Development of a monoclonal therapy for neonatal herpes

Project Summary Neonatal infections caused by herpes simplex virus 1 or 2 (HSV-1, HSV-2) result in significant morbidity and mortality. Current medical treatment of neonatal HSV infections (nHSV) is limited to small molecule antivirals such as acyclovir, but even with high dose treatment, mortality subsequent to disseminated disease remains high (30%), and central nervous system (CNS) disease is associated with ∼70% neurological morbidity and 25% mortality. Monoclonal antibodies (mAbs) offer a class of intervention that provides immediate protection and a well-established development path, with over 200 mAb products licensed by U.S. and European regulatory bodies. Passive immunization with mAbs has been shown to be effective against a wide variety of infectious agent, with mAbs against Ebola virus, SARS-CoV-2, and Respiratory Syncytial Virus (RSV) approved by the FDA. Members of the ZabBio team have previously advanced 3 mAb products to clinical trials, including one which contained the broadly neutralizing HSV mAb, HSV8, which is the focus of this product development Fast Track SBIR proposal for neonatal HSV infection. More recently, ZabBio scientists have collaborated with Drs. Margaret Ackerman and David Leib (Dartmouth) who have demonstrated the utility of HSV8 in a mouse model of nHSV. These data support the hypothesis that HSV8 may be a useful clinical intervention for nHSV in humans. Phase 1 of this proposal contains 2 aims: 1) Assess the neutralization potency of HSV8 against a panel of HSV-1 and HSV-2 isolates from neonatal herpes patients; 2) Test whether HSV8 selects for HSV-1 and HSV-2 escape mutants. These two aims will result in a rigorous Go/No decision for proceeding to Phase 2. In Phase 2, the proposal transitions to traditional product development with 3 aims: 1) Manufacture HSV8 under cGMP in the Nicotiana benthamiana based Rapid Protein Production Platform (RP3) system; 2) Submit pre-IND to FDA; 3) Perform IND-enabling pharmacology/toxicology studies. This work scope will culminate in an Investigational New Drug (IND) submission.