Adonis Alexandre Rubio

All Publications

• Oriented Multivalent Display Drives Consistent Serum Immunodominance to the Ebola Virus Glycoprotein ACS CENTRAL SCIENCE Zheng, C., Rubio, A. A., Vasquez, S., Pham, D., Pan, Z., Barnes, C. O., Kim, P. S. 2026

  View details for DOI 10.1021/acscentsci.5c01886

  View details for Web of Science ID 001659224400001

• Bispecific antibodies targeting the N-terminal and receptor binding domains potently neutralize SARS-CoV-2 variants of concern. Science translational medicine Rubio, A. A., Baharani, V. A., Dadonaite, B., Parada, M., Abernathy, M. E., Wang, Z., Lee, Y. E., Eso, M. R., Phung, J., Ramos, I., Chen, T., El Nesr, G., Bloom, J. D., Bieniasz, P. D., Nussenzweig, M. C., Barnes, C. O. 2025; 17 (788): eadq5720

  Abstract

  The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized amino-terminal domain (NTD)- and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from coronavirus disease 2019 (COVID-19) convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo-electron microscopy structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596's favorable binding profile, we designed a series of bispecific antibodies (bsAbs), termed CoV2-biRNs, that featured both NTD and RBD specificities. Two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, BA.2.86, and JN.1, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 reduced the viral load within the lungs of K18-hACE2 mice after challenge with SARS-CoV-2 XBB.1.5. In conclusion, NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.

  View details for DOI 10.1126/scitranslmed.adq5720

  View details for PubMedID 40043139

• A derivative of the D5 monoclonal antibody that targets the gp41 N-heptad repeat of HIV-1 with broad tier-2 neutralizing activity. Journal of virology Rubio, A. A., Filsinger Interrante, M. V., Bell, B. N., Brown, C. L., Bruun, T. U., LaBranche, C. C., Montefiori, D. C., Kim, P. S. 2021

  Abstract

  HIV-1 infection is initiated by the viral glycoprotein Env, which, after interaction with cellular coreceptors, adopts a transient conformation known as the pre-hairpin intermediate (PHI). The N-heptad repeat (NHR) is a highly conserved region of gp41 exposed in the PHI; it is the target of the FDA-approved drug enfuvirtide and of neutralizing monoclonal antibodies (mAbs). However, to date these mAbs have only been weakly effective against tier-1 HIV-1 strains, which are most sensitive to neutralizing antibodies. Here, we engineered and tested 11 IgG variants of D5, an anti-NHR mAb, by recombining previously described mutations in four of D5's six antibody complementarity-determining regions. One variant, D5_AR, demonstrated 6-fold enhancement in ID50 against lentivirus pseudotyped with HXB2 Env. D5_AR exhibited weak cross-clade neutralizing activity against a diverse set of tier-2 HIV-1 viruses, which are less sensitive to neutralizing antibodies than tier-1 viruses and are the target of current antibody-based vaccine efforts. In addition, the neutralization potency of D5_AR IgG was greatly enhanced in target cells expressing FcgammaRI, with ID50 values below 0.1 mug/mL; this immunoglobulin receptor is expressed on macrophages and dendritic cells, which are implicated in the early stages of HIV-1 infection of mucosal surfaces. D5 and D5_AR have equivalent neutralization potency in IgG, Fab, and scFv formats, indicating that neutralization is not impacted by steric hindrance. Taken together, these results provide support for vaccine strategies that target the PHI by eliciting antibodies against the gp41 NHR and support investigation of anti-NHR mAbs in non-human primate passive immunization studies.ImportanceDespite advances in anti-retroviral therapy, HIV remains a global epidemic and has claimed more than 32 million lives. Accordingly, developing an effective HIV vaccine remains an urgent public health need. The gp41 N-heptad repeat (NHR) of the HIV-1 pre-hairpin intermediate (PHI) is highly conserved (>90%) and is inhibited by the FDA-approved drug enfuvirtide, making it an attractive vaccine target. However, to date anti-NHR antibodies have not been potent. Here, we engineered D5_AR, a more potent variant of the anti-NHR antibody D5, and established its ability to inhibit HIV-1 strains that are more difficult to neutralize and are more representative of circulating strains (tier-2 strains). The neutralizing activity of D5_AR was greatly potentiated in cells expressing FcgammaRI; FcgammaRI is expressed on cells that are implicated at the earliest stages of sexual HIV-1 transmission. Taken together, these results bolster efforts to target the gp41 NHR and the PHI for vaccine development.

  View details for DOI 10.1128/JVI.02350-20

  View details for PubMedID 33980592

• The high-affinity immunoglobulin receptor FcgammaRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat. Proceedings of the National Academy of Sciences of the United States of America Montefiori, D. C., Filsinger Interrante, M. V., Bell, B. N., Rubio, A. A., Joyce, J. G., Shiver, J. W., LaBranche, C. C., Kim, P. S. 2021; 118 (3)

  Abstract

  The HIV-1 gp41 N-heptad repeat (NHR) region of the prehairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the Food and Drug Administration (FDA)-approved drug enfuvirtide. However, vaccine candidates targeting the NHR have yielded only modest neutralization activities in animals; this inhibition has been largely restricted to tier-1 viruses, which are most sensitive to neutralization by sera from HIV-1-infected individuals. Here, we show that the neutralization activity of the well-characterized NHR-targeting antibody D5 is potentiated >5,000-fold in TZM-bl cells expressing FcgammaRI compared with those without, resulting in neutralization of many tier-2 viruses (which are less susceptible to neutralization by sera from HIV-1-infected individuals and are the target of current antibody-based vaccine efforts). Further, antisera from guinea pigs immunized with the NHR-based vaccine candidate (ccIZN36)3 neutralized tier-2 viruses from multiple clades in an FcgammaRI-dependent manner. As FcgammaRI is expressed on macrophages and dendritic cells, which are present at mucosal surfaces and are implicated in the early establishment of HIV-1 infection following sexual transmission, these results may be important in the development of a prophylactic HIV-1 vaccine.

  View details for DOI 10.1073/pnas.2018027118

  View details for PubMedID 33431684