Xiaobing Han

Novel Clostridium difficile Anti-Toxin (TcdA and TcdB) Humanized Monoclonal Antibodies Demonstrate In Vitro Neutralization across a Broad Spectrum of Clinical Strains and In Vivo Potency in a Hamster Spore Challenge Model

Clostridium difficile (C. difficile) infection (CDI) is the main cause of nosocomial antibiotic-associated colitis and increased incidence of community-associated diarrhea in industrialized countries. At present, the primary treatment of CDI is antibiotic administration, which is effective but often associated with recurrence, especially in the elderly. Pathogenic strains produce enterotoxin, toxin A (TcdA), and cytotoxin, toxin B (TcdB), which are necessary for C. difficile induced diarrhea and gut pathological changes. Administration of anti-toxin antibodies provides an alternative approach to treat CDI, and has shown promising results in preclinical and clinical studies. In the current study, several humanized anti-TcdA and anti-TcdB monoclonal antibodies were generated and their protective potency was characterized in a hamster infection model. The humanized anti-TcdA (CANmAbA4) and anti-TcdB (CANmAbB4 and CANmAbB1) antibodies showed broad spectrum in vitro neutralization of toxins from clinical strains and neutralization in a mouse toxin challenge model. Moreover, co-administration of humanized antibodies (CANmAbA4 and CANmAbB4 cocktail) provided a high level of protection in a dose dependent manner (85% versus 57% survival at day 22 for 50 mg/kg and 20 mg/kg doses, respectively) in a hamster gastrointestinal infection (GI) model. This study describes the protective effects conferred by novel neutralizing anti-toxin monoclonal antibodies against C. difficile toxins and their potential as therapeutic agents in treating CDI.

Modulation of the Local Neutrophil Response by a Novel Hyaluronic Acid-Binding Peptide Reduces Bacterial Burden during Staphylococcal Wound Infection

ABSTRACT Novel approaches targeting the hosts immune response to treat Staphylococcus aureus infections have significant potential to improve clinical outcomes, in particular during infection with antibiotic-resistant strains. The hyaluronic acid-binding peptide (HABP) PEP35 was assessed for its ability to treat S. aureus infections using a clinically relevant murine model of surgical wound infection. PEP35 demonstrated no direct antimicrobial activity against a range of antibiotic-susceptible and antibiotic-resistant clinical isolates of Staphylococcus aureus. However, when this peptide was administered at the onset of infection and up to 4 h postchallenge with a methicillin-susceptible (MSSA) or a methicillin-resistant (MRSA) strain of S. aureus, it significantly reduced the bacterial burden at the wound infection site. PEP35 reduced the tissue bacterial burden by exclusively modulating the local neutrophil response. PEP35 administration resulted in a significant early increase in local CXCL1 and CXCL2 production, which resulted in a more rapid influx of neutrophils to the infection site. Importantly, neutrophil influx was not sustained after treatment with PEP35, and administration of PEP35 alone did not induce a local inflammatory response. The immunomodulatory effects of PEP35 on CXC chemokine production were TLR2 and NF-κB dependent. We propose a novel role for a HABP as an innate immunomodulator in the treatment of MSSA and MRSA surgical wound infection through enhancement of the local CXC chemokine-driven neutrophil response.

Characterization of a humanized amyloid beta oligomer monoclonal antibody (5E3) under preclinical development for passive immunotherapy of Alzheimer’s disease

Adapted ADA Adapted ADL Composite ADAS-cog 11 ADCS-ADL CDR-sb NPI QOL Caregive QOL Patient Right Hippoca Left Hippocam AMYLOID BETA OLIGOMER MONOCLONAL ANTIBODY (5E3) UNDER PRECLINICAL DEVELOPMENT FOR PASSIVE IMMUNOTHERAPY OFALZHEIMER’S DISEASE Cory L. Nykiforuk, Darrell Johnstone, Ross Reid, Bryce Hrehorak, John Merluza, Peter Cheung, Shantha Kodihalli, Brian Dupas, Melanie Leonhardt, Harmoni Hoffman, Xiaobing Han, Laura Saward, Andrew Goertzen, Michael Jackson, Judith M. Silverman, Ebrima Gibbs, Neil R. Cashman, Emergent BioSolutions, Winnipeg, MB, Canada; University of Manitoba, Winnipeg, MB, Canada; University of British Columbia, Vancouver, BC, Canada.

MICE IMMUNIZED WITH CYCLIC-SER-ASN-LYS (CSNK) PEPTIDE GENERATE POLYCLONAL ANTIBODIES SELECTIVE FOR Aβ OLIGOMERS: A VACCINE STRATEGY FOR ALZHEIMER'S DISEASE

Plasma anti-Ab antibody levels, and plasma and brain Ab levels were measured by ELISA. In cynomolgus monkeys, DT (500 m L/head, s.c.) were administered, and three weeks later, peptide (0.5 or 2.5 mg/head, s.c.) were administered at intervals of two weeks. Serum anti-Ab antibody levels and plasma Ab levels were measured by ELISA. Results: Ab peptide vaccination produced an increase in the plasma antiAb antibody level and reduction of the brain Ab40 level in guinea pigs. A negative correlation between the plasma antiAb antibody level and brain Ab40 level, and a positive correlation between the plasma antiAb antibody level and plasma Ab level were observed. In monkeys treated with the Ab peptide vaccine, the levels of serum antiAb antibody and plasma Ab42 increased. The binding profiles of the anti-Ab antibodies produced in guinea pigs and monkeys were similar. Conclusions: These results suggested that our Ab peptide vaccine alone, in the absence of any adjuvant, produced antiAb antibody in guinea pigs and monkeys. We propose that this peptide would be a possible therapeutic candidate for AD.