Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)

Zhang, Yanyan; Saavedra, Erika; Tang, Ruoping; Gu, Yin; Lappin, Patrick B.; Trajkovic, Dusko; Liu, Shuhui; Smeal, Tod; Fantin, Valeria R.; Botton, Stéphane de; Legrand, Ollivier; Delhommeau, François; Pernasetti, Flavia; Louache, Fawzia

doi:10.1038/s41598-017-07848-8

Cited by 28 publications

(27 citation statements)

References 36 publications

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“…In addition, two independent studies have recently targeted CXCR4 with an IgG antibody (PF-06747143), which revealed a strong affinity to AML cells and inhibited their chemotaxis towards CXCL12. It also reduced the tumor burden in other hematological malignancies and in a xenotransplantation model for AML Zhang et al, 2017).…”

Section: Targeting the Bmm In Hematological Malignanciesmentioning

confidence: 93%

The bone marrow microenvironment in health and disease at a glance

Kumar

Godavarthy

Krause

2018

Journal of Cell Science

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The bone marrow microenvironment (BMM) is the 'domicile' of hematopoietic stem cells, as well as of malignant processes that can develop there. Multiple and complex interactions with the BMM influence hematopoietic stem cell (HSC) physiology, but also the pathophysiology of hematological malignancies. Reciprocally, hematological malignancies alter the BMM, in order to render it more hospitable for malignant progression. In this Cell Science at a Glance article and accompanying poster, we highlight concepts of the normal and malignant hematopoietic stem cell niches. We present the intricacies of the BMM in malignancy and provide approaches for targeting the interactions between malignant cells and their BMM. This is done in an effort to augment existing treatment strategies in the future.

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Section: Targeting the Bmm In Hematological Malignanciesmentioning

confidence: 93%

The bone marrow microenvironment in health and disease at a glance

Kumar

Godavarthy

Krause

2018

Journal of Cell Science

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“…LY2624587 is another anti-CXCR4 IgG4 antibody with similar mode of action, which has also reached the clinical trial phase (Table 2) (Peng et al, 2016b). The combination of CXCR4 inhibition, induction of apoptosis, and ADCC and CDC effector functions is employed in an IgG1 from Pfizer, PF-06747143, and shows a strong effect in multiple hematologic tumor models (Table 2) (Kashyap et al, 2017;Liu et al, 2017;Zhang et al, 2017). Utilization of different antibody formats and Fc engineering strategies provides an attractive flexibility in pursuing specific therapeutic needs.…”

Section: Targeting Cxcr4 and Ackr3 With Antibodiesmentioning

confidence: 99%

Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3

et al. 2019

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Dysregulation of the chemokine system is implicated in a number of autoimmune and inflammatory diseases, as well as cancer. Modulation of chemokine receptor function is a very promising approach for therapeutic intervention. Despite interest from academic groups and pharmaceutical companies, there are currently few approved medicines targeting chemokine receptors. Monoclonal antibodies (mAbs) and antibody-based molecules have been successfully applied in the clinical therapy of cancer and represent a potential new class of therapeutics targeting chemokine receptors belonging to the class of G protein-coupled receptors (GPCRs). Besides conventional mAbs, single-domain antibodies and antibody scaffolds are also gaining attention as promising therapeutics. In this review, we provide an extensive overview of mAbs, singledomain antibodies, and other antibody fragments targeting CXCR4 and ACKR3, formerly referred to as CXCR7. We discuss their unique properties and advantages over smallmolecule compounds, and also refer to the molecules in preclinical and clinical development. We focus on singledomain antibodies and scaffolds and their utilization in GPCR research. Additionally, structural analysis of antibody binding to CXCR4 is discussed. SIGNIFICANCE STATEMENT Modulating the function of GPCRs, and particularly chemokine receptors, draws high interest. A comprehensive review is provided for monoclonal antibodies, antibody fragments, and variants directed at CXCR4 and ACKR3. Their advantageous functional properties, versatile applications as research tools, and use in the clinic are discussed.

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“…Similarly, CXCR4+ cancer cells are metastatic stem cells in several solid tumors [12][13][14][15][16][17]. Consequently, different groups are developing small drug CXCR4 inhibitors for AML therapy [5,7,18] aimed at eliminating CXCR4+ LSCs, responsible for AML aggressiveness and patient death.…”

Section: (Continued From Previous Page)mentioning

confidence: 99%

An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination

et al. 2020

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Background: Current acute myeloid leukemia (AML) therapy fails to eliminate quiescent leukemic blasts in the bone marrow, leading to about 50% of patient relapse by increasing AML burden in the bone marrow, blood, and extramedullar sites. We developed a protein-based nanoparticle conjugated to the potent antimitotic agent Auristatin E that selectively targets AML blasts because of their CXCR4 receptor overexpression (CXCR4+) as compared to normal cells. The therapeutic rationale is based on the involvement of CXCR4 overexpression in leukemic blast homing and quiescence in the bone marrow, and the association of these leukemic stem cells with minimal residual disease, dissemination, chemotherapy resistance, and lower patient survival. Methods:Monomethyl Auristatin E (MMAE) was conjugated with the CXCR4 targeted protein nanoparticle T22-GFP-H6 produced in E. coli. Nanoconjugate internalization and in vitro cell viability assays were performed in CXCR4+ AML cell lines to analyze the specific antineoplastic activity through the CXCR4 receptor. In addition, a disseminated AML animal model was used to evaluate the anticancer effect of T22-GFP-H6-Auristatin in immunosuppressed NSG mice (n = 10/group). U of Mann-Whitney test was used to consider if differences were significant between groups.Results: T22-GFP-H6-Auristatin was capable to internalize and exert antineoplastic effects through the CXCR4 receptor in THP-1 and SKM-1 CXCR4+ AML cell lines. In addition, repeated administration of the T22-GFP-H6-Auristatin nanoconjugate (9 doses daily) achieves a potent antineoplastic activity by internalizing specifically in the leukemic cells (luminescent THP-1) to selectively eliminate them. This leads to reduced involvement of leukemic cells in the bone marrow, peripheral blood, liver, and spleen, while avoiding toxicity in normal tissues in a luminescent disseminated AML mouse model.(Continued on next page)

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Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)

Cited by 28 publications

References 36 publications

The bone marrow microenvironment in health and disease at a glance

The bone marrow microenvironment in health and disease at a glance

Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3

An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination

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