TY - JOUR
T1 - Generation and testing anti-influenza human monoclonal antibodies in a new humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO. IL-2Rγc KO. NOD)
AU - Mendoza, Mirian
AU - Ballesteros, Angela
AU - Qiu, Qi
AU - Pow Sang, Luis
AU - Shashikumar, Soumya
AU - Casares, Sofia
AU - Brumeanu, Teodor D.
N1 - Funding Information:
This work was supported by USUHS grants (RO83193816 and G287252016) to TDB.
Funding Information:
This work was supported by USUHS grants (RO83193816 and G287252016) to TDB. We thank Xinyue Qiu for assistance with ELISA, RT-qPCR, and WB assays, and Mike Flora for assistance with FPLC assays. TDB, and SC are US Government employees. The work of these individuals was prepared as part of official government duties. Title 17 U.S.C. ?105 provides that ?Copyright protection under this title is not available for any work of the United States Government.? Title 17 U.S.C. ?101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person's official duties. The views expressed in this paper are those of the authors and do not necessarily represent the views of Uniformed Services University, Department of Defense, or other Federal Agencies.
Publisher Copyright:
© 2018, This article not subject to US copyright law.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - Pandemic outbreaks of influenza type A viruses have resulted in numerous fatalities around the globe. Since the conventional influenza vaccines (CIV) provide less than 20% protection for individuals with weak immune system, it has been considered that broadly cross-neutralizing antibodies may provide a better protection. Herein, we showed that a recently generated humanized mouse (DRAGA mouse; HLA-A2. HLA-DR4. Rag1KO. IL-2Rgc KO. NOD) that lacks the murine immune system and expresses a functional human immune system can be used to generate cross-reactive, human anti-influenza monoclonal antibodies (hu-mAb). DRAGA mouse was also found to be suitable for influenza virus infection, as it can clear a sub-lethal infection and sustain a lethal infection with PR8/A/34 influenza virus. The hu-mAbs were designed for targeting a human B-cell epitope (180WGIHHPPNSKEQ QNLY195) of hemagglutinin (HA) envelope protein of PR8/A/34 (H1N1) virus with high homology among seven influenza type A viruses. A single administration of HA180-195 specific hu-mAb in PR8-infected DRAGA mice significantly delayed the lethality by reducing the lung damage. The results demonstrated that DRAGA mouse is a suitable tool to (i) generate heterotype cross-reactive, anti-influenza human monoclonal antibodies, (ii) serve as a humanized mouse model for influenza infection, and (iii) assess the efficacy of anti-influenza antibody-based therapeutics for human use.
AB - Pandemic outbreaks of influenza type A viruses have resulted in numerous fatalities around the globe. Since the conventional influenza vaccines (CIV) provide less than 20% protection for individuals with weak immune system, it has been considered that broadly cross-neutralizing antibodies may provide a better protection. Herein, we showed that a recently generated humanized mouse (DRAGA mouse; HLA-A2. HLA-DR4. Rag1KO. IL-2Rgc KO. NOD) that lacks the murine immune system and expresses a functional human immune system can be used to generate cross-reactive, human anti-influenza monoclonal antibodies (hu-mAb). DRAGA mouse was also found to be suitable for influenza virus infection, as it can clear a sub-lethal infection and sustain a lethal infection with PR8/A/34 influenza virus. The hu-mAbs were designed for targeting a human B-cell epitope (180WGIHHPPNSKEQ QNLY195) of hemagglutinin (HA) envelope protein of PR8/A/34 (H1N1) virus with high homology among seven influenza type A viruses. A single administration of HA180-195 specific hu-mAb in PR8-infected DRAGA mice significantly delayed the lethality by reducing the lung damage. The results demonstrated that DRAGA mouse is a suitable tool to (i) generate heterotype cross-reactive, anti-influenza human monoclonal antibodies, (ii) serve as a humanized mouse model for influenza infection, and (iii) assess the efficacy of anti-influenza antibody-based therapeutics for human use.
KW - Anti-flu antibody therapy
KW - Human influenza infection model
KW - Human monoclonal antibodies
KW - Humanized mice
UR - http://www.scopus.com/inward/record.url?scp=85038639863&partnerID=8YFLogxK
U2 - 10.1080/21645515.2017.1403703
DO - 10.1080/21645515.2017.1403703
M3 - Article
C2 - 29135340
AN - SCOPUS:85038639863
SN - 2164-5515
VL - 14
SP - 345
EP - 360
JO - Human Vaccines and Immunotherapeutics
JF - Human Vaccines and Immunotherapeutics
IS - 2
ER -