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Plasmid DNA encoding neutralizing human monoclonal antibody without enhancing activity protects against dengue virus infection in mice

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Asian Pacific Journal of Tropical Medicine 2021年第7期14卷 299-308页

作者： Surachet Benjathummarak Atsushi Yamanaka Thanyaluk Krasae Chonlatip Pipattanaboon Subenya Injampa pannamthip pitaksajjakul Pongrama Ramasoota Department of Social and Environmental Medicine Faculty of Tropical MedicineMahidol UniversityBangkokThailand Center of Excellence for Antibody Research(CEAR) Faculty of Tropical MedicineMahidol UniversityBangkokThailand Mahidol-Osaka Center for Infectious Diseases(MOCID) Faculty of Tropical MedicineMahidol UniversityBangkokThailand Mahidol-Osaka Center for Infectious Diseases Research Institute for Microbial DiseasesOsaka UniversityOsakaJapan Laboratory Animal Science Unit Faculty of Tropical MedicineMahidol UniversityBangkokThailand Department of Microbiology Faculty of MedicineKhon Kaen UniversityThailand Faculty of Medicine King Mongkut’s Institute of Technology LadkrabangBangkokThailand

Objective: To evaluate the expression of DNA plasmid-harboring modified antibody gene that produces neutralizing human monoclonal antibodies against four serotypes of dengue virus(DENV) without enhancing activity in BALB/c mice. Methods: We constructed pFUSE-based vectors(pFUSE1 G7 C2hVH and pFUSE1 G7 C2hVL) containing genes encoding the variable domains of the heavy or light chain of the anti-dengue virus antibody 1 G7 C2, a human IgG1 that has been characterized for its neutralizing activity to DENV-1-4. Leucine(L) at positions 234 and 235 on the Fc CH2 domain in pFUSE1 G7 C2hVH was mutated to alanine(A)(LALA mutation) by site direct mutagenesis, and the new plasmid was termed pFUSE1 G7 C2hVHLALA. An equal amount of pFUSE1 G7 C2hVL and 1 G7 C2hG1-LALA plasmids were co-transfected into Chinese hamster ovary cells(CHO-K1) and a single dose of 100 μg 1 G7 C2hG1-LALA plasmid was intramuscularly injected, followed by electroporation in BALB/c mice. The secreted 1 G7 C2hG1-LALA antibodies in cell culture supernatant and mouse serum were examined for their biological functions, neutralization and enhancing activity. Results: The co-transfection of heavy-and light-chain 1 G7 C2hG1-LALA plasmids in CHO-K1 cells produced approximately 3 900 ng/mL human IgG and neutralized 90%-100% all four DENV, with no enhancing activity. Furthermore, the modified human IgG was produced more than 1 000 ng/mL in mouse serum on day 7 post plasmid injection and showed cross-neutralization to four DENV serotypes. Subsequently, antibody production and neutralization decreased rapidly. Nevertheless, the secreted neutralizing 1 G7 C2hG1-LALA in mouse serum demonstrated complete absence of enhancing activities to all DENV serotypes. Conclusions: These findings reveal that a new modified 1 G7 C2h G1-LALA expressing plasmid based on gene transfer is a possible therapeutic antibody candidate against DENV infection.

关键词： Dengue virus LALA mutation Antibodydependent enhancement(ADE) Antibody plasmid Electroporation

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