Daniel C. Adelman

Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis☆☆☆★★★

BACKGROUNDnIncreased serum levels of antigen-specific IgE are often associated with allergic respiratory disorders. RhuMAb-E25, a recombinant humanized monoclonal antibody, decreases free serum IgE by forming biologically inactive immune complexes with free IgE.nnnOBJECTIVEnWe hypothesized that rhuMAb-E25 would decrease total serum IgE and reduce symptoms.nnnMETHODSnTwo hundred forty subjects were enrolled into five groups to determine the safety, tolerance, and efficacy of repeated administration of rhuMAb-E25 in adults with ragweed-induced allergic rhinitis and to explore the pharmacodynamic relationship of rhuMAb-E25 and IgE. One hundred eighty-one subjects received an initial intravenous loading dose (day 0, 1 month before ragweed season), followed by administration of rhuMAb-E25 (in mg/kg body weight) of 0.15 mg/kg subcutaneously, 0.15 mg/kg intravenously, or 0.5 mg/kg intravenously on days 7, 14, 28, 42, 56, 70, and 84. A subcutaneous placebo group and an intravenous placebo group were included. The total evaluation time included the 84-day treatment period, followed by a 42-day observation period.nnnRESULTSnAdverse events were mild, and no differences were observed in the rates between the three active and two placebo treatment groups. Ragweed-specific IgE levels correlated with symptom scores. RhuMAb-E25 decreased serum free IgE levels in a dose- and baseline IgE-dependent fashion. However, only 11 subjects had IgE levels that were suppressed to undetectable levels (< or = 24 ng/ml), a sample too small to demonstrate significant differences and clinical efficacy. Thus the case for efficacy was not proven. Nonetheless, the study confirms that it is safe to repeatedly administer rhuMAb-E25 over a period of months.nnnCONCLUSIONSnBecause rhuMAb-E25 decreased serum free IgE in a dose-dependent fashion and because symptom scores correlated with antigen-specific IgE levels, the results suggest that if given in adequate doses, rhuMAb-E25 should be an effective therapy for allergic diseases.

Photoangioplasty for Human Peripheral Atherosclerosis Results of a Phase I Trial of Photodynamic Therapy With Motexafin Lutetium (Antrin)

BackgroundIn photoangioplasty, light activation of a photosensitive drug offers the potential for treatment of long segments of vascular disease. This is a brief description of a study designed to evaluate the safety and tolerability of a new photosensitizer, Antrin (motexafin lutetium), in the endovascular treatment of atherosclerosis. Methods and ResultsAn open-label, single-dose, escalating drug- and light-dose study was performed in patients with atherosclerotic peripheral arterial insufficiency. Clinical evaluation, serial quantitative angiography, and intravascular ultrasonography were performed. Therapy was well tolerated, and only minor side effects were observed. Treatment produced no deleterious vascular effects. Although this study was not designed to examine clinical efficacy, several secondary end points suggested a favorable therapeutic effect. ConclusionsThis phase I study demonstrates that photoangioplasty with motexafin lutetium is well tolerated and safe. Preliminary efficacy data suggest a future role for the treatment of flow-limiting atherosclerosis.

Phase I Drug and Light Dose-Escalation Trial of Motexafin Lutetium and Far Red Light Activation (Phototherapy) in Subjects With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention and Stent Deployment Procedural and Long-Term Results

Background—Motexafin lutetium (MLu; Antrin) is a photosensitizer that is taken up by atherosclerotic plaque and concentrated within macrophages and vascular smooth muscle cells. After photoactivation with far red light, MLu facilitates production of cytotoxic oxygen radicals that mediate apoptosis. We assessed the safety and tolerability of phototherapy (PT) with MLu in patients undergoing percutaneous coronary intervention with stent deployment. Methods and Results—An open-label, phase I, drug and light dose-escalation clinical trial of MLu PT enrolled 80 patients undergoing de novo coronary stent deployment. MLu was administered to 79 patients by intravenous infusion 18 to 24 hours before procedure, and photoactivation was performed after balloon predilatation and before stent deployment. Clinical evaluation, serial quantitative angiography, and intravascular ultrasound were performed periprocedurally and at 6 months follow-up. MLu PT was well tolerated without serious dose-limiting toxicities, and side effects (paresthesia and rash) were minor. No adverse angiographic outcomes were attributed to phototherapy. Conclusions—This study demonstrates that coronary MLu PT seems safe, and the maximum well-tolerated MLu dose and range of tolerated light doses were identified. These data can be used in phase II efficacy trials of MLu PT for the treatment of coronary atherosclerosis or vulnerable plaque.

Allergen skin tests and free IgE levels during reduction and cessation of omalizumab therapy

BACKGROUNDnThe recombinant humanized anti-IgE antibody omalizumab rapidly reduces serum free IgE concentrations and alleviates allergic airway disease. It is not known whether stopping or reducing the dose of omalizumab maintains adequate suppression of free IgE levels and IgE-mediated mast cell activation.nnnOBJECTIVEnTo determine the effects of omalizumab on serum free IgE and immediate allergen skin test reactivity during initial therapy followed by treatment reduction and cessation.nnnMETHODSnForty patients with perennial allergic rhinitis were randomized to receive 0.015 or 0.030 mg/kg/IU/mL open-label intravenous omalizumab every 2 weeks for 28 weeks, followed by 0.0015 or 0.0050 mg/kg/IU/mL every 2 weeks for 18 weeks. Serum free IgE levels were measured and titrated dust mite allergen skin tests conducted throughout.nnnRESULTSnAt day 98, serum free IgE concentrations were decreased by 96% to 99%, and wheal-and-flare reactions to skin tests were markedly suppressed. After reduced omalizumab doses (day 322), serum free IgE and allergen skin test reactivity increased significantly. On complete discontinuation of therapy (day 378), serum free IgE levels and skin test reactivity returned to baseline levels. Patients with lower initial levels of IgE had significantly less suppression of skin test reactivity.nnnCONCLUSIONnOmalizumab reduced serum free IgE and immediate skin test reactivity to allergen during initial, high-dose administration. These effects were not fully maintained during dose reduction and returned to baseline after cessation of chronic treatment.

Photodynamic therapy: applications in atherosclerotic vascular disease with motexafin lutetium.

Photodynamic therapy (PDT) has been approved as a tissue‐specific light‐activated cytotoxic therapy for many diseases. The ability of PDT to destroy target tissues selectively is especially appealing for atherosclerotic plaque. Biotechnology has developed a new generation of selective photosensitizers and catheter‐based technological advances in light delivery have allowed the introduction of PDT into the vasculature. The largest experience to date is with motexafin lutetium (MLu, Antrin), an expanded porphyrin (texaphyrin) that accumulates in plaque. The combination of the motexafin lutetium and endovascular illumination, or Antrin phototherapy, has been shown to reduce plaque in animal models. Antrin phototherapy generates cytotoxic singlet oxygen that has been shown to induce apoptosis in macrophages and smooth muscle cells. The safety, tolerability, and preliminary efficacy of Antrin phototherapy has been assessed in a phase 1 dose‐ranging clinical trial in subjects with peripheral artery disease and is currently being examined in a phase 1 study in subjects with lesions of the native coronary arteries undergoing stent implantation. The preliminary results suggest that Antrin phototherapy is safe, well tolerated, and nontraumatic. Cathet Cardiovasc Intervent 2002;57:387–394.

Elevated serum interleukin-6 associated with a failur in B cell differentiation in common variable immunodeficiecy

Interleukin-6 (IL-6/B cell stimulatory factor 2) has been found to drive activated human B-lymphocytes through the final stages of differentiation to become immunoglobulin-producing cells. Most patients with common variable immunodeficiency (CVI) have B-lymphocytes that fail to differentiate into high-rate immunoglobulin-secreting cells in vivo and in vitro. In view of (1) the known effects of IL-6 to promote B-lymphocyte terminal differentiation and (2) the defect in differentiation in B-lymphocytes of patients with CVI, we believed that it was important to analyze the role of this cytokine in patients with CVI. Using an IL-6-dependent murine hybridoma cell line in a bioassay, serum IL-6 levels were determined in 17 patients with CVI and in eight normal control subjects. Thirteen of the 17 patients with CVI exhibited serum IL-6 levels that were twofold to 18-fold higher than the range (mean, +2 SD) of normal control subjects. Spontaneous IL-6 production by peripheral blood mononuclear cells (PBMC) of patients with CVI was significantly higher than that from normal control subjects, whereas lipopolysaccharide maximally stimulated IL-6 production by PBMCs of patients with CVI or PBMCs of normal control subjects was equivalent. A substance inhibitory of IL-6 bioactivity was found in equivalent amounts in sera of both patients and normal control subjects. Sera from patients with CVI with high IL-6 bioactivity were found to have saturated this IL-6 inhibitory substance, thus resulting in large amounts of free IL-6 in the sera. These studies suggest that the failure of B cells from patients with CVI to terminally differentiate into high-rate immunoglobulin-secreting cells cannot be attributed to a decrease in the serum levels of IL-6 and that the increased circulating IL-6 levels in patients with CVI result from hyperproduction rather than decreased use of IL-6. The persistently elevated levels of IL-6 observed in some patients with CVI may secondarily result in the induction of the neoplastic and autoimmune phenomena associated with this disease.

