Population pharmacokinetic–pharmacodynamic modeling of PB2452, a monoclonal antibody fragment being developed as a ticagrelor reversal agent, in healthy volunteers

Kathman, Steven J.; Wheeler, Jeffery J.; Bhatt, Deepak L.; Arnold, Susan; Lee, John S.

doi:10.1002/psp4.12734

Cited by 5 publications

(2 citation statements)

References 19 publications

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“…Bentracimab (PB2452), being developed by PhaseBio as a reversal agent for the anti-blood clotting drug Brilinta® (ticagrelor), is a Fab of an anti-ticagrelor mAb. 63 It is in a Phase 3 clinical trial, and a biologics license application (BLA) is expected to be submitted by mid to late 2022. 2 It is currently produced in E. coli as an extracellular protein.…”

Section: Production In Escherichia Colimentioning

confidence: 99%

Full-length recombinant antibodies from Escherichia coli : production, characterization, effector function (Fc) engineering, and clinical evaluation

Rashid

2022

mAbs

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Although several antibody fragments and antibody fragment-fusion proteins produced in Escherichia coli ( E. coli ) are approved as therapeutics for various human diseases, a full-length monoclonal or a bispecific antibody produced in E. coli has not yet been approved. The past decade witnessed substantial progress in expression of full-length antibodies in the E. coli cytoplasm and periplasm, as well as in cell-free expression systems. The equivalency of E. coli -produced aglycosylated antibodies and their mammalian cell-produced counterparts, with respect to biochemical and biophysical properties, including antigen binding, in vitro and in vivo serum stability, pharmacokinetics, and in vivo serum half-life, has been demonstrated. Extensive engineering of the Fc domain of aglycosylated antibodies enables recruitment of various effector functions, despite the lack of N -linked glycans. This review summarizes recent research, preclinical advancements, and clinical development of E. coli -produced aglycosylated therapeutic antibodies as monoclonal, bispecific, and antibody-drug conjugates for use in autoimmune, oncology, and immuno-oncology areas. Abbreviations: ADA Anti-drug antibody; ADCC Antibody-dependent cellular cytotoxicity; ADCP Antibody-dependent cellular phagocytosis; ADC Antibody-drug conjugate; aFc Aglycosylated Fc; AMD Age-related macular degeneration aTTP Acquired thrombotic thrombocytopenic purpura; BCMA B-cell maturation antigen; BLA Biologics license application; BsAb Bispecific antibody; C1q Complement protein C1q; CDC Complement-dependent cytotoxicity; CDCC Complement-dependent cellular cytotoxicity; CDCP Complement-dependent cellular phagocytosis; CEX Cation exchange chromatography; CFPS Cell-free protein expression; CHO Chinese Hamster Ovary; CH1-3 Constant heavy chain 1-3; CL Constant light chain; DLBCL Diffuse large B-cell lymphoma; DAR Drug antibody ratio; DC Dendritic cell; dsFv Disulfide-stabilized Fv; EU European Union; EGFR Epidermal growth factor receptor; E. coli Escherichia coli; EpCAM Epithelial cell adhesion molecule; Fab Fragment antigen binding; FACS Fluorescence activated cell sorting; Fc Fragment crystallizable; FcRn Neonatal Fc receptor; FcɣRs Fc gamma receptors; FDA Food and Drug Administration; FL-IgG Full-length immunoglobulin; Fv Fragment variable; FolRαa Folate receptor alpha; gFc Glycosylated Fc; GM-CSF Granulocyte macrophage-colony stimulating factor; GPx7 Human peroxidase 7; HCL Hairy cell leukemia; HIV Human immunodeficiency virusl; HER2 Human epidermal growth factor receptor 2; HGF Hepatocyte growth factor; HIC Hydrophobic interaction chromatography; HLA Human leukocyte antigen; IBs Inclusion bodies; IgG1-4 Immunoglobulin 1-4; IP Intraperitoneal; ITC Isothermal titration calorimetry; ITP Immune...

