Safety, Tolerability, and Pharmacokinetics of a Long-Acting Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01LS in HIV-1-Exposed Newborn Infants

2021 ◽  
Author(s):  
Elizabeth J McFarland ◽  
Coleen K Cunningham ◽  
Petronella Muresan ◽  
Edmund V Capparelli ◽  
Charlotte Perlowski ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Half Life ◽  
Newborn Infants ◽  
Adjunct Treatment ◽  
Perinatal Hiv ◽  
Antiretroviral Prophylaxis ◽  
Terminal Half Life ◽  
Local Reactions ◽  
Long Acting ◽  
Hiv 1

Abstract Background Perinatal HIV-1 continues to occur due to barriers to effective antiretroviral prevention that might be mitigated by long-acting broadly neutralizing monoclonal antibodies (bNAbs). Methods Extended half-life bNAb, VRC01LS, was administered subcutaneously (SC) at 80 mg/dose after birth to HIV-1-exposed, non-breastfed (Cohort 1, n=10) and breastfed (Cohort 2, n=11) infants. Cohort 2 received a second dose (100mg) at 12 weeks. All received antiretroviral prophylaxis. VRC01LS levels were compared to VRC01 levels determined in a prior cohort. Results Local reactions (all Grade <2) occurred in 67% and 20% after Dose 1 and Dose 2, respectively. The weight-banded dose (mean 28.8 mg/kg) of VRC01LS administrated SC achieved a mean +SD plasma level of 222.3 + 71.6 mcg/mL by 24 hours and 44.0 + 11.6 mcg/mL at week 12, prior to Dose 2. The pre-established target of > 50 mcg/mL was attained in 95% and 32% at week 8 and 12, respectively. The terminal half-life was 37-41 days. VRC01LS level after one dose was significantly greater (p=<0.002) than after a VRC01 dose (20mg/kg). No infants acquired HIV-1. Conclusions VRC01LS was well tolerated with pharmacokinetics that support further studies of more potent long-acting bNAbs as adjunct treatment with ARVs to prevent infant HIV-1 transmission.

scholarly journals Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action

Viruses ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 811 ◽  
Author(s):  
Chen Wang ◽  
Shuihong Cheng ◽  
Yuanyuan Zhang ◽  
Yibo Ding ◽  
Huihui Chong ◽  
...  
Keyword(s):  
Half Life ◽  
Mechanisms Of Action ◽  
Effective Concentration ◽  
Fusion Inhibitor ◽  
Inhibitory Peptides ◽  
Long Acting ◽  
Peg Chain Length ◽  
Plasma Half Life ◽  
Anti Hiv ◽  
Hiv 1

The clinical application of HIV fusion inhibitor, enfuvirtide (T20), was limited mainly because of its short half-life. Here we designed and synthesized two PEGylated C34 peptides, PEG2kC34 and PEG5kC34, with the PEG chain length of 2 and 5 kDa, respectively, and evaluated their anti-HIV-1 activity and mechanisms of action. We found that these two PEGylated peptides could bind to the HIV-1 peptide N36 to form high affinity complexes with high α-helicity. The peptides PEG2kC34 and PEG5kC34 effectively inhibited HIV-1 Env-mediated cell–cell fusion with an effective concentration for 50% inhibition (EC50) of about 36 nM. They also inhibited infection of the laboratory-adapted HIV-1 strain NL4-3 with EC50 of about 4–5 nM, and against 47 HIV-1 clinical isolates circulating in China with mean EC50 of PEG2kC34 and PEG5kC34 of about 26 nM and 32 nM, respectively. The plasma half-life (t1/2) of PEG2kC34 and PEG5kC34 was 2.6 h and 5.1 h, respectively, and the t1/2 of PEGylated C34 was about 2.4-fold and 4.6-fold longer than C34 (~1.1 h), respectively. These findings suggest that PEGylated C34 with broad-spectrum anti-HIV-1 activity and prolonged half-life can be further developed as a peptide fusion inhibitor-based long-acting anti-HIV drug for clinical use to treat HIV-infected patients who have failed to respond to current anti-retrovirus drugs.

Hazard to Newborn Infants of Administration of Long-acting Sulfonamides to Pregnant Women

PEDIATRICS ◽  
1959 ◽  
Vol 24 (3) ◽  
pp. 498-499
Author(s):  
JEROLD F. LUCEY ◽  
TIMOTHY J. DRISCOLL
Keyword(s):  
Pregnant Women ◽  
Blood Level ◽  
Half Life ◽  
Newborn Infants ◽  
Blood Levels ◽  
Oral Ingestion ◽  
Human Adult ◽  
Low Toxicity ◽  
Long Acting

Recently there have appeared on the market several new long-acting sulfonamides. One of these is sulfadimethoxine (Madribon®). It is reported to have low toxicity and a sustained chemotherapeutic action in vivo. After oral ingestion, blood levels in the human adult have been shown to be maximal in 4 to 12 hours, and to decline gradually thereafter with a half-life of 36 hours. This sustained blood level occurs because the excretion of sulfadimethoxine is determined primarily by its rate of conversion to a glucuronide in the liver.

