Bronchial mucosal IFN-α/ß and pattern recognition receptor expression in patients with experimental rhinovirus-induced asthma exacerbations.

BACKGROUND: The innate immune system senses viral infection through pattern recognition receptors (PRRs), leading to type I interferon production. The role of type I interferon and PPRs in rhinovirus-induced asthma exacerbations in vivo are uncertain. OBJECTIVES: We sought to compare bronchial mucosal type I interferon and PRR expression at baseline and after rhinovirus infection in atopic asthmatic patients and control subjects. METHODS: Immunohistochemistry was used to detect expression of IFN-α, IFN-ß, and the PRRs: Toll-like receptor 3, melanoma differentiation-associated gene 5, and retinoic acid-inducible protein I in bronchial biopsy specimens from 10 atopic asthmatic patients and 15 nonasthmatic nonatopic control subjects at baseline and on day 4 and 6 weeks after rhinovirus infection. RESULTS: We observed IFN-α/ß deficiency in the bronchial epithelium at 3 time points in asthmatic patients in vivo. Lower epithelial IFN-α/ß expression was related to greater viral load, worse airway symptoms, airway hyperresponsiveness, and reductions in lung function during rhinovirus infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-α/ß in asthmatic patients during infection. Interferon deficiency at baseline was not accompanied by deficient PRR expression in asthmatic patients. Both epithelial and subepithelial PRR expression were induced during rhinovirus infection. Rhinovirus infection-increased numbers of subepithelial interferon/PRR-expressing inflammatory cells were related to greater viral load, airway hyperresponsiveness, and reductions in lung function. CONCLUSIONS: Bronchial epithelial IFN-α/ß expression and numbers of subepithelial IFN-α/ß-expressing monocytes/macrophages during infection were both deficient in asthmatic patients. Lower epithelial IFN-α/ß expression was associated with adverse clinical outcomes after rhinovirus infection in vivo. Increases in numbers of subepithelial cells expressing interferon/PRRs during infection were also related to greater viral load/illness severity.

Mechanisms of monoclonal antibody-drug interactions.

The concept of monoclonal antibodies (mAbs) as pharmacotherapeutics was validated in the mid-1980s with the successful clinical development of the fully murine mAb muromonab-CD3 for prevention of acute organ rejection. However, clinical applications of fully murine mAbs are restricted, owing to the high incidence of serious immune-mediated side effects, particularly upon repeated exposure. The rate and severity of immune-mediated toxicities of these agents were significantly attenuated by the development of mouse/human chimeric, fully human, and humanized mAbs. These refinements in molecular structure allowed repeated, long-term administration, where therapeutically warranted, which, in turn, broadened the scope of indications for this class of therapy. Presently, numerous mAbs are approved or are undergoing clinical evaluation for treatment of oncologic and chronic inflammatory diseases. The current experimental development landscape spans respiratory, metabolic, and central nervous system disorders as well as infectious disease. A consequence of the expanding numbers of mAb indications is concomitant administration of these agents with established small molecule pharmacotherapies, which necessitates a comprehensive understanding of mAb-small molecule drug interactions as well as mAb-mAb interactions. Current knowledge indicates that mAbs do not elicit a direct effect on the metabolic/clearance pathways for small molecular therapeutics. However, the immunomodulatory properties of mAbs can indirectly alter clearance of certain small molecule entities through the attenuation of noncatabolic enzymatic pathways.

Molecular, biologic, and pharmacokinetic properties of monoclonal antibodies: impact of these parameters on early clinical development.

