A randomized controlled trial with an anti‐CCL2 (anti–monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis

Haringman, Jasper J.; Gerlag, Daniëlle M.; Smeets, Tom; Baeten, Dominique; Bosch, Filip Van den; Bresnihan, Barry; Breedveld, Ferdinand C.; Dinant, Huibert J.; Legay, François; Gram, Hermann; Loetscher, Pius; Schmouder, Robert; Woodworth, Thasia; Tak, Paul P.

doi:10.1002/art.21975

Cited by 240 publications

(163 citation statements)

References 15 publications

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“…15,16 CCL2 plasma level was 10-fold higher in animals receiving blocking antibody than in untreated mice (Figure 4A), and in vitro recruitment of splenocytes by plasma of animals treated with aCCL2 compared to untreated was improved (Supplementary Fig. S4E).…”

Section: Resultsmentioning

confidence: 99%

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

et al. 2018

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Through whole-transcriptome profiling of HER2+ breast carcinomas (BCs), we previously showed that those sensitive to trastuzumab are addicted to this oncoprotein and are enriched in immune pathways, raising the hypothesis that HER2 itself regulates immune cell recruitment. In the present study we investigated the relationship between HER2 activity and the pro-trastuzumab tumor immune milieu. Gene expression profiling and immunohistochemistry analysis of 53 HER2+ BCs showed that trastuzumab-sensitive tumors expressed significantly higher levels of chemokines involved in immune cell recruitment, with higher infiltration of T cells and monocytes, and higher levels of PD-1 ligands than tumors that do not benefit from trastuzumab. In vitro analysis in HER2+ BC cells revealed that CCL2 production was induced by HER2 stimulation with EGF/HRG via the PI3K-NF-kB axis, and down-modulated by HER2 inhibition with trastuzumab. CCL2 expression was higher in HER2+/ER− than HER2+/ER+ BC cell lines, and degradation of ER by fulvestrant induced an enhancement in NF-κB transcriptional activity and consequent CCL2 expression. Trastuzumab efficacy relied on CCL2 levels and monocytes present in the tumor microenvironment in FVB mice bearing HER2+ mammary carcinoma cells. HER2 signals were also found to sustain the expression of PD-1 ligands in tumor cells via the MEK pathway.Overall, our results support the concept that the activated HER2 oncogene regulates recruitment and activation of tumor infiltrating immune cells and trastuzumab activity by inducing CCL2 and PD-1 ligands and that ER activity negatively controls the HER2-driven pro-trastuzumab tumor microenvironment.

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Section: Resultsmentioning

confidence: 99%

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

et al. 2018

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“…Apart from findings of an impaired activation-induced cell death (14), the increased number of Gr-1ϩ monocytes in the bone marrow of CCR2-deficient mice (33) might contribute to the aggravation of arthritis, provided that the leukocytes in the bone marrow have access to the inflamed joints, which appears possible in view of the extensive destruction of the bone architecture in this model. In addition, a recent clinical trial showed that blockade of the MCP-1-CCR2 interaction by a humanized antibody against MCP-1 was associated with a worsening of rheumatoid arthritis (34). Indeed, CCR2 might not be the ideal target for an antibody-mediated depletion of monocytes as a therapeutic approach in arthritis, since crosslinkage of CCR2 on basophils activates basophils to release IL-6, and activation of basophils markedly aggravates arthritis.…”