PRO 140, a monoclonal antibody targeting CCR5, as a long-acting, single-agent maintenance therapy for HIV-1 infection

2018 ◽  
Vol 19 (3) ◽  
pp. 85-93 ◽  
Author(s):  
Kush Dhody ◽  
Nader Pourhassan ◽  
Kazem Kazempour ◽  
Derry Green ◽  
Shide Badri ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Maintenance Therapy ◽  
Single Agent ◽  
Antibody Targeting ◽  
Long Acting ◽  
Hiv 1

Balugrastim: A long-acting, once-per-cycle, recombinant human albumin-fusion filgrastim.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13551-e13551
Author(s):  
Laurie Pukac ◽  
Steven Barash ◽  
Noa Avisar ◽  
Hermann Allgaier ◽  
Jason Bock ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Half Life ◽  
Human Albumin ◽  
Biologically Active ◽  
Severe Neutropenia ◽  
Fixed Dose ◽  
Terminal Half Life ◽  
Long Acting ◽  
Dose Dependent

e13551 Background: Balugrastim is a once-per-cycle fixed-dose genetic fusion protein composed of human serum albumin (HSA) and granulocyte colony-stimulating factor (G-CSF) in development for prevention of severe neutropenia in cancer patients receiving chemotherapy. Albumin fusion is a clinically validated technology that extends product half-life, allowing for infrequent dosing, better tolerability, lower cost, and improves drug design, potentially lowering immunogenicity risk. Here, we describe the technology used to produce balugrastim and summarize preclinical findings compared with pegfilgrastim (Neulasta). Methods: Design and production of balugrastim was described previously (Halpern et al. Pharmaceut Res 2002;19:1720−1729). Biologic activity of balugrastim was assessed in an NFS-60 cell line proliferation assay vs filgrastim and pegfilgrastim. PK and PD properties were studied in healthy and neutropenic animal models. Results: Albumin fusion produces a long-acting G-CSF with comparable pharmacologic properties to pegfilgrastim. In vitro, balugrastim had binding affinity and cell proliferation activity comparable to pegfilgrastim, and both were lower than non-PEGylated filgrastim on a molar basis. Overall increases in leukocytes, neutrophilic granulocytes, and monocytes were dose dependent and consistent with the effects expected for a long-acting G-CSF with some variation based on the specific animal model used. A single balugrastim dose in BDF1 mice elicited a dose-dependent increase in peripheral granulocytes and mobilized hematopoietic progenitor cells. In cynomolgus monkeys, balugrastim caused an increase in peripheral neutrophils similar to pegfilgrastim, with higher responses after 2nd, 3rd, and 4th doses. In mice, balugrastim had shorter terminal half-life and mean residence time, and faster clearance than pegfilgrastim. In monkeys, terminal half-life of balugrastim was slightly longer than pegfilgrastim. Conclusions: An albumin fusion technology platform was used to produce balugrastim – a novel, biologically active albumin G-CSF fusion protein with greater structural homogeneity and comparable pharmacologic properties to conventionally PEGylated G-CSFs.

scholarly journals Lipophilic Nanocrystal Prodrug-Release Defines the Extended Pharmacokinetic Profiles of a Year-Long Cabotegravir

2021 ◽  
Author(s):  
Nagsen Gautam ◽  
JoEllyn M. McMillan ◽  
Devendra Kumar ◽  
Aditya N. Bade ◽  
Qiaoyu Pan ◽  
...  
Keyword(s):  
Half Life ◽  
Inhibitory Concentration ◽  
Mammalian Species ◽  
Lymphoid Tissues ◽  
Immunodeficiency Virus ◽  
Liver Homogenates ◽  
One Year ◽  
Long Acting ◽  
Spleen And Lymph Nodes ◽  
Hiv 1

AbstractA single, once every eight-week cabotegravir (CAB) long-acting parenteral is more effective than daily oral emtricitabine and tenofovir disoproxil fumarate in preventing human immunodeficiency virus type one (HIV-1) transmission. Extending CAB dosing to a yearly injectable can advance efforts leading to the elimination of viral transmission. The current submission adds rigor, reproducibility and mechanistic insights for the extended apparent half-life of a yearlong antiretroviral injectable. Pharmacokinetic (PK) profiles of a nanoformulated fatty acid ester CAB prodrug (named NM2CAB) were affirmed at two academic and one contract research laboratory. PK profiles showed plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for up to one year after a single dose. Measures of drug biodistribution demonstrated sustained native drug at the muscle injection site and in lymphoid tissues (spleen and lymph nodes). The results paralleled NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals were stable in blood, tissue and liver homogenates. The long apparent drug half-life followed pH-dependent slow prodrug release in weeks from the nanocrystal. In contrast, solubilized prodrug was hydrolyzed in hours in plasma and tissues recorded from multiple mammalian species at basic pH. No measurable toxicities were recorded. These results, taken together, affirm the pharmacological mechanistic properties of a year-long nanoformulated CAB prodrug supporting the established protocol design for formulation safety, rigor and reproducibility.

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