更新于：2024-11-09

HLX-71

更新于：2024-11-09

概要

研发状态

概要

基本信息

药物类型

融合蛋白

别名

ACE2-Fc fusion protein、Recombinant Human Angiotensin-Converting Enzyme 2-Fc Fusion Protein、Recombinant Human Angiotensin-converting Enzyme 2-Fc Fusion Protein for COVID-19

靶点

SARS-CoV-2 S protein

作用机制

SARS-CoV-2 S protein抑制剂(冠状病毒刺突糖蛋白抑制剂)

治疗领域

感染呼吸系统疾病

在研适应症-

非在研适应症

新型冠状病毒感染

原研机构

上海复宏汉霖生物技术股份有限公司

在研机构-

非在研机构

Hengenix Biotech, Inc.

最高研发阶段无进展临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

登录后查看时间轴

关联

项与 HLX-71 相关的临床试验

NCT04583228 / Completed临床1期

A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalating Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacodynamics, Pharmacokinetics, and Immunogenicity of HLX71 in Healthy Adult Subjects

开始日期2021-04-08

申办/合作机构

Hengenix Biotech, Inc.

100 项与 HLX-71 相关的临床结果

登录后查看更多信息

100 项与 HLX-71 相关的转化医学

登录后查看更多信息

100 项与 HLX-71 相关的专利（医药）

登录后查看更多信息

项与 HLX-71 相关的文献（医药）

2023-03-23·Respiratory research

The IL-33:ST2 axis is unlikely to play a central fibrogenic role in idiopathic pulmonary fibrosis.

Article

作者: Kelly, Aoife ; Stephenson, Katherine E ; Overed-Sayer, Catherine L ; Jenkins, R Gisli ; Wallace, William A ; John, Alison E ; Porte, Joanne ; Cohen, E Suzanne ; Huntington, Catherine E

BACKGROUND:

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) with limited treatment options. Interleukin-33 (IL-33) is proposed to play a role in the development of IPF however the exclusive use of prophylactic dosing regimens means that the therapeutic benefit of targeting this cytokine in IPF is unclear.

METHODS:

IL-33 expression was assessed in ILD lung sections and human lung fibroblasts (HLFs) by immunohistochemistry and gene/protein expression and responses of HLFs to IL-33 stimulation measured by qPCR. In vivo, the fibrotic potential of IL-33:ST2 signalling was assessed using a murine model of bleomycin (BLM)-induced pulmonary fibrosis and therapeutic dosing with an ST2-Fc fusion protein. Lung and bronchoalveolar lavage fluid were collected for measurement of inflammatory and fibrotic endpoints. Human precision-cut lung slices (PCLS) were stimulated with transforming growth factor-β (TGFβ) or IL-33 and fibrotic readouts assessed.

RESULTS:

IL-33 was expressed by fibrotic fibroblasts in situ and was increased by TGFβ treatment in vitro. IL-33 treatment of HLFs did not induce IL6, CXCL8, ACTA2 and COL1A1 mRNA expression with these cells found to lack the IL-33 receptor ST2. Similarly, IL-33 stimulation had no effect on ACTA2, COL1A1, FN1 and fibronectin expression by PCLS. Despite having effects on inflammation suggestive of target engagement, therapeutic dosing with the ST2-Fc fusion protein failed to reduce BLM-induced fibrosis measured by hydroxyproline content or Ashcroft score.

CONCLUSIONS:

Together these findings suggest the IL-33:ST2 axis does not play a central fibrogenic role in the lungs with therapeutic blockade of this pathway unlikely to surpass the current standard of care for IPF.

