Antibodies for HIV Treatment and Prevention: Window of Opportunity?

Huber, Michael; Olson, William C.; Trkola, Alexandra

doi:10.1007/978-3-540-72146-8_2

Cited by 20 publications

(12 citation statements)

References 172 publications

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“…Notably, the entire procedure works equally well when the virus-based magnICON expression system was used, resulting in yields of up to 500 mg of functional mAbs per kg of fresh leaf biomass (29). 3 Additionally, a virtually unlimited number of different mAbs can be generated within 1 week post-DNA construct delivery, and the system is easily adaptable for the use of other expression vectors allowing high protein production (8). Interestingly, galactosylation works very efficiently when ST-GalT is transiently expressed, indicating that time-consuming transformation procedures as needed for the generation of GalT ϩ plants may be dispensable.…”

Section: Discussionmentioning

confidence: 99%

Improved Virus Neutralization by Plant-produced Anti-HIV Antibodies with a Homogeneous β1,4-Galactosylated N-Glycan Profile

Strasser

Castilho

Stadlmann

et al. 2009

Journal of Biological Chemistry

160

174

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It is well established that proper N-glycosylation significantly influences the efficacy of monoclonal antibodies (mAbs). However, the specific immunological relevance of individual mAbassociated N-glycan structures is currently largely unknown, because of the heterogeneous N-glycan profiles of mAbs when produced in mammalian cells. Here we report on the generation of a plant-based expression platform allowing the efficient production of mAbs with a homogeneous ␤1,4-galactosylated N-glycosylation structure, the major N-glycan species present on serum IgG. This was achieved by the expression of a highly active modified version of the human ␤1,4-galactosyltransferase in glycoengineered plants lacking plant-specific glycosylation. Moreover, we demonstrate that two anti-human immunodeficiency virus mAbs with fully ␤1,4-galactosylated N-glycans display improved virus neutralization potency when compared with other glycoforms produced in plants and Chinese hamster ovary cells. These findings indicate that mAbs containing such homogeneous N-glycan structures should display improved in vivo activities. Our system, using expression of mAbs in tobacco plants engineered for post-translational protein processing, provides a new means of overcoming the two hurdles that limit the therapeutic use of anti-human immunodeficiency virus mAbs in global health initiatives, low biological potency and high production costs.

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Section: Discussionmentioning

confidence: 99%

Improved Virus Neutralization by Plant-produced Anti-HIV Antibodies with a Homogeneous β1,4-Galactosylated N-Glycan Profile

Strasser

Castilho

Stadlmann

et al. 2009

Journal of Biological Chemistry

160

174

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“…Further, in initial experiments using less effective nAbs than used now, it was observed that nAbs could not control HIV infection in humans despite their ability to neutralize patient samples ex vivo (Mehandru et al, 2007; Poignard et al, 1999; Trkola et al, 2005). Upon subsequent analysis, it was estimated that at least 10x more Ab would be required to achieve a 50% response in HIV-infected patients (Huber et al, 2008; Trkola et al, 2008), suggesting diminished Ab effector activity during persistent infections of humans as well. Herein, we demonstrate that high amounts of ICs generated during viral persistence suppress FcγR-dependent, Ab-mediated effector functions including the killing of infected cells and antigen presentation for T cell activation, thus compounding the overall immunosuppression that potentiates persistent viral infection.…”

Section: Introductionmentioning

confidence: 99%

Suppression of Fcγ-Receptor-Mediated Antibody Effector Function during Persistent Viral Infection

et al. 2015

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SUMMARY Understanding how viruses subvert host immunity and persist is essential for developing strategies to eliminate infection. T cell exhaustion during chronic viral infection is well described, but effects on antibody-mediated effector activity are unclear. Herein, we show that increased amounts of immune complexes generated in mice persistently infected with lymphocytic choriomeningitis virus (LCMV) suppressed multiple Fcγ-receptor (FcγR) functions. The high amounts of immune complexes suppressed antibody-mediated cell depletion, therapeutic antibody-killing of LCMV infected cells, and human CD20-expressing tumors, as well as reduced immune complex-mediated cross-presentation to T cells. Suppression of FcγR activity was not due to inhibitory FcγRs or high concentrations of free antibody, and proper FcγR functions were restored when persistently infected mice specifically lacked immune complexes. Thus, we identify a mechanism of immunosuppression during viral persistence with implications for understanding effective antibody activity aimed at pathogen control.

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“…47 This has added to the interest in developing long acting antiretroviral agents that enhance compliance, especially in the setting of preexposure prophylaxis. [48][49][50] Antibody-based products have a long history of clinical utility for preventing viral infections and might represent improvements over existing approaches, [51][52][53] especially since by their nature they would be administered by a directly observed modality of therapy.…”

Section: Discussionmentioning

confidence: 99%

Full Length Single Chain Fc Protein (FLSC IgG1) as a Potent Antiviral Therapy Candidate: Implications forIn VivoStudies

Latinovic

Medina‐Moreno

Schneider

et al. 2016

AIDS Research and Human Retroviruses

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We have previously shown that FLSC, a chimeric protein containing HIV-1 BAL gp120 and the D1 and D2 domains of human CD4, blocks the binding and entry of HIV-1 into target cells by occluding CCR5, the major HIV-1 coreceptor. In an effort to improve the antiviral potential of FLSC, we fused it with the hinge-C H 2-C H 3 region of human IgG1. The IgG moiety should increase both the affinity and stability in vivo of FLSC, due to the resultant bivalency and an extended serum half-life, thereby increasing its antiviral potency. We previously showed that (FLSC) IgG1 indeed had greater antiviral activity against T cell infections. Here we extend these results to macrophages, for which (FLSC) IgG1 has a more potent antiviral activity than FLSC alone, due in part to its higher binding affinity for CCR5. We also test both compounds in a relevant humanized mouse model and show that, as anticipated, the IgG1 moiety confers a greatly extended half-life. These data, taken together with previous results, suggest potential clinical utility for (FLSC) IgG1 and support further developmental work toward eventual clinical trials.

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Antibodies for HIV Treatment and Prevention: Window of Opportunity?

Cited by 20 publications

References 172 publications

Improved Virus Neutralization by Plant-produced Anti-HIV Antibodies with a Homogeneous β1,4-Galactosylated N-Glycan Profile

Improved Virus Neutralization by Plant-produced Anti-HIV Antibodies with a Homogeneous β1,4-Galactosylated N-Glycan Profile

Suppression of Fcγ-Receptor-Mediated Antibody Effector Function during Persistent Viral Infection

Full Length Single Chain Fc Protein (FLSC IgG1) as a Potent Antiviral Therapy Candidate: Implications forIn VivoStudies

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