Section: Discussionmentioning

confidence: 99%

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

Brühl¹,

Cihak²,

Plachý

et al. 2007

Arthritis & Rheumatism

109

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Objective. The chemokine receptor CCR2 is highly expressed on monocytes and considered a promising target for treatment of rheumatoid arthritis. However, blockade of CCR2 with a monoclonal antibody (mAb) during progression of collagen-induced arthritis results in a massive aggravation of the disease. In this study we investigated why CCR2 antibodies have proinflammatory effects, how these effects can be avoided, and whether CCR2؉ monocytes are useful targets in the treatment of arthritis.Methods. Arthritis was induced in DBA/1 mice by immunization with type II collagen. Mice were treated with mAb against CCR2 (MC-21), IgE, or isotype control antibodies at various time points. Activation of basophils and depletion of monocyte subsets were determined by fluorescence-activated cell sorter analysis and enzyme-linked immunosorbent assay.Results. Crosslinkage of CCR2 activated basophils to release interleukin-6 (IL-6) and IL-4. In vivo, IL-6 release occurred only after exposure to high doses of MC-21, whereas application of low doses of the mAb circumvented the release of IL-6. Regardless of the dose level used, the antibody MC-21 efficiently depleted Gr-1؉,CCR2؉ monocytes from the synovial tissue, peripheral blood, and spleen of DBA/1 mice. Activation of basophils with high doses of MC-21 or with antibodies against IgE resulted in a marked aggravation of collagen-induced arthritis and an increased release of IL-6. In contrast, low-dose treatment with MC-21 in this therapeutic setting had no effect on IL-6 and led to marked improvement of arthritis.Conclusion. These results show that depletion of CCR2؉ monocytes may prove to be a therapeutic option in inflammatory arthritis, as long as the dosedependent proinflammatory effects of CCR2 mAb are taken into account.CCR2, a chemokine (CC motif) receptor, is considered a promising target for disorders such as multiple sclerosis, type II diabetes, and rheumatoid arthritis, and Phase I and II clinical trials are currently in progress (1). Data on CCR2 expression in humans and results from studies of CCR2-deficient mice (2-4) support the blockade of CCR2 as an effective strategy in the treatment of multiple sclerosis and diabetes. In patients with rheumatoid arthritis, we and other investigators have found an increased frequency of CCR2ϩ cells in the synovial fluid and synovial tissue (5-7). In addition, increased levels of the CCR2 ligand monocyte chemoattractant protein 1 (MCP-1; CCL2) were found in patients with rheumatoid arthritis (8). Monocytes are thought to play a major role in joint destruction, and their recruitment to sites of inflammation is crucially dependent on CCR2, as shown in several murine disease models (9-12).However, thus far, data from murine models of collagen-induced arthritis do not support CCR2 as a target for treatment of rheumatoid arthritis. We have previously shown that treatment with a blocking monoDrs. Brühl, Luckow,

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“…This was attributed to the expression of CCR2 on regulatory T cells (Tregs) in the mouse and suggests that care should be taken not to interfere with Treg trafficking in autoimmune disease. Unfortunately, the first clinical trial inhibiting the CCL2-CCR2 axis conducted on rheumatoid arthritis patients with an anti-CCL2 antibody was disappointing in that although reduction of macrophage accumulation into the joints was observed, the end-point of reduction in clinical score was not achieved [19].…”

Section: Introductionmentioning

confidence: 99%

An engineered monomer of CCL2 has anti-inflammatory properties emphasizing the importance of oligomerization for chemokine activity in vivo

Handel

Johnson

Rodrigues

et al. 2008

Journal of Leukocyte Biology

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We demonstrated recently that P8A-CCL2, a monomeric variant of the chemokine CCL2/MCP-1, is unable to induce cellular recruitment in vivo, despite full activity in vitro. Here, we show that this variant is able to inhibit CCL2 and thioglycollate-mediated recruitment of leukocytes into the peritoneal cavity and recruitment of cells into lungs of OVA-sensitized mice. This anti-inflammatory activity translated into a reduction of clinical score in the more complex inflammatory model of murine experimental autoimmune encephalomyelitis. Several hypotheses for the mechanism of action of P8A-CCL2 were tested. Plasma exposure following s.c. injection is similar for P8A-CCL2 and wild-type (WT) CCL2, ruling out the hypothesis that P8A-CCL2 disrupts the chemokine gradient through systemic exposure. P8A-CCL2 and WT induce CCR2 internalization in vitro and in vivo; CCR2 then recycles to the cell surface, but the cells remain refractory to chemotaxis in vitro for several hours. Although the response to P8A-CCL2 is similar to WT, this finding is novel and suggests that despite the presence of the receptor on the cell surface, coupling to the signaling machinery is retarded. In contrast to CCL2, P8A-CCL2 does not oligomerize on glycosaminoglycans (GAGs). However, it retains the ability to bind GAGs and displaces endogenous JE (murine MCP-1) from endothelial surfaces. Intravital microscopy studies indicate that P8A-CCL2 prevents leukocyte adhesion, while CCL2 has no effect, and this phenomenon may be related to the mechanism. These results suggest that oligomerization-deficient chemokines can exhibit anti-inflammatory properties in vivo and may represent new therapeutic modalities.

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A randomized controlled trial with an anti‐CCL2 (anti–monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis

Cited by 240 publications

References 15 publications

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

An engineered monomer of CCL2 has anti-inflammatory properties emphasizing the importance of oligomerization for chemokine activity in vivo

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