Acceleron Pharma (United States)

Since space exploration agencies and private companies are preparing for deep-space missions, executing interplanetary missions between Earth, Mars and Ceres is now much more practical in the years ahead. By being motivated in this way, we have improved mission concepts that maximize energy savings and outstanding science, assisted in major ways by our roundtrip plan based on Interplanetary Trajectory Analysis and Resource Study (ITARS) technology. Therefore, to demonstrate our framework’s usefulness, we offer optimized ways to travel between planets and the setups of the propulsion systems. A range of assessments include studying gravity techniques, setting delta velocities and defining mission durations to fit specified planetary situations. We also study how different propulsion methods affect the possible path of the spacecraft and the effects of bigger gravitational forces on the spacecraft’s stability.

Abstract Myostatin is a paracrine myokine that regulates muscle mass in a variety of species, including humans. Here, we report a functional role for myostatin as an endocrine hormone directly promoting pituitary follicle-stimulating hormone (FSH) synthesis and thereby ovarian function. Previously, this FSH-stimulating role was attributed to other members of the transforming growth factor β family, the activins. The results both challenge activin’s eponymous role in FSH synthesis and establish an endocrine axis between skeletal muscle and the pituitary gland. The data also suggest that efforts to antagonize myostatin to treat muscle wasting disorders may have unintended consequences on fertility.One-Sentence SummaryHormone synthesis and reproduction depend on crosstalk between skeletal muscle and the pituitary gland.

<div>Abstract<p><b>Purpose:</b> Vascular endothelial growth factor (VEGF) expression is a critical component in tumor growth and metastasis. Capabilities to monitor VEGF expression <i>in vivo</i> can potentially serve as a useful tool for diagnosis, prognosis, treatment planning, monitoring, and research. Here, we present the first report of <i>in vivo</i> hyperspectral molecular imaging strategy capable of monitoring treatment-induced changes in VEGF expression.</p><p><b>Experimental Design:</b> VEGF was targeted with an anti-VEGF antibody conjugated with a fluorescent dye and was imaged <i>in vivo</i> using a hyperspectral imaging system. The strategy was validated by quantitatively monitoring VEGF levels in three different tumors as well as following photodynamic treatment. Specificity of the molecular imaging strategy was tested using <i>in vivo</i> competition experiments and mathematically using a quantitative pharmacokinetic model.</p><p><b>Results:</b> The molecular imaging strategy successfully imaged VEGF levels quantitatively in three different tumors and showed concordance with results from standard ELISA. Changes in tumoral VEGF concentration following photodynamic treatment and Avastin treatment were shown. Immunohistochemistry shows that (<i>a</i>) the VEGF-specific contrast agent labels both proteoglycan-bound and unbound VEGF in the extracellular space and (<i>b</i>) the bound VEGF is released from the extracellular matrix in response to photodynamic therapy. <i>In vivo</i> competition experiments and quantitative pharmacokinetic model-based analysis confirmed the high specificity of the imaging strategy.</p><p><b>Conclusion:</b> This first report of <i>in vivo</i> quantitative optical molecular imaging-based monitoring of a secreted cytokine in tumors may have implications in providing tools for mechanistic investigations as well as for improved treatment design and merits further investigation.</p></div>

Acetylcholine receptor (AChR) autoantibodies, found in patients with autoimmune myasthenia gravis (MG), can directly contribute to disease pathology through activation of the classical complement pathway. Activation of the complement pathway in autoimmune diseases can lead to a secondary complement deficiency resulting in reduced complement activity, due to consumption, during episodes of disease activity. It is not clear whether complement activity in MG patients associates with measurements of disease activity or the titer of circulating pathogenic AChR autoantibodies. To explore such associations, as a means to identify a candidate biomarker, we measured complement activity in AChR MG samples (N = 51) using a CH50 hemolysis assay, then tested associations between these values and both clinical status and AChR autoantibody titer. The majority of the study subjects (88.2%) had complement activity within the range defined by healthy controls, while six patients (11.8%) showed reduced activity. No significant association between complement activity and disease status or AChR autoantibody titer was observed.

