MEDI6389 / AstraZeneca - LARVOL DELTA

[VIRTUAL] Toxin Neutralization Therapy Protected Against Staphylococcal Septic Shock - Results from an Experimental Intensive Care Unit Using Outbred Rabbits (ATS-I 2020) - "Mortality rates were 90% (9/10) for rabbits that were administered prophylactically with nonspecific control IgG (c-IgG, 30mg/kg) compared to 20% (2/10) for those administered with MEDI6389 comprising of 30 mg/kg each of the three aforementioned mAbs (P <0.001)... These results demonstrate the potential clinical utility of a rabbit model that reproduces hallmark features of human septic shock in a rigorous experimental ICU setting and the translational potential of immunotherapy targeting S. aureus virulence factors for the prevention of staphylococcal septic shock."

IO Biomarker • Critical care • Hypotension • Infectious Disease • Septic Shock

Efficacy of a multimechanistic monoclonal antibody combination against Staphylococcus aureus surgical site infections in mice. (PubMed, Antimicrob Agents Chemother) - "Surgical site infections (SSI) are commonly caused by Staphylococcus aureus Here, we report that a combination of three monoclonal antibodies (MEDI6389) that neutralize S. aureus α-toxin, clumping factor A and four leukocidins (LukSF, LukED, HlgAB and HlgCB) plus vancomycin had enhanced efficacy than control antibody plus vancomycin in two mouse models of S. aureus SSI. Therefore, mAb-based neutralization of multiple S. aureus virulence factors could provide an adjunctive perioperative approach to combat S. aureus SSI."

Journal

Toxin Neutralization Therapy Protected Against Staphylococcal Septic Shock - Results from an Experimental Intensive Care Unit Using Outbred Rabbits (ATS 2020) - "These results demonstrate the potential clinical utility of a rabbit model that reproduces hallmark features of human septic shock in a rigorous experimental ICU setting and the translational potential of immunotherapy targeting S. aureus virulence factors for the prevention of staphylococcal septic shock."

IO Biomarker

Preventive administration of MEDI6389, a combination of monoclonal antibodies (mAbs) targeting alpha-toxin (AT), Panton-Valentine leukocidin (PVL), leukocidin ED (LukED), gamma-hemolysin and clumping factor A (ClfA), in a rabbit model of USA300 MRSA prosthetic joint infection (PJI) (IDWeek 2019) - "TEM of synovitis harvested from infected knee joints of control animals showed significant greater number of abnormal neutrophils that appeared rounded, with condensed nucleus and no granules, compared to those pretreated with MEDI6389 (P=0.002). This classical leukocidin-induced neutrophilic killing phenotype could be neutralized with anti-leukocidin mAbs using ex vivo human neutrophils incubated with PVL, LukED, HlgAB, or HlgCB. Conclusion : The preventive administration of MEDI6389 allows a reduction of local inflammation and bacterial burden in this USA300 MRSA rabbit PJI model."

Preclinical