Humanized Monoclonal Antibody to Treat Acinetobacter Infections

治疗不动杆菌感染的人源化单克隆抗体

• 批准号: 9321166
• 负责人: Khalid Islam
• 金额: $ 107万
• 依托单位: BIOLOGICAL ANTI-INFECTIVE MEDICINES, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321166
• 关键词: Acinetobacter Infections; Acinetobacter baumannii; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antibodies; Aspiration Pneumonia; Bacteria; Binding; Blood Circulation; Cessation of life; Clinical; Contracts; Developed Countries; Developing Countries; Development; Drug resistance; Funding; Future; Grant; Health Care Costs; Immune; Immune Sera; Immune system; Immunization; Immunize; Immunodominant Epitopes; Immunotherapy; In Vitro; Infection; Intensive Care Units; Lung; Mediating; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Passive Immunization; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Positioning Attribute; Prevention strategy; Process; Proteins; Recombinants; Running; Sepsis; Sepsis Syndrome; Series; Serum Immunologic; Small Business Technology Transfer Research; Staining method; Stains; Surface; Syndrome; TLR4 gene; Therapeutic; Therapeutic Monoclonal Antibodies; Toxic effect; Vendor; Virulence; Whole Organism; bacterial resistance; base; cell bank; commercialization; cost; design; experience; extensive drug resistance; humanized monoclonal antibodies; improved; improved outcome; in vivo; killings; meetings; mouse model; national surveillance; pathogen; periplasm; pre-clinical; public health relevance; scale up; surveillance data; treatment strategy; virtual

 DESCRIPTION (provided by applicant): National surveillance data confirm that 50% of A. baumannii isolates from US intensive care units are extreme drug resistance (XDR), far higher than other pathogens. At least 23,000 and 75,000 cases of XDR A. baumannii infections occur annually in the US and globally (in developed countries), respectively. These infections result in ~10,000 and 30,000 deaths and excess healthcare costs of $390 million and $742 million in the US and globally, annually. Furthermore, in contrast to other resistant bacteria, virtually no antibiotics are in the pipeline to deal with XDR A. baumannii. New prevention and treatment strategies are critically needed. We will develop a therapeutic monoclonal antibody to treat A. baumannii infections, as an adjunct to antibiotics. In a series of pathogenesis studies, we found that A. baumannii virulence was driven by an initial evasion of innate immune-mediated clearance, resulting in sustained LPS-TLR4 activation that drove sepsis syndrome. Thus enhancement of innate immune mediated clearance was a promising immune-therapeutic strategy to improve outcomes from infection. Furthermore, passive immunization with polyclonal immune serum targeting A. baumannii improved survival of infected recipient mice, validating the approach. We have a MAb, BioAIM1 that binds to the surface of multiple strains of A. baumannii as well as polyclonal immune serum, and is nearly completely protective in otherwise fatal models of XDR A. baumannii bacteremic sepsis and aspiration pneumonia, the most common clinical syndromes of A. baumannii infection. During phase I of the funded STTR grant, we humanized the MAb. In phase II, we seek to advance it towards IND filing: Aim 1. Establish GMP manufacturing for our candidate MAbs. GMP scale up will be established by STC Biologics. The GMP process will include establishment of a master cell bank, completion of scale up including an initial GMP-like manufacturing run followed by repeat runs and a final 50 L reactor run, as well as stability studies. We will confirm the in vitro and in vivo activity of the material produced. Our highly experienced team, which has taken prior companies to IPO and taken drugs through NDA/BLA, will manage the vendor. Aim 2. Complete pre-clinical toxicity studies to support an IND application. Toxicity studies have been designed based on FDA guidance, and their execution will be contracted to a qualified vendor. We will hold a pre-IND meeting with the FDA to confirm our plans for toxicity studies and the future phase I clinical tria. Completion of pre-clinical toxicity studies using GMP-like material and will be targeted for year 2. Upon completion of funding we will be positioned to file an IND that will allow subsequent initiation of a phase I clinical trial. The impact of the MAb once developed will be to markedly improve survival and morbidity from highly lethal, XDR and pan-drug resistant (PDR) A. baumannii infections. The impact will be particularly great given the absence of new antibiotics in development to treat A. baumannii.