Acquirement of Rituximab Resistance in Lymphoma Cell Lines Is Associated with Both Global<i>CD20</i>Gene and Protein Down-Regulation Regulated at the Pretranscriptional and Posttranscriptional Levels

Czuczman, Myron S.; Olejniczak, Scott H.; Gowda, Aruna; Kotowski, Adam; Binder, Arvinder; Kaur, Harman; Knight, Joy; Starostik, Petr; Deans, Julie P.; Hernandez‐Ilizaliturri, Francisco J.

doi:10.1158/1078-0432.ccr-07-1254

Cited by 217 publications

(238 citation statements)

References 43 publications

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“…5 Failure has been attributed to target downregulation or heterogeneity, as well as lack of potency. 6 FDA-approved strategies enhancing mAb therapy potency include the attachment of potent small molecule drugs or b-emitting radioactive elements to mAb, and the creation of truncated Ig bi-specific constructs (BiTEs) for T-cell recruitment. [7][8][9][10] These hybrid molecules have alternative modes of action to ADCC/ADCP, and while more potent, have significantly increased toxicity, result in off-target organ damage, and display difficult pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of leukemia resistance to antibody dependent cellular cytotoxicity

et al. 2016

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Specific immunotherapy for acute leukemia remains a great unmet need. Native unmodified monoclonal antibody therapies, while promising, are inadequately effective for these malignancies, and multiple mechanisms for failure have been described. Antibody-dependent cellular cytotoxicity or phagocytosis is the primary modality of mAb-mediated cell killing in vivo, but ultimately leads to relapse of the leukemias, in model systems and in humans. By use of a T-cell receptor mimic mAb ESKM, derived against a WT1 peptide expressed in complex with HLA-A Ã 02:01, whose only mechanism of therapeutic action is ADCC, we evaluated the mechanisms of leukemic relapse from its potent therapeutic action in mouse xenograft models of human leukemia. Leukemia escape was not associated with loss of the antigenic target, downregulation of cell surface HLA, antibody pharmacokinetic or biodistribution issues, or development of leukemia cell-intrinsic resistance to ADCC. Interestingly, the rapidity of leukemic growth determined whether leukemia was able to evade cytotoxicity independent of the presence of sufficient effector cells. By engineering leukemia cells with upregulated p27Kip1 and slower cell cycling times, we show that relapse was inversely correlated with growth rates resulting in the eventual inadequacy of effector to target ratio. Moreover, lack of migration of effector cells into lymphomatous pockets of ALL also allowed local escape. Successful leukemia therapy with mAb might therefore be improved in similar situations by combination with measures to reduce burden and slow leukemia cell growth.

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Section: Introductionmentioning

confidence: 99%

Mechanisms of leukemia resistance to antibody dependent cellular cytotoxicity

et al. 2016

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“…4 However, a significant proportion of NHL patients still remains not curable to date and there is a need to identify new targets for therapy. [5][6][7] A majority of genes expressed by malignant cells are shared with genes expressed in their non-transformed cellular progenitor. Most B-cell NHLs in humans are derived from germinal center (GC) and post-GC B cells consequently to genetic abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Lectin-like transcript 1 is a marker of germinal center-derived B-cell non-Hodgkin's lymphomas dampening natural killer cell functions

et al. 2015

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“…The mechanisms of rituximab resistance may be host and/or tumor-related, but are still poorly understood. [22][23][24][25] Therefore, the need to study rituximab-resistance as well as the development of more potent CD20-directed immunotherapy is imperative.…”

Section: Introductionmentioning

confidence: 99%

HuMab-7D8, a monoclonal antibody directed against the membrane-proximal small loop epitope of CD20 can effectively eliminate CD20low expressing tumor cells that resist rituximab-mediated lysis

Meerten¹,

Rozemuller²,

Hol³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundIncorporation of the chimeric CD20 monoclonal antibody rituximab in the treatment schedule of patients with non-Hodgkin's lymphoma has significantly improved outcome. Despite this success, about half of the patients do not respond to treatment or suffer from a relapse and additional therapy is required. A low CD20-expression level may in part be responsible for resistance against rituximab. We therefore investigated whether the CD20-expression level related resistance to rituximab could be overcome by a new group of CD20 mAbs (HuMab-7D8 and ofatumumab) targeting a unique membrane-proximal epitope on the CD20 molecule. Design and MethodsBy retroviral transduction of the CD20 gene into CD20-negative cells and clonal selection of transduced cells a system was developed in which the CD20-expression level is the only variable. These CD20 transduced cells were used to study the impact of rituximab and HuMab-7D8 mediated complement-dependent cytotoxicity. To study the in vivo efficacy of these mAbs an in vivo imaging system was generated by retroviral expression of the luciferase gene in the CD20-positive cells. ResultsWe show that HuMab-7D8 efficiently killed CD20 low cells that are not susceptible to rituximabinduced killing in vitro. In a mouse xenograft model, we observed a comparable increase in survival time between HuMab-7D8 and rituximab-treated mice. Most significantly, however, HuMab-7D8 eradicated all CD20-expressing cells both in the periphery as well as in the bone marrow whereas after rituximab treatment CD20 low cells survived. ConclusionsCells that are insensitive to in vitro and in vivo killing by rituximab as the result of their low CD20-expression profile may be efficiently killed by an antibody against the membrane-proximal epitope on CD20. Such antibodies should, therefore, be explored to overcome rituximab resistance in the clinic. © F e r r a t a S t o r t i F o u n d a t i o n

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Acquirement of Rituximab Resistance in Lymphoma Cell Lines Is Associated with Both GlobalCD20Gene and Protein Down-Regulation Regulated at the Pretranscriptional and Posttranscriptional Levels

Cited by 217 publications

References 43 publications

Mechanisms of leukemia resistance to antibody dependent cellular cytotoxicity

Mechanisms of leukemia resistance to antibody dependent cellular cytotoxicity

Lectin-like transcript 1 is a marker of germinal center-derived B-cell non-Hodgkin's lymphomas dampening natural killer cell functions

HuMab-7D8, a monoclonal antibody directed against the membrane-proximal small loop epitope of CD20 can effectively eliminate CD20low expressing tumor cells that resist rituximab-mediated lysis

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