1, similar to the situation reported for FGF and FGFR.

Phase I clinical study of atacicept in patients with relapsed and refractory B-cell non-Hodgkin's lymphoma.

Purpose: B-lymphocyte stimulator and a proliferation-inducing ligand regulate B-cell homeostasis and immunoglobulin production and are overexpressed in B-cell malignancies. Atacicept (TACI-Ig), a recombinant fusion protein that inhibits both B-lymphocyte stimulator and a proliferation-inducing ligand, may be a novel treatment for B-cell malignancies.

Experimental Design: A phase 1, open-label, dose-escalation study of atacicept in patients with relapsed or refractory B-cell lymphoma was done.

Safety, pharmacokinetics and pharmacodynamics of recombinant human tumour necrosis factor-binding protein-1 (Onercept) injected by intravenous, intramuscular and subcutaneous routes into healthy volunteers.

The safety, pharmacokinetics and pharmacodynamics of recombinant human tumour necrosis factor-binding protein-1 (r-hTBP-1, Onercept) were investigated after intravascular and extravascular injection, in three studies in healthy volunteers. Subjects received Onercept as single intravenous doses of 5, 15, 50 and 150 mg, or single IV, IM, SC injection of 50 mg, or six repeated SC injections of 50 mg. Based on vital signs, hematology and blood chemistry, antibodies to study drug and local tolerability, r-hTBP-1 exhibited a remarkably safe profile.

Influence of interferon beta-1a dose frequency on PBMC cytokine secretion and biological effect markers.

Interferon-beta regimens for immune-mediated diseases, such as multiple sclerosis (MS), have not been compared regarding their biological effects. In this randomized, parallel-group, placebo-controlled study, cytokine secretion by mitogen-stimulated PBMCs and serum response markers were assessed in volunteers receiving subcutaneous recombinant IFN beta-1a (Rebif, Ares-Serono) 22 microg once a week (QW), 22 microg three times a week, 66 microg QW, or placebo. The production of IL-1beta, IL-6, IFN-gamma, TNF-alpha and TNF-beta markedly decreased during 24-48 h after each injection, with limited dose-dependency and no evidence of tolerance or effect augmentation over 1 month.