Generation, characterization and biological activity of CCL2 (MCP-1/JE) and CCL12 (MCP-5) specific antibodies

Tsui, Ping; Das, Anuk; Whitaker, Brian; Tornetta, Mark A.; Stowell, Nicole; Kesavan, Prabakaran; Kaiser, Elisabeth; Lacy, Eilyn R.; Li, Yan; Snyder, Linda A.; Sweet, Raymond W.

doi:10.3233/hab-2007-163-406

Cited by 30 publications

(52 citation statements)

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“…Both bind to the CCR2 receptor, although CCL2 is a better agonist of murine CCR2 (14). Most functions described for CCL12 are similar to those found for CCL2 (15). We found that each of these mAbs exerted some effect on tumor growth, but significantly more growth inhibition was evident when the two mAbs were co-administered (20).…”

Section: Discussionmentioning

confidence: 47%

“…We used a combination of monoclonal antibody (mAb) C1142, a rat/ mouse chimeric antibody that neutralizes mouse CCL2 (MCP-1), and mAb C1450, a human/mouse chimeric antibody that neutralizes the second mouse homologue, CCL12 (MCP-5) (4,9,15,20). Both mAbs were produced at Centocor, Inc. (Malvern, PA).…”

Section: Anti-ccl2/ccl12 Monoclonalmentioning

confidence: 99%

“…We evaluated the effects of blocking both murine CCL2 and murine CCL12, using a mixture of monoclonal antibodies (termed a-CCL2 mAbs) that specifically neutralize these chemokines (4,15). We found that CCL2 blockade exerted a modest but statistically significant effect in reducing tumor growth in five syngeneic flank tumor models of NSCLC and mesothelioma, demonstrated a trend toward improving survival in two orthotopic models of NSCLC, and reduced the extent of spontaneous lung metastases in immunocompetent mice in a new model of spontaneous lung metastases.…”

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confidence: 99%

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Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8⁺ Cells

Fridlender

Kapoor²,

Buchlis³

et al. 2011

Am J Respir Cell Mol Biol

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133

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The role of chemokines in the pathogenesis of lung cancer has been increasingly appreciated. Monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) is secreted from tumor cells and associated tumor stromal cells. The blockade of CCL2, as mediated by neutralizing antibodies, was shown to reduce tumorigenesis in several solid tumors, but the role of CCL2 in lung cancer remains controversial, with evidence of both protumorigenic and antitumorigenic effects. We evaluated the effects and mechanisms of CCL2 blockade in several animal models of non-small-cell lung cancer (NSCLC). Anti-murine-CCL2 monoclonal antibodies were administered in syngeneic flank and orthotopic models of NSCLC. CCL2 blockade significantly slowed the growth of primary tumors in all models studied, and inhibited lung metastases in a model of spontaneous lung metastases of NSCLC. In contrast to expectations, no significant effect of treatment was evident in the number of tumor-associated macrophages recruited into the tumor after CCL2 blockade. However, a change occurred in the polarization of tumorassociated macrophages to a more antitumor phenotype after CCL2 blockade. This was associated with the activation of cytotoxic CD8 1 T lymphocytes (CTLs). The antitumor effects of CCL2 blockade were completely lost in CB-17 severe combined immunodeficient mice or after CD8 T-cell depletion. Our data from NSCLC models show that CCL2 blockade can inhibit the tumor growth of primary and metastatic disease. The mechanisms of CCL2 blockade include an alteration of the tumor macrophage phenotype and the activation of CTLs. Our work supports further evaluation of CCL2 blockade in thoracic malignancies.Keywords: tumor immunology; CCL2; lung cancer; mesothelioma; tumor-associated macrophages Tumor-induced immunosuppression is one of the most important ways by which cancer cells alter their microenvironments and inhibit endogenous antitumor immune responses (1, 2). One important, immunologically active factor secreted from tumor cells and associated tumor stromal cells is monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), a member of the CC (b) chemokine superfamily. Although first identified as a chemokine produced by tumors and macrophages that could induce the migration of monocytes (3), CCL2 has a number of immunosuppressive properties, such as the attraction of T-regulatory cells and endothelial cells to sites of inflammation (3-5), and the direct inhibition of CD8 1 T-cell effector functions (6, 7).CCL2 was shown to play a role in tumorigenesis and metastases in several solid tumors, including breast cancer, melanoma, and prostate cancer (8, 9). The role of CCL2 in non-small-cell lung cancer (NSCLC) remains controversial, with evidence of both protumorigenic and antitumorigenic effects. Human NSCLC tumors secrete CCL2 at higher levels than normal lung tissue, and in some studies, high concentrations were associated with metastatic disease (10, 11). In contrast, the transfection of NSCLC lines with CCL2 does not alter the metastatic pote...

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Section: Discussionmentioning

confidence: 47%

Section: Anti-ccl2/ccl12 Monoclonalmentioning

confidence: 99%

mentioning

confidence: 99%

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Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8⁺ Cells

Fridlender

Kapoor²,

Buchlis³

et al. 2011

Am J Respir Cell Mol Biol

Self Cite

133

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“…[59][60][61][62][63][64][65][66][67] Furthermore, Ccl12, Ccl2, Cxcl3, Ccr1, Cxcl12, Cxcl2, Ccl7, Ccl5, and Cxcl5 have been shown to play a role in angiogenesis. 50,51,[68][69][70][71][72][73][74][75][76][77][78] Therefore, chemokines/receptors upregulated in wild-type eyes may contribute to monocyte/macrophage and neutrophil recruitment and angiogenesis found in CNV lesions.…”

Section: Discussionmentioning

confidence: 99%

The Role of Macrophage Class A Scavenger Receptors in a Laser-Induced Murine Choroidal Neovascularization Model

Jawad

Liu

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Laser-induced choroidal neovascularization (CNV) is a widely used model to mimic many features of CNV resulting from wet AMD. Macrophages have been implicated in the pathogenesis of AMD. Class A scavenger receptors, scavenger receptor-