UMMS Affiliation

Horae Gene Therapy Center; Department of Microbiology and Physiological Systems

Publication Date

2019-03-06

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Genetics and Genomics | Immunology and Infectious Disease | Microbiology | Molecular Biology | Therapeutics | Viruses

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.

Keywords

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

Rights and Permissions

© 2019 The Author(s). User License Creative Commons Attribution (CC BY 4.0).

DOI of Published Version

10.1016/j.ymthe.2019.01.004

Source

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

Journal/Book/Conference Title

Molecular therapy : the journal of the American Society of Gene Therapy

Related Resources

Link to Article in PubMed

PubMed ID

30704961

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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