HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned. However, recently developed ...single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30 mg kg(-1) infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8-2.5 log10 and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.
Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117,a ...broad and potent neutralizing antibody against the CD4 binding site of the HIV-1 Env protein, during analytical treatment interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Results show that two or four 30 mg kg(-1) 3BNC117 infusions,separated by 3 or 2 weeks, respectively, are generally well tolerated.Infusions are associated with a delay in viral rebound of 5-9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks, respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals,emerging viruses show increased resistance, indicating escape.However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg ml(-1), and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks.We conclude that the administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans.
3BNC117 is a broad and potent neutralizing antibody to HIV-1 that targets the CD4 binding site on the viral envelope spike. When administered passively, this antibody can prevent infection in animal ...models and suppress viremia in HIV-1–infected individuals. Here we report that HIV-1 immunotherapy with a single injection of 3BNC117 affects host antibody responses in viremic individuals. In comparison to untreated controls that showed little change in their neutralizing activity over a 6-month period, 3BNC117 infusion significantly improved neutralizing responses to heterologous tier 2 viruses in nearly all study participants. We conclude that 3BNC117-mediated immunotherapy enhances host humoral immunity to HIV-1.
HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned
1
–
3
. However, recently ...developed single cell based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies (bNAbs) to HIV-1
4
,
5
. These antibodies can prevent infection and suppress viremia in humanized mice (hu-mice) and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated
6
–
10
. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody
11
, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favorable pharmacokinetics. A single 30 mg/kg infusion of 3BNC117 reduced the viral load (VL) in HIV-1-infected individuals by 0.8 – 2.5 log
10
and viremia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that as a single agent 3BNC117 is safe and effective in reducing HIV-1 viremia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy, and cure.
The reduction of a carbene‐coordinated, sterically encumbered terphenyl‐substituted aluminium diiodide, (LRAlI2), yielded a “masked” dialumene (LRAl=AlRL), self‐stabilised through 2+2 cycloaddition ...with a peripheral aromatic group. During the course of the reaction, a carbene‐stabilised arylalumylene (LRAl:) was generated in situ, which was trapped using an alkyne, generating an aluminacyclopropene or a C−H activated product thereof, depending on the steric bulk of the alkyne. The masked dialumene also underwent intramolecular cycloreversion and dissociation into alumylene fragments, which reacted with various organic azides to yield monomeric or dimeric iminoalanes depending on the sterics of the azide substituent. The thermodynamics of monomeric and dimeric iminoalane formation were probed by theoretical calculations.
An NHC‐stabilised aluminium(III) terphenyl dihalide was reduced in the presence of alkynes to trap the in‐situ‐formed alumylene NHC(Ter)Al:. In the absence of an alkyne the reduction yielded a self‐stabilised dialumene, which showed alumylene‐like reactivity towards organic azides.
Isolable Phospha- and Arsaalumenes Fischer, Malte; Nees, Samuel; Kupfer, Thomas ...
Journal of the American Chemical Society,
03/2021, Letnik:
143, Številka:
11
Journal Article
Recenzirano
The combination of (AlCp*)4, a source of monomeric :AlCp* at elevated temperatures, with DipTerPnPMe3 (Pn = P, As), so-called pnicta-Wittig reagents, at 80 °C cleanly gives the pnictaalumenes ...DipTerPnAlCp* with polarized Pn–Al double bonds and intramolecular stabilization through interactions of Al with a flanking aryl group of the terphenyl substituent on Pn. In contrast, using MesTerPPMe3, the reaction with 2 equiv of :AlCp3t or :AlCp* afforded the three-membered 2π-aromatic ring systems MesTerP(AlCp x )2 (x = 3t, *).
Cyclo‐Dipnictadialanes Nees, Samuel; Fantuzzi, Felipe; Wellnitz, Tim ...
Angewandte Chemie (International ed.),
November 2, 2021, Letnik:
60, Številka:
45
Journal Article
Recenzirano
Odprti dostop
Using the AlI precursor Cp3tAl in conjunction with triphosphiranes (PAr)3 (Ar=Mes, Dip, Tip) we have succeeded in preparing Lewis base‐free cyclic diphosphadialanes with both the Al and P atoms ...bearing three substituents. Using the sterically more demanding Dip and Tip substituents the first 1,2‐diphospha‐3,4‐dialuminacyclobutanes were obtained, whereas with Mes substituents Cp3tAl(μ‐PMes)2 is formed. This divergent reactivity was corroborated by DFT studies, which indicated the thermodynamic preference for the 1,2‐diphospha‐3,4‐dialuminacyclobutane form for sterically more demanding groups on phosphorus. Using Cp*Al we could extend this concept to the corresponding cyclic diarsadialanes Cp*Al(μ‐AsAr)2 (Ar=Dip, Tip) and additionally add the phosphorus variants Cp*Al(μ‐PAr)2 (P=Mes, Dip, Tip). The reactivity of one variant Cp3tAl(μ‐PPh)2 towards NHCs was tested and resulted in double NHC‐stabilised Cp3t(IiPr2)Al(μ‐PPh)2.
Pnictaalenes with a pnictogen−aluminium double bond are inherently unstable and prone to dimerization. The synthesis of Lewis‐base‐free dipnictadialenes is revealed. It is shown that depending on the steric profile of the substituents either the alternating CpxAl(μ‐PAr)2 dimers or the head‐to‐head species ArPnAlCp3t2 are formed. DFT studies corroborate that the different outcomes are thermodynamically driven.
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