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Pharmacokinetics and immunogenicity of broadly neutralizing HIV monoclonal antibodies in macaques.

PloS one (2015-03-26)
Yvonne Rosenberg, Markus Sack, David Montefiori, Celia Labranche, Mark Lewis, Lori Urban, Lingjun Mao, Rainer Fischer, Xiaoming Jiang
ABSTRACT

The identification of highly potent broadly neutralizing antibodies (bnAbs) against HIV-1, and success in preventing SHIV infection following their passive administration, have increased the likelihood that immunotherapeutic strategies can be adopted to prevent and treat HIV-1 infection. However, while broad and potent neutralizing activity is an essential prerequisite, in vivo properties such as good circulatory stability and non-immunogenicity are equally critical for developing a human treatment. In the present study, glycoforms of the bnAbs 10-1074, NIH45-46G54W, 10E8, PGT121, PGT128, PGT145, PGT135, PG9, PG16, VRC01 and b12 were produced by Agrobacterium-mediated transient transfection of Nicotiana benthamiana and assessed following administration in rhesus macaques. The results indicate that (i) N-glycans within the VL domain impair plasma stability of plant-derived bnAbs and (ii) while PGT121 and b12 exhibit no immunogenicity in rhesus macaques after multiple injections, VRC01, 10-1074 and NIH45-46G54W elicit high titer anti-idiotypic antibodies following a second injection. These anti-idiotypic antibodies specifically bind the administered bnAb or a close family member, and inhibit the bnAb in neutralization assays. These findings suggest that specific mutations in certain bnAbs contribute to their immunogenicity and call attention to the prospect that these mutated bnAbs will be immunogenic in humans, potentially compromising their value for prophylaxis and therapy of HIV-1.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
3,3′,5,5′-Tetramethylbenzidine, ≥99%
Sigma-Aldrich
Anti-Human IgG (Fc specific)−Peroxidase antibody produced in goat, affinity isolated antibody
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3,3′,5,5′-Tetramethylbenzidine, ≥98% (TLC)
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3,3′,5,5′-Tetramethylbenzidine, tablet, 1 mg substrate per tablet
Sigma-Aldrich
3,3′,5,5′-Tetramethylbenzidine, ≥98.0% (NT)
Sigma-Aldrich
Anti-Human Kappa Light Chain (Bound and Free) antibody produced in goat, affinity isolated antibody, lyophilized powder
Supelco
3,3′,5,5′-Tetramethylbenzidine, standard for GC

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