Publications by authors named "Seth Lederman"

Article Synopsis
  • PMN-MDSCs are dysfunctional immune cells that hinder the effectiveness of cancer immunotherapy, particularly by affecting the immune response in gastric cancer.
  • The study developed a fusion protein, TFF2-MSA, that acts as a partial agonist for the CXCR4 receptor, enhancing the effects of anti-PD-1 therapy to reduce tumor growth and improve survival in various gastric cancer models.
  • TFF2-MSA specifically reduces harmful PMN-MDSCs while keeping helpful neutrophils intact, which boosts the CD8 T cell-mediated anti-tumor response, contrasting with traditional CXCR4 antagonism that did not show similar benefits.
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Convalescent sera, rich in pathogen-specific antibodies, offers passive immunity to patients with infectious diseases. Screening assays using convalescent sera are crucial for evaluating therapeutic efficacy, selecting suitable serum donors, and standardizing assays. They measure antibody levels, neutralizing potential, and specificity against viruses like SARS-CoV-2, ensuring therapeutic serum contains potent antibodies.

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Background: Xenotransplantation has made significant advances recently using pigs genetically engineered to remove carbohydrate antigens, either alone or with addition of various human complement, coagulation, and anti-inflammatory ''transgenes''. Here we evaluated results associated with gene-edited (GE) pig hearts transplanted in baboons using an established costimulation-based immunosuppressive regimen and a cold-perfused graft preservation technique.

Methods: Eight baboons received heterotopic abdominal heart transplants from 3-GE (GalKO.

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Article Synopsis
  • Antibody-mediated rejection (AMR) is a problem that can cause organs from pigs to fail when transplanted into other animals like baboons, even with special pig breeding.
  • Researchers studied two baboon cases and found new factors that might start AMR, like kidney issues and infections.
  • The study suggests that certain kidney problems or infections could lead to organ rejection because the body mistakenly attacks the pig organ, which hasn't been discussed much before.
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Sleep disturbances in posttraumatic stress disorder (PTSD) are a potential target for improving PTSD severity with pharmacotherapy. TNX-102 SL is a bedtime sublingual formulation of cyclobenzaprine with potent binding and antagonist activity at 5-HT, α-adrenergic, H histaminergic, and M muscarinic receptors, which play roles in the pharmacological management of sleep disturbances. This Phase 3 trial evaluated the efficacy and safety of TNX-102 SL in patients with military-related PTSD.

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Chronic overlapping pain conditions (COPCs) refer to conditions that have similar central nervous system pathophysiologic mechanisms driving widespread pain as well as common comorbid symptoms such as fatigue and problems with sleep, memory, and mood. If COPCs predict the onset of long COVID, this could offer a valuable orientation for long COVID-related research and clinical care. This retrospective cohort study aimed to determine whether having a COPC predicts the onset of long COVID features using US electronic health records and 1:1 propensity score matching without replacement.

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TNX-1800 is a synthetically derived live recombinant chimeric horsepox virus (rcHPXV) vaccine candidate expressing Wuhan SARS-CoV-2 spike (S) protein. The primary objective of this study was to evaluate the immunogenicity and efficacy of TNX-1800 in two nonhuman primate species challenged with USA-WA1/2020 SARS-CoV-2. TNX-1800 vaccination was well tolerated with no serious adverse events or significant changes in clinical parameters.

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TNX-1800 is a preclinical stage synthetic-derived live attenuated chimeric horsepox virus vaccine engineered to express the SARS-CoV-2 spike (S) gene. The objectives of this study were to assess the safety, tolerability, and immunogenicity of TNX-1800 administration in Syrian golden hamsters and New Zealand white rabbits. Animals were vaccinated at three doses via percutaneous inoculation.

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Objective: To evaluate the efficacy and safety of TNX-102 SL, a once-nightly sublingual formulation of cyclobenzaprine, in reducing pain in patients with fibromyalgia (FM).

Methods: RELIEF was a double-blind, randomized, placebo-controlled trial. Overall, 503 patients received TNX-102 SL 2.

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Blockade of the CD40/CD154 T cell costimulation pathway is a promising approach to supplement or replace current clinical immunosuppression in solid organ transplantation. We evaluated the tolerability and activity of a novel humanized anti-CD154 monoclonal antibody, TNX-1500 (TNX), in a nonhuman primate heterotopic cardiac allogeneic (allo) transplant model. TNX-1500 contains a rupluzimab fragment antigen-binding region and an immunoglobin G4 crystallizable fragment region engineered to reduce binding to the crystallizable fragment gamma receptor IIa and associated risks of thrombosis.

