Measuring Biotherapeutics with Endogenous Counterparts and Pre-Existing Antibodies: an Interferon Case Study

Myler, Heather; Felix, Tonya; Zhu, Jie; Hruska, Matt; Piccoli, Steven P.

doi:10.4155/bio.14.37

Cited by 7 publications

(13 citation statements)

References 7 publications

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“…It should be noted that other studies have shown pre-existing AIAb rates to be higher than what was observed in this testing [16]. Sample means were 79 (NHS) and 84 (HCV), and standard deviations were similar, 18 (NHS) and 24 (HCV).…”

Section: Cut Pointcontrasting

confidence: 45%

“…Negative control is prepared by pooling individual normal human serum screened in the PK and ADA assays to eliminate reactive individuals, those with endogenous interferon Lambda and/or pre-existing antibodies [16]. Positive control is prepared at the LPC (50 ng/ml) and HPC (500 ng/ml) by spiking the AGP4 IgM APAb (Sinica) into the NHS pool described above.…”

Section: Bridge Apab Assaymentioning

confidence: 99%

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Anti-Peg Antibody Bioanalysis: A Clinical Case Study with Peg-Ifn-λ-1A and Peg-Ifn-α2A in Naive Patients

et al. 2015

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The bridge assay detected IgM and IgG APAb reactive with common PEG sizes and derivatives at sufficient sensitivity, 15-500 ng/ml. Of subjects evaluated, 6% of PEG-IFN-λ and 9% of PEG-IFN-α subjects had persistent APAb while 60% of PEG-IFN-λ and 33% of PEG-IFN-α subjects had persistent anti-interferon antibodies (AIAb). Pre-existing APAb and AIAb prevalence was comparable (approximately 10% of subjects). APAb were earlier onset, less frequent, less persistent and lower titer than AIAb. No associated hypersensitivity events were reported.

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Section: Cut Pointcontrasting

confidence: 45%

Section: Bridge Apab Assaymentioning

confidence: 99%

Anti-Peg Antibody Bioanalysis: A Clinical Case Study with Peg-Ifn-λ-1A and Peg-Ifn-α2A in Naive Patients

et al. 2015

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“…The bioanalytical assays consisted of several independent measures of the ADC including: T-Ab, A-ADC, T-ADC, antibody conj-payload and unconj-payload; soluble target, a panel of biomarkers indicative of programed cell death and a series of immunogenicity assays designed to elucidate ADA specificity [13][14][15] and clinical impact [16][17][18], as described in Table 1. The A-ADC and the conjugated active payload assays were presumed to be most relevant to bioactivity.…”

Section: Resultsmentioning

confidence: 99%

An Integrated Multiplatform Bioanalytical Strategy for Antibody–Drug Conjugates: A Novel Case Study

et al. 2015

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“…Assay specificity is described in detail in Myler et al . . The Lambda detection assay is cross‐reactive with the endogenous lambda counterpart.…”

Section: Bioanalytical Methodsmentioning

confidence: 99%

The pharmacokinetics of peginterferon lambda‐1a following single dose administration to subjects with impaired renal function

Hruska

Adamczyk

Colston

et al. 2015

Brit J Clinical Pharma

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AIMSThis open label study was conducted to assess the effect of renal impairment (RI) on the pharmacokinetics (PK) of peginterferon lambda-1a (Lambda). METHODSSubjects (age 18-75 years, BMI 18-35 kg m -2 ) were enrolled into one of five renal function groups: normal (n = 12), mild RI (n = 8), moderate RI (n = 8), severe RI (n = 7), end-stage renal disease (ESRD, n = 8) based on estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) equation. Subjects received a single dose of Lambda (180 μg) subcutaneously on day 1 followed by PK serum sample collections through day 29. Safety, tolerability and immunogenicity data were collected through day 43. PK parameters were estimated and summarized by group. Geometric mean ratios (GMR) and 90% confidence intervals (CIs) were calculated between normal and RI groups. RESULTSWith decreasing eGFR, Lambda exposure (C max , AUC) increased while apparent clearance (CL/F) and apparent volume of distribution (V/F) decreased. Relative to subjects with normal renal function (geometric mean AUC = 99.5 ng ml CONCLUSIONSThe results demonstrated that RI reduces the clearance of Lambda and suggests that dose modifications may not be required in patients with mild RI but may be required in patients with moderate to severe RI or ESRD. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Peginterferon lambda-1a is a novel type III interferon having potent antiviral effects in subjects with hepatitis C virus (HCV).• The kidneys are a major site of proteolysis and facilitate the elimination of therapeutic proteins.• Following administration of pegylated interferons to subjects with impaired renal function clearances of these proteins have been shown to be decreased WHAT THIS STUDY ADDS• Renal insufficiency reduces the clearance of peginterferon lambda-1a, similarly to other pegylated interferon products used in the treatment of HCV.

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Measuring Biotherapeutics with Endogenous Counterparts and Pre-Existing Antibodies: an Interferon Case Study

Abstract: Prescreening of serum to exclude reactive individuals resulted in successful cross-validation and the establishment of a high integrity pharmacokinetic assay in support of global clinical trials.

Cited by 7 publications

References 7 publications

Anti-Peg Antibody Bioanalysis: A Clinical Case Study with Peg-Ifn-λ-1A and Peg-Ifn-α2A in Naive Patients

Anti-Peg Antibody Bioanalysis: A Clinical Case Study with Peg-Ifn-λ-1A and Peg-Ifn-α2A in Naive Patients

An Integrated Multiplatform Bioanalytical Strategy for Antibody–Drug Conjugates: A Novel Case Study

The pharmacokinetics of peginterferon lambda‐1a following single dose administration to subjects with impaired renal function

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