Stratification of Antibody-Positive Subjects by Antibody Level Reveals an Impact of Immunogenicity on Pharmacokinetics

Zhou, Lei; Hoofring, Sarah A; Wu, Yu Hsueh; Vu, Thuy; Ma, Pelosi; Swanson, Steven J.; Chirmule, Narendra; Starcevic, Marta

doi:10.1208/s12248-012-9408-8

Cited by 39 publications

(27 citation statements)

References 33 publications

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“…ADAs are known to affect the clearance of monoclonal antibodies in certain subjects . In this analysis, the ADA presence (as a binary variable and as a time course of ADA titers) was examined for correlation with ABT‐122 clearance.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of the TNF‐α and IL‐17A Dual‐Variable Domain Antibody ABT‐122 in Healthy Volunteers and Subjects With Psoriatic or Rheumatoid Arthritis: Analysis of Phase 1 and 2 Clinical Trials

Khatri

Othman

2018

The Journal of Clinical Pharma

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ABT-122 is an IgG1 dual-variable domain immunoglobulin that specifically blocks TNF-α and IL-17A. This work characterized ABT-122 pharmacokinetics using nonlinear mixed-effects modeling and ABT-122 serum concentrations from 72 healthy subjects, 196 subjects with rheumatoid arthritis (RA), and 144 subjects with psoriatic arthritis (PsA) enrolled in 4 phase 1 and 2 phase 2 studies (0.1-10 mg/kg intravenously and 0.3-3 mg/kg subcutaneous single doses and 0.3-3.0 mg/kg subcutaneous and 60-240 mg subcutaneous doses weekly or every other week). A 2-compartment model with a combination of linear clearance (0.419 L/day) and nonlinear clearance (relevant only at low doses; V and K of 0.155 mg/day and 0.0458 mg/L, respectively) described ABT-122 pharmacokinetics. Subcutaneous bioavailability was 35%-58% across formulations and populations. Body weight was a significant covariate for ABT-122 clearance, with subjects with body weight of 140 and 40 kg estimated to have 38% lower and 43% higher ABT-122 AUC, respectively, compared with a 70-kg reference subject. ABT-122 antidrug antibody (ADA) titer (ADA incidence, 47%; 0 to 519 000 titer range in the data set) was a continuous covariate on ABT-122 clearance. An ADA titer of 100 units resulted in a 5-fold increase in clearance. Sex, age, and baseline serum albumin or baseline C-reactive protein level did not impact ABT-122 exposure. Fixed-effects and random-effects parameters were estimated with a relative standard error of ≤17% and ≤28%, respectively, and the model was qualified using bootstrap analysis and visual predictive checks. This analysis characterized ABT-122 exposure across populations and supported exposure-response analyses of ABT-122 efficacy in RA and PsA.

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of the TNF‐α and IL‐17A Dual‐Variable Domain Antibody ABT‐122 in Healthy Volunteers and Subjects With Psoriatic or Rheumatoid Arthritis: Analysis of Phase 1 and 2 Clinical Trials

Khatri

Othman

2018

The Journal of Clinical Pharma

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“…Adverse immunogenicity of the peptide and protein materials could compromise their functionality by blocking the materials’ interactions with their targets, shortening their half-lives, (52, 53) and decreasing their bioavailablity. (54) Immunogenicity can also be life-threating.…”

Section: Discussionmentioning

confidence: 99%

Immune-tolerant elastin-like polypeptides (iTEPs) and their application as CTL vaccine carriers

Cho

Dong²,

Parent

et al. 2015

Journal of Drug Targeting

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Background Cytotoxic T lymphocyte (CTL) vaccine carriers are known to enhance the efficacy of vaccines, but a search for more effective carriers is warranted. Elastin-like polypeptides (ELPs) have been examined for many medical applications but not as CTL vaccine carriers. Purpose We aimed to create immune tolerant ELPs using a new polypeptide engineering practice and create CTL vaccine carriers using the ELPs. Results Four sets of novel ELPs, termed immune-tolerant elastin-like polypeptide (iTEP) were generated according to the principles dictating humoral immunogenicity of polypeptides and phase transition property of ELPs. The iTEPs were non-immunogenic in mice. Their phase transition feature was confirmed through a turbidity assay. An iTEP nanoparticle (NP) was assembled from an amphiphilic iTEP copolymer plus a CTL peptide vaccine, SIINFEKL. The NP facilitated the presentation of the vaccine by dendritic cells and enhanced vaccine-induced CTL responses. Discussion A new ELP design and development practice was established. The non-canonical motif and the immune tolerant nature of the iTEPs broaden our insights about ELPs. ELPs, for the first time, were successfully used as carriers for CTL vaccines. Conclusion It is feasible to concurrently engineer both immune-tolerant and functional peptide materials. ELPs are a promising type of CTL vaccine carriers.

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“…[ 25 ] Results also demonstrated a modified pharmacokinetic of drugs in patients having an anti‐drug antibody titer over 100 ng mL −1 . [ 26 ] Despite this, a modified pharmacokinetic profiles of drugs in patients having an anti‐drug antibody titer over 100 ng mL −1 are widely reported. These results also suggest that patients with an anti‐PEG antibody titer below 500 ng mL −1 could demonstrate a modified pharmacokinetic profile of PEGylated drugs that are injected.…”

Section: Anti‐peg Antibodiesmentioning

confidence: 99%

Immunogenicity of Polyethylene Glycol Based Nanomedicines: Mechanisms, Clinical Implications and Systematic Approach

d’Avanzo

Celia

Barone

et al. 2020

Advanced Therapeutics

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PEGylation technique is currently considered the gold standard approach to provide a long and safe circulation of drugs. Although this is the accepted dogma, various clinical reports and animal studies show the occurrence of immunogenic responses against polyethylene glycol (PEG) after systemic injection. These side effects, associated with complement activation and/or anti‐PEG antibody production, result in hypersensitivity reactions and lack of therapeutic efficacy of the drug during clinical protocols. Furthermore, different healthy patients show the presence of anti‐PEG antibodies in their blood stream, even though they have not received PEGylated drugs. The aim of this review is to discuss the main mechanisms based on PEG immunogenicity and its clinical implications and report the most promising approaches to reduce these unexpected side effects.

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Stratification of Antibody-Positive Subjects by Antibody Level Reveals an Impact of Immunogenicity on Pharmacokinetics

Cited by 39 publications

References 33 publications

Population Pharmacokinetics of the TNF‐α and IL‐17A Dual‐Variable Domain Antibody ABT‐122 in Healthy Volunteers and Subjects With Psoriatic or Rheumatoid Arthritis: Analysis of Phase 1 and 2 Clinical Trials

Population Pharmacokinetics of the TNF‐α and IL‐17A Dual‐Variable Domain Antibody ABT‐122 in Healthy Volunteers and Subjects With Psoriatic or Rheumatoid Arthritis: Analysis of Phase 1 and 2 Clinical Trials

Immune-tolerant elastin-like polypeptides (iTEPs) and their application as CTL vaccine carriers

Immunogenicity of Polyethylene Glycol Based Nanomedicines: Mechanisms, Clinical Implications and Systematic Approach

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