Impact of FcγRIIa-FcγRIIIa Polymorphisms and <i>KRAS</i> Mutations on the Clinical Outcome of Patients With Metastatic Colorectal Cancer Treated With Cetuximab Plus Irinotecan

Bibeau, Frédéric; Lopez-Crapez, Evelyne; Fiore, Frédéric Di; Thézenas, Simon; Ychou, Marc; Blanchard, F.; Lamy, Aude; Penault‐Llorca, Frédérique; Frébourg, Thierry; Michel, Pierre; Sabourin, Jean‐Christophe; Boissière‐Michot, Florence

doi:10.1200/jco.2008.18.0463

Cited by 461 publications

(362 citation statements)

References 41 publications

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“…Consistent with the mechanisms of action for antibodies used to target cell-surface molecules in B-cell malignancies and in solid tumors (29)(30)(31)(32), ADCC mediated by NK cells was found to be an important mode of action for killing of human AML cells. In contrast, neither of the anti-IL1RAP antibodies mediated specific cell death by ADCP or CDC of MA9Ras cells in vitro, suggesting that these mechanisms may be less critical for the observed effects.…”

Section: Discussionmentioning

confidence: 62%

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Ågerstam

Karlsson

Hansen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Acute myeloid leukemia (AML) is associated with a poor survival rate, and there is an urgent need for novel and more efficient therapies, ideally targeting AML stem cells that are essential for maintaining the disease. The interleukin 1 receptor accessory protein (IL1RAP; IL1R3) is expressed on candidate leukemic stem cells in the majority of AML patients, but not on normal hematopoietic stem cells. We show here that monoclonal antibodies targeting IL1RAP have strong antileukemic effects in xenograft models of human AML. We demonstrate that effector-cell-mediated killing is essential for the observed therapeutic effects and that natural killer cells constitute a critical human effector cell type. Because IL-1 signaling is important for the growth of AML cells, we generated an IL1RAP-targeting antibody capable of blocking IL-1 signaling and show that this antibody suppresses the proliferation of primary human AML cells. Hence, IL1RAP can be efficiently targeted with an anti-IL1RAP antibody capable of both achieving antibody-dependent cellular cytotoxicity and blocking of IL-1 signaling as modes of action. Collectively, these results provide important evidence in support of IL1RAP as a target for antibody-based treatment of AML.A cute myeloid leukemia (AML) is a genetically heterogeneous disease characterized by clonal expansion of leukemic cells. Despite an increased understanding of the underlying disease biology in AML, the standard treatment with cytotoxic chemotherapy has remained largely unchanged over the last decades and the overall 5-y survival remains poor, being <30% (1, 2). Hence, there is a pressing need for novel therapies with increased efficacy and decreased toxicity, ideally targeting the AML stem cells because these cells are believed to be critical in the pathogenesis of AML, and their inadequate eradication by standard therapy is thought to contribute to the high incidence of relapse (3, 4). Although therapeutic antibodies directed at cell-surface molecules have proven effective for the treatment of malignant disorders such as lymphomas and acute lymphoblastic leukemia, as well as solid tumors (5, 6), no antibody-based therapy is currently approved for AML.The interleukin 1 receptor accessory protein (IL1RAP), also called IL1R3, is a coreceptor of type 1 interleukin 1 receptor (IL1R1) and is indispensable for transmission of IL-1 signaling (7). We have previously reported that IL1RAP is a biomarker for putative chronic myeloid leukemia stem cells (8). In a recent study, we showed that IL1RAP is expressed on the cell surface in ∼80% of AML patients and that candidate CD34 + CD38 − AML stem cells can be selectively killed in vitro by antibody-dependent cellular cytotoxicity (ADCC) (9). Furthermore, IL1RAP is upregulated on immature cells in high-risk AML with chromosome 7 aberrations, and increased IL1RAP expression correlates with poor prognosis (10). These findings could suggest IL1RAP as a novel and specific target for an antibody-based therapy in AML; however, in vivo evidences for therapeuti...

