A novel CXCR4 antagonist IgG1 antibody (PF-06747143) for the treatment of hematologic malignancies

Liu, Shuhui; Gu, Yin; Pascual, Bernadette; Yan, Zhengming; Hallin, Max; Zhang, Cathy; Fan, Conglin; Wang, Wenlian; Lam, Justine L.; Spilker, Mary E.; Yafawi, Rolla; Blasi, Eileen; Simmons, Brett H.; Huser, Nanni; Ho, Wei-Hsien; Lindquist, Kevin C.; Tran, Thomas-Toan; Kudaravalli, Jyothirmayee; Ma, Jing-Tyan; Jimenez, Gretchen; Barman, Ishita; Brown, Colleen; Chin, Sherman M.; Costa, Maria José; Shelton, David L.; Smeal, Tod; Fantin, Valeria R.; Pernasetti, Flavia

doi:10.1182/bloodadvances.2016003921

Cited by 40 publications

(25 citation statements)

References 43 publications

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“…High CXCR4 expression is also an independent risk factor for total survival time in patients with AML [114]. Finally, in multiple myeloma (MM) cells, CXCR4 expression correlated with disease progression [115], chemotherapy resistant MRD [116], and poor prognosis [117], while an increase in the CXCL12 serum expression level was associated with increased osteolytic disease and increased BM angiogenesis [118].…”

Section: Cxcl12/cxcr4 Axis In Hematological Tumors: a Crucial Hub Formentioning

confidence: 99%

“…A phase 3 trial (NCT03246529) is currently evaluating the use of motixafortide for stem cell mobilization [167]. Actually, there are two fully human anti-CXCR4 antibodies-PF-06747143 [116] and ulocuplumab [168]-used for the treatment of hematologic malignancies. Finally, LY2510924, is a potent cyclic peptide antagonist of CXCR4 with acceptable in vivo stability and a pharmacokinetic profile similar to a typical small molecule inhibitor [169], which is being evaluated in phase 1/2 clinical trials in extensive small cell lung cancer (NCT01439568), renal cancer (NCT 01391130), and in association with durvalumab (an anti Programmed Death-Ligand 1 (PD-L1) in solid tumors (NCT02737072).…”

Section: Cxcr4 Targeting In Hematological Tumorsmentioning

confidence: 99%

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New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

et al. 2020

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Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom’s macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy.

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Section: Cxcl12/cxcr4 Axis In Hematological Tumors: a Crucial Hub Formentioning

confidence: 99%

Section: Cxcr4 Targeting In Hematological Tumorsmentioning

confidence: 99%

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

et al. 2020

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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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“…C-X-C motif chemokine receptor 4 (CXCR4) serves an important role in cell migration, with certain studies hypothesizing that cell migration is predominantly dependent on the CXCR4/stromal-derived factor-1 (SDF-1) axis (11). CXCR4 and its ligand SDF-1 are primarily studied for their crucial roles in the homing of stem and progenitor cells in the bone marrow, chemotaxis, cell arrest, angiogenesis, metastasis and cell survival (12). Tavor et al (13) reported that AML cells constitutively secrete and express SDF-1-dependent cell surface elastase, which regulates their migration and proliferation.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‑144 targets APP to regulate AML1/ETO+ leukemia cell migration via the p‑ERK/c‑Myc/MMP‑2 pathway

Jiang

Wang

et al. 2019

Oncol Lett

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Extramedullary infiltration (EMI) is common in patients with acute myeloid leukemia (AML) and is closely associated with the prognosis of disease. We previously reported that patients carrying the AML1/ETO (A/E) fusion gene and expressing the amyloid precursor protein (APP) tended to develop EMI, and had a poor prognosis. In the present study, the relapse-free survival (RFS) time and overall survival (OS) time were significantly lower in patients with EMI. The results demonstrated that the EMI incidence was significantly higher (P<0.05), while the RFS and OS rates were significantly lower (P<0.05), in patients with high APP expression. Kasumi-1 cells, which are A/E + , and the APP gene were used as the in vitro cell model to detect the mechanism of action in detail. Following the knockdown of APP expression, cell migration was significantly reduced (P<0.05). Furthermore, western blotting demonstrated that the protein expression of phosphorylated extracellular-signal-regulated kinase (p-ERK), matrix metalloproteinase-2 (MMP-2) and c-Myc was markedly reduced following interference of APP, while the expression of CXCR4 and MMP-9 was not altered. Kasumi-1 cells were co-cultured with p-ERK or c-Myc inhibitors and demonstrated that the APP/p-ERK/c-Myc/MMP-2 pathway was involved in signal transduction and regulation of cell migration. mimics and transfected Kasumi-1 cells were generated. Reverse transcription-quantitative polymerase chain reaction and western blotting demonstrated that miR-144 was a negative regulator of APP. Taken together, the findings of the present study suggest that miR-144 negatively targets the APP gene and regulates cell migration via the APP/p-ERK/c-Myc/MMP-2 pathway.

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A novel CXCR4 antagonist IgG1 antibody (PF-06747143) for the treatment of hematologic malignancies

Abstract: Key Points PF-06747143, a novel CXCR4 antagonist IgG1 Ab, mobilizes malignant cells from the BM and induces their death via Fc-effector function. PF-06747143 reduces tumor burden in NHL, AML, and MM models, both as a monotherapy or in combination with standard-of-care agents.

Cited by 40 publications

References 43 publications

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3

MicroRNA‑144 targets APP to regulate AML1/ETO+ leukemia cell migration via the p‑ERK/c‑Myc/MMP‑2 pathway

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