Author: Windsor, Ian W ; Kuraoka, Masayuki ; Almo, Steven C ; Garforth, Scott J ; Mahant, Aakash Mahant ; Achkar, Jacqueline M ; Kong, Susan Luozheng ; Herold, Betsy C ; Kelsoe, Garnett ; Aschner, Clare Burn

There is an unmet need for monoclonal antibodies (mAbs) for prevention or as adjunctive treatment of herpes simplex virus (HSV) disease. Most vaccine and mAb efforts focus on neutralizing antibodies, but for HSV this strategy has proven ineffective. Preclinical studies with a candidate HSV vaccine strain, ΔgD-2, demonstrated that non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC) provide active and passive protection against HSV-1 and HSV-2. We hypothesized that this vaccine provides a tool to identify and characterize protective mAbs. We isolated HSV-specific mAbs from germinal center and memory B cells and bone marrow plasmacytes of ΔgD-2-vaccinated mice and evaluated these mAbs for binding, neutralizing, and FcγR-activating activity and for protective efficacy in mice. The most potent protective mAb, BMPC-23, was not neutralizing but activated murine FcγRIV, a biomarker of ADCC. The cryo-electron microscopic structure of the Fab-glycoprotein B (gB) assembly identified domain IV of gB as the epitope. A single dose of BMPC-23 administered 24 hours before or after viral challenge provided significant protection when configured as mouse IgG2c and protected mice expressing human FcγRIII when engineered as a human IgG1. These results highlight the importance of FcR-activating antibodies in protecting against HSV.

01 Jun 2020·Cell Host & MicrobeQ1 · MEDICINE

Non-neutralizing Antibodies from a Marburg Infection Survivor Mediate Protection by Fc-Effector Functions and by Enhancing Efficacy of Other Antibodies

Q1 · MEDICINE

Article

Author: Karim, Marcus M ; Huang, Kai ; Ilinykh, Philipp A ; Fouch, Mallorie E ; Kimble, James B ; Parekh, Diptiben V ; Bukreyev, Alexander ; Zeitlin, Larry ; Santos, Rodrigo I ; Alter, Galit ; Davidson, Edgar ; Saphire, Erica Ollmann ; Crowe, James E ; Meyer, Michelle ; Pietzsch, Colette A ; Kuzmina, Natalia A ; Liang, Jenny ; Gilchuk, Pavlo ; Gunn, Bronwyn M

Marburg virus (MARV) and Ebola virus (EBOV) belong to the family Filoviridae. MARV causes severe disease in humans with high fatality. We previously isolated a large panel of monoclonal antibodies (mAbs) from B cells of a human survivor with previous naturally acquired MARV infection. Here, we characterized functional properties of these mAbs and identified non-neutralizing mAbs targeting the glycoprotein (GP) 2 portion of the mucin-like domain (MLD) of MARV GP, termed the wing region. One mAb targeting the GP2 wing, MR228, showed therapeutic protection in mice and guinea pigs infected with MARV. The protection was mediated by the Fc fragment functions of MR228. Binding of another GP2 wing-specific non-neutralizing mAb, MR235, to MARV GP increased accessibility of epitopes in the receptor-binding site (RBS) for neutralizing mAbs, resulting in enhanced virus neutralization by these mAbs. These findings highlight an important role for non-neutralizing mAbs during natural human MARV infection.

01 Sep 2010·Molecular Cancer TherapeuticsQ2 · MEDICINE

Molecular Therapy Targeting Sonic Hedgehog and Hepatocyte Growth Factor Signaling in a Mouse Model of Medulloblastoma

Q2 · MEDICINE

Article

Author: Pedone, Carolyn A. ; Kim, K. Jin ; Laukert, Tamara ; Coon, Valerie ; Laterra, John ; Fults, Daniel W.

AbstractThe use of genetically engineered mice has provided insights into the molecular pathogenesis of the pediatric brain tumor medulloblastoma and revealed promising therapeutic targets. Ectopic expression of Sonic hedgehog (Shh) in cerebellar neural progenitor cells induces medulloblastomas in mice, and coexpression of hepatocyte growth factor (HGF) enhances Shh-induced tumor formation. To determine whether Shh + HGF–driven medulloblastomas were responsive to Shh signaling blockade and whether treatment response could be enhanced by combination therapy targeting both HGF and Shh signaling pathways, we carried out a survival study in mice. We induced medulloblastomas by retrovirus-mediated expression of Shh and HGF, after which we treated the mice systemically with (a) HGF-neutralizing monoclonal antibody L2G7, (b) Shh signaling inhibitor cyclopamine, (c) Shh-neutralizing monoclonal antibody 5E1, (d) L2G7 + cyclopamine, or (e) L2G7 + 5E1. We report that monotherapy targeting either HGF signaling or Shh signaling prolonged survival and that anti-HGF therapy had a more durable response than Shh-targeted therapy. The effect of L2G7 + 5E1 combination therapy on cumulative survival was equivalent to that of L2G7 monotherapy and that of L2G7 + cyclopamine therapy was worse. The principal mechanism by which Shh- and HGF-targeted therapies inhibited tumor growth was a potent apoptotic death response in tumor cells, supplemented by a weaker suppressive effect on proliferation. Our observation that combination therapy either failed to improve or even reduced survival in mice bearing Shh + HGF–induced medulloblastomas compared with monotherapy underscores the importance of preclinical testing of molecular-targeted therapies in animal models of tumors in which the targeted pathways are known to be active. Mol Cancer Ther; 9(9); 2627–36. ©2010 AACR.

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Indication	Highest Phase	Country/Location	Organization	Date
Marburg Virus Disease	Preclinical	US	Vanderbilt University Medical Center	-
Marburg Virus Disease	Preclinical	US	University of Texas Medical Branch	-

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