Anti-drug Antibody Responses Impair Prophylaxis Mediated by AAV-Delivered HIV-1 Broadly Neutralizing Antibodies

Matthew R. Gardner, Ina Fetzer, Lisa M. Kattenhorn, Meredith E. Davis-Gardner, Amber S. Zhou, Barnett Alfant, Jesse A. Weber, Hema R. Kondur, Jose M. Martinez-Navio, Sebastian P. Fuchs, Ronald C. Desrosiers, Guangping Gao, Jeffrey D. Lifson, Michael Farzan

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Adeno-associated virus (AAV) delivery of potent and broadly neutralizing antibodies (bNAbs is a promising approach for the prevention of HIV-1 infection. The immunoglobulin G (IgG)1 subtype is usually selected for this application, because it efficiently mediates antibody effector functions and has a somewhat longer half-life. However, the use of IgG1-Fc has been associated with the generation of anti-drug antibodies (ADAs) that correlate with loss of antibody expression. In contrast, we have shown that expression of the antibody-like molecule eCD4-Ig bearing a rhesus IgG2-Fc domain showed reduced immunogenicity and completely protected rhesus macaques from simian-HIV (SHIV)-AD8 challenges. To directly compare the performance of the IgG1-Fc and the IgG2-Fc domains in a prophylactic setting, we compared AAV1 expression of rhesus IgG1 and IgG2 forms of four anti-HIV bNAbs: 3BNC117, NIH45-46, 10-1074, and PGT121. Interestingly, IgG2-isotyped bNAbs elicited significantly lower ADA than their IgG1 counterparts. We also observed significant protection from two SHIV-AD8 challenges in macaques expressing IgG2-isotyped bNAbs, but not from those expressing IgG1. Our data suggest that monoclonal antibodies isotyped with IgG2-Fc domains are less immunogenic than their IgG1 counterparts, and they highlight ADAs as a key barrier to the use of AAV1-expressed bNAbs. Vectored delivery of broadly neutralizing antibodies (bNAbs) could afford vaccine-like protection from HIV-1. Gardner et al. show that IgG2 forms of bNAbs raised fewer anti-bNAbs in rhesus macaques than did IgG1 forms. Further, protection from SHIV-AD8 decreased with higher levels of anti-bNAbs and lower bNAb concentrations.

Original languageEnglish (US)
Pages (from-to)650-660
Number of pages11
JournalMolecular Therapy
Volume27
Issue number3
DOIs
StatePublished - Mar 6 2019

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Keywords

  • 10-1074
  • 3BNC117
  • AAV
  • ADA
  • HIV-1
  • NIH45-46
  • PGT121
  • anti-drug antibodies
  • bNAbs
  • broadly neutralizing antibodies

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Gardner, M. R., Fetzer, I., Kattenhorn, L. M., Davis-Gardner, M. E., Zhou, A. S., Alfant, B., Weber, J. A., Kondur, H. R., Martinez-Navio, J. M., Fuchs, S. P., Desrosiers, R. C., Gao, G., Lifson, J. D., & Farzan, M. (2019). Anti-drug Antibody Responses Impair Prophylaxis Mediated by AAV-Delivered HIV-1 Broadly Neutralizing Antibodies. Molecular Therapy, 27(3), 650-660. https://doi.org/10.1016/j.ymthe.2019.01.004