The magnitude and duration of the ongoing COVID-19 pandemic have underscored the need to
have a well-equipped—and ideally prepositioned—arsenal of antiviral weapons to mount an
adequate public health response. A key lesson is that multiple medical countermeasures (MCMs)
are needed to maintain potency and efficacy in the face of a rapidly evolving virus. Several
approved SARS-CoV-2 vaccines have been paramount to gaining control over the pandemic,
reducing both the number of infections and severity of disease for much of the global population.
Unfortunately, these vaccines provide little to no protection to immunocompromised individuals
who are unable to mount an effective immune response. Half-life extended monoclonal antibodies
(mAbs) offer an attractive alternative, as their long half-life and high potency offer instantaneous
immunity and vaccine-like protection without requiring the generation of a robust immune
response. While >10,000 mAbs and multiple mAb cocktails have been explored over the course
of the pandemic and several advanced as therapeutic candidates, they have largely failed to
maintain potent activity in the face of prevalent antigenic drift within the SARS-CoV-2 spike
protein. Moreover, currently approved vaccines and immunotherapeutics offer no protection from
a related b-CoV, Middle East respiratory syndrome (MERS) virus. While small molecule inhibitors
such as Paxlovid have shown broad in vitro activity against SARS and MERS, significant issues
with COVID-19 rebound following treatment suggest it may not remain efficacious against the
more lethal MERS virus. A recently identified antibody, 1249A8 (renamed AR-703), that
recognizes a unique and highly conserved epitope in the S2 domain of the coronavirus spike
protein offers a potential solution, being refractory to antigenic drift and having broad activity b-
CoV activity, inclusive of SARS and MERS. The goal of the proposal is to maximize the clinical
utility of AR-703 through multidimensional structure-based approach to increase neutralization
potency and expand breadth of AR-703. In parallel, bispecific antibody engineering utilizing a
novel bovine ultra-long CDR3 (UL-CDR3) based bispecific platform technology will be explored
to introduce synergistic neutralization and resist viral escape. The structures of bovine UL-CDR3s
have a demonstrated ability to independently target cryptic highly conserved epitopes, vital to
maintaining efficacy to novel viral variants. Combining AR-703 and pan-b-CoV UL-CDR3 into a
single bispecific would enable dual engagement of highly conserved neutralizing epitopes offering
a potent solution to SARS2 antigenic drift for the immunocompromised while also guarding
against related lethal b-CoVs should they emerge in the future.
