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Development of Human Monoclonal Antibody Therapeutic against Klebsiella pneumoniae Infection

Description:

TECHNOLOGY AREA(S): Bio Medical

OBJECTIVE: Develop human monoclonal antibodies against K. pneumoniae for therapeutic use.Candidate antibodies will be tested for binding to the surface of the target bacterium and evaluated for efficacy as a prophylactic and therapeutic with and without standard of care antibiotics in relevant animal models and downstream human clinical trials. Infection rates occur in 20-35% of combat-associated traumatic injuries; K. pneumoniae has been responsible for 8-10% of these infections resulting loss of life, limb, and delayed or prohibited return to duty at an estimated cost of $1M-$2M per injured military member. A monoclonal antibody therapeutic is a promising solution to prevent these infections, deaths, amputations, and to enhance return to duty.

DESCRIPTION: U.S. military members medically evacuated from theater because of combat injuries sustain high impact insults such as explosions, gunshot wounds and motor vehicle accidents, leading to significant injuries that are frequently contaminated. Without timely treatment, injuries are at increased risk for infectious complications, especially skin and soft tissue, wound, osteomyelitis and sepsis1. K. pneumoniae poses a serious threat and will be a threat in future conflicts because:(1) K. pneumoniae has grown significantly resistant to antibiotics, and there are now multidrug-resistant (MDR), extensively drug-resistant (XDR) and even pandrug-resistant (PDR) strains leaving clinicians in the military health system (MHS) with few or no treatment options.(2) Although antibiotic discovery has caught up with drug-resistant Gram-positive pathogens, such as S. aureus, the same is not true for drug-resistant Gram-negatives. Specifically, the recently approved antibiotic, ceftolozane-tazobactam, provides coverage against P. aeruginosa infections, but is not effective against K. pneumoniae. Similarly, although ceftazidime-avibactam is effective against most serine carbapenemase-producing bacteria, but not many K. pneumoniae isolates.(3) Irrespective, monotherapy is subject to resistance.Therefore, because of the looming threat of drug resistance and a paucity of effective antibiotics, wound infections caused by K. pneumoniae will not be resolved by traditional antibiotics, and investment in alternative strategies is paramount. Monoclonal antibody therapy is a non-traditional, antibacterial approach, which works on its own or as an adjunct to antibiotics, both prophylactically or as treatment, to resolve infection. In the 19th century, serum was successfully used to treat bacterial infections2. Now, with 21st century technology, generation of human monoclonal antibodies (Hu-mAb) is a viable and attractive antibacterial strategy that can be somewhat fast-tracked through clinical trials given the inherent lack of toxicity and stability issues, which often accompany other traditional antibacterial approaches. Other advantages of Hu-mAb therapy are: (1) longevity, as this product is not cleared by the immune system as fast as mAbs from other animal sources; (2) confers inherent pathogen specificity without disrupting the microbiome; (3) potentiates rapid and sustained killing via multiple mechanisms including: direct killing, anti-virulence, neutralization, complement deposition, and opsonization by phagocytes2.Furthermore, mAbs with Fc domains that bind to the host phagocyte receptor FcγRII result in downstream suppression of inflammation and sepsis caused by Gram-negative bacteria3. Killing bacteria by multiple mechanisms limits toxic shock seen in sepsis and limits emerging resistance.Recently, companies have successfully developed Hu-mAb to treat bacterial infections.The FDA approved two Hu-mAb products: Bezlotoxumab for Clostridium difficile infection and Raxibacumab for Bacillus anthracis infection4.There are six additional Hu-mAb antibacterial solutions in the development pipeline.Preferred Features of monoclonal antibody deliverable:• human or humanized antibodies will be given highest priority • if non-human antibodies will be made, a plan for humanization must be included in Phase III

PHASE I: Selected performer determines the feasibility of the concept by identifying at least 100 unique mAbs that bind to at least 5 unique targets on the native, bacterial surface or secreted factors of a clinically-relevant strain of K. pneumoniae by ELISA, fluorescent microscopy, or other like methods. 50% of mAbs must bind to biofilm-grown bacteria or supernatants of biofilm-grown bacteria and 50% must bind planktonically grown bacteria or secreted factors. Half of each group of mAbs must bind in the presence of capsule. Further, these 100 mAbs may not bind either the capsule or lipopolysaccharide (LPS). Selected performer will coordinate with WRAIR/NMRC for required bacterial strains to help facilitate assay results, and any work by WRAIR/NMRC with respect to this deliverable will be done at no cost. Deliverable 1: The selected performer will provide the COR with 100 unique mAb sequences (to a minimum of 5 unique bacterial proteins) and mAbs.

