Antiretroviral Activity of the Anti‐CD4 Monoclonal Antibody TNX‐355 in Patients Infected with HIV Type 1

Kuritzkes, Daniel R.; Jacobson, Jeffrey M.; Powderly, William G.; Godofsky, Eliot; DeJesus, Edwin; Haas, Frances; Reimann, Keith A.; Larson, Jeffrey; Yarbough, Patrice O.; Curt, Valentin; Shanahan, William R.

doi:10.1086/380802

Cited by 185 publications

(141 citation statements)

References 18 publications

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“…To this end, we constructed more than two dozen bispecific Abs, using the humanized anti-CD4 Ab ibalizumab (iMab) (25)(26)(27) as the scaffold onto which to engraft antigen-binding domains of select human anti-Env bNAbs. IMab was chosen because of its established safety record (well tolerated without serious adverse events) and anti-HIV-1 activity (>1 log reduction in viral load) in infected patients in phase 1a, 1b, 2a, and 2b clinical trials (25,26,28). This monoclonal Ab binds to domain 2 of human CD4, on a face opposite to the site of gp120 and MHC class II binding, and potently inhibits HIV-1 entry via a noncompetitive mechanism after virus attachment (29,30).…”

mentioning

confidence: 99%

Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1

Pace

Song

Ochsenbauer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In the absence of an effective HIV-1 vaccine, passive immunization using broadly neutralizing Abs or Ab-like molecules could provide an alternative to the daily administration of oral antiretroviral agents that has recently shown promise as preexposure prophylaxis. Currently, no single broadly neutralizing Ab (bNAb) or combination of bNAbs neutralizes all HIV-1 strains at practically achievable concentrations in vivo . To address this problem, we created bispecific Abs that combine the HIV-1 inhibitory activity of ibalizumab (iMab), a humanized mAb directed to domain 2 of human CD4, with that of anti-gp120 bNAbs. These bispecific bNAbs (BibNAbs) exploit iMab’s potent anti–HIV-1 activity and demonstrated clinical efficacy and safety to anchor and thereby concentrate a second broadly neutralizing agent at the site of viral entry. Two BibNabs, PG9-iMab and PG16-iMab, exhibit exceptional breadth and potency, neutralizing 100% of the 118 viruses tested at low picomolar concentrations, including viruses resistant to both parental mAbs. The enhanced potency of these BibNAbs was entirely dependent on CD4 anchoring, not on membrane anchoring per se, and required optimal Ab geometry and linker length. We propose that iMab-based BibNAbs, such as PG9-iMab and PG16-iMab, are promising candidates for passive immunization to prevent HIV-1 infection.

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mentioning

confidence: 99%

Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1

Pace

Song

Ochsenbauer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Engagement of CD4 by therapeutic mAbs triggers various effects actually exploited in cancerology (11), HIV infection (12), and tolerance induction (13). CD4 epitope recognition by Abs has not been taken into consideration in clinical studies, except in the case of HIV infection.…”

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confidence: 99%

Recombinant Anti-CD4 Antibody 13B8.2 Blocks Membrane-Proximal Events by Excluding the Zap70 Molecule and Downstream Targets SLP-76, PLCγ1, and Vav-1 from the CD4-Segregated Brij 98 Detergent-Resistant Raft Domains

