Pharmacokinetics of the Protein Microbicide 5P12-RANTES in Sheep following Single-Dose Vaginal Gel Administration

McBride, J.W.; Dias, Nicola; Cameron, David; Offord, Robin E.; Hartley, Oliver; Boyd, Peter; Kett, Vicky L.; Malcolm, R. Karl

doi:10.1128/aac.00965-17

Cited by 12 publications

(11 citation statements)

References 74 publications

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“…Each lactobacilli-expressed CCL5 mutant generated here is prone to live microbicide development, a relevant option in protein-based HIV-1 prophylaxis 18 , 44 . Interestingly, the prospective clinical use of these new CCL5 variants is reinforced by the efforts made on 5p12-RANTES as vaginal and rectal microbicide 45 , 46 . In addition to the commitment to combat HIV-1 via systemic therapy and pre-exposure prophylaxis, these CCL5 variants (available from engineered lactobacilli, recombinant E .…”

Section: Discussionmentioning

confidence: 99%

Rational CCL5 mutagenesis integration in a lactobacilli platform generates extremely potent HIV-1 blockers

Secchi

Grampa

Vangelista

2018

Sci Rep

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Efforts to improve existing anti-HIV-1 therapies or develop preventatives have identified CCR5 as an important target and CCL5 as an ideal scaffold to sculpt potent HIV-1 entry inhibitors. We created novel human CCL5 variants that exhibit exceptional anti-HIV-1 features using recombinant lactobacilli (exploited for live microbicide development) as a screening platform. Protein design, expression and anti-HIV-1 activity flowed in iterative cycles, with a stepwise integration of successful mutations and refinement of an initial CCL5 mutant battery towards the generation of two ultimate CCL5 derivatives, a CCR5 agonist and a CCR5 antagonist with similar anti-HIV-1 potency. The CCR5 antagonist was tested in human macrophages and against primary R5 HIV-1 strains, exhibiting cross-clade low picomolar IC50 activity. Moreover, its successful combination with several HIV-1 inhibitors provided the ground for conceiving therapeutic and preventative anti-HIV-1 cocktails. Beyond HIV-1 infection, these CCL5 derivatives may now be tested against several inflammation-related pathologies where the CCL5:CCR5 axis plays a relevant role.

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Section: Discussionmentioning

confidence: 99%

Rational CCL5 mutagenesis integration in a lactobacilli platform generates extremely potent HIV-1 blockers

Secchi

Grampa

Vangelista

2018

Sci Rep

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“…Previously, we have reported the pharmacokinetics of 5P12-RANTES in sheep following vaginal administration of a 5P12-RANTES aqueous gel formulation and a 5P12-RANTES vaginal ring (McBride et al, 2019(McBride et al, , 2017. Also, Holt et al, have previously Ring-004) (Holt et al, 2015).…”

Section: Pharmacokineticsmentioning

confidence: 98%

“…5P12-RANTES solution was freeze-dried to produce a lyophilised powder, following a previously reported method (McBride et al, 2019(McBride et al, , 2017. Briefly, 5P12-RANTES was aliquoted into flat bottomed glass petri dishes (diameter 200 mm) and freeze-dried (AdVantage Pro BenchTop Freeze Dryer, VirTis, Gardiner, NY, USA) using the following parameters: 5 to -40°C ramp for 1 h followed by an additional freeze for 2 h. The condenser was then set to -50°C and a chamber pressure of 50 mTorr.…”

