Phase 1b dose-escalation, safety, and pharmacokinetic study of IC14, a monoclonal antibody against CD14, for the treatment of amyotrophic lateral sclerosis.

BACKGROUND: The primary objective was to demonstrate the safety and tolerability of monoclonal antibody against CD14 (IC14) (atibuclimab) in amyotrophic lateral sclerosis patients. The secondary objectives were pharmacokinetics, pharmacodynamics, and preliminary effects on disease status and biomarkers. METHODS: In this open-label, dose-escalation trial, IC14 was administered at 2 mg/kg intravenous (IV) followed by 1 mg/kg/d IV × 3 (n = 3) and in subsequent patients at 4 mg/kg IV followed by 2 mg/kg/d IV × 3 (n = 7) (NCT03487263). Disease status was measured using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, Edinburgh Cognitive and Behavioural ALS Screen, and Revised ALS-Specific Quality-of-Life Score. Disease biomarkers included cerebrospinal fluid and serum levels of neurofilament light chain (NfL) and urinary p75 neurotrophin receptor. RESULTS: IC14 was safe and well tolerated. No antidrug antibodies were detected. The drug target saturation of monocyte CD14 receptors was rapid and sustained through day 8. There was no significant change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, or Revised ALS-Specific Quality-of-Life Score following a single cycle of treatment. Cerebrospinal fluid NfL levels decreased in 6 of 9 patients sampled with declines of 15% to 40% between baseline (not significant [ns]) and day 8 in 3 patients. Serum NfL modestly decreased in 5 of 10 patients (ns) at day 8 and was sustained in 4 (4%-37%, ns) over 33 days of follow up. CONCLUSION: IC14 quickly and durably saturated its target in all patients. This study demonstrated safety and tolerability in patients with amyotrophic lateral sclerosis. Even though only a single cycle of treatment was given, there were promising beneficial trends in the neurofilament light chain, a disease biomarker. The emerging understanding of the role of systemic inflammation in neurodegenerative diseases, and the potential for IC14 to serve as a safe, potent, and broad-spectrum inhibitor of immune dysregulation merits further clinical study. CLINICAL TRIAL REGISTRATION: NCT03487263.

Schistosomiasis elimination strategies and potential role of a vaccine in achieving global health goals.

In March 2013, the National Institute of Allergy and Infectious Diseases and the Bill and Melinda Gates Foundation co-sponsored a meeting entitled "Schistosomiasis Elimination Strategy and Potential Role of a Vaccine in Achieving Global Health Goals" to discuss the potential role of schistosomiasis vaccines and other tools in the context of schistosomiasis control and elimination strategies. It was concluded that although schistosomiasis elimination in some focal areas may be achievable through current mass drug administration programs, global control and elimination will face several significant scientific and operational challenges, and will require an integrated approach with other, additional interventions. These challenges include vector (snail) control; environmental modification; water, sanitation, and hygiene; and other future innovative tools such as vaccines. Defining a clear product development plan that reflects a vaccine strategy as complementary to the existing control programs to combat different forms of schistosomiasis will be important to develop a vaccine effectively.

Pediatric vaccines in HIV-infected children.

PURPOSE OF REVIEW: Current pediatric immunization recommendations in HIV infection are reviewed. RECENT FINDINGS: Following initiation of highly active antiretroviral therapy and restoration of immune responsiveness, consideration should be given to repeat boosting of childhood vaccines. Human papillomavirus vaccine is recommended for young girls since this virus is associated with an increased risk of anogenital cancers in HIV infection. HIV-infected infants immunized at birth with bacillus Calmette-Guerin who later developed AIDS were at increased risk of disseminated bacillus Calmette-Guerin infection so it is no longer recommended for known HIV-infected infants. SUMMARY: Despite suboptimal immune responses, routine inactivated immunizations are recommended. Live attenuated vaccines are generally not recommended with the exception of measles, mumps, rubella vaccine and varicella vaccines which can still be given to children who are not severely immunocompromised (CD4 lymphocytes >15%). Additional data are pending on rotavirus and human papillomavirus vaccine in HIV. A theoretical concern is enhanced HIV virus replication due to immune activation following immunization, but this is predicted to be greater following infection so the consensus has been to immunize. HIV viral replication may be enhanced transiently without increased progression of HIV disease.

Long-term acquisition of allergen-specific IgE and asthma following allogeneic bone marrow transplantation from allergic donors.

Adoptive transfer of allergen-specific immunoglobulin E (IgE) from atopic donors to nonatopic recipients occurs during the first year following bone marrow transplantation (BMT). Mature B- and T-cell clones with allergen-specific memory and hematopoietic progenitor cells are transferred through BMT. The objective of this study was to characterize the long-term rate of allergic sensitization and development of clinical allergic diseases following BMT from atopic donors. A long-term follow-up study was conducted in a cohort of donor and recipient pairs with moderate-to-severe allergic disease in the donor prior to BMT. Assessments of allergen-specific IgE, clinical rhinitis, and asthma were made in the donors prior to BMT and in the recipients with a mean follow-up of 15.5 years after BMT. From an initial cohort of 12 bone marrow transplant recipients who received marrow from allergic donors, 5 long-term survivors were identified. Allergen-specific IgE transferred from donor to recipient following BMT frequently persisted, and a high rate of de novo allergic sensitization was observed between 1 and 14 years after BMT. These events were associated with elevation in total IgE, and development of allergic rhinitis and asthma at long-term follow-up. We conclude that marrow-derived immune cells from allergic donors can transfer the predisposition to allergy and asthma.