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Section: Production In Escherichia Colimentioning

confidence: 99%

Full-length recombinant antibodies from Escherichia coli : production, characterization, effector function (Fc) engineering, and clinical evaluation

Rashid

2022

mAbs

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“…This initial analysis from the REVERSE-IT study suggests that bentracimab may be a reversal agent for ticagrelor in patients requiring an invasive procedure or a surgery, and in patients who experienced a major bleeding. Termination of patient recruitment is planned at the end of 2023 [10,11].…”

Section: Reverse-it Trial -It Is Possible To Reverse the Effect Of Ti...mentioning

confidence: 99%

A report from the American Heart Association Scientific Sessions 2021

Polańska¹,

Kasprzak²

2022

Folia Cardiologica

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The present report summarizes the most interesting new clinical studies that were reported during the American Heart Association Scientific Sessions 2021. The AVATAR study evaluated earlier surgical aortic valve replacement. A study by Cardiothoracic Surgical Trials Network focused on concomitant mitral and tricuspid valve surgery. The CRAVE study provided important data for coffee lovers. Use of empagliflozin in heart failure was evaluated in the EMPULSE and EMPEROR-Preserved trials. A study of an oral PCSK9 inhibitor is an initial step towards full evaluation of the efficacy of this drug. Reversal of ticagrelor action was reported in the REVERSE-IT study.

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Population pharmacokinetic–pharmacodynamic modeling of PB2452, a monoclonal antibody fragment being developed as a ticagrelor reversal agent, in healthy volunteers

Kathman

Wheeler

Bhatt

et al. 2021

CPT Pharmacom & Syst Pharma

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PB2452, a neutralizing monoclonal antibody fragment that binds the antiplatelet drug ticagrelor with high affinity, is being developed as a ticagrelor reversal agent.To identify a clinically useful intravenous (i.v.) reversal regimen, a semimechanistic exposure-response model was developed during the PB2452 first-in-human phase I study. From a randomized, double-blind, placebo-controlled, single-dose trial to evaluate the safety, efficacy, and pharmacokinetics (PKs) of PB2452 in 61 healthy volunteers pretreated with ticagrelor, sequential dose cohort data were used to build and refine an exposure-response model that combined population PK models for ticagrelor (TICA), ticagrelor active metabolite (TAM), and PB2452, and related their binding relationships to the PK of uncomplexed TICA and TAM which is predictive of platelet inhibition. Platelet function was assessed by multiple assays. The model was developed using Bayesian methods in NONMEM.Human PK and pharmacodynamic data from sequential dose cohorts were used to initially define and then refine model parameters. Model simulations indicated that an initial i.v. bolus of PB2452, followed by a high-rate infusion, and then a slower-rate infusion would provide immediate and sustained reversal of the antiplatelet effects of ticagrelor. Based on model predictions, a 6 g i.v. bolus followed by 6 g infused over 4 h and then 6 g over 12 h was identified and tested in study subjects and shown to provide complete reversal within 5 min of infusion onset that was sustained for 20-24 h. The model is predictive of the reversal profile of PB2452 and will inform future trials of PB2452. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Ticagrelor (TICA) is a direct acting, reversibly binding, oral P2Y 12 receptor antagonist. PB2452 (bentracimab), a neutralizing monoclonal antibody fragment that binds the antiplatelet drug TICA with high affinity, is being developed as a TICA reversal agent.

show abstract

Population pharmacokinetic–pharmacodynamic modeling of PB2452, a monoclonal antibody fragment being developed as a ticagrelor reversal agent, in healthy volunteers

Cited by 5 publications

References 19 publications

Full-length recombinant antibodies from Escherichia coli : production, characterization, effector function (Fc) engineering, and clinical evaluation

Full-length recombinant antibodies from Escherichia coli : production, characterization, effector function (Fc) engineering, and clinical evaluation

A report from the American Heart Association Scientific Sessions 2021

Population pharmacokinetic–pharmacodynamic modeling of PB2452, a monoclonal antibody fragment being developed as a ticagrelor reversal agent, in healthy volunteers

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