Immunogenicity to Therapeutic Proteins: Impact on PK/PD and Efficacy

Chirmule, Narendra; Jawa, Vibha; Meibohm, Bernd

doi:10.1208/s12248-012-9340-y

Cited by 275 publications

(247 citation statements)

References 42 publications

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“…ATA generally does not have an effect on the early phase of PK because it takes some time to develop an immune response (i.e., ATA generation). 12 The initial exposure AUC 0-4 of PRO304397 in mice is not dose proportional between 1 and 10 mg¢kg ¡1 and approximately dose proportional between 10 and 30 mg¢kg ¡1 . Similarly, the initial exposure AUC 0-7 of MPDL3280A in monkeys is not dose proportional between 0.5 and 5 mg¢kg ¡1 and approximately dose proportional between 5 and 20 mg¢kg ¡1 .…”

Section: Discussionmentioning

confidence: 97%

“…Because the PK of MPDL3280A was affected by ATAs, the PK linearity of MPDL3280A in cynomolgus monkeys was assessed based on initial exposure up to 7 d post-dose, by which ATAs have not taken effect yet. 12 The mean area under the serum concentration-time curve from time 0 to Day 7 (AUC 0¡7 ) values were 29.0, 409, and 1940 day¢mg¢mL ¡1 and the observed maximum serum concentration (C max ) values were 8.55, 123, and 610 mg¢mL ¡1 following administration of 0.5, 5, or 20 mg¢kg ¡1 MPDL3280A, respectively (Table S2). From 0.5 mg¢kg ¡1 to 5 mg¢kg ¡1 , while dose increase was only 10-fold, the increase in both AUC 0-7 and C max was »15-fold; whereas from 5 mg¢kg ¡1 to 20 mg¢kg ¡1 , with a 4-fold dose increase, both the AUC 0-7 and C max increased »5-fold.…”

Section: Pharmacokinetics Of Mpdl3280a In Cynomolgus Monkeysmentioning

confidence: 99%

See 1 more Smart Citation

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor

Deng¹,

Bumbaca²,

Pastuskovas³

et al. 2016

mAbs

169

167

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MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose of the study reported here was to characterize the pharmacokinetics, pharmacodynamics, tissue distribution and tumor penetration of MPDL3280A and/or a chimeric anti-PD-L1 antibody PRO304397 to help further clinical development.The pharmacokinetics of MPDL3280A in monkeys at 0.5, 5 and 20 mg¢kg ¡1 and the pharmacokinetics / pharmacodynamics of PRO304397 in mice at 1, 3 10 mg¢kg ¡1 were determined after a single intravenous dose. Tissue distribution and tumor penetration for radiolabeled PRO304397 in tumor-bearing mouse models were determined.The pharmacokinetics of MPDL3280A and PRO304397 were nonlinear in monkeys and mice, respectively. Complete saturation of PD-L1 in blood in mice was achieved at serum concentrations of PRO304397 above »0.5 mg¢mL ¡1 . Tissue distribution and tumor penetration studies of PRO304397 in tumor-bearing mice indicated that the minimum tumor interstitial to plasma radioactivity ratio was »0.3; saturation of target-mediated uptake in non-tumor tissues and desirable exposure in tumors were achieved at higher serum concentrations, and the distribution into tumors was dose-and time-dependent.The biodistribution data indicated that the efficacious dose is mostly likely higher than that estimated based on simple pharmacokinetics/pharmacodynamics in blood. These data also allowed for estimation of the target clinical dose for further development of MPDL3280A.

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Section: Discussionmentioning

confidence: 97%

Section: Pharmacokinetics Of Mpdl3280a In Cynomolgus Monkeysmentioning

confidence: 99%

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor

Deng¹,

Bumbaca²,

Pastuskovas³

et al. 2016

mAbs

169

167

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“…The in-depth delineation of this interplay between ADA and PK interactions that can have a significant clinical impact is still evolving. Recent work from other groups has also demonstrated ADA-mediated clearance as a covariate in PK models (3,(6)(7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

“…A thorough understanding of dose-exposure and efficacy relationships is an integral part of any therapeutic protein development. The changes in PK profile of a therapeutic protein can be caused either by target-mediated drug disposition (TMDD) (1,2) or due to an increased clearance caused by ADA responses to the TP (3). Not all ADA induced by the TP has an impact on drug clearance.…”

