Influence of FCGR3A-158V/F Genotype and Baseline CD20 Antigen Count on Target-Mediated Elimination of Rituximab in Patients with Chronic Lymphocytic Leukemia: A Study of FILO Group

Tout, Mira; Gagez, Anne-Laure; Leprêtre, Stéphane; Gouilleux-Gruart, Valérie; Azzopardi, Nicolas; Delmer, Alain; Mercier, Mélanie; Ysebaert, Loïc; Laribi, Kamel; Gonzalez, Hugo; Paintaud, Gilles; Cartron, Guillaume; Ternant, David

doi:10.1007/s40262-016-0470-8

Cited by 24 publications

(32 citation statements)

References 51 publications

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“…Three other approximations of TMDD models were made: -a combination of constant target amount and irreversible binding assumptions, as for elotuzumab [51] (anti-CD319), rituximab [52] (anti-CD20) and alirocumab [53] (anti-PCSK9); -a combination of rapid binding and constant target amount assumptions (Wagner's approximation [25] , as made for abciximab [54] (anti-GPIIb/IIIa); -Michaelis-Menten approximation (see section 3.3.3).…”

Section: Approximations Of Tmdd Modelsmentioning

confidence: 99%

“…To overcome this drawback, antigen mass measurements can be added as covariates on pharmacokinetic parameters (figure 1E): for instance, target-mediated clearance of rituximab was found to increase with circulating CD20 target. [52] Indirect antigen burden measurements, such as tumor size, were used as covariates,. For pembrolizumab (anti-PD-1), increased tumour size was associated with maximum time-varying clearance value of pembrolizumab (anti-PD1), whereas better clinical response was associated with decreased time to reach minimum clearance.…”

Section: Antigen Mass As a Covariate On Target-mediated Elimination Pmentioning

confidence: 99%

“…Trastuzumab showed either presence [69,93] or absence [94,95] of nonlinear elimination. Rituximab showed nonlinear pharmacokinetics for chronic lymphocytic leukemia (CLL) [52,90] but not for other B-cell malignancies [96][97][98] or RA. [99,100] For some of them, as anti-TNF mAbs, nonlinearity was never observed in 26 publications, with infliximab [101][102][103][104][105][106][107][108][109][110][111][112][113][114] , adalimumab [115][116][117][118][119][120][121][122] , certolizumab pegol [123,124] and golimumab.…”

Section: Antigen Mass As a Covariate On Target-mediated Elimination Pmentioning

confidence: 99%

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Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

et al. 2018

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Therapeutic antibodies are increasingly used to treat various diseases, including neoplasms and chronic inflammatory diseases. Antibodies exhibit complex pharmacokinetic properties, notably due to the influence of antigen mass, i.e. the amount of antigenic targets to which the monoclonal antibody binds specifically. This review focuses on the influence of antigen mass on the pharmacokinetics of therapeutic antibodies quantified by pharmacokinetic modelling in humans. Out of 159 pharmacokinetic studies, 85 reported an influence of antigen mass. This influence led to nonlinear elimination decay in 50 publications which was described using target-mediated drug disposition (TMDD) or derived models, as quasi-steady-state, irreversible binding and Michaelis-Menten models. In 35 publications, the pharmacokinetics was apparently linear and the influence of antigen mass was described as covariate of pharmacokinetic parameters. If some reported covariates, such as circulating antigen concentration or tumor size, are likely to be correlated to antigen mass, others, such as disease activity or disease type, may contain little information on the amount of antigenic targets. In some cases, antigen targets exist in different forms, notably in the circulation and expressed at cell surface. The influence of antigen mass should be soundly described during the early clinical phases of drug development. To maximize therapeutic efficacy, sufficient antibody doses should be administered to ensure the saturation of antigen targets by therapeutic antibody in all patients. If necessary, antigen mass should be taken into account in routine clinical practice. Key points-Current knowledge on the pharmacokinetics of monoclonal antibodies (mAbs) states that higher antigen amount was associated with mAb concentrations and higher mAb clearance. -Beacause of antigen mass, mAb pharmacokinetics may display nonlinear elimination shape. The influence of antigen mass on mAb pharmacokinetics is described using target-mediated drug disposition (TMDD) model, or approximations of this model. Antigen mass influence may be quantified using covariates. -Current mAb clinical development and use in clinical practice may be improved by optimization of dose, which should ensure the saturation of antigen targets in all patients.3

