Preclinical development of an anti-Dengue virus antibody that neutralizes all four serotypes
Project Completed
Please click to see the final report.
  • RFP Year
  • Awarded Amount
  • Disease
  • Intervention
  • Development Stage
    Preclinical development
  • Collaboration Partners
    Chugai Pharmaceutical Co., Ltd. ,  A*STAR′s Singapore Immunology Network (SIgN)

Introduction and Background of the Project


Dengue virus (DENV) has rapidly spread throughout the tropical and subtropical urbanized regions. Dengue disease is a mosquito-borne febrile illness caused by any one of four distinct but closely related DENV serotypes and occasionally develops into a potentially lethal complication called severe dengue (dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS)). Today, severe dengue has become a leading cause of hospitalization and death among children and adults in most Asian and Latin American countries. According to the World Health Organization (WHO), approximately 390 million people are infected with DENV, and ~500,000 people are hospitalized each year; however, a therapy for dengue fever has yet to be established.


Project objective

This project is aimed at developing a safe and highly effective monoclonal antibody (mAb) treatment for dengue fever to relieve the severe symptoms, accelerate recuperation and prevent fatal severe dengue disease. This would reduce the burden of dengue in epidemic areas including many developing countries.


Project design

This project aims to:

1) develop the formulation and manufacturing process for the novel anti-Dengue virus antibody, 2) conduct nonclinical pharmacology and preliminary toxicological evaluation to prepare for GLP-toxicology studies and IND application,

3) conduct large-scale production and supply the antibody for GLP-toxicology studies.

How can your partnership (project) address global health challenges?

A novel and unique human DENV mAb was isolated by the Singapore Immunology Network (SIgN), part of the Biomedical Research Council of the Agency for Science, Technology and Research (A*STAR). This antibody is capable of neutralizing all four DENV serotypes, and can be used for both prevention and therapy of DENV infections. It has been further optimized as an antibody-drug by an excellent collaborative relationship of SIgN and Chugai starting on 2015, and a clinical candidate mAb has been identified. We enter to preclinical development studies for clinical application of the mAb, in order to develop effective interventions for treating and preventing DENV.

What sort of innovation are you bringing in your project?

Current approaches of DENV vaccine development have focused on achieving a rapid and balanced tetravalent response in a single injection. If a candidate vaccine cannot induce strong immunity against all four viruses, there is the theoretical possibility of an adverse immune response in individuals who are left unprotected against one or more virus serotypes. Therefore, therapeutic mAb is a complementary intervention that may be useful for patients who contract dengue because they did not receive an approved dengue vaccine or for whom prior vaccination was ineffective.

In addition, anti-DENV mAb can be used to passively vaccinate key personnel such as healthcare professionals and police officers in outbreak scenarios, therefore preventing potential public healthcare paralysis.

Role and Responsibility of Each Partner

SIgN has extensive expertise in DENV biology and is part of the dengue research network in Singapore, one of the epidemic areas of dengue fever. Chugai, including its Singapore subsidiary company Chugai Pharmabody Research (CPR), has various advanced antibody technologies and years of experience in developing antibody drugs from preclinical to clinical stages.

To further develop the mAb, SIgN will be responsible for conducting and reporting the pharmacology studies, including the in vitro and in vivo anti-viral testing. Chugai will be the designated grantee for nonclinical studies of this project, such as creating MCB, production and supply of the mAb for the nonclinical studies including formulation study and preliminary toxicological evaluation. Once these studies are completed without any serious issues, Chugai will continue responsibility for GLP-toxicology studies and drug substance production for such studies.

Others (including references if necessary)

Xu M. et al. A potent neutralizing antibody with therapeutic potential against all four serotypes of dengue virus. npj Vaccines 2, 2 (2017).

Final Report

1. Project objective 

There are 4 distinct, but related, serotypes of dengue virus (DENV) that cause dengue fever. It is hypothesized that antibody-dependent enhancement (ADE) is related to severe disease during secondary DENV infection. This Project aims to develop a safe and highly effective anti-DENV antibody that neutralizes all 4 serotypes for treatment of dengue fever without the risk of ADE.


2. Project design 

In partnership with the GHIT Fund, Chugai and SIgN are working on preclinical development of the novel anti-DENV antibody. The following activities were completed in this project (G2016-217).

1)    Nonclinical pharmacology studies

2)    Preliminary toxicity and tissue cross reactivity (TCR) studies

3)    Process development for manufacturing

4)    Antibody manufacturing for GLP toxicity study


3. Results, lessons learned

In nonclinical pharmacology studies, clinical candidate antibody showed inhibitory activity against all four dengue serotypes with high potency. The antibody effectively reduced viremia against all four serotypes of DENV in a mouse therapeutic model, in which the antibody was administered after virus infection. In the ADE assay using a human cell line, clinical candidate antibody did not enhance dengue virus infection in all four serotypes, indicating a low risk of ADE with the novel antibody.

A preliminary toxicity study in cynomolgus monkey showed no significant toxicological findings related to the antibody. A preliminary TCR study using positive control tissues was also completed to determine the experimental conditions.

A highly productive parental seed stock was established and process development for manufacturing was successfully completed. Master cell bank was established to manufacture the clinical trial material.

Drug substance was manufactured and delivered for IND-enabling preclinical studies.

With these achievements, the clinical candidate antibody is expected to be a novel treatment and prophylaxis option for dengue fever regardless of DENV serotype. Under a strong partnership with the GHIT Fund, we are moving forward towards preparation for initiating the clinical study in the continued project (G2018-106).