Section: Introductionmentioning

confidence: 99%

Utility of a Bayesian Mathematical Model to Predict the Impact of Immunogenicity on Pharmacokinetics of Therapeutic Proteins

Kathman

Thway

Zhou

et al. 2016

AAPS J

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Abstract. The impact of an anti-drug antibody (ADA) response on pharmacokinetic (PK) of a therapeutic protein (TP) requires an in-depth understanding of both PK parameters and ADA characteristics. The ADA and PK bioanalytical assays have technical limitations due to high circulating levels of TP and ADA, respectively, hence, significantly hindering the interpretation of this assessment. The goal of this study was to develop a population-based modeling and simulation approach that can identify a more relevant PK parameter associated with ADA-mediated clearance. The concentrationtime data from a single dose PK study using five monoclonal antibodies were modeled using a noncompartmental analysis (NCA), one-compartmental, and two-compartmental Michaelis-Menten kinetic model (MMK). A novel PK parameter termed change in clearance time of the TP (α) derived from the MMK model could predict variations in α much earlier than the time points when ADA could be bioanalytically detectable. The model could also identify subjects that might have been potentially identified as false negative due to interference of TP with ADA detection. While NCA and onecompartment models can estimate loss of exposures, and changes in clearance, the two-compartment model provides this additional ability to predict that loss of exposure by means of α. Modeling data from this study showed that the two-compartment model along with the conventional modeling approaches can help predict the impact of ADA response in the absence of relevant ADA data.

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“…Another type of possible assay interference is caused by antibodies against the therapeutic that can emerge after a single or several doses. This type of interference most commonly occurs when the detection reagent is the labeled biotherapeutic and emerging anti‐drug antibodies (ADA) 10 specifically bind the detection reagent resulting in either inhibition or crosslinking of the detection reagent 8. Validation guidelines for flow cytometric assays are beginning to be proposed 11, 12; however, the specific aspects of RO assays are not yet considered in these guidelines.…”

mentioning

confidence: 99%

Evaluation of assay interference and interpretation of CXCR4 receptor occupancy results in a preclinical study with MEDI3185, a fully human antibody to CXCR4

Schwickart¹,

Chavez²,

Henderson³

et al. 2015

Cytometry Part B Clinical

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BackgroundReceptor occupancy (RO) assays provide a means to measure the direct interaction of therapeutics with their cell surface targets. Free receptor assays quantify cell‐surface receptors not bound by a therapeutic while total receptor assays quantify the amount of target on the cell surface.MethodsWe developed both a flow cytometry‐based free RO assay to detect free surface CXCR4, and a total surface CXCR4 assay. In an effort to evaluate potential displacement interference, we performed in vitro experiments to compare on‐cell affinity with the IC50 values from in vitro and in vivo from the free CXCR4 assay. We determined free and total surface CXCR4 on circulating blood cells in cynomolgus monkeys dosed with MEDI3185, a fully human monoclonal antibody to CXCR4.ResultsWe devised an approach to evaluate displacement interference during assay development and showed that our free assay demonstrated little to no displacement interference. After dosing cynomolgus monkeys with MEDI3185, we observed dose‐dependence in the magnitude and duration of receptor occupancy and found CXCR4 to increase on lymphocytes, monocytes, and granulocytes. In a multiple dose study, we observed time points where surface CXCR4 appeared fully occupied but MEDI3185 was not detectable in serum. These paradoxical results represented a type of assay interference, and by comparing pharmacokinetic, ADA and total CXCR4 results, the most likely reason for the free CXCR4 results was the emergence of neutralizing anti‐drug antibodies (ADA). The total CXCR4 assay was unaffected by ADA and provided a reliable marker of target modulation in both in vivo studies. © 2015 The Authors Cytometry Part B: Clinical Cytometry Published byWiley Periodicals, Inc.

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Immunogenicity to Therapeutic Proteins: Impact on PK/PD and Efficacy

Cited by 275 publications

References 42 publications

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor

Utility of a Bayesian Mathematical Model to Predict the Impact of Immunogenicity on Pharmacokinetics of Therapeutic Proteins

Evaluation of assay interference and interpretation of CXCR4 receptor occupancy results in a preclinical study with MEDI3185, a fully human antibody to CXCR4

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