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Multi-faceted mAb Development Program for Multi-Drug Resistant Wound Infections

Description:

OUSD (R&E) CRITICAL TECHNOLOGY AREA(S): Military Infectious Disease OBJECTIVE: The objective of this topic would be to develop human monoclonal antibodies (mAbs) that have demonstrated efficacy and safety in a screening infected wound animal model against multi-drug resistant bacteria. DESCRIPTION: Multi-drug resistant (MDR) infections have caused significant morbidity and mortality for US Service Members with battlefield wounds.1 Among MDR bacteria, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Entrobacter spp.) have been identified as particularly problematic pathogens that complicate wounds of U.S. military casualties.2 These species are commonly pan-resistant to most commercially available antibiotics. Monoclonal antibodies (mAbs) that specifically target and kill MDR are a promising alternative to antibiotics and vaccines. Passive immunotherapy with mAbs can provide protection against bacterial infection via multiple mechanisms, including neutralization, complement-mediated killing and opsonic phagocytosis. The use of biologics can also slow resistance development. Their long half-lives allow for minimal dosing which is optimal for prolonged field care. Typically mAbs storage conditions are minimal, (4oC) and have long shelf lives lasting 12 months or more allowing for reduced logistical challenges for deployed medical units. A targeted mAb would have utility at all roles of care within the military health spectrum. Utilizing the right techniques/methods, MDR specific mAbs can be generated significantly faster than small molecules or vaccines. Thus far, development of therapeutic mAbs for use in bacterial infections have lagged behind other areas such as viral infections and cancer.3 Concentrated program efforts are needed instead of the typical use of a singular source through one development pathway. This program would require the combination of multiple sources and pathways with state of the art tools to maximize the efficiency and success rate. This project would require a company to be able to draw from multiple sources of material for antibody generation: plasma cells from infected patients, Memory B cells from convalescent patients and plasma and Memory B cells from transgenic humanized animals. Each source of antibodies would undergo different screening and identification pathways using advanced methods such as single cell-based screening on Beacon instruments and the 10X Genomics Chromium system. Combining multiple antibody sources from human and humanized animals with different pathways will enable high affinity antibodies that need no further modification to humanize them. The end product from this project will be at least 1 humanized antibody that has demonstrated in vitro and in vivo high affinity, safety and efficacy against one ESKAPE pathogen. This approach to therapeutic antibody development will allow for a rapid, modifiable capability that should improve antibody therapeutic development timelines by months. This platform can be utilized for all the ESKAPE pathogens. In addition, it provides a mechanism for developing therapeutic antibodies for any emerging pathogen, greatly enhancing pandemic response capabilities. PHASE I: This phase will be focused on antigen selection, synthesizing and purification. Based on available evidence, the most likely antigens to provide the most specific and robust immune response will be created and then purified. The company will need to demonstrate experience and capability in identifying ideal antigen candidates either through methods such as analysis of known surface protein sequences/structures or through antigen/phage library creation and down selection. Once candidates are selected, the synthesizing and purification of identified peptides will need to be demonstrated. The company should have partners that they can collaborate with that has the ability to obtain human samples from infected patients. By the end of Phase 1 all necessary requirements to initiate human sample collection and animal immunization with target antigens will be performed. PHASE II: This phase will focus on the development, purification, screening and testing of antibodies to generate at least 1 antibody specific for an ESKAPE pathogen. Antibodies that have undergone single cell screening and purification regardless of whether they came from human or transgenic animal sources will be further screened using rigorous in vitro tests. Any resulting antibody will be evaluated for efficacy and safety on a wound infection animal model validated for that ESKAPE pathogen. The resulting deliverable will be at least one antibody that has demonstrated in vitro and in vivo affinity, safety and efficacy in treating an ESKAPE pathogen. These antibodies will be ready for more advanced development. The multiple simultaneous approaches as part of this program allows for maximum opportunity for a successful antibody to be discovered and screened in a short time frame. A regulatory strategy that reflects a clinical Target Product Profile will need to be developed during this phase. It should include relevant in vitro/in vivo cross reactivity testing, immunogenicity, small and large animal toxicology studies and plans for pre-Investigational New Drug FDA meetings. PHASE III DUAL USE APPLICATIONS: This phase would focus on in vivo and human research needed to obtain FDA approval. Starting with dose ranging and animal toxicology studies and progressing to the first in human Phase 1 study. Any company should have capabilities or partners with large scale Good Manufacturing Practices (GMP) manufacturing capabilities. Funding for further development efforts could be sought from such programs as the Joint Warfighter Medical Research Program, Biomedical Advanced Research and Development Authority or Medical Technology Enterprise Consortium. The end state would be an FDA approved therapeutic antibody to treat a multi-drug resistant ESKAPE pathogen. This would serve as a significant therapeutic tool to military and civilian caregivers. Once FDA approved, this product should have immediate interest from tertiary care civilian and military hospitals in treating highly resistant infections in intensive care or post-operative patients. REFERENCES: 1. David R Tribble, MD, DrPH, Clinton K Murray, USA, MC, Bradley A Lloyd, USAF, MC, Anuradha Ganesan, MBBS, MPH, Katrin Mende, PhD, Dana M Blyth, USAF, MC, Joseph L Petfield, USA, MC, Jay McDonald, MD, After the Battlefield: Infectious Complications among Wounded Warriors in the Trauma Infectious Disease Outcomes Study, Military Medicine, Volume 184, Issue Supplement_2, November-December 2019, Pages 18–25, https://doi.org/10.1093/milmed/usz027 2. Katrin Mende, PhD, Kevin S Akers, MC, USA, Stuart D Tyner, MSC, USA, Jason W Bennett, MC, USA, Mark P Simons, USN, MSC, Dana M Blyth, USAF, MC, Ping Li, MS, Laveta Stewart, MSc, MPH, PhD, David R Tribble, MD, DrPH, Multidrug-Resistant and Virulent Organisms Trauma Infections: Trauma Infectious Disease Outcomes Study Initiative, Military Medicine, Volume 187, Issue Supplement_2, May-June 2022, Pages 42–51, https://doi.org/10.1093/milmed/usab131 3. Zurawski DV, McLendon MK. Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens. Antibiotics (Basel). 2020 Apr 1;9(4):155. doi: 10.3390/antibiotics9040155. PMID: 32244733; PMCID: PMC7235762 KEYWORDS: Monoclonal antibodies, multi-drug resistant organisms, bacterial infections, monoclonal antibody development, wound infections, ESKAPE pathogens
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