Dataset Information

The efficacy of an anti-CD4 monoclonal antibody for HIV-1 treatment.

ABSTRACT: The availability of 24 antiretroviral (ARV) drugs within six distinct drug classes has transformed HIV-1 infection (AIDS) into a treatable chronic disease. However, the ability of HIV-1 to develop resistance to multiple classes continues to present challenges to the treatment of many ARV treatment-experienced patients. In this case report, we describe the response to ibalizumab, an investigational CD4-binding monoclonal antibody (mAb), in a patient with advanced immunodeficiency and high-level five-class antiretroviral resistance. After starting an ibalizumab-based salvage regimen, the patient had an approximately 4.0 log(10) reduction in viral load. An inadvertently missed infusion at week 32 led to the rapid loss of virologic response and decreased susceptibility to the remainder of the patient's salvage therapy regimen. Following the reinstitution of ibalizumab, phenotypic and genotypic resistance to ibalizumab was detected. Nonetheless, plasma HIV-1 RNA levels stabilized at ?2.0 log(10) copies/ml below pre-ibalizumab levels. Continued ARV drug development may yield additional clinical and public health benefits. This report illustrates the promise of mAbs for HIV-1 therapy in highly treatment-experienced patients. Therapeutic mAbs may also have a role in pre-exposure prophylaxis in high-risk uninfected populations and may facilitate directly observed therapy (DOT) if two or more synergistic long acting agents become available.

SUBMITTER: Fessel WJ

PROVIDER: S-EPMC4388049 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The efficacy of an anti-CD4 monoclonal antibody for HIV-1 treatment.

Fessel W Jeffrey WJ Anderson Brooke B Follansbee Stephen E SE Winters Mark A MA Lewis Stanley T ST Weinheimer Steven P SP Petropoulos Christos J CJ Shafer Robert W RW

Antiviral research 20111004 3

The availability of 24 antiretroviral (ARV) drugs within six distinct drug classes has transformed HIV-1 infection (AIDS) into a treatable chronic disease. However, the ability of HIV-1 to develop resistance to multiple classes continues to present challenges to the treatment of many ARV treatment-experienced patients. In this case report, we describe the response to ibalizumab, an investigational CD4-binding monoclonal antibody (mAb), in a patient with advanced immunodeficiency and high-level f ...[more]

PMID: 22001594

Similar Datasets

Project description:Four randomized placebo-controlled efficacy trials of a candidate vaccine or passively infused monoclonal antibody for prevention of HIV-1 infection are underway (HVTN 702 in South African men and women; HVTN 705 in sub-Saharan African women; HVTN 703/HPTN 081 in sub-Saharan African women; HVTN 704/HPTN 085 in U.S., Peruvian, Brazilian, and Swiss men or transgender persons who have sex with men). Several challenges are posed to the optimal design of the sequel efficacy trials, including: (1) how to account for the evolving mosaic of effective prevention interventions that may be part of the trial design or standard of prevention; (2) how to define viable and optimal sequel trial designs depending on the primary efficacy results and secondary "correlates of protection" results of each of the ongoing trials; and (3) how to define the primary objective of sequel efficacy trials if HIV-1 incidence is expected to be very low in all study arms such that a standard trial design has a steep opportunity cost. After summarizing the ongoing trials, I discuss statistical science considerations for sequel efficacy trial designs, both generally and specifically to each trial listed above. One conclusion is that the results of "correlates of protection" analyses, which ascertain how different host immunological markers and HIV-1 viral features impact HIV-1 risk and prevention efficacy, have an important influence on sequel trial design. This influence is especially relevant for the monoclonal antibody trials because of the focused pre-trial hypothesis that potency and coverage of serum neutralization constitutes a surrogate endpoint for HIV-1 infection. Another conclusion is that while assessing prevention efficacy against a counterfactual placebo group is fraught with risks for bias, such analysis is nonetheless important and study designs coupled with analysis methods should be developed to optimize such inferences. I draw a parallel with non-inferiority designs, which are fraught with risks given the necessity of making unverifiable assumptions for interpreting results, but nevertheless have been accepted when a superiority design is not possible and a rigorous/conservative non-inferiority margin is used. In a similar way, counterfactual placebo group efficacy analysis should use rigorous/conservative inference techniques that formally build in a rigorous/conservative margin to potential biases that could occur due to departures from unverifiable assumptions. Because reliability of this approach would require new techniques for verifying that the study cohort experienced substantial exposure to HIV-1, currently it may be appropriate as a secondary objective but not as a primary objective.

Project description:BackgroundThe chimeric antigen receptor NK-92 (CAR NK-92) cell targeting the prostate-specific membrane antigen (PSMA) has shown antitumour effects in castration-resistant prostate cancer (CRPC). However, the expression changes of programmed death ligand 1 (PD-L1) and its mechanisms on CAR NK-92 and CRPC cells and the effect of the anti-PD-L1 monoclonal antibody (mAb) on PD-L1 expressed on CAR NK-92 cells remain unknown.MethodsHuman dendritic cells and CD8+ T cells were acquired from blood samples of healthy donors and cocultured with C4-2 cells. Changes in PD-L1 expression were detected by flow cytometry. Differential gene expressions were investigated by RNA sequence analysis, while the regulation of PD-L1 molecular signaling was explored using western blotting. In vitro cytotoxicity was evaluated using the Cell Counting Kit-8 assay and the bioluminescent intensity (BLI) of green fluorescent protein-labelled C4-2 cells. CRPC growth in vivo was monitored using callipers and BLI in male NOD/SCID mice subcutaneously injected with C4-2 cells and treated intravenously with anti-PD-L1/PD-1 mAb, CAR NK-92 or cocultured CD8+ T cells.ResultsSignificantly upregulated expression of PD-L1k was observed in cocultured C4-2 and CAR NK-92 cells. In addition, upregulation of PD-L1 expression was dependent on interferon-γ in C4-2 cells, while it was dependent on direct cell-to-cell interaction via the NK group 2 member D/ phosphatidylinositol 3-kinase/AKT pathway in CAR NK-92 cells. The anti-PD-L1 mAb directly acted on PD-L1 expressed on CAR NK-92 cells and augmented the cytotoxicity of CAR NK-92 cells against C4-2 and CRPC cells from one patient in vitro. Anti-PD-L1 mAb significantly enhanced the antitumour effect of CAR NK-92 cells against CRPC cells in vivo when compared to treatment with CAR NK-92 cells or combined with anti-PD-1 mAb in the absence or presence of cocultured CD8+ T cells.ConclusionCombined treatment with CAR NK-92 and anti-PD-L1 mAb improved the antitumour efficacy against CRPC, which is of extraordinary translational value in the clinical treatment of CRPC.

Dataset Information

The efficacy of an anti-CD4 monoclonal antibody for HIV-1 treatment.

Publications

The efficacy of an anti-CD4 monoclonal antibody for HIV-1 treatment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets