Tumor burden influences exposure and response to rituximab: pharmacokinetic-pharmacodynamic modeling using a syngeneic bioluminescent murine model expressing human CD20

Daydé, David; Ternant, David; Ohresser, Marc; Lerondel, Stéphanie; Pesnel, Sabrina; Watier, Hervé; Pape, Alain Le; Bardos, P.; Paintaud, Gilles; Cartron, Guillaume

doi:10.1182/blood-2008-08-175125

Cited by 114 publications

(106 citation statements)

References 25 publications

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“…Les études analysant l'influence de la masse tumorale sur la PK du rituximab dans le lymphome malin non hodgkinien ont donné des résultats contradictoires, ce qui pourrait être expliqué par la difficulté à évaluer de façon précise la masse tumorale en pratique clinique [36] (➜). L'influence de la masse tumorale sur la relation dose-concentration-effet du rituximab a été étudiée à l'aide d'un modèle murin développant un lymphome exprimant le CD20 humain [37]. Les concentrations sériques de rituximab étaient inversement corrélées à la masse tumorale, les souris avec une masse tumorale faible ayant des concentrations élevées.…”

Section: Variabilité Pk Interindividuelleunclassified

“…Il a par ailleurs été montré que le nombre de sites métastati-ques influence la PK du trastuzumab chez les patientes traitées [35]. Pour décrire l'interdépendance entre la PK et la pharmacodynamie, des modèles pharmacocinétiques-pharmacodynamiques (PK-PD) spécifiques doivent être développés [37,38]. [39].…”

Section: Variabilité Pk Interindividuelleunclassified

“…Influence de la masse tumorale sur la pharmacociné-tique des Acm. L'influence de la masse tumorale (ronds rouges, exprimée en ln d'activité) sur la relation dose-concentrationeffet du rituximab a été étu-diée à l'aide d'un modèle murin développant un lymphome exprimant le CD20 humain [37]. Les concentrations d'infliximab (ne reconnaissant aucune cible dans ce modèle murin, losanges bleus) et de rituximab (carrés verts) ont une décroissance log-linéaire chez les souris ayant une réponse totale (figure de gauche).…”

Section: Summary Pharmacokinetics (Pk) Of Mabsunclassified

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Pharmacocinétique des anticorps monoclonaux

Paintaud

2009

Med Sci (Paris)

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Section: Variabilité Pk Interindividuelleunclassified

Section: Summary Pharmacokinetics (Pk) Of Mabsunclassified

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Pharmacocinétique des anticorps monoclonaux

Paintaud

2009

Med Sci (Paris)

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“…18,19 Dayde et al have shown in a preclinical model that exposure to rituximab influences response and survival. 20 Additional investigations are clearly warranted to better define parameters influencing pharmacokinetic parameters of rituximab.…”

Section: Parameters Correlated With Rituximab Activity and Resistancementioning

confidence: 99%

Understanding and circumventing resistance to anticancer monoclonal antibodies

Reslan

Dalle

Dumontet

2009

mAbs

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With the widespread use of therapeutic monoclonal antibodies in the treatment of patients with cancer, resistance to these agents has become a major issue. Preclinical models of drug action or resistance have contributed to unravel the main mechanisms of resistance, involving both tumor-associated and host related factors. However our understanding of how a monoclonal antibody destroys cancer cells in a patient and why it one day stops being effective are still far from being complete. This review focuses on the available data on mechanisms of action and resistance to rituximab and includes some additional information for other monoclonal antibodies. Innovative approaches designed to overcome resistance, such as combination immunotherapy, costimulation with cytokines or growth factors are presented.

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“…Further studies demonstrated that PK-guided RTX dosing to maintain sufficient RTX concentrations in indolent non-Hodgkin lymphomas (iNHLs), 41 or an increased number of RTX infusions in DLBCL, 42 failed to demonstrate any clinical advantage. As suggested in a murine model, 43 antigen burden is probably, at least in DLBCL, the main parameter affecting RTX exposure. A recent study confirmed that antigenic mass assessed by total metabolic volume before treatment influenced exposure to RTX.…”

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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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Tumor burden influences exposure and response to rituximab: pharmacokinetic-pharmacodynamic modeling using a syngeneic bioluminescent murine model expressing human CD20

Cited by 114 publications

References 25 publications

Pharmacocinétique des anticorps monoclonaux

Pharmacocinétique des anticorps monoclonaux

Understanding and circumventing resistance to anticancer monoclonal antibodies

Obinutuzumab: what is there to learn from clinical trials?

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