Section: Freeze-drying Of 5p12-rantesmentioning

confidence: 99%

Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide 5P12-RANTES

McBride

Malcolm

Dias

et al. 2019

International Journal of Pharmaceutics

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P. (2019). Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide 5P12-RANTES. International Journal of Pharmaceutics, 564, 207-213. Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide Abstract The past fifteen years have witnessed a resurgence of interest in vaginal ring technologies for drug delivery applications, mostly driven by the impetus for development of vaginallyadministered antiretroviral microbicides to help reduce the high acquisition rates for human immunodeficiency virus (HIV) among Sub-Saharan African women. Currently, the lead candidate microbicide is a 28-day silicone elastomer vaginal ring releasing dapivirine (Ring-004), an experimental non-nucleoside reverse transcriptase inhibitor. The ring was tested in two pivotal Phase III clinical studies in 2016 and is currently undergoing review by the European Medicines Agency. Recently, we described a new type of silicone elastomer vaginal ring offering sustained release of the protein molecule 5P12-RANTES, a potent experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. Building on our previous work, here we report the preclinical development of a new combination vaginal ring that offers sustained release of both 5P12-RANTES and dapivirine, in which the 5P12-RANTES isincorporated into an exposed core within the ring body and the dapivirine in the sheath. In this way, in vitro release of dapivirine matches closely that for Ring-004. Also, we report the pharmacokinetic testing of this combination ring formulation in sheep, where vaginal concentrations of both drugs are maintained over 28 days at levels potentially useful for preventing HIV infection in women.

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“…Following successful pre‐clinical studies in animal models, a Phase I clinical trial (sponsored by the Population Council) is currently recruiting participants for safety and pharmacokinetics evaluation of a vaginal Griffithsin gel in women (ClinicalTrials.gov Identifier: NCT02875119, with expected completion date in late 2018), and evaluations of a rectal Griffithsin gel are ongoing as part of PREVENT (“ Pre ‐exposure prevention of v iral ent ry”), an integrated pre‐clinical/clinical program. The protein‐based HIV entry inhibitor 5P12‐RANTES (5P12R) has recently undergone further successful pre‐clinical evaluation as a vaginal gel in sheep and has also shown stability in human rectal lavage . According to the Mintaka Foundation, human clinical trials involving the 5P12‐RANTES microbicide are expected to begin soon in Geneva, Switzerland.…”

Section: Hiv Preventionmentioning

confidence: 99%

Pharmaceutical Approaches to HIV Treatment and Prevention

Yavuz

Morgan

Showalter

et al. 2018

Advanced Therapeutics

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Human immunodeficiency virus (HIV) infection continues to pose a major infectious disease threat worldwide. It is characterized by the depletion of CD4 + T cells, persistent immune activation, and increased susceptibility to secondary infections. Advances in the development of antiretroviral drugs and combination antiretroviral therapy have resulted in a remarkable reduction in HIV-associated morbidity and mortality. Antiretroviral therapy (ART) leads to effective suppression of HIV replication with partial recovery of host immune system and has successfully transformed HIV infection from a fatal disease to a chronic condition. Additionally, antiretroviral drugs have shown promise for prevention in HIV pre-exposure prophylaxis and treatment as prevention. However, ART is unable to cure HIV. Other limitations include drug-drug interactions, drug resistance, cytotoxic side effects, cost, and adherence. Alternative treatment options are being investigated to overcome these challenges including discovery of new molecules with increased anti-viral activity and development of easily administrable drug formulations. In light of the difficulties associated with current HIV treatment measures, and in the continuing absence of a cure, the prevention of new infections has also arisen as a prominent goal among efforts to curtail the worldwide HIV pandemic. In this review, the authors summarize currently available anti-HIV drugs and their combinations for treatment, new molecules under clinical development and prevention methods, and discuss drug delivery formats as well as associated challenges and alternative approaches for the future.

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Pharmacokinetics of the Protein Microbicide 5P12-RANTES in Sheep following Single-Dose Vaginal Gel Administration

Cited by 12 publications

References 74 publications

Rational CCL5 mutagenesis integration in a lactobacilli platform generates extremely potent HIV-1 blockers

Rational CCL5 mutagenesis integration in a lactobacilli platform generates extremely potent HIV-1 blockers

Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide 5P12-RANTES

Pharmaceutical Approaches to HIV Treatment and Prevention

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