CDR3 Variants of the TXB2 Shuttle with Increased TfR1 Association Rate and Enhanced Brain Penetration.

Since the delivery of biologic drugs to the brain is greatly hampered by the existence of the blood-brain barrier (BBB), brain shuttles are being developed to enhance therapeutic efficacy. As we have previously shown, efficient and selective brain delivery was achieved with TXB2, a cross-species reactive, anti-TfR1 VNAR antibody. To further explore the limits of brain penetration, we conducted restricted randomization of the CDR3 loop, followed by phage display to identify improved TXB2 variants. The variants were screened for brain penetration in mice using a 25 nmol/kg (1.875 mg/kg) dose and a single 18 h timepoint. A higher kinetic association rate to TfR1 correlated with improved brain penetration in vivo. The most potent variant, TXB4, showed a 3.6-fold improvement over TXB2, which had on average 14-fold higher brain levels when compared to an isotype control. Like TXB2, TXB4 retained brain specificity with parenchymal penetration and no accumulation in other organs. When fused with a neurotensin (NT) payload, it led to a rapid drop in body temperature upon transport across the BBB. We also showed that fusion of TXB4 to four therapeutic antibodies (anti-CD20, anti-EGFRvIII, anti-PD-L1 and anti-BACE1) improved their brain exposure between 14- to 30-fold. In summary, we enhanced the potency of parental TXB2 brain shuttle and gained a critical mechanistic understanding of brain delivery mediated by the VNAR anti-TfR1 antibody.

Dynamic Metabolic Control: From the Perspective of Regulation Logic.

Establishing microbial cell factories has become a sustainable and increasingly promising approach for the synthesis of valuable chemicals. However, introducing heterologous pathways into these cell factories can disrupt the endogenous cellular metabolism, leading to suboptimal production performance. To address this challenge, dynamic pathway regulation has been developed and proven effective in improving microbial biosynthesis. In this review, we summarized typical dynamic regulation strategies based on their control logic. The applicable scenarios for each control logic were highlighted and perspectives for future research direction in this area were discussed.

Blood-brain barrier transport using a high affinity, brain-selective VNAR antibody targeting transferrin receptor 1.

Transfer across the blood-brain barrier (BBB) remains a significant hurdle for the development of biopharmaceuticals with therapeutic effects within the central nervous system. We established a functional selection method to identify high affinity single domain antibodies to the transferrin receptor 1 (TfR1) with efficient biotherapeutic delivery across the BBB. A synthetic phage display library based on the variable domain of new antigen receptor (VNAR) was used for in vitro selection against recombinant human TfR1 ectodomain (rh-TfR1-ECD) followed by in vivo selection in mouse for brain parenchyma penetrating antibodies. TXB2 VNAR was identified as a high affinity, species cross-reactive VNAR antibody against TfR1-ECD that does not compete with transferrin or ferritin for receptor binding. IV dosing of TXB2 when fused to human Fc domain (TXB2-hFc) at 25 nmol/kg (1.875 mg/kg) in mice resulted in rapid binding to brain capillaries with subsequent transport into the brain parenchyma and specific uptake into TfR1-positive neurons. Likewise, IV dosing of TXB2-hFc fused with neurotensin (TXB2-hFc-NT) at 25 nmol/kg resulted in a rapid and reversible pharmacological response as measured by body temperature reduction. TXB2-hFc did not elicit any acute adverse reactions, bind, or deplete circulating reticulocytes or reduce BBB-expressed endogenous TfR1 in mice. There was no evidence of target-mediated clearance or accumulation in peripheral organs except lung. In conclusion, TXB2 is a high affinity, species cross-reactive, and brain-selective VNAR antibody to TfR1 that rapidly crosses the BBB and exhibits a favorable pharmacokinetic and safety profile and can be readily adapted to carry a wide variety of biotherapeutics from blood to brain.

Facilitating medication adherence in patients with multiple sclerosis.

This article reviews adherence to medication in multiple sclerosis (MS) patients from the perspective of nurse and social worker authors. It reviews data on patient adherence and offers practical, evidence-based strategies that health-care providers can use to facilitate adherence. In addition, it examines how emerging MS therapies may affect patient adherence and associated interventions. To promote adherence, interventions need to incorporate new and creative approaches. A proactive approach includes assessing patient needs and lifestyle before the start of medication and selecting the most appropriate disease-modifying therapy for each individual patient. Including multidisciplinary expertise and services in the treatment plan can be part of a comprehensive, holistic approach to helping patients and families. Optimization of health-care provider roles is likely to facilitate improved adherence.

Current and emerging therapies in multiple sclerosis: a systematic review.

Multiple sclerosis (MS) is a potentially disabling chronic autoimmune neurological disease that mainly affects young adults. Our understanding of the pathophysiology of MS has significantly advanced in the past quarter of a century. This has led to the development of many disease-modifying therapies (DMTs) that prevent exacerbations and new lesions in patients with relapsing remitting MS (RRMS). So far there is no drug available that can completely halt the neurodegenerative changes associated with the disease. It is the purpose of this review to provide concise information regarding mechanism of action, indications, side effects and safety of Food and Drug Administration and European Medicines Agency approved agents for MS, emerging therapies, and drugs that can be considered for off-label use in MS.

Symptomatic therapy in multiple sclerosis.

Multiple sclerosis is the most common disabling neurological disease of young adults. The ability to impact the quality of life of patients with multiple sclerosis should not only incorporate therapies that are disease modifying, but should also include a course of action for the global multidisciplinary management focused on quality of life and functional capabilities.

Impact of traumatic birth experience on Latina adolescent mothers.

BACKGROUND: The childbirth experience can be a wonderful event, or one of horror. One in 3 adult mothers appraises her childbirth experience as traumatic, with up to 10% of women reporting a severe traumatic stress response post-delivery. The impact of the birth experience on adolescents is unknown. METHODS: Eighty-five Latinas ages 13 to 19 appraised their childbirth experience and reported symptoms of trauma impact as measured via the Impact of Event Scale (IES) within 72 hours of delivery. Descriptive statistics included demographic, obstetrical, and personal factors, and trauma scores. ANOVAs were used to examine differences in birth appraisal and trauma impact by demographic, obstetrical, and personal factors. Spearman rho and Pearson's r was used to compute correlations between birth appraisal, depression, and trauma impact. RESULTS: One-third of adolescents appraised their childbirth as traumatic; one-half displayed symptoms of trauma impact. Items influencing appraisal of the birth experience included marital status, fear of dying, fear of loss of control, and partner violence. Birth appraisal and symptoms of depression were found to influence trauma impact. CONCLUSIONS: One-third of teens appraised childbirth as traumatic with 50% displaying symptoms suggestive of acute trauma at immediate postpartum. Nursing recommendations focus on providing a non-traumatic birth experience and follow-up by mental health professionals for assessment of potential chronic trauma, posttraumatic stress and depression. Teens can enter labor and delivery with stressors, depression, and past traumas; collaboration of care between maternal-child and mental health professionals is encouraged.