First-in-Human Clinical Trial to Assess the Safety, Tolerability and Pharmacokinetics of Single Doses of NTM-1633, a Novel Mixture of Monoclonal Antibodies against Botulinum Toxin E.

Botulism is a rare, life-threatening paralytic disease caused by botulinum neurotoxin (BoNT). Available treatments including an equine antitoxin and human immune globulin are given postexposure and challenging to produce and administer. NTM-1633 is an equimolar mixture of 3 human IgG monoclonal antibodies, E1, E2, and E3, targeting BoNT serotype E (BoNT/E). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1633. This double-blind, single-center, placebo-controlled dose escalation study randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1633 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at prespecified time points for PK and immunogenicity analyses. Twenty-four subjects received study product (18 NTM-1633; 6 placebo), and no deaths were reported. An unrelated serious adverse event was reported in a placebo subject. Adverse events in the NTM-1633 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1633 has a favorable PK profile with a half-life >10 days for the 0.330 mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1633 also demonstrated low immunogenicity. NTM-1633 is well tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile supports further development as a treatment for BoNT/E intoxication and postexposure prophylaxis.

Safety, Tolerability, and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B.

Botulism is a rare, life-threatening paralytic disease caused by Clostridium botulinum neurotoxin (BoNT). Available treatments, including an equine antitoxin and human immune globulin, are given postexposure and challenging to produce and administer. NTM-1632 is an equimolar mixture of 3 human IgG monoclonal antibodies, B1, B2, and B3, targeting BoNT serotype B (BoNT/B). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1632. This double-blind, single-center, placebo-controlled dose escalation study randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1632 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at prespecified time points for PK and immunogenicity analyses. Twenty-four subjects received study product (18 NTM-1632; 6 placebo), and no deaths or serious adverse events were reported. Adverse events in the NTM-1632 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1632 has a favorable PK profile with a half-life of >20 days for the 0.330-mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC0→t). NTM-1632 demonstrated low immunogenicity with only a few treatment-emergent antidrug antibody responses in the low and middle dosing groups and none at the highest dose. NTM-1632 is well tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile of NTM-1632 supports further clinical development as a treatment for BoNT/B intoxication and postexposure prophylaxis. (This study has been registered at ClinicalTrials.gov under identifier NCT02779140.).

Characterization of CD4 and CD8 T cell responses in MuSK myasthenia gravis.

Muscle specific tyrosine kinase myasthenia gravis (MuSK MG) is a form of autoimmune MG that predominantly affects women and has unique clinical features, including prominent bulbar weakness, muscle atrophy, and excellent response to therapeutic plasma exchange. Patients with MuSK MG have predominantly IgG4 autoantibodies directed against MuSK on the postsynaptic muscle membrane. Lymphocyte functionality has not been reported in this condition. The goal of this study was to characterize T cell responses in patients with MuSK MG. Intracellular production of IFN-gamma, TNF-alpha, IL-2, IL-17, and IL-21 by CD4+ and CD8+ T cells was measured by polychromatic flow cytometry in peripheral blood samples from 11 Musk MG patients and 10 healthy controls. Only one MuSK MG patient was not receiving immunosuppressive therapy. Regulatory T cells (Treg) were also included in our analysis to determine if changes in T cell function were due to altered Treg frequencies. CD8+ T cells from MuSK MG patients had higher frequencies of polyfunctional responses than controls, and CD4+ T cells had higher IL-2, TNF-alpha, and IL-17. MuSK MG patients had a higher percentage of CD4+ T cells producing combinations of IFN-gamma/IL-2/TNF-gamma, TNF-alpha/IL-2, and IFN-gamma/TNF-alpha. Interestingly, Treg numbers and CD39 expression were not different from control values. MuSK MG patients had increased frequencies of Th1 and Th17 cytokines and were primed for polyfunctional proinflammatory responses that cannot be explained by a defect in CD39 expression or Treg number.

Is the decremental pattern in Lambert-Eaton syndrome different from that in myasthenia gravis?

OBJECTIVE: We reviewed our experience to determine if the decremental pattern during low frequency repetitive nerve stimulation (LF-RNS) distinguishes between the Lambert-Eaton myasthenic syndrome (LEMS) and myasthenia gravis (MG). METHODS: LF-RNS studies were reviewed from 34 LEMS and 44 MG patients, 4 of whom had antibodies to muscle specific kinase (MuSK). In each train we calculated the ratio between the early and the later decrement. Receiver-operator characteristic curves were calculated to determine the ratio that best distinguished between LEMS and MG. RESULTS: The late decrement was more often greater in LEMS and the converse was true in MG, but with some overlap in values in individual patients. A late decrement more than 102% of the early decrement discriminated between LEMS and MG in 90% of studies. The decremental pattern in MG patients with MuSK antibodies resembled that in LEMS. CONCLUSION: When the decrement becomes progressively greater during low frequency RNS, the patient is more likely to have LEMS than MG, and in MG, is more likely to have MuSK antibodies. SIGNIFICANCE: A progressive decrement in patients otherwise felt to have MG should prompt further clinical, serological and electrodiagnostic tests. Further studies are needed to assess the decremental pattern in MuSK MG.

Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study.

Neuropathological studies in autistic brains have shown small neuronal size and increased cell packing density in a variety of limbic system structures including the hippocampus, a change consistent with curtailment of normal development. Based on these observations in the hippocampus, a series of quantitative receptor autoradiographic studies were undertaken to determine the density and distribution of eight types of neurotransmitter receptors from four neurotransmitter systems (GABAergic, serotoninergic [5-HT], cholinergic, and glutamatergic). Data from these single concentration ligand binding studies indicate that the GABAergic receptor system (3[H]-flunitrazepam labeled benzodiazepine binding sites and 3[H]-muscimol labeled GABA(A) receptors) is significantly reduced in high binding regions, marking for the first time an abnormality in the GABA system in autism. In contrast, the density and distribution of the other six receptors studied (3[H]-80H-DPAT labeled 5-HT1A receptors, 3[H]-ketanserin labeled 5-HT2 receptors, 3[H]-pirenzepine labled M1 receptors, 3[H]-hemicholinium labeled high affinity choline uptake sites, 3[H]-MK801 labeled NMDA receptors, and 3[H]-kainate labeled kainate receptors) in the hippocampus did not demonstrate any statistically significant differences in binding.