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.
Highlights
Developments in large scale screening for HIV+ individuals producing broadly neutralizing HIV antibodies, together with efficient single cell antibody cloning techniques, have led to the identification of increasingly potent HIV bnAbs [1,2,3]
Several bnAbs produced in mammalian cells (VRC01(H) produced in HEK293 cells, PGT128 (C) produced in CHO cells, and CHO1–31, a pool of two mAbs, known to efficiently neutralize most HIV variants) were used as positive controls
With the exception of NIH45–46G54W, all plant-derived bnAb IC50s were similar to control mAbs; PGT121 exhibiting the highest potency with an IC50 of
Summary
Developments in large scale screening for HIV+ individuals producing broadly neutralizing HIV antibodies, together with efficient single cell antibody cloning techniques, have led to the identification of increasingly potent HIV bnAbs [1,2,3]. Since protection against challenge with chimeric simian-HIV (SHIV) isolates through the use of first-generation bnAb cocktails has previously been achieved in macaques [4,5,6,7], the availability of bnAbs with superior.
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