The success of the Severe Acute Respiratory Syndrome Coronavirus 2 mRNA vaccines to lessen/prevent severe COVID-19 opened new opportunities to develop RNA vaccines to fight other infectious agents. HIV-1 is a lentivirus that integrates into the host cell genome and persists for the lifetime of infected cells. Multiple mechanisms of immune evasion have posed significant obstacles to the development of an effective HIV-1 vaccine over the last four decades since the identification of HIV-1. Recently, attempts to address some of these challenges have led to multiple studies that manufactured, optimized, and tested, in different animal models, mRNA-based HIV-1 vaccines. Several clinical trials have also been initiated or are planned to start soon. Here, we review the current strategies applied to HIV-1 mRNA vaccines, discuss different targeting approaches, summarize the latest findings, and offer insights into the challenges and future of HIV-1 mRNA vaccines.

2023-05-12·Vaccines

Optimizing the Production of gp145, an HIV-1 Envelope Glycoprotein Vaccine Candidate and Its Encapsulation in Guanosine Microparticles.

Article

作者: Akamine, Pearl ; Morell, Gloriner ; Capó-Vélez, Coral M ; Pino, Ignacio ; Rivera, Javier ; Ortiz-Ubarri, José ; Rivera, José M ; Lasalde-Dominicci, José A ; Rivera, José H ; Eichinger, Daniel ; Almodóvar, Ruth ; Baerga-Ortiz, Abel ; Delgado-Vélez, Manuel ; Madera, Bismark ; González-Feliciano, José A ; Prieto-Costas, Luis

We have developed a pipeline to express, purify, and characterize HIV envelope protein (Env) gp145 from Chinese hamster ovary cells, to accelerate the production of a promising vaccine candidate. First in shake flasks, then in bioreactors, we optimized the growth conditions. By adjusting the pH to 6.8, we increased expression levels to 101 mg/L in a 50 L bioreactor, nearly twice the previously reported titer value. A battery of analytical methods was developed in accordance with current good manufacturing practices to ensure a quality biopharmaceutical. Imaged capillary isoelectric focusing verified proper glycosylation of gp145; dynamic light scattering confirmed the trimeric arrangement; and bio-layer interferometry and circular dichroism analysis demonstrated native-like properties (i.e., antibody binding and secondary structure). MALDI-TOF mass spectrometry was used as a multi-attribute platform for accurate mass determination, glycans analysis, and protein identification. Our robust analysis demonstrates that our gp145 product is very similar to a reference standard and emphasizes the importance of accurate characterization of a highly heterogeneous immunogen for the development of an effective vaccine. Finally, we present a novel guanosine microparticle with gp145 encapsulated and displayed on its surface. The unique properties of our gp145 microparticle make it amenable to use in future preclinical and clinical trials.

2018-08-01·Immunity1区 · 医学

Electron-Microscopy-Based Epitope Mapping Defines Specificities of Polyclonal Antibodies Elicited during HIV-1 BG505 Envelope Trimer Immunization

1区 · 医学

Article

作者: Nogal, Bartek ; Wilson, Ian A ; Bastidas, Raiza ; Turner, Hannah L ; Ward, Andrew B ; Pauthner, Matthias ; Nedellec, Rebecca ; Burton, Dennis R ; Oyen, David ; Cottrell, Christopher A ; McCoy, Laura E ; Hangartner, Lars ; Bianchi, Matteo

Characterizing polyclonal antibody responses via currently available methods is inherently complex and difficult. Mapping epitopes in an immune response is typically incomplete, which creates a barrier to fully understanding the humoral response to antigens and hinders rational vaccine design efforts. Here, we describe a method of characterizing polyclonal responses by using electron microscopy, and we applied this method to the immunization of rabbits with an HIV-1 envelope glycoprotein vaccine candidate, BG505 SOSIP.664. We detected known epitopes within the polyclonal sera and revealed how antibody responses evolved during the prime-boosting strategy to ultimately result in a neutralizing antibody response. We uncovered previously unidentified epitopes, including an epitope proximal to one recognized by human broadly neutralizing antibodies as well as potentially distracting non-neutralizing epitopes. Our method provides an efficient and semiquantitative map of epitopes that are targeted in a polyclonal antibody response and should be of widespread utility in vaccine and infection studies.

项与 HIV-1 RNA vaccine (HDT Bio) 相关的新闻（医药）

2022-12-09

·BioSpace

Angiocrine Bioscience Announces Poster Presentation of AB-205 Trial during the 64th Annual Meeting of the American Society of Hematology (ASH)

SAN DIEGO, Dec. 9, 2022 /PRNewswire/ -- Angiocrine Bioscience, Inc., a clinical-stage biopharmaceutical company today announced that it has been selected by the American Society of Hematology (ASH) for a poster presentation on its Phase 3 registration study AB-205-301 (E-CELERATE), a multi-center, randomized, double-blind, placebo-controlled study of AB-205 in adults with lymphoma undergoing high-dose chemotherapy (HDT) and autologous hematopoietic cell transplantation (AHCT). AB-205 is an intravenous investigational engineered cell therapy product being developed for multiple indications. "Our investigators and Angiocrine are honored to be selected by ASH to present at its annual meeting this December," commented Paul Finnegan, MD, Angiocrine CEO. "We look forward to Dr. Michael Scordo's presentation on the trial design of our AB-205 Phase 3 multi-center study (E-CELERATE)." E-CELERATE has been designed to evaluate the efficacy and safety of AB-205 as a treatment for damaged organ vascular stem cell niches caused by off-target cytotoxicity of HDT and prevent the progression of severe multi-organ complications, which can be life threatening and prolong hospitalization. The US Food and Drug Administration has conferred special regulatory status to AB-205 via the Regenerative Medicine Advanced Therapy and Orphan Drug designations for this indication. ASH Meeting Details Program: Oral and Poster Abstracts Session Name: 731. Autologous Transplantation: Clinical and Epidemiological Program: Poster III Session Date: Monday, December 12, 2022 Session Time: 6:00 PM - 8:00 PM ET Location: Ernest N. Morial Convention Center, Hall D Poster Number: 4743 Title: A Phase 3 Double-Blind, Randomized, Placebo Controlled Study to Evaluate the Efficacy and Safety of AB-205 Plus Standard of Care (SOC) Versus Placebo Plus Standard of Care in Adults with Lymphoma Undergoing High-Dose Therapy and Autologous Hematopoietic Cell Transplantation (E–CELERATE) (NCT05181540) - Trials in Progress About AB-205 AB-205 is an experimental engineered cell therapy consisting of allogeneic E4ORF1+ human umbilical vein endothelial cells (E-CEL® cells). AB-205 is currently being studied in a single, pivotal Phase 3 registration trial, designed to evaluate the efficacy and safety of AB-205 in the treatment of severe multi-organ complications related to systemic, diffuse injury to the vascular stem cell niches of multiple organs sustained during high-dose chemotherapy. More information about the E-CELERATE trial and participating sites may be found at the National Institute of Health's ClinicalTrials.gov website - NCT05181540. About Severe Toxicities and Complications during High-Dose Chemotherapy (HDT) and Autologous Hematopoietic Cell Transplant (AHCT) HDT followed by AHCT is a curative treatment option for eligible patients with aggressive systemic lymphoma. Although highly effective in eradicating aggressive cancer cells, HDT also causes collateral damage to healthy tissue. The initial damage can quickly progress to serious and expensive complications despite state-of-the-art prophylactic measures. Most frequent complications involve the gastrointestinal and immune systems (low blood counts, infections); vital organ involvement can be life-threatening and prolong hospital stay. About Angiocrine Bioscience, Inc. Angiocrine Bioscience, Inc. is a clinical-stage biopharmaceutical company developing Advanced Reparative Medicines consisting of engineered human endothelial cells (E-CEL cells). Angiocrine utilizes its proprietary E-CEL Platform to create multiple versions of E-CEL cells to repair damaged tissues and organs and to treat serious medical conditions. For additional information, please contact: Investor Relations (877) 784-8496 IR@angiocrinebio.com

