Anti-drug Antibody Responses Impair Prophylaxis Mediated by AAV-Delivered HIV-1 Broadly Neutralizing Antibodies
AuthorsGardner, Matthew R.
Kattenhorn, Lisa M.
Davis-Gardner, Meredith E.
Zhou, Amber S.
Weber, Jesse A.
Kondur, Hema R.
Martinez-Navio, Jose M.
Fuchs, Sebastian P.
Desrosiers, Ronald C.
Lifson, Jeffrey D.
UMass Chan AffiliationsDepartment of Microbiology and Physiological Systems
Horae Gene Therapy Center
broadly neutralizing antibodies
Amino Acids, Peptides, and Proteins
Genetics and Genomics
Immunology and Infectious Disease
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AbstractAdeno-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.
Mol Ther. 2019 Mar 6;27(3):650-660. doi: 10.1016/j.ymthe.2019.01.004. Epub 2019 Jan 12. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/40939
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Except where otherwise noted, this item's license is described as © 2019 The Author(s). User License Creative Commons Attribution (CC BY 4.0).