2022-11-01·Acta biomaterialia

An albumin-angiotensin converting enzyme 2-based SARS-CoV-2 decoy with FcRn-driven half-life extension

Article

作者: Rudnik-Jansen, Imke ; Pedersen, Finn Skou ; Fuchs, Elisabeth ; Dinesen, Anders ; Selnihhin, Denis ; Kjems, Jørgen ; Thiam, Kader ; Mandrup, Ole Aalund ; Howard, Kenneth A

The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants and breakthrough infections despite available coronavirus disease 2019 (COVID-19) vaccines calls for antiviral therapeutics. The application of soluble angiotensin converting enzyme 2 (ACE2) as a SARS-CoV-2 decoy that reduces cell bound ACE2-mediated virus entry is limited by a short plasma half-life. This work presents a recombinant human albumin ACE2 genetic fusion (rHA-ACE2) to increase the plasma half-life by an FcRn-driven cellular recycling mechanism, investigated using a wild type (WT) albumin sequence and sequence engineered with null FcRn binding (NB). Binding of rHA-ACE2 fusions to SARS-CoV-2 spike protein subdomain 1 (S1) was demonstrated (WT-ACE2 K_D = 32.8 nM and NB-ACE2 K_D = 31.7 nM) using Bio-Layer Interferometry and dose-dependent in vitro inhibition of host cell infection of pseudotyped viruses displaying surface SARS-CoV-2 spike (S) protein. FcRn-mediated in vitro recycling was translated to a five times greater plasma half-life of WT-ACE2 (t_½ β = 13.5 h) than soluble ACE2 (t_½ β = 2.8 h) in humanised FcRn/albumin double transgenic mice. The rHA-ACE2-based SARS-CoV-2 decoy system exhibiting FcRn-driven circulatory half-life extension introduced in this work offers the potential to expand and improve the anti-COVID-19 anti-viral drug armoury. STATEMENT OF SIGNIFICANCE: The COVID-19 pandemic has highlighted the need for rapid development of efficient antiviral therapeutics to combat SARS-CoV-2 and new mutants to lower morbidity and mortality in severe cases, and for people that are unable to receive a vaccine. Here we report a therapeutic albumin ACE2 fusion protein (rHA-ACE2), that can bind SARS-CoV-2 S protein decorated virus-like particles to inhibit viral infection, and exhibits extended in vivo half-life compared to ACE2 alone. Employing ACE2 as a binding decoy for the virus is expected to efficiently inhibit all SARS-CoV-2 mutants as they all rely on binding with endogenous ACE2 for viral cell entry and, therefore, rHA-ACE2 constitutes a versatile addition to the therapeutic arsenal for combatting COVID-19.

2021-12-01·Pulmonary therapy

Effects of Recombinant Human Angiotensin-Converting Enzyme 2 on Response to Acute Hypoxia and Exercise: A Randomised, Placebo-Controlled Study

Article

作者: Hewens, Deborah ; Budd, David C ; Siederer, Sarah ; Hanrott, Kate ; Powley, William M ; Hall, David A ; Hohlfeld, Jens M ; Lazaar, Aili L ; Berliner, Dominik ; Badorrek, Philipp ; Eames, Rhena ; Cahn, Anthony

INTRODUCTION:

Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system (RAS) that has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). Enhancing ACE2 activity using GSK2586881, a recombinant form of human ACE2, could be beneficial in diseases such as ARDS but may blunt the hypoxic pulmonary vasoconstriction (HPV) response and potentially impact systemic and tissue oxygenation. This study aimed to evaluate the effect of GSK2586881 0.8 mg/kg on HPV response in healthy adult volunteers during exercise under hypoxic conditions.

METHODS:

In this phase I, randomised, double-blind (sponsor open) study, GSK2586881 or placebo was administered as a single intravenous (IV) dose in a two-period crossover design. Treatment periods were separated by a washout period of 3-14 days. The primary endpoint was change from baseline in pulmonary artery systolic pressure (PASP) measured by echocardiography. Secondary endpoints included RAS peptides and oxygen saturation.

RESULTS:

Seventeen adults aged 18-40 years were randomised to treatment. There were no clinically relevant differences (defined as a reduction of ≥ 5 mmHg) in change from baseline in PASP between GSK2586881 and placebo. GSK2586881 was well tolerated, with no serious adverse events, no worsening of hypoxaemia and no evidence of immunogenicity. The study was terminated early after review of the data, which showed that the predefined success criteria had not been met. Following GSK2586881 administration, levels of the RAS peptide angiotensin II decreased while angiotensin (1-7) increased, as expected, indicating that GSK2586881 was pharmacologically active.

CONCLUSIONS:

A single IV dose of GSK2586881 0.8 mg/kg was well tolerated but did not impact the acute HPV response in healthy volunteers.