Chentouf

Ghannam

Bès

et al. 2007

The Journal of Immunology

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The biological effects of rIgG1 13B8.2, directed against the CDR3-like loop on the D1 domain of CD4, are partly due to signals that prevent NF-κB nuclear translocation, but the precise mechanisms of action, particularly at the level of membrane proximal signaling, remain obscure. We support the hypothesis that rIgG1 13B8.2 acts by interfering with the spatiotemporal distribution of signaling or receptor molecules inside membrane rafts. Upon cross-linking of Jurkat T lymphocytes, rIgG1 13B8.2 was found to induce an accumulation/retention of the CD4 molecule inside polyoxyethylene-20 ether Brij 98 detergent-resistant membranes at 37°C, together with recruitment of TCR, CD3ζ, p56 Lck, Lyn, and Syk p70 kinases, linker for activation of T cells, and Csk-binding protein/phosphoprotein associated with glycosphingolipid adaptor proteins, and protein kinase Cθ, but excluded Zap70 and its downstream targets Src homology 2-domain-containing leukocyte protein of 76 kDa, phospholipase Cγ1, and p95vav. Analysis of key upstream events such as Zap70 phosphorylation showed that modulation of Tyr292 and Tyr319 phosphorylation occurred concomitantly with 13B8.2-induced Zap70 exclusion from the membrane rafts. 13B8.2-induced differential raft partitioning was epitope, cholesterol, and actin dependent but did not require Ab hyper-cross-linking. Fluorescence confocal imaging confirmed the spatiotemporal segregation of the CD4 complex inside rafts and concomitant Zap70 exclusion, which occurred within 10–30 s following rIgG1 13B8.2 ligation, reached a plateau at 1 min, and persisted until the end of the 1-h experiment. The differential spatiotemporal partitioning between the CD4 receptor and the Zap70-signaling kinase inside membrane rafts interrupts the proximal signal cross-talk leading to subsequent NF-κB nuclear translocation and explains how baculovirus-expressed CD4-CDR3-like-specific rIgG1 13B8.2 acts to induce its biological effects.

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“…Investigators are also under study of the function of bNAbs and their development during the HIV-I infection. As a result, many bNAbs have been isolated from the patients who are chronically infected by HIV and also been under detailed study [80][81][82][83][84][85][86][87][88][89][90][91]. Although antigens which are performing the reaction of these antibodies have not been yet identified.…”

Section: Developmental Study Of Hiv Vaccinementioning

confidence: 99%

“…Meanwhile, many clinical trials are under discussion to develop powerful bNAbs as monoclonal antibodies. VRC01 is a monoclonal antibody which gets involved in clinical trials in 2013 [86]. After its safety and pharmacokinetics study, main objective is that to test the whether the bNAbs presence protect the infection from HIV.…”

Section: Developmental Study Of Hiv Vaccinementioning

confidence: 99%

Efficacy Trials and Progress of HIV Vaccines

Asif¹,

Irshad²

2017

J Cell Sci Ther

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Discovery of HIV as causative agent of AIDS let to the belief that a vaccine for AIDS will be available shortly but was not that easy, and it took more than 30 years of hard laboratory and clinical work toward HIV vaccine development. Efficacy trials of RV144 and their results revealed that HIV vaccine is accomplishable. Clinical trials for developing bNAbs has monoclonal antibodies and to increase its half-life are also underway to achieve a proper HIV vaccine. In this review article, we see that how these efficacy trials are highlighting HIV vaccine concepts in clinical development. Therapeutic vaccines are proving to be a functional cure toward HIV treatment and progress is ongoing in such HIV vaccine development which will attack HIV before it fuses with cell and cause infection thus preventing AIDS. So, in near future it will be possible to cure HIV and bring an end to this epidemic.

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Antiretroviral Activity of the Anti‐CD4 Monoclonal Antibody TNX‐355 in Patients Infected with HIV Type 1

Abstract: Single doses of TNX-355 reduced plasma HIV-1 RNA loads and increased CD4+ T cell counts in HIV-infected subjects. The further assessment of therapeutic potential awaits data from longer-duration trials.

Cited by 185 publications

References 18 publications

Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1

Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1

Recombinant Anti-CD4 Antibody 13B8.2 Blocks Membrane-Proximal Events by Excluding the Zap70 Molecule and Downstream Targets SLP-76, PLCγ1, and Vav-1 from the CD4-Segregated Brij 98 Detergent-Resistant Raft Domains

Efficacy Trials and Progress of HIV Vaccines

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