临床3期细胞疗法ASH会议孤儿药

2022-07-25

·BioSpace

Ashvattha Therapeutics Announces Publication of Data in Science Translational Medicine from Phase 2a Clinical Trial for OP-101 in Severe COVID-19

REDWOOD CITY, Calif., July 25, 2022 (GLOBE NEWSWIRE) -- Ashvattha Therapeutics (“Ashvattha”), a clinical stage company developing novel hydroxyl dendrimer therapeutics, today announced the publication of the results from a Phase 2a clinical study demonstrating a significant reduction in inflammatory and neuroinflammatory markers and improved clinical outcomes with OP-101, a hydroxyl dendrimer therapeutic (HDT), delivered intravenously in patients with severe COVID-19. The paper, titled, “Dendrimer nanotherapy for severe COVID-19 attenuates inflammation and neurological injury markers and improves outcomes in a phase 2a clinical trial,” was published in the peer-reviewed scientific journal Science Translational Medicine. The Phase 2a trial (PRANA), a multi-center, double-blind, placebo-controlled, single sequential, ascending dose study, evaluated the safety, tolerability and preliminary efficacy of OP-101 intravenously dosed at 2 mg/kg, 4 mg/kg and 8 mg/kg across three cohorts compared to a single intravenous dose of placebo in patients with severe COVID-19. Key findings published in Science Translational Medicine include: OP-101 was shown to improve survival, corresponding with an increase in dosage (2 mg/kg: 67%; 4 mg/kg: 100%; 8 mg/kg: 80%) versus placebo (43%). Risk for the composite outcome of mechanical ventilation or death at 30 and 60 days after treatment was 71% for placebo and 18% for the pooled OP-101 treatment arms. At 60 days, three of seven patients given placebo and 14 of 17 OP-101 treated patients were surviving, and the surviving patients treated with OP-101 did not require mechanical ventilation by day 30 or day 60. Treatment with OP-101 was associated with attenuating neuronal injury markers NfL and GFAP, lasting until day 30 of the study. OP-101 dosed at 4 mg/kg treatment significantly decreased markers of hyperinflammation TNF-α, IL-6 and IL-8. No drug-related adverse events were reported. “We are incredibly pleased with these positive results that support the potential of OP-101 to significantly improve clinical outcomes and survival for patients with severe COVID-19,” said Jeffrey Clelland, Ph.D., Chairman & CEO of Ashvattha Therapeutics. “This data also validates the ability of our hydroxyl dendrimer therapies to cross tissue barriers, including blood-brain barriers, selectively targeting areas of inflammation with an excellent safety profile, which could benefit patients with other diseases characterized by inflammation. We are hopeful that we may see similar results in patients suffering from Long COVID.” This paper was published in its entirety in volume 14, issue number 654 of Science Translational Medicine and can be accessed here. About OP-101 OP-101 is an HDT with N-acetyl cysteine (NAC) that selectively targets reactive macrophages and microglia, which are responsible for hyperinflammation, lung injury and multi-organ failure caused by viral or bacterial infections, including COVID-19. About Ashvattha Therapeutics Ashvattha Therapeutics is a clinical-stage biotech company developing novel hydroxyl dendrimer therapeutics (HDTs) targeting unmet medical needs in ophthalmology, neurology, inflammatory diseases and neuro-oncology. The therapies are based on hydroxyl dendrimers (HDs), a targeted platform technology exclusively licensed from our founders, Kannan Rangaramanujam and Sujatha Kannan at Johns Hopkins University. HDs chemically conjugated to disease-modifying drugs create novel proprietary HD therapeutics (HDTs) selectively targeting reactive inflammatory cells in disease tissue with localized sustained effects. Ashvattha has initiated multiple programs with HDTs focused on neurology, ocular neovascular disease including neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME), and hyperinflammation in diseases. For more information, visit: . Media Contact Jordyn Temperato LifeSci Communications jtemperato@lifescicomms.com

2022-07-25

·GlobeNewswire-Health Care

Ashvattha Therapeutics Announces Publication of Data in Science Translational Medicine from Phase 2a Clinical Trial for OP-101 in Severe COVID-19 Showing Significant Reduction in Inflammatory and Neuroinflammatory Markers and Improved Clinical Outcomes