项与 HLX-71 相关的新闻（医药）

2022-10-07

·BioSpace

Avirmax Inc. Announces Issuance of U.S. Patent Covering Catalysis Deactivated Angiotensin-Converting Enzyme 2 (ACE2) Variants for Treatment of Beta Group SARS-COV Viral Infection

HAYWARD, Calif., Oct. 7, 2022 /PRNewswire/ -- Avirmax, Inc. ( ), a company focused on delivering protein therapeutics via recombinant adeno-associated viral (rAAV) vectors announced today that the United States Patent and Trademark Office (USPTO) has issued U.S. Patent No. 11,453,869, which is directed to the composition and methods related to the use and administration of catalysis deactivated angiotensin-converting enzyme 2 (ACE2) for preventing SARS-COV-1 and SARS-COV-2 infection. Novel Decoy Proteins Blocking COVID-19 Variants Patent Summary Human ACE2 has been confirmed as a specific receptor for several β group coronaviruses including severe respiratory syndrome (SARS) coronavirus (SARS-CoV-1), a low pathogenic coronavirus of HCoV-NL63, a member in α-coronavirus group and SARS-CoV-2, the causative agent of COVID-19. The patent covers the extracellular domain (ECD) polypeptide of ACE2 with one or more mutations in the enzyme catalytic center that cause the loss of ACE2 catalytic activity (herein referred as ACE2-vECD) and enhance the binding affinity to the SARS-CoV1 and SARS-COV-2 S1 spike proteins. The ACE2-vECD fused to the Fc fragment of human IgG1 (ACE2-vECD-Fc1) can function as a common blocking reagent, similar to neutralization antibodies, preventing COVID-19 variants or SARS-COV1 to enter host cells and the viral replication cycle. The rAAV mediated expression of the catalysis deactivated ACE2 in nasal/olfactory epithelium therefore acts as a decoy receptor for SARS-COV blocking infection of epithelial cells and the following viral replication. About Avirmax Inc: Avirmax, Inc., based in the San Francisco Bay Area, is dedicated to the innovation, development, and manufacture of adeno-associated virus (AAV) vector mediated biotherapeutics using its proprietary protein therapeutics and Bac-to-AAV technologies. Avirmax's AAV Innovation Platform, a robust streamlined assembly line of novel AAV vector discovery and development, enables us to become a powerhouse of rAAV therapeutics due to its highly transducible AAV vectors with high titers at production and enhanced expression of gene of interest (GOI) in target cells. Our ultimate goal is to deliver patients with effective, safe, long-acting AAV-mediated biotherapeutics in the most affordable and accessible manner possible. (For more information, please visit .) Contact: For more information, please contact June Song Executive Administration Email: business@avirmax.com Tel: +1-510-641-0201

抗体

2021-07-26

·医药笔记

复宏汉霖新冠中和抗体对多种突变株有效

2021年7月，复宏汉霖在Cell Discovery期刊上发表文章，其ACE2-Fc融合蛋白及中和抗体对多种突变株有效。 HLX71为ACE-2-Fc融合蛋白，HLX70为新冠RBD中和抗体。 HLX70和HLX71都具有很高的亲和力，两者按1:5混合时抑制效率最高。体内试验中，HLX70/HLX71鸡尾酒也表现出更强的抑制病毒效应。 HLX71融合蛋白对巴西突变株（P.1）、英国突变株（B.1.1.7）、美国加州突变株（B.1.429）、纽约突变株（B.1.526）、印度突变株（B.1.617）等多种突变株都保持高度的抑制活性。总结新冠突变株给中和抗体带来巨大挑战。再生元中和抗体Casirvimab对巴西突变株和南非突变株无效，礼来/Abcellera的Bamlanivimab和礼来/君实的Etesevimab对巴西突变株和南非突变株无效，不过礼来/君实的Etersevimab对印度突变株（delta）有效。目前仅Vir Bio的VIR-7831、腾盛博药的BRII-196+BRII-198、复宏汉霖的HLX71表现出广泛的抗突变效应。从机制上也容易理解，病毒S蛋白不论如何突变，都需要通过结合ACE2受体进入细胞，ACE2-Fc融合蛋白能够有效对抗各种突变株也就在意料之中。