On June 1st, 2007, the Eijkman Winkler Center for Microbiology, Infectious Diseases and Inflammation of the University Medical Center Utrecht, the department of Medical Microbiology and Infectious Diseases of the Erasmus University Medical Center Rotterdam and IQ Corporation have started a Top Institute Pharma project on the joint generation of a non-antibiotic-dependent treatment strategy for Klebsiella pneumoniae infections. The project agreement was signed by the partners on April 20, 2007.
About the project
This project is about development of a non-antibiotic-dependent treatment strategy for K. pneumoniae infections using human monoclonal antibodies (humAbs), and a set of in vitro assays to predict in vivo efficacy of potential leads in an early stage of drug discovery. The project rationale is the urgent medical need for new medication of K. pneumoniae infections in view of the increasing emergence of resistance of K. pneumoniae against all commonly used antibiotics.
Our objectives and approach are to generate humAbs from people recovered from K. pneumoniae infections and to test these humAbs for a number of functional properties in a set of assays validated during the project. Based on their differential functional profiles, a selection of antibodies will be made for study in vivo, using antibiotic-resistant and antibiotic-susceptible K. pneumoniae strains. The in vivo efficacy of the antibodies will be translated back to the in vitro functional profile to establish a predictability between these two sets of experiments. This predictive relationship will be very important for future drug discovery and development in the context of infections caused by K. pneumoniae or other pathogens.
Upon conclusion of this project we expect to have elaborated and validated in vitro assays for functional and physicochemical properties of humAbs and in vivo assays for evaluation of therapeutic potential of humAbs against antibiotic-susceptible and antibiotic-resistant K. pneumoniae organisms. The predictive value of in vitro assays for in vivo therapeutic efficacy will be established. Upon completion, the parties involved expect to have jointly developed a prototype humAb displaying both in vitro and in vivo K. pneumoniae-neutralizing activity, which will be suitable for further pre-clinical and clinical/ pharmaceutical development outside the scope of this project.
Klebsiella pneumoniae
Klebsiella pneumoniae is an important cause of nosocomial infections in Intensive Care Units (ICUs). In a 1997-1999 study of nearly 4,000 clinically relevant isolates from patients at ICUs from 20 European university hospitals K. pneumoniae ranked 6th for nosocomial pneumonia. The annual incidence of nosocomial pneumonias alone is 5-10 cases per 1,000 admissions, with a possible 20-fold increase when patients are ventilated for over 48 hours. The prevalence of K. pneumoniae among these infections is approximately 12%. Unfortunately, the treatment options for these infections with K. pneumoniae have become increasingly problematic as K .pneumoniae has shown to develop resistance against all commonly, including empirically used antibiotics. Already in 1991, resistance to 3rd generation cephalosporins such as ceftriaxone and ceftazidime reached 36% in French ICUs. Similar percentages were reached for fluoroquinolones such as ciprofloxacin, and aminoglycosides like gentamicin. Reduced susceptibility for piperacillin, a frequently used ß-lactam antibiotic for empiric therapy, even reached 74%. Resistance rates for K. pneumoniae in ICUs in The Netherlands were generally lower, but still reached 12% for 3rd generation cephalosporins, 5% for fluoroquinolones, and 10% for aminoglycosides, but 86% for piperacillin. These resistance levels have most likely only increased since the publication of these studies, but newer studies are to our knowledge unfortunately not available. Data from UMCU – from research into the epidemiology of resistance of Klebsiella, the mechanism of resistance and the pathogenesis of this micro-organism – also show an overall increase in resistance. Among the high levels of resistance, also multi-resistance has been reported. With the efficacy of last resort antibiotics becoming increasingly threatened it becomes more and more evident that alternative routes will have to be explored for the treatment these life-threatening infections.
Human monoclonal antibodies as a non-antibiotic alternative
The above clearly illustrates that there is an urgent unmet medical need for new adequate medication for the intervention of K. pneumoniae infections. We have chosen to approach this problem by applying IQ’s ‘Cloning the Human Response’ technology to generate human monoclonal antibodies (humAbs) against the bacterium as antibodies play a crucial role in the natural defense against bacterial infections. Complement-mediated lysis and phagocytosis by macrophages and monocytes are the two most important mechanisms for the clearance of bacteria, and antibodies are instrumental for effective phagocytosis and are the tools triggering complement activation. Human antibodies are therefore ideal candidates to serve as an alternative for antibiotic therapy, especially, of course, in the case of multi-resistant bacterial strains. In addition, human antibodies are expected to provide protection also in late stages of infection, and also in infections in immunocompromised individuals, or in patients with underlying diseases such as COPD, heart disease and diabetes.