The jawless vertebrates (lamprey and hagfish) evolved a novel adaptive immune system with many similarities to that found in the jawed vertebrates, including the production of antigen-specific circulating antibodies in response to immunization. However, the jawless vertebrates use leucine-rich repeat (LRR)-based antigen receptors termed variable lymphocyte receptors (VLRs) for immune recognition, instead of immunoglobulin (Ig)-based receptors. VLR genes are assembled in developing lymphocytes through a gene conversion-like process, in which hundreds of LRR gene segments are randomly selected as template donors to generate a large repertoire of distinct antigen receptors, similar to that found within the mammalian adaptive immune system. Here we describe the development of a robust platform using immunized lampreys (Petromyzon marinus) for generating libraries of anti-carbohydrate (anti-glycan) variable lymphocyte receptor B, or VLRBs. The anti-carbohydrate VLRBs are isolated using a yeast surface display (YSD) expression platform and enriched by binding to glycan microarrays through the anti-glycan VLRB. This enables both the initial identification and enrichment of individual yeast clones against hundreds of glycans simultaneously. Through this enrichment strategy a broad array of glycan-specific VLRs can be isolated from the YSD library. Subsequently, the bound yeast cells are directly removed from the microarray, the VLR antibody clone is sequenced, and the end product is expressed as a VLR-IgG-Fc fusion protein that can be used for ELISA, Western blotting, flow cytometry, and immunomicroscopy. Thus, by combining yeast surface display with glycan microarray technology, we have developed a rapid, efficient, and novel method for generating chimeric VLR-IgG-Fc proteins that recognize a broad array of unique glycan structures with exquisite specificity.

Cysteine-rich knob domains found in the ultralong complementarity determining regions of a subset of bovine antibodies are capable of functioning autonomously as 3-6 kDa peptides. While they can be expressed recombinantly in cellular systems, in this paper we show that knob domains are also readily amenable to a chemical synthesis, with a co-crystal structure of a chemically synthesized knob domain in complex with an antigen showing structural equivalence to the biological product. For drug discovery, following the immunization of cattle, knob domain peptides can be synthesized directly from antibody sequence data, combining the power and diversity of the bovine immune repertoire with the ability to rapidly incorporate nonbiological modifications. We demonstrate that, through rational design with non-natural amino acids, a paratope diversity can be massively expanded, in this case improving the efficacy of an allosteric peptide. As a potential route to further improve stability, we also performed head-to-tail cyclizations, exploiting the proximity of the N and C termini to synthesize functional, fully cyclic antibody fragments. Lastly, we highlight the stability of knob domains in plasma and, through pharmacokinetic studies, use palmitoylation as a route to extend the plasma half-life of knob domains in vivo. This study presents an antibody-derived medicinal chemistry platform, with protocols for solid-phase synthesis of knob domains, together with the characterization of their molecular structures, in vitro pharmacology, and pharmacokinetics.

BackgroundPulmonary arterial hypertension is characterized by pulmonary vascular remodeling, cellular proliferation, and poor long-term outcomes. Dysfunctional bone morphogenetic protein pathway signaling is associated with both hereditary and idiopathic subtypes. Sotatercept, a novel fusion protein, binds activins and growth differentiation factors in the attempt to restore balance between growth-promoting and growth-inhibiting signaling pathways.MethodsIn this 24-week multicenter trial, we randomly assigned 106 adults who were receiving background therapy for pulmonary arterial hypertension to receive subcutaneous sotatercept at a dose of 0.3 mg per kilogram of body weight every 3 weeks or 0.7 mg per kilogram every 3 weeks or placebo. The primary end point was the change from baseline to week 24 in pulmonary vascular resistance.ResultsBaseline characteristics were similar among the three groups. The least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline to week 24 in pulmonary vascular resistance was −145.8 dyn·sec·cm−5 (95% confidence interval [CI], −241.0 to −50.6; P=0.003). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was −239.5 dyn·sec·cm−5 (95% CI, −329.3 to −149.7; P<0.001). At 24 weeks, the least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline in 6-minute walk distance was 29.4 m (95% CI, 3.8 to 55.0). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was 21.4 m (95% CI, −2.8 to 45.7). Sotatercept was also associated with a decrease in N-terminal pro–B-type natriuretic peptide levels. Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest.ConclusionsTreatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension. (Funded by Acceleron Pharma; PULSAR ClinicalTrials.gov number, NCT03496207.)