Development of a Human Antibody Cocktail that Deploys Multiple Functions to Confer Pan-Ebolavirus Protection

Anna Z. Wec, Zachary A. Bornholdt, Shihua He, Andrew S. Herbert, Eileen Goodwin, Ariel S. Wirchnianski, Bronwyn M. Gunn, Zirui Zhang, Wenjun Zhu, Guodong Liu, Dafna M. Abelson, Crystal L. Moyer, Rohit K. Jangra, Rebekah M. James, Russell R. Bakken, and others, Laura M. Walker, John M. Dye, Larry Zeitlin, Xiangguo Qiu, Kartik Chandran 

Cell Host Microbe 25, 39–48.e5. DOI: 10.1016/j.chom.2018.12.004 

Overview  

All Ebola monoclonal antibody (mAb) therapies that have reached clinical development target only Ebola virus (EBOV) and are ineffective against other outbreak-causing ebolaviruses, such as Bundibugyo virus (BDBV) and Sudan virus (SUDV). They also offer no protection against novel ebolaviruses such as Bombali virus (BOMV), discovered in bats. This study presents MBP134AF, a two-antibody cocktail combining a broadly neutralizing human mAb (ADI-15878) with a partner mAb (ADI-23774) engineered for improved SUDV binding. Both antibodies were further enhanced by Fc glycan engineering to better engage natural killer (NK) cells, which play a critical role in protection against EBOV infection. 

Study rationale and objectives 

The lead antibody, ADI-15878, potently neutralizes all ebolaviruses by targeting a conserved fusion-loop epitope on the viral glycoprotein (GP), and fully protects mice against EBOV and SUDV. However, it only partially protects ferrets and guinea pigs, consistent with prior evidence that antibody cocktails targeting multiple GP sites may be needed for complete protection. This motivated a search for a second mAb that targets a distinct binding site to pair with ADI-15878. 

The objectives of the study were to: 

• Identify and characterize a suitable partner mAb to pair with ADI-15878. 

• Optimize and assess neutralization potency and breadth of both antibodies individually and as a cocktail. 

• Engineer a second-generation cocktail (MBP134AF) with improved NK cell engagement. 

• Evaluate the prophylactic and therapeutic efficacy of MBP134AF against EBOV and SUDV. 

Approach and techniques 

Existing human and nonhuman primate mAb panels were comprehensively screened to identify a suitable partner to ADI-15878 based on:  

• their host origin (human or nonhuman primate); 

• neutralization potency and breadth across EBOV, BDBV, and SUDV;  

• activity against both intact and cleaved forms of ebolavirus glycoprotein; 

• lack of cross-reactivity with secreted glycoprotein (sGP) to avoid sGP acting as a sink; 

• and post-exposure protection against EBOV in mice.  

This identified ADI-15946, which binds a distinct, non-competing GP site. ADI-15946 was then engineered using Adimab’s yeast presentation technology to improve its binding to SUDV, producing ADI-23774. Pairing ADI-15878 with ADI-23774 created the cocktail MBP134. The antibodies were further modified, by afucosylation, to improve NK cell engagement, producing the optimized cocktail MBP134AF with the desired enhanced Fc effector function (antibody-dependent cellular cytotoxicity). Both cocktails were assessed for neutralization breadth against all known ebolaviruses and for protective efficacy in guinea pig models of lethal EBOV and SUDV challenge. 

Major findings and results 

• Pan-ebolavirus neutralization: MBP134 potently neutralized all ebolaviruses tested and offered greater protection than ADI-15878 alone in EBOV-challenged guinea pigs. 

• Fc engineering for enhanced effector function: The Fc-engineered MBP134AF further improved protection against both EBOV and SUDV by enhancing NK cell activation. 

• Single low dose is sufficient for protection: A single 10 mg/kg dose of MBP134AF administered as late as 3–5 days after virus exposure fully protected guinea pigs against EBOV and SUDV challenge. 

• Clinical development candidate: MBP134AF represents an optimized cocktail suitable for evaluation as a pan-ebolavirus therapeutic in nonhuman primates. 

Implications for therapeutic antibody development 

This study illustrates a full antibody discovery and development process, from selecting a survivor-derived mAb, through engineering a partner mAb for broader specificity, to Fc engineering for enhanced immune engagement. The result, per the study, is a therapeutic candidate that shows greater breadth and potency against ebolaviruses than any previously described antibody or antibody cocktail.