Pan-ebolavirus protective therapy by two multifunctional human antibodies

Area of Science:

• Virology
• Immunology
• Therapeutics

Background:

• Ebolaviruses cause severe, potentially fatal hemorrhagic fevers with pandemic potential.
• Current monoclonal antibody treatments are specific to Ebola virus (EBOV) and ineffective against other ebolaviruses like Bundibugyo (BDBV) and Sudan (SUDV).

Purpose of the Study:

• To develop a broadly neutralizing antibody cocktail effective against multiple ebolavirus species.
• To provide preclinical data supporting the clinical development of a pan-ebolavirus therapy.

Main Methods:

• Development of a two-antibody cocktail (rEBOV-515 and rEBOV-442) targeting distinct sites on the ebolavirus glycoprotein (GP).
• Assessment of synergistic neutralizing activity, viral escape resistance, and Fc-region requirements for in vivo efficacy.
• Evaluation of the cocktail's therapeutic effectiveness in non-human primates challenged with EBOV, BDBV, and SUDV.
• High-resolution structural analysis of antibody-GP complexes to understand neutralization mechanisms.

Main Results:

• The antibody cocktail demonstrated synergistic neutralization and resistance to viral escape.
• The cocktail provided high therapeutic effectiveness in protecting non-human primates against EBOV, BDBV, and SUDV.
• Structural studies elucidated the molecular basis for the cocktail's broad neutralization and potency.

Conclusions:

• The developed antibody cocktail offers broad protection against diverse ebolaviruses.
• This preclinical data supports the advancement of this cocktail as a potential pan-ebolavirus therapeutic agent.