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Section: Approximations Of Tmdd Modelsmentioning

confidence: 99%

Section: Antigen Mass As a Covariate On Target-mediated Elimination Pmentioning

confidence: 99%

Section: Antigen Mass As a Covariate On Target-mediated Elimination Pmentioning

confidence: 99%

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Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

et al. 2018

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“…In these patients, RTX population pharmacokinetic (PK) was assessed using a semi-mechanistic pharmacokinetic model, as previously described. 6 Exposure to RTX was assessed by the area under the concentration-time curve (AUC) from the beginning of treatment to the last concentration measurement time at M12 (6 months after the end of the FCR treatment, AUC0-12M) or D22 (before C1 of FCR treatment in the Dense-FCR arm, AUC0-22D). RTX AUC0-12M and AUC0-22D values were obtained by integrating the concentrations predicted in the PK model.…”

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confidence: 99%

Increased rituximab exposure does not improve response and outcome of patients with chronic lymphocytic leukemia after fludarabine, cyclophosphamide, rituximab. A French Innovative Leukemia Organization (FILO) study

Cartron¹,

Letestu²,

Dartigeas³

et al. 2018

Haematologica

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“…48 In CLL, the inverse correlation between antigenic mass and RTX clearance suggests a consumption of the antibody by the tumor ("sink effect"), which could not be overcome by an increase the dosing regimen. 45,48,49 How do OBZ pharmacokinetics differ from that of RTX? OBZ clinical development attempted to answer unresolved questions raised by RTX development.…”

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confidence: 99%

Obinutuzumab: what is there to learn from clinical trials?

Cartron

Watier

2017

Blood

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Obinutuzumab (OBZ) is a recombinant type II anti-CD20 and immunoglobulin G1 Fc-optimized monoclonal antibody (mAb), recently approved in chronic lymphocytic leukemia (CLL; B-cell CLL) and follicular lymphoma (FL). Rituximab (RTX) is frequently considered as its "ancestor" and OBZ clinical development was justified by the importance of FcgRIIIAmediated mechanisms in RTX clinical activity. However, RTX differs from OBZ in 2 critical independent properties: being a type I anti-CD20 mAb and not being Fcoptimized. Moreover, the use of a different dosing regimen for RTX and OBZ further complicates any interpretation of clinical results. The results obtained for OBZ in CLL provide new arguments for FcgRIIIAmediated mechanisms when the target antigen is expressed at a low density. Results of OBZ in FL confirm the interest for FcgRIIIA-mediated mechanisms, with some limitations, some of them being possibly due to lack of OBZ-induced complement activation. The situation in diffuse large B-cell lymphoma is deceiving, as the possible gains of activity of OBZ appear to be annihilated by the lack of complement activation. Although RTX was by chance an anti-CD20 mAb with equilibrated pharmacodynamic properties, the reinforcement of some of these properties, which has been done at the expense of complement activation, has conferred an advantage in some B-cell disorders while restricting OBZ indications. The OBZ story nicely demonstrates that the future of naked mAbs is to design agents with optimized and tailored properties, and that this must be done step by step, with a full clinical validation. (Blood. 2017;130(5):581-589) Introduction Obinutuzumab (OBZ) is the first recombinant type II anti-CD20 and immunoglobulin G1 (IgG1) Fc-optimized monoclonal antibody (mAb) approved by the US Food and Drug Administration (FDA) and European Medicines Agency. It is currently labeled in first-line chronic lymphocytic leukemia (CLL) patients in association with chlorambucil, and in combination with bendamustine followed by OBZ monotherapy for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab (RTX)-containing regimen. RTX was the first anti-CD20 mAb approved and largely contributed to establish the therapeutic value of anti-CD20 strategies in almost all CD201 malignancies. Experimental studies demonstrated that RTX is able to induce CD20 1 cell death by several mechanisms.1 RTX is sometimes presented as the "ancestor" of OBZ. First of all, OBZ is in no way a RTX biosimilar: not only are their variable domains totally different but also, in addition, RTX does not recognize the same CD20 epitope as OBZ and is a human IgG1 non-Fc-optimized antibody, 2 characteristics independent from each other and having functional and pharmacological consequences that need to be taken into consideration when trying to compare the 2 drugs. OBZ development was largely based on the presumed importance of FcgRIIIA-mediated mechanisms in RTX clinical activity, this being mainly supported by the influ...

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Influence of FCGR3A-158V/F Genotype and Baseline CD20 Antigen Count on Target-Mediated Elimination of Rituximab in Patients with Chronic Lymphocytic Leukemia: A Study of FILO Group

Abstract: NCT01370772.

Cited by 24 publications

References 51 publications

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

Increased rituximab exposure does not improve response and outcome of patients with chronic lymphocytic leukemia after fludarabine, cyclophosphamide, rituximab. A French Innovative Leukemia Organization (FILO) study

Obinutuzumab: what is there to learn from clinical trials?

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