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Section: Discussionmentioning

confidence: 62%

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Ågerstam

Karlsson

Hansen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Additionally, in some cases, patients bearing the higher affinity Fc␥RIIa polymorphism, His 131 , have improved clinical responses to bacterial infections (69) and improved IgG2-mediated phagocytosis of opsonized bacteria (70). These correlations between higher affinity Fc␥R-mAb interactions and efficacy are also in line with the observation that in some cases patients bearing higher affinity Fc receptor polymorphisms have a more favorable clinical response to IgG1 mAb-mediated cancer therapies (71)(72)(73). For these reasons, one common goal for Fc engineering efforts is to generate Fc variants that demonstrate improved effector functions in patients bearing lower affinity Fc␥R polymorphisms (35,74).…”

Section: Discussionmentioning

confidence: 67%

Engineered Protease-resistant Antibodies with Selectable Cell-killing Functions

Kinder

Greenplate

Grugan

et al. 2013

Journal of Biological Chemistry

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Background: Proteases can cleave human IgG1 antibodies, resulting in loss of cell-killing functions. Results: Mutation of the lower hinge of IgG1 confers protease resistance but disrupts Fc effector functions. Conclusion: Compensating mutations in the C H 2 domain can selectively restore Fc effector functions on a protease-resistant backbone. Significance: Protease-resistant antibodies may be desirable for microenvironments with high protease content and/or when selected cell-killing functions are needed.

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“…Further studies have consolidated these findings and, in addition, have demonstrated the importance of an additional polymorphism, FcgRIIA 131H/H (Weng and Levy, 2003), although the mechanism by which this polymorphism achieves superior engagement is not yet fully defined, as it does not show differential IgG1 affinity (Desjarlais et al, 2007). More recently, data relating to the prognostic significance of these polymorphisms in response to other antibodies, including trastuzumab (Musolino et al, 2008) and cetuximab (Bibeau et al, 2009), have been reported, which indicate similar trends. However, it should be noted that such data are not without controversy.…”

Section: Data Supporting the Role Of Fc-mediated Mechanisms In Antibomentioning

confidence: 63%

“…This will inform a variety of strategies aimed at maximising patient response, including genotyping patients to predict response and development of next-generation antibodies, which achieve efficacy irrespective of Fc-receptor polymorphism status. Such analysis may be confounded by other, independent factors that influence responses to targeting functional tumour antigens, for example, PI3-kinase mutation status in trastuzumab therapy (Junttila et al, 2009) and K-ras mutation status in cetuximab treatment (Bibeau et al, 2009). …”

Section: Data Supporting the Role Of Fc-mediated Mechanisms In Antibomentioning

confidence: 99%

The state of the art: immune-mediated mechanisms of monoclonal antibodies in cancer therapy

Griggs¹,

Zinkewich-Péotti²

2009

Br J Cancer

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A number of antibody products have now become accepted as effective anti-cancer therapies. Despite being mainly designed to act by inhibiting functional tumour antigens, there is increasing evidence that Fc-mediated engagement of the immune system is an important contributor to the efficacy of several of these therapies. The optimisation of this engagement offers the potential not only to augment efficacy against existing targets, but also to exploit non-functional tumour antigens. Antibodies that achieve efficacy wholly or predominantly through Fc-mediated mechanisms, represent rich opportunities for future therapeutics in oncology. This mini review summarises some of the key challenges, which need to be addressed to select the most effective molecules. These include the identification of optimal antibody characteristics and improvement of the drug discovery process, in particular, the relevance and predictive power of existing in vitro and in vivo screening methods. Advances in our understanding of tumour immunobiology and successful application of technologies designed to enhance immune system engagement will further aid this process.

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Impact of FcγRIIa-FcγRIIIa Polymorphisms and KRAS Mutations on the Clinical Outcome of Patients With Metastatic Colorectal Cancer Treated With Cetuximab Plus Irinotecan

Abstract: Combined FcgammaRIIa/FcgammaRIIIa polymorphisms are prognostic factors for disease progression in mCRC patients treated with cetuximab plus irinotecan. As these polymorphisms are also clinically relevant in mutated-KRAS mCRC, an important role of ADCC in cetuximab efficacy is presumed.

Cited by 461 publications

References 41 publications

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Engineered Protease-resistant Antibodies with Selectable Cell-killing Functions

The state of the art: immune-mediated mechanisms of monoclonal antibodies in cancer therapy

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