– Data showed OP-101 delivered intravenously may have the potential to treat systemic inflammation and neuronal injury, reducing morbidity and mortality in hospitalized patients with severe COVID-19 –REDWOOD CITY, Calif., July 25, 2022 (GLOBE NEWSWIRE) -- Ashvattha Therapeutics (“Ashvattha”), a clinical stage company developing novel hydroxyl dendrimer therapeutics, today announced the publication of the results from a Phase 2a clinical study demonstrating a significant reduction in inflammatory and neuroinflammatory markers and improved clinical outcomes with OP-101, a hydroxyl dendrimer therapeutic (HDT), delivered intravenously in patients with severe COVID-19. The paper, titled, “Dendrimer nanotherapy for severe COVID-19 attenuates inflammation and neurological injury markers and improves outcomes in a phase 2a clinical trial,” was published in the peer-reviewed scientific journal Science Translational Medicine. The Phase 2a trial (PRANA), a multi-center, double-blind, placebo-controlled, single sequential, ascending dose study, evaluated the safety, tolerability and preliminary efficacy of OP-101 intravenously dosed at 2 mg/kg, 4 mg/kg and 8 mg/kg across three cohorts compared to a single intravenous dose of placebo in patients with severe COVID-19. Key findings published in Science Translational Medicine include: OP-101 was shown to improve survival, corresponding with an increase in dosage (2 mg/kg: 67%; 4 mg/kg: 100%; 8 mg/kg: 80%) versus placebo (43%).Risk for the composite outcome of mechanical ventilation or death at 30 and 60 days after treatment was 71% for placebo and 18% for the pooled OP-101 treatment arms.At 60 days, three of seven patients given placebo and 14 of 17 OP-101 treated patients were surviving, and the surviving patients treated with OP-101 did not require mechanical ventilation by day 30 or day 60.Treatment with OP-101 was associated with attenuating neuronal injury markers NfL and GFAP, lasting until day 30 of the study.OP-101 dosed at 4 mg/kg treatment significantly decreased markers of hyperinflammation TNF-α, IL-6 and IL-8.No drug-related adverse events were reported. “We are incredibly pleased with these positive results that support the potential of OP-101 to significantly improve clinical outcomes and survival for patients with severe COVID-19,” said Jeffrey Clelland, Ph.D., Chairman & CEO of Ashvattha Therapeutics. “This data also validates the ability of our hydroxyl dendrimer therapies to cross tissue barriers, including blood-brain barriers, selectively targeting areas of inflammation with an excellent safety profile, which could benefit patients with other diseases characterized by inflammation. We are hopeful that we may see similar results in patients suffering from Long COVID.” This paper was published in its entirety in volume 14, issue number 654 of Science Translational Medicine and can be accessed here. About OP-101OP-101 is an HDT with N-acetyl cysteine (NAC) that selectively targets reactive macrophages and microglia, which are responsible for hyperinflammation, lung injury and multi-organ failure caused by viral or bacterial infections, including COVID-19. About Ashvattha Therapeutics Ashvattha Therapeutics is a clinical-stage biotech company developing novel hydroxyl dendrimer therapeutics (HDTs) targeting unmet medical needs in ophthalmology, neurology, inflammatory diseases and neuro-oncology. The therapies are based on hydroxyl dendrimers (HDs), a targeted platform technology exclusively licensed from our founders, Kannan Rangaramanujam and Sujatha Kannan at Johns Hopkins University. HDs chemically conjugated to disease-modifying drugs create novel proprietary HD therapeutics (HDTs) selectively targeting reactive inflammatory cells in disease tissue with localized sustained effects. Ashvattha has initiated multiple programs with HDTs focused on neurology, ocular neovascular disease including neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME), and hyperinflammation in diseases. For more information, visit: www.avttx.com. Media Contact Jordyn Temperato LifeSci Communications jtemperato@lifescicomms.com

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适应症	最高研发状态	国家/地区	公司	日期
HIV感染	临床前	美国	University of Washington	-
HIV感染	临床前	美国	HDT Bio Corp.初创企业	-
HIV感染	临床前	美国	Seattle Children's Research Institute	-