Currently, 14 intact, unconjugated, monoclonal antibodies (Mabs) are approved for therapeutic use in the United States, and more than 100 Mabs are presently undergoing clinical development or regulatory review. Mabs are large molecular weight glycoproteins that embody structural, biochemical, and pharmacologic properties distinct from other biologics or chemically synthesized compounds. Early therapeutic Mabs were murine proteins, and clinical testing of these agents revealed serious immune-mediated toxicities. The side effect profile of murine Mab therapeutic agents restricted the clinical development of these agents to indications with high morbidity and/or mortality (ie, oncology, graft vs host rejection). Advances in genetic engineering and protein expression technologies resulted in the development of Mabs composed either predominately (ie, mouse/human chimeric, "humanized") or completely (ie, "fully human" Mabs) of the human amino acid sequence. The production of chimeric, humanized, and fully human Mabs significantly reduced the immune-mediated toxicities and expanded the utility for these agents in numerous therapeutic areas, particularly in chronic disorders requiring either long-term administration (ie, rheumatoid arthritis) or treatment upon the flare up of disease (Crohn's disease, psoriasis). This review provides an overview of the molecular, biochemical, and pharmacokinetic properties and clinical development history of Mabs and details how these factors currently affect the scope and design of early clinical development strategies for these drug candidates. Emphasis is placed on the criteria for selecting appropriate subject populations for phase I testing of Mabs.

Pharmacokinetics and safety of golimumab, a fully human anti-TNF-alpha monoclonal antibody, in subjects with rheumatoid arthritis.

Golimumab is a fully human antitumor necrosis factor alpha (TNF-alpha) monoclonal antibody that is being developed for intravenous and subcutaneous administration. To assess the pharmacokinetics and safety of the intravenous formulation of golimumab, 36 adult subjects with rheumatoid arthritis were randomly assigned to receive a single infusion of placebo or golimumab (0.1, 0.3, 1, 3, 6, or 10 mg/kg). Serum concentrations of golimumab were determined using a validated enzyme-linked immunosorbent assay method. In addition to the noncompartmental analysis and compartmental modeling, a population pharmacokinetics analysis using NONMEM was also conducted. Both the maximum serum concentration and the area under the serum concentrationtime curve appeared to increase in a dose-proportional manner. The median half-life ranged from 7 to 20 days. A 2-compartment population pharmacokinetic model adequately described the pharmacokinetics of golimumab. The following pharmacokinetic parameters (typical value [% coefficient of variation]) were estimated from the population pharmacokinetic model: clearance (CL: 0.40 [10.1%] L/d), volume of distribution in the central compartment (V(c): 3.07 [6.4%] L), intercompartmental clearance (Q: 0.42 [15.5%] L/d), and volume of distribution in the peripheral compartment (V(p): 3.68 [11.8%] L). Interindividual variability of the pharmacokinetic parameters was quantified for CL (44.3%), V(c) (25.5%), Q (44.6%), and V(p) (44.6%). Residual variability was estimated to be 15.0%. Body weight was found to be an important covariate on V(c). Golimumab was generally well tolerated. The pharmacokinetics of golimumab appeared to be linear over the dose range evaluated in this study.

A phase I trial of an interleukin-12/23 monoclonal antibody in relapsing multiple sclerosis.

OBJECTIVE: To assess the safety, tolerability and pharmacokinetics of an interleukin (IL)-12/23 monoclonal antibody (mAb) in subjects with a relapsing form of multiple sclerosis (MS). METHODS: A phase I, double-blind, placebo-controlled, sequential dose escalation study was conducted in 20 subjects with MS. Subjects were randomized (4:1) to receive a single subcutaneous injection of either IL-12/23 mAb (0.3, 0.75, 1.5, and 3.0 mg/kg) or placebo. Clinical and laboratory evaluations were performed through 16 weeks following administration. RESULTS: IL-12/23 mAb was well tolerated in this study. Adverse events were generally mild or moderate, with no apparent dose-related trends. One subject with a family history of breast cancer was diagnosed during the study with breast cancer 21 days after IL-12/23 mAb administration. There were no significant changes in laboratory indicators of systemic or neurotoxicity. There was a large degree of variability in T2 lesion volume and total number of gadolinium-positive lesions, both unaffected by dose escalation. Three relapses of MS occurred in two placebo-treated subjects. Over the range of single doses studied, the median Tmax ranged from 9.0 to 16.5 days, and the median T1/2 ranged from 20.2 to 30.9 days. CONCLUSION: Single subcutaneous administrations of IL-12/23 mAb in this first study of relapsing MS were generally well tolerated. Safety of the agent will need to be tested in a study of longer duration and involving a larger cohort of subjects.