PHASE II: : Selected performer will epitope map mAbs and establish broad reactivity (80% or greater reactivity) of mAbs against a diverse set of at least 100 clinically-relevant K. pneumoniae strains. Performer will determine mAb function by using secondary screens to include, at minimum: anti-growth, anti-biofilm, anti-virulence, complement, and opsonizing activity against the bacteria of interest. Performer will determine identity of bacterial targets of mAbs with activity in any assay listed above. The results of the secondary screen must yield at least 10 antibodies (to at least five unique bacterial targets) that bind to the surface of the bacterium or to secreted bacterial factors and have some antibacterial or enhanced immunologic function, such as increased bacterial killing via complement or opsonophagocytosis. Ultimately, candidates need to be narrowed to at least 10 mAb that reduce bacterial numbers or show in a tissue culture assay that bacteria can no longer kill or intoxicate host cells.Finally, this set of antibodies will be tested in an in vivo efficacy model to identify the best single or combination of antibodies for Phase III.WRAIR/NMRC could assist with this work, and this work would be at no cost. Deliverable 2: Performer will deliver results of in vitro assays to COR.

PHASE III: Positive Phase II results infers that the product will move forward with a series of preclinical experiments to support Deliverable 4: an IND and clinical trial for a Hu-mAb product against K. pneumoniae.This phase will encompass both small and large animal models such as mouse,rabbit, mini-pig and/or pig, for survival, sepsis and SSTI/wound infections. These should be in addition to the animal model done in Phase II to address both safety and efficacy.The models should consider endpoints such as: survival, bacterial burden, and time to wound closure, which reflects the requirements for the U.S. Food and Drug Administration (FDA) with regard to a product for ABSSSI. Promising antibodies will be combined into a defined mix or cocktail and in vivo efficacy experiments repeated. Performer will investigate efficacy of the mixture alone and in combination with antibiotics to evaluate synergy in an appropriate animal model. This phase will also include a formal clinical indication for the cocktail, which would be SSTI, ABSSSI and/or other relevant clinical indication. Additionally, the selected performer will establish an escalating toxicity model to establish a therapeutic window for the FDA. Finally, the performer will address the serum longevity of the final product(s) in a representative animal model of infection. All experiments should be completed GLP-like/GMP-like as best as possible. Funding for this effort could come from the Joint Warfighter Medical Research Program (JWMRP) or from awards in Congressionally Directed Medical Research Program (CDMRP), Additionally, CARB-X a spin off programs of the Biomedical Advanced Research and Development Authority (BARDA) is an additional potential funding source. The Government customer would use this product a number of ways to include prophylactic therapy or treatment along with the standard of care for wound infections. The market value of a product would be estimated around $100M-$150M as there are about 50,000 of these infections worldwide and current pricing for novel antibiotics is at least $3000 a dose4.Once developed and demonstrated, the technology can be used both commercially in civilian or military settings. The selected performer shall make this product available to potential military and non-military users throughout the world.

KEYWORDS: Wound Infections, ESKAPE, AMR, monoclonal antibodies, prolonged field care, bacteria, pathogens, antibacterial treatments

References:

1. Blyth DM, Yun HC, Tribble DR, Murray CK. (2015) Lessons of war: Combat-related injury infections during the Vietnam War and Operation Iraqi and Enduring Freedom. J Trauma Acute Care Surg. 2015 Oct;79(4 Suppl 2):S227-35.2. Casadevall A. (1996) Antibody-based therapies for emerging infectious diseases. Emerg Infect Dis. 1996 Jul-Sep;2(3):200-8.3. Dunn-Siegrist I, Leger O, Daubeuf B, Poitevin Y, Dépis F, Herren S, Kosco-Vilbois M, Dean Y, Pugin J, Elson G. (2007) Pivotal involvement of Fcgamma receptor IIA in the neutralization of lipopolysaccharide signaling via a potent novel anti-TLR4 monoclonal antibody 15C1. J Biol Chem. 282:34817-27. 4. Czaplewski L, Bax R, Clokie M, Dawson M, Fairhead H, Fischetti VA, Foster S, Gilmore BF, Hancock RE, Harper D, Henderson IR, Hilpert K, Jones BV, Kadioglu A, Knowles D, Ólafsdóttir S, Payne D, Projan S, Shaunak S, Silverman J, Thomas CM, Trust TJ, Warn P, Rex JH. (2016) Alternatives to antibiotics-a pipeline portfolio review.Lancet Infect Dis. Feb;16(2):239-51.

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