The pertussis hypothesis: Bordetella pertussis colonization in the etiology of asthma and diseases of allergic sensitization.

Decades of peer reviewed evidence demonstrate that: 1)Bordetellapertussisand pertussis toxin are potent adjuvants, inducing asthma and allergic sensitization in animal models of human disease, 2)Bordetella pertussisoften colonizes the human nasopharynx, and is well documented in highly pertussis-vaccinated populations and 3) in children, a history of whooping cough increases the risk of asthma and allergic sensitization disease. We build on these observations with six case studies and offer a pertussis-based explanation for the rapid rise in allergic disease in former East Germany following the fall of the Berlin Wall; the current asthma, peanut allergy, and anaphylaxis epidemics in the United States; the correlation between the risk of asthma and gross national income per capita by country; the lower risk of asthma and allergy in children raised on farms; and the reduced risk of atopy with increased family size and later sibling birth order. To organize the evidence for the pertussis hypothesis, we apply the Bradford Hill criteria to the association between Bordetella pertussisand asthma and allergicsensitization disease. We propose that, contrary to conventional wisdom that nasopharyngealBordetella pertussiscolonizing infections are harmless, subclinicalBordetella pertussiscolonization is an important cause of asthma and diseases of allergic sensitization.

The pertussis hypothesis: Bordetella pertussis colonization in the pathogenesis of Alzheimer's disease.

While a number of endogenous risk factors including age and genetics are established for Alzheimer's disease (AD), identification of acquired, potentially preventable or treatable causes, remains limited. In this paper, we review three epidemiologic case studies and present extensive biologic, immunologic and anatomic evidence to support a novel hypothesis that Bordetella pertussis (BP), the bacterium better known to cause whooping cough, is an important potential cause of AD. Cross-cultural documentation of nasopharyngeal subclinical BP colonization reflecting BP-specific mucosal immunodeficiency, proximate anatomy of intranasal mucosal surfaces to central nervous system (CNS) olfactory pathways, and mechanisms by which BP and BP toxin account for all hallmark pathology of AD are reviewed, substantiating biologic plausibility. Notably, respiratory BP infection and BP toxin secreted from subclinical BP colonization can account for the initiation and accumulation of amyloid ß plaques and tau tangles. Additional mechanisms consistent with the immunobiologic effects of subclinical BP colonization include microglial activation and inflammation, atrophy and neurodegeneration, excitotoxicity, distinctive anatomic distribution and sequential spread of disease, impaired glucose utilization, and other characteristic CNS pathology of AD. We conclude by assessing the evidence for causation against the Bradford Hill criteria, and advocate for further investigation into the potential role of BP in the etiology of AD.

The potential role of subclinical Bordetella Pertussis colonization in the etiology of multiple sclerosis.

It is established that (1) subclinical Bordetella pertussis colonization of the nasopharynx persists in highly vaccinated populations, and (2) B. pertussis toxin is a potent adjuvant that, when co-administered with neural antigens, induces neuropathology in experimental autoimmune encephalomyelitis, the principle animal model of multiple sclerosis. Building on these observations with supporting epidemiologic and biologic evidence, we propose that, contrary to conventional wisdom that subclinical pertussis infections are innocuous to hosts, B. pertussis colonization is an important cause of multiple sclerosis.

Single-dose TB-402 or rivaroxaban for the prevention of venous thromboembolism after total hip replacement. A randomised, controlled trial.

TB-402 is a long-acting monoclonal antibody that partially inhibits factor VIII. A single administration of TB-402 was effective and well-tolerated for the prevention of venous thromboembolism (VTE) after total knee replacement. In this study, the efficacy and safety of a single administration of TB-402 for the extended prophylaxis of VTE after total hip replacement (THR) was investigated. This was a phase II, randomised, active-controlled, double-blind study that included patients undergoing elective THR surgery. Patients were randomised to TB-402 25 mg or TB-402 50 mg, administered as a single intravenous administration 2-4 hours postoperatively, or to rivaroxaban 10 mg once daily for 35 days. The primary efficacy outcome was total VTE defined as symptomatic VTE and asymptomatic deep-vein thrombosis (DVT) detected by bilateral venography at day 35. The principal safety outcome was the incidence of major bleeding and clinically relevant non-major bleeding until day 35. Total VTE was similar in all groups: 5.3% (95%CI 2.9-9.6), 5.2% (95%CI 2.8-9.3) and 4.7% (95%CI 2.5-8.7) for TB-402 25 mg, TB-402 50 mg and rivaroxaban, respectively. All were asymptomatic DVTs. Major or clinically relevant non-major bleedings were observed in 5.8% (95%CI 3.3-9.9), 7.2% (95%CI 4.4-11.6) and 1.4% (95%CI 0.5-4.2) for TB-402 25 mg, TB-402 50 mg and rivaroxaban, respectively. In conclusion, TB-402, administered as a single postoperative dose, had a similar efficacy compared to rivaroxaban for the prevention of VTE after THR. The incidence of major and clinically relevant non-major bleeding was higher in the TB-402 groups than in the rivaroxaban group.

Monoclonal antibody TB-403: a first-in-human, Phase I, double-blind, dose escalation study directed against placental growth factor in healthy male subjects.

BACKGROUND: TB-403 (RO5323441) is a humanized monoclonal antibody directed against placental growth factor (PlGF). Preclinical studies have demonstrated that targeting PlGF can result in significant inhibition of tumor growth and metastasis. OBJECTIVES: The purpose of this study was to assess the safety profile, tolerability, and pharmacokinetics of TB-403, developed for the treatment of solid tumors. METHODS: Healthy male subjects were exposed to a single intravenous infusion of TB-403 or placebo. Blood samples for hematology, clinical chemistry, coagulation factors, and urinalysis were collected; vital signs and ECGs were recorded; and serial blood samples were drawn for pharmacokinetic and immunogenicity measurements and circulating levels of pharmacodynamics markers PlGF and (VEGF) vascular endothelial growth factor. Sixteen subjects received either placebo or TB-403 at doses ranging from 0.3 to 5.0 mg/kg. RESULTS: Mild (grade 1 or 2) nasopharyngitis, headache, neck pain, and joint pain were the most frequently reported adverse events (AEs). There were no serious AEs in the study, and none of the AEs led to withdrawal. None of the safety laboratory assessments was considered clinically significant, and none was reported as an AE. There were no apparent differences in terms of safety profiles among the 3 dose levels of active treatment compared with placebo. Clearance, volume of distribution, and terminal t(½) (mean values) for TB-403 in all 3 cohorts were in the range of 4.2 to 4.9 (mL/d/kg), 56 to 79 (mL/kg), and 8 to 13 (days), respectively. CONCLUSION: The highest dose of TB-403 (5.0 mg/kg) was well tolerated in this study of a single intravenous infusion to healthy males. This result allowed a higher starting dose level in a subsequent Phase I study in cancer patients, the patient population for which this antibody is developed.

Tolerability and pharmacokinetics of TB-402 in healthy male volunteers.

BACKGROUND: TB-402, a human monoclonal antibody that partially inhibits Factor VIII activity (FVIII:C), is being developed as a long-acting antithrombotic agent. OBJECTIVES: The primary goal of this study was to investigate the tolerability of TB-402 in healthy male volunteers. Secondary objectives were to determine the pharmacokinetics and pharmacodynamics of TB-402. METHODS: In this ascending-dose study, healthy subjects aged 18 to 45 years were randomly assigned in a 2:1 ratio to receive TB-402 administered as a single intravenous bolus at 0.015, 0.1, 0.5, 2.5, 12.5, 37.5, 188, 620, or 1860 microg/kg or matching inactive vehicle (placebo). An older group (55-75 years) was also administered the highest dose that was well tolerated in the younger group (1860 microg/kg). Adverse events (AEs) were obtained from spontaneous reporting and from answers to nonleading questions asked by the principal investigator and study staff during follow-up visits on days 4, 7 (+/-1 day), 14 (+/-1 day), 21 (+/-2 days), 28 (+/-3 days), 42 (+/-3 days), and 56 (+/-3 days) after TB-402 administration. AEs were monitored up to the last study visit on day 56 after the administration of TB-402 or placebo, with special attention to bleeding events. The pharma-codynamic assessment of TB-402 included changes in FVIII:C, activated partial thromboplastin time (APTT), and prothrombin time (PT). RESULTS: The study enrolled 56 subjects (mean ages: younger group, 28 years [range, 20-45 years]; older group, 65 years [range, 58-76 years]; weight, 79 kg [range, 60-104 kg] and 81 kg [range, 64-94 kg], re-spectively). Thirty-one of the 38 subjects who received TB-402 (82%) experienced a total of 85 treatment-emergent AEs (TEAEs), and 14 of 18 subjects who received placebo (78%) experienced 35 TEAEs. A total of 34 bleeding events were reported in 13 of 38 subjects (34%) who received TB-402 and 7 of 18 subjects (39%) who received placebo. Most common AEs reported in subjects who received TB-402 were headache (11 [29%]), vessel puncture-site hematoma (7 [18%]), and traumatic hematoma (5 [13%]); with placebo, these AEs were vessel puncture-site hematoma (4 [22%]), headache (3 [17%]), vasovagal reaction (3 [17%]), and hematuria (3 [17%]). No serious AEs considered to be related to TB-402 were reported, and no dose-dependent increases in bleeding events were observed. On pharmacokinetic analysis of TB-402, the t(1/2) values across doses were 22.9 days (age 18-45 years) and 19.5 days (age 55-75 years). TB-402 was associated with a reduction in FVIII:C over a period of approximately 48 hours in the d37.5-microg/kg dose groups. TB-402 was associated with a prolonged APTT at doses >or=2.5 microg/kg approximately 1.1-1.2-fold predose APTT). Administration of a higher dose of TB-402 was associated with an extended duration of APTT prolongation. No significant effect on PT was found. CONCLUSIONS: In this study in healthy male volunteers, TB-402 was well tolerated in the population studied. Based on the findings from this study, the long t(1/2) of TB-402 may allow a pharmacodynamic effect over a prolonged period after single-dose administration. Further trials are needed to address the tolerability and efficacy of this agent in preventing thromboembolism. Clinicaltrials.gov identifier: NCT00612196.

Antibodies against oxidized low-density lipoprotein for the treatment of vulnerable plaques.

Inflammation caused by the accumulation of oxidized low-density lipoprotein (oxLDL) in the arterial wall is a key factor in the development of atherosclerosis. Accumulating evidence suggests that adaptive immune responses to oxLDL are of major importance in regulating the inflammatory response, and that humoral immunity largely has a protective effect in this process. This concept is supported by animal studies demonstrating that treatment with antibodies against oxLDL inhibits atherosclerosis. Human antibodies with high affinity and specificity for epitopes on oxLDL have been developed and are now, after appropriate safety testing and non-clinical toxicology, ready to be tested in humans. Patients that may benefit front antibody treatment are most likely to be high-risk individuals in which conventional treatments, including lipid-lowering statins, do not provide sufficient protection.