Photodynamic Therapy With Motexafin Lutetium Induces Redox-Sensitive Apoptosis of Vascular Cells

Abstract—Motexafin lutetium is a photosensitizer that accumulates in atherosclerotic plaque and, after activation by far-red light, produces cytotoxic singlet oxygen. The combination of photosensitizer and illumination, known as photodynamic therapy (PDT), has been shown to reduce atheroma formation in animal models and is under clinical investigation. However, the effects of PDT with motexafin lutetium on isolated vascular cells are unknown. This study was designed to characterize the effects of PDT on vascular cell viability and to define the cell-death pathway for this agent. Fluorescence microscopy of RAW macrophages and human vascular smooth muscle cells revealed time-dependent uptake of motexafin lutetium. Illumination of motexafin lutetium-loaded cells with 732-nm light (2 J/cm2) impaired cellular viability and growth (IC50 5 to 20 &mgr;mol/L). Depletion of intracellular glutathione potentiated (P =0.035) and the addition of antioxidant N-acetylcysteine attenuated (P =0.002) cell death, suggesting that the intracellular redox state influences motexafin lutetium action. PDT was associated with the loss of mitochondrial membrane potential, mitochondrial release of cytochrome c, and caspase activation. PDT promoted phosphatidylserine externalization and induced apoptotic DNA fragmentation, with the number of apoptotic cells increasing from 7±2% to 34±3% of total cells. Reducing plaque cellularity by the induction of apoptosis may be one mechanism by which PDT reduces plaque burden, possibly modulates plaque vulnerability, and inhibits restenosis in vivo.

13-Cis retinoic acid enhances in vivo B-lymphocyte differentiation in patients with common variable immunodeficiency

Retinoic acid (RA) has been demonstrated to drive both phenotypic and functional in vitro differentiation of B cell hybridomas from patients with common variable immunodeficiency (CVI) who manifest an intrinsic defect in terminal B cell differentiation (J Exp Med 1988;168: 55-71). Therefore, we conducted an open trial to determine the effects of oral 13-cis RA (0.5 mg/kg/day; 12 weeks receiving and 12 weeks without drug) on in vivo B cell differentiation in subjects with CVI. At various times before, during, and after drug administration, patients B cells were tested for changes in cell-surface phenotype and in vitro immunoglobulin production in response to recombinant cytokines. Before 13-cis RA, all patients had decreased Leu-8 coexpression on CD20+ cells. Seven of eight subjects demonstrated normalization of this phenotype after 8 to 16 weeks of 13-cis RA administration. Patients whose B cells demonstrated more than normal CD20 display also had a fall toward normal in this parameter. These effects persisted for 6 to 12 weeks after drug was stopped. It appears that 13-cis RA drives B cells of patients with CVI to express a more differentiated cell-surface phenotype and may promote functional differentiation in some patients.

CD45 isoforms on human CD4+ T-cell subsets

We have examined the level of surface expression and functional properties of leukocyte function associated antigen-1, very late antigen-4, and CD45 isoforms on a panel of human CD4+ T-cell clones representative of TH0, TH1, and TH2 cells. There were no qualitative differences in the expression of these antigens among the three types of CD4+ T-cell clones. However, CD45RB was the only CD45 isoform that provided a costimulatory signal in a solid-phase antibody-induced cellular proliferation assay. Additionally, the antigen-induced proliferative response of T-cell clones was inhibited by soluble anti-CD45RO and anti-CD45RB antibodies. Our results suggest that CD45 isoforms differentially provide costimulatory signals to T cells. However, the ability of each CD45 isoform to provide a costimulatory signal does not differ among the TH0, TH1, or TH2 T-cell populations.

Motexafin lutetium phototherapy decreases vascular inflammation in rabbit atheroma: Implications for vulnerable plaque therapy

ed retrosoectivelv for demoaraohics. oeri-orocedural medications and details ~ _. that might impact on outcome of CPK release. CPK enzymes were routinely ordered at 6, 12. and 18 hours after PCI. IC-CCB or NTG use was soecificallv noted and reflected _ operators standard choice. Post-procedural CPK levels were analyzed using both a repeated measures (ANOVA) and a random coefficient model using a quadratic function. Results: CCB (n=401) and the NTG (n=415) had similar background characteristics and net elevations of CPK. IC-CCB group had an earlier rise in CPK (p=.OOO2 by 8 hrs) and an earlier peak (16.3 hrs vs 26.1 hrs) compared with the IC-NTG group. Conclusions: Routine IC-CCB use is associated with an earlier rise of CPK enzymes after PCI. This supports the role of CCB as vasodilators of the microcirculation and suggests further avenues for research In enhancing blood flow at the tissue level of the myocardium during PCI. 1053-l 99 Effect of Simvastatin on the Inflammatory Response to Coronary Angioplasty Christopher J. Hammett, Ralph A. Stewart, John K. French, Cheuk-Kit Wang, Mark W. Webster, John A. Ormiston, Wanzhen Gao. Harvey D. White, Green Lane Hospital, Auckland, New Zealand Background: Previous studies have reported treatment with the HMG-CoA reductase inhibitor simvastatin reduces serum C-reactive protein (CRP) levels, suggesting an antiinflammatory effect that appears to be fully established within 4 weeks of commencing therapy. Coronary angloplasty is associated with an acute increase rn serum inflammatory markers which may predict early complications. The effect of simvastatin on this inflammatory marker rise is unknown. The aim of this study was to determine whether pre-treatment with slmvastatin reduces the inflammatory response to coronary angioplasty. Methods: We studied 92 patients (mean age 60*10 years) randomised to simvastatin 40mgld (n=52) or placebo (n=40) a median of 1.9 months (IQR 0.9 to 3.6 months) before elective coronary angioplasty. All patients were taking aspirin 150mgIday unless there was a specific contraindication (aspirin use 92% for simvastatin group, 95% for placebo group, p=ns). CRP was measured by high sensitivity immunoassay on serum samples taken immediately prior to and 48 hours after angioplasty. Results: The CRP (median[lQR]) immediately prior to angioplasty was 1.3mgIl (0.712.43) for the placebo group, versus 1.46mgA (0.67-2.14) for the simvastatin group, p=O.79. CRP increased post-PC1 for both groups (p<O.OOi for both simvastatin and placebo). Simvastatin did not alter this inflammatory response; the increase in CRP (preangioplasty to 48 hours post-angioplasty) for patients randomised to simvastatin was 4.68mgIl (IQR 2.9 to 10.3) compared to 5.1fJmg/l (IQR 2.2-9.3) for placebo, (p=O.96). Exclusion of patients on simvastatin for less than 4 weeks prior to angioplasty did not alter this result. Conclusion: There is an increase in CRP measured 48 hours after angioplasty, confirming an inflammatory response. Simvastatin did not significantly influence this inflammatory response. 1053-200 Neither Periprocedural Pregnancy-Associated Plasma Protein A nor C-Reactive Protein Levels Predict Restenosis Christopher J. Hammett, John K. French. Michael Christiansen, Claus Oxvig. Michael T. Overgaard. Bruce J. Webber, Ralph A. Stewart, Cheuk-Kit Wang, Mark W. Webster, John A. Ormiston, Wanzhen Gao, Harvey D. White, Green Lane Hospital, Auckland, New Zealand, Statens Serum Institut, Copenhagen, Denmark Background: Matrix metalloproteinases including Pregnancy-Associated Plasma Protein A (PAPP-A) are abundantly expressed at sites of atherosclerotic plaque rupture, are predictive of acute coronary syndromes when circulating levels are elevated, and may play an important role in the development of restenosis following percutaneous coronary intervention (PCI). C-reactive protein (CRP) levels increase following PCI. peaking at 48 to 72 hours, but the effect of this inflammatory response on restenosis IS unclear. The aim of this study was to determine whether peri-procedural levels of PAPP-A and/or CRP predict restenosis. Methods: We studied 136 patients with stable angina who underwent elective PCI with stored peri-procedural blood samples and corresponding pre-. post-, and six month coronary angiograms; age (meanD CRP prior to PCI 1.2mgA (0.7-2.2), post-PC1 6.6mg/l (4.0.13.2), pcO.0001, PAPP-A prior to PCI 4.lmlUll (3.3&l), post-PC1 b.BmlU/I (4.3-7.2), p<O.OOOl. The median stenosis at six months was 46% (IQR 34.63%) and the binary restenosis rate was 42%. There were