ENGINEERED ?MUCO-TRAPPING? ANTIBODIES FOR INHALED THERAPY OF PARAINFLUENZA AND HUMAN METAPNEUMOVIRUS INFECT…

Assistance award details

Assistance award identifier

ASST_NON_R01AI165853_075

FAIN

R01AI165853

Recipient

UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$3,076,249

Period

Sep 19, 2022 – Jul 31, 2027

Fiscal year

2022

Place of performance state

NC

Source file

FY2022_All_Assistance_Full_20261006.zip

Description

ENGINEERED ?MUCO-TRAPPING? ANTIBODIES FOR INHALED THERAPY OF PARAINFLUENZA AND HUMAN METAPNEUMOVIRUS INFECTIONS - HUMAN PARAINFLUENZA VIRUS (PIV) AND METAPNEUMOVIRUS (MPV) ARE COMMON CAUSES OF LOWER RESPIRATORY TRACT INFECTIONS IN INFANTS AND YOUNG CHILDREN, AND MAJOR CAUSES OF RESPIRATORY ILLNESS IN IMMUNE COMPROMISED ADULTS AND THE ELDERLY. UNFORTUNATELY, THERE ARE NO THERAPY OR VACCINE FOR EITHER VIRUSES, AND ONLY SUPPORTIVE MEDICAL CARE IS AVAILABLE. INTERESTINGLY, PIV AND MPV SHARE MANY PATHOLOGICAL AND CLINICAL MANIFESTATIONS AS RESPIRATORY SYNCYTIAL VIRUS (RSV). INDEED, NEITHER PIV NOR MPV ARE KNOWN TO CAUSE VIREMIA IN THE BLOOD OF INFECTED PATIENTS, INDICATING BOTH INFECTIONS ARE STRICTLY LOCALIZED IN THE AIRWAYS SIMILAR TO RSV THAT SHED PROGENY VIRUSES EXCLUSIVELY FROM THE APICAL SURFACE OF INFECTED CELLS. SUCH UNIQUE PATHOPHYSIOLOGY IMPLIES PROGENY VIRUSES MUST TRAVERSE AIRWAY MUCUS (AM) BEFORE SPREADING TO NEIGHBORING CELLS. THIS IN TURN MOTIVATED US TO DEVELOP A PATHOGEN-SPECIFIC ANTIVIRAL THAT COULD PHYSICALLY LIMIT THE SPREAD OF THE INFECTIONS WITHIN THE AIRWAYS. WE RECENTLY DISCOVERED A NOVEL AB EFFECTOR FUNCTION IN MUCUS – TRAPPING INDIVIDUAL PATHOGENS IN MUCUS BASED ON CAREFULLY-TUNED AFFINITY BETWEEN IGG-FC AND MUCINS – AND DEVELOPED A PLATFORM FOR ENHANCING MAB FUNCTION AT MUCOSAL SURFACES. WE HYPOTHESIZE THAT “MUCO-TRAPPING” MAB DELIVERED TO THE AIRWAYS CAN DIRECTLY INTERVENE WITH THE VIRAL LIFE CYCLE BY INTERCEPTING AND TRAPPING SHED PROGENY VIRUSES IN AM, RAPIDLY ELIMINATE TRAPPED VIRUSES FROM THE AIRWAYS BY NATURAL MUCOCILIARY CLEARANCE, AND ENABLE EFFECTIVE THERAPY IN VIVO. IN SUPPORT OF THIS STRATEGY, WE ENGINEERED MABS THAT POTENTLY TRAP RSV IN AM, AND SHOWED THAT NEBULIZED DELIVERY OF “MUCO-TRAPPING” MAB TO RSV-INFECTED NEONATAL LAMBS BEGINNING ON DAY 3 POST INFECTION EFFECTIVELY REDUCED THE INFECTIOUS VIRAL LOAD IN LUNG TISSUES TO NON-DETECTIBLE LEVELS WITHIN 3 DAYS, WITH VIRAL RNA IN BRONCHIAL TISSUES REDUCED BY 11-FOLD COMP