Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia

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Abstract

Background

The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL.

Methods

Patient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model.

Results

PF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine.

Conclusions

We show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients.

Electronic supplementary material

The online version of this article (doi:10.1186/s13045-017-0435-x) contains supplementary material, which is available to authorized users.

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Most cited references 50

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CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment.

Jan A Burger, Thomas J Kipps (2006)

Signals from the microenvironment have a profound influence on the maintenance and/or progression of hematopoietic and epithelial cancers. Mesenchymal or marrow-derived stromal cells, which constitute a large proportion of the non-neoplastic cells within the tumor microenvironment, constitutively secrete the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). CXCL12 secretion by stromal cells attracts cancer cells, acting through its cognate receptor, CXCR4, which is expressed by both hematopoietic and nonhematopoietic tumor cells. CXCR4 promotes tumor progression by direct and indirect mechanisms. First, CXCR4 is essential for metastatic spread to organs where CXCL12 is expressed, and thereby allows tumor cells to access cellular niches, such as the marrow, that favor tumor-cell survival and growth. Second, stromal-derived CXCL12 itself can stimulate survival and growth of neoplastic cells in a paracrine fashion. Third, CXCL12 can promote tumor angiogenesis by attracting endothelial cells to the tumor microenvironment. CXCR4 expression is a prognostic marker in various types of cancer, such as acute myelogenous leukemia or breast carcinoma. Promising results in preclinical tumor models indicate that CXCR4 antagonists may have antitumor activity in patients with various malignancies. Collectively, these observations reveal that CXCR4 is an important molecule involved in the spread and progression of a variety of different tumors. As such, CXCR4 antagonists, although initially developed for treatment of AIDS, actually may become effective agents for the treatment of neoplastic disease.

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Mitochondrial reactive oxygen species in cell death signaling.

Christophe Fleury, Bernard Mignotte, Jean-Luc Vayssière (2002)

During apoptosis, mitochondrial membrane permeability (MMP) increases and the release into the cytosol of pro-apoptotic factors (procaspases, caspase activators and caspase-independent factors such as apoptosis-inducing factor (AIF)) leads to the apoptotic phenotype. Apart from this pivotal role of mitochondria during the execution phase of apoptosis (documented in other reviews of this issue), it appears that reactive oxygen species (ROS) produced by the mitochondria can be involved in cell death. These toxic compounds are normally detoxified by the cells, failing which oxidative stress occurs. However, ROS are not only dangerous molecules for the cell, but they also display a physiological role, as mediators in signal transduction pathways. ROS participate in early and late steps of the regulation of apoptosis, according to different possible molecular mechanisms. In agreement with this role of ROS in apoptosis signaling, inhibition of apoptosis by anti-apoptotic Bcl-2 and Bcl-x(L) is associated with a protection against ROS and/or a shift of the cellular redox potential to a more reduced state. Furthermore, the fact that active forms of cell death in yeast and plants also involve ROS suggests the existence of an ancestral redox-sensitive death signaling pathway that has been independent of caspases and Bcl-2.

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Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1.

A. M. Dell'Aquila, T J Kipps, Andreas Burger … (2000)

A subset of blood cells from patients with B-cell chronic lymphocytic leukemia (CLL) spontaneously differentiates in vitro into large, round, or fibroblast-like adherent cells that display stromal cell markers, namely vimentin and STRO-1. These cells also express stromal cell-derived factor-1 (SDF-1), a CXC chemokine that ordinarily is secreted by marrow stromal cells. Leukemia B cells attach to these blood-derived adherent cells, down-modulate their receptors for SDF-1 (CXCR4), and are protected from undergoing spontaneous apoptosis in vitro. Neutralizing antibodies to SDF-1 inhibit this effect. Moreover, the rapid deterioration in the survival of CLL B cells, when separated from such cells, is mitigated by exogenous SDF-1. This chemokine also results in the rapid down-modulation of CXCR4 and activation of p44/42 mitogen-activated protein-kinase (ERK 1/2) by CLL B cells in vitro. It is concluded that the blood of patients with CLL contains cells that can differentiate into adherent nurse-like cells that protect leukemia cells from undergoing spontaneous apoptosis through an SDF-1-dependent mechanism. In addition to its recently recognized role in CLL B-cell migration, SDF-1-mediated CLL B-cell activation has to be considered a new mechanism involved in the microenvironmental regulation of CLL B-cell survival. (Blood. 2000;96:2655-2663)

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Author and article information

Contributors

Flavia Pernasetti:

ORCID: http://orcid.org/0000-0002-1781-5607

858-622-7587 , flavia.pernasetti@pfizer.com

Januario E. Castro: 858-822-6386 , jecastro@ucsd.edu

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 19 May 2017

Publication date PMC-release: 19 May 2017

Publication date Collection: 2017

Volume: 10

Electronic Location Identifier: 112

Affiliations

[1 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, , Moores Cancer Center, University of California San Diego, ; 3855 Health Science Drive, La Jolla, CA 92093-0820 USA

[2 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, CLL Research Consortium, and Department of Medicine, , University of California San Diego, ; La Jolla, CA USA

[3 ]Oncology Research & Development, Pfizer Worldwide Research & Development, 10646 Science Center Drive, San Diego, CA 92121 USA

[4 ]Oncology Research & Development—Rinat Biotechnology Unit, Pfizer Worldwide Research & Development, South San Francisco, CA USA

[5 ]Drug Safety Research & Development, Pfizer Worldwide Research & Development, La Jolla, CA USA

[6 ]ISNI 0000 0000 2220 2544, GRID grid.417540.3, , Present Address: Eli Lilly and Company, Lilly Corporate Center, ; Indianapolis, IN USA

[7 ]Present Address: ORIC Pharmaceuticals, South San Francisco, CA USA

[8 ]GRID grid.421297.b, , Present Address: Mirati Therapeutics, ; San Diego, CA USA

Author information

Flavia Pernasetti http://orcid.org/0000-0002-1781-5607

Article

Publisher ID: 435

DOI: 10.1186/s13045-017-0435-x

PMC ID: 5438492

PubMed ID: 28526063

SO-VID: db967d99-25d6-47aa-b5b0-d44015c3d5b9

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 15 December 2016

Date accepted : 27 February 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: PO1-CA081534

Award Recipient : Flavia Pernasetti

Funded by: UC San Diego Foundation-Blood Cancer Research Fund

Funded by: Bennett Family Foundation

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: chronic lymphocytic leukemia,pf-06747143,cxcr4,cxcl12,chemokine,adcc,cdc,cell death,reactive oxygen species

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: chronic lymphocytic leukemia, pf-06747143, cxcr4, cxcl12, chemokine, adcc, cdc, cell death, reactive oxygen species

Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia

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Background

Methods

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Conclusions

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Karger: Oncology

Most cited references 50

CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment.

Mitochondrial reactive oxygen species in cell death signaling.

Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1.

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