Horae Gene Therapy Center; Department of Microbiology and Physiological Systems
Amino Acids, Peptides, and Proteins | Genetics and Genomics | Immunology and Infectious Disease | Microbiology | Molecular Biology | Therapeutics | Viruses
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.
10-1074, 3BNC117, AAV, ADA, HIV-1, NIH45-46, PGT121, anti-drug antibodies, bNAbs, broadly neutralizing antibodies
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DOI of Published Version
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
Molecular therapy : the journal of the American Society of Gene Therapy
Gardner, Matthew R.; Fetzer, Ina; Kattenhorn, Lisa M.; Davis-Gardner, Meredith E.; Zhou, Amber S.; Alfant, Barnett; Weber, Jesse A.; Kondur, Hema R.; Martinez-Navio, Jose M.; Fuchs, Sebastian P.; Desrosiers, Ronald C.; Gao, Guangping; Lifson, Jeffrey D.; and Farzan, Michael, "Anti-drug Antibody Responses Impair Prophylaxis Mediated by AAV-Delivered HIV-1 Broadly Neutralizing Antibodies" (2019). Open Access Articles. 3739.
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