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The blockade of the CD154-CD40 pathway with anti-CD154 monoclonal antibody has been a promising immunomodulatory approach to prevent allograft rejection. However, clinical trials of immunoglobulin G1 antibodies targeting this pathway revealed thrombogenic properties, which were subsequently shown to be mediated by crystallizable fragment (Fc)-gamma receptor IIa-dependent platelet activation. To prevent thromboembolic complications, an immunoglobulin G4 anti-CD154 monoclonal antibody, TNX-1500, which retains the fragment antigen binding region of ruplizumab (humanized 5c8, BG9588), was modified by protein engineering to decrease Fc binding to Fc-gamma receptor IIa while retaining certain other effector functions and pharmacokinetics comparable with natural antibodies.

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Article Synopsis
  • - The global Monkeypox outbreak that began in 2022 highlights the need for safer live virus vaccines, particularly those based on the vaccinia virus (VACV), to protect populations against both Monkeypox and the persistent threat of smallpox.
  • - Due to safety concerns about VACV, there's a push for a single-dose vaccine alternative, with the horsepox virus (HPXV) being a promising candidate because of its historical use and genetic links to VACV.
  • - A study using a recombinant horsepox virus (TNX-801) showed it provoked strong immune responses and effectively protected macaques from monkeypox without causing severe side effects, paving the way for future vaccine development.
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Antibody-based therapy is emerging as a critical therapeutic countermeasure to treat acute viral infections by offering rapid protection against clinical disease. The advancements in structural biology made it feasible to rationalize monoclonal antibodies (mAbs) by identifying key and, possibly, neutralizing epitopes of viral proteins for therapeutic purposes. A critical component in assessing mAbs during pandemics requires the development of rapid but detailed methods to detect and quantitate the neutralization activity.

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Randomization-based inference is a useful alternative to traditional population model-based methods. In trials with missing data, multiple imputation is often used. We describe how to construct a randomization test in clinical trials where multiple imputation is used for handling missing data.

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The current study is an analysis of predictors of posttraumatic stress disorder (PTSD) treatment response in a clinical trial comparing (1) prolonged exposure plus placebo (PE + PLB), (2) PE + sertraline (PE + SERT), and (3) sertraline + enhanced medication management (SERT + EMM) with predictors including time since trauma (TST), self-report of pain, alcohol use, baseline symptoms, and demographics. Participants (N = 196) were veterans with combat-related PTSD () of at least 3 months' duration recruited between 2012 and 2016 from 4 sites in the 24-week PROlonGed ExpoSure and Sertraline (PROGrESS) clinical trial (assessments at weeks 0 [intake], 6, 12, 24, 36, and 52). Across treatment conditions, (1) longer TST was predictive of greater week 24 PTSD symptom improvement (β = 1.

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Effective posttraumatic stress disorder (PTSD) pharmacotherapy is needed. This 12-week randomized multicenter trial evaluated efficacy and safety of TNX-102 SL, a bedtime sublingual formulation of cyclobenzaprine, in patients with military-related PTSD randomized to TNX-102 SL 2.8 mg or 5.

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For the first 80-90 years after Jenner's discovery of vaccination in 1796, the main strategy used to disseminate and maintain the smallpox vaccine was arm-to-arm vaccination, also known as Jennerian or humanized vaccination. A major advance occurred after 1860 with the development of what was known as "animal vaccine", which referred to growing vaccine material from serial propagation in calves before use in humans. The use of "animal vaccine" had several advantages over arm-to-arm vaccination: it would not transmit syphilis or other human diseases, it ensured a supply of vaccine even in the absence of the spontaneous occurrence of cases of cowpox or horsepox, and it allowed the production of large amounts of vaccine.

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Edward Jenner and his contemporaries believed that his variolae vaccinae originated in horses and molecular analyses show that modern vaccinia virus (VACV) strains share common ancestry with horsepox virus (HPXV). Given concerns relating to the toxicity of modern VACV vaccines, we asked whether an HPXV-based vaccine might provide a superior alternative. Since HPXV may be extinct and the only specimen of HPXV that has been identified is unavailable for investigation, we explored whether HPXV could be obtained by large-scale gene synthesis.

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Objective: To determine the effects of bedtime very low dose (VLD) cyclobenzaprine (CBP) on symptoms and sleep physiology of patients with fibromyalgia (FM), unrefreshing sleep, and the α-nonREM sleep electroencephalographic (EEG) anomaly at screening.

Methods: Of 37 patients with FM in the screened population, 36 were randomized and treated in this 8-week, double-blind, placebo-controlled, dose-escalating study of VLD CBP 1-4 mg at bedtime. We evaluated changes in subjective symptoms including pain, tenderness, fatigue, mood [Hospital Anxiety and Depression Scale (HAD)], and objective EEG sleep physiology (at screening, baseline, and Weeks 2, 4, and 8).

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