About IQ Corporation
IQ Corporation is a life sciences company based in The Netherlands. Its mission is to contribute to human healthcare through the development and worldwide commercialization of products for diagnostic and therapeutic applications. The company's therapeutics division (IQ Therapeutics) is applying its Cloning the Human Response™ technology for its own pipeline and third parties' to generate and develop fully human antibodies from immunized or vaccinated donors for the prevention and treatment of infectious diseases. The company's diagnostic products division (IQ Products) has developed a range of products for flow cytometry and for perinatal and transplantation related diagnosis, which are sold in more than 50 countries. For more information, please visit http://www.IQCorporation.nl.
About the Eijkman Winkler Center of the UMC Utrecht
The Eijkman-Winkler Center for Medical Microbiology, infectious diseases and inflammation (EWI) is a cohort of diagnostics and research in the fields of microbiology, infectious diseases and inflammation embedded in the University Medical Center (UMC) Utrecht. Both activities are intertwined at several levels and involve several disciplines. The medical microbiology involves the subdivisions bacteriology, virology and infection prevention. The EWI participates in the Immunology and Infectious Diseases research program that aims to understand the interactions between pathogens and human hosts. From the pathogen-side, population structures, transmission dynamics and escape mechanisms from inflammatory responses and antimicrobial agents are studied. Here, a strong focus is on innate immunity and antimicrobial as well as antiviral resistance. In all these research lines state of the art molecular and analytical techniques are utilized to stay in the international front lines of the field. For more information, visit: http://www.ewi.med.uu.nl/ewi_en/.
About the Medical Microbiology and Infectious Diseases (MMI) of the EMC Rotterdam
Within the department of MMI, the activities of their three units, Diagnostics, Research & Development, and Infection Prevention are intertwined at multiple levels and the medical microbiology itself involves the subdivisions bacteriology, mycology, parasitology and infection prevention. MMI aims to center its core functions (patient care, scientific research and education & training) as multidisciplinary as possible on the main theme ‘Infectious Diseases’. MMI cooperates closely with other departments within Erasmus MC such as the department of Dermatology & Venereology, Immunology, Virology and Internal Medicine / Pediatrics and also collaborates on a global scale with several (inter)national parties.
MMI participates in the Immunology and Hematology research program (sub cluster Infectious diseases: micro-organisms & host response) and focuses on the infectious complications related to recent developments in clinical medicine, such as new therapeutic modalities or resistance, an increased use of medical devices, frequent diagnostic and therapeutic intervention, and an increasing number of immunocompromized patients. The focus of its scientific research is on medical and clinical microbiological problems that are of direct importance for patient care, revolving around the molecular mechanism of infection, the epidemiology, the early diagnosis using molecular techniques, the prevention of infections, as well as treatment using alternative methods. The approach is partly fundamental/animal-experimental and partly clinical/epidemiological.
About TI Pharma
TI Pharma conducts groundbreaking and cross-disciplinary research and offers advanced training programs aimed at improving the efficiency of the entire drug discovery and development chain. This will eventually reduce the 'time- & cost-to-patient' of new drugs and contribute to the well-being of people in our society. The Institute pays special attention to the Priority Medicines project of the World Health Organization. TI Pharma also connects academia and industry by training a new generation of biomedical researchers who will have experience in both spheres.
As a research consortium, involving more than 400 PhD students and post-docs, TI Pharma is funded by participants from the public and private sector, as well as by a grant from the Dutch government. The Institute is dedicated to fostering new, strategic collaborations between top-quality academic research groups in The Netherlands and innovative industrial partners.
TI Pharma conducts translational research into multiple therapeutic areas. Within those areas, its projects involve pre-competitive drug R&D, as well as research into enabling technologies such as in silico modeling, toxicology and drug delivery, up to and including (clinical) “Proof of Concept”. A special program focuses on efficiency improvements and early regulatory input in the chain of drug discovery, drug development and drug utilization. TI Pharma narrows the gap between academic research and industry. In so doing, the institute helps science to bring new drugs and vaccines onto the market more quickly.
A unique training program enables PhD students as well as post-docs to cooperate intensively with colleagues from elsewhere in the development chain, while educating them on highly relevant topics such as intellectual property rights, business development and drug regulation.
For more information, please visit: http://www.tipharma.com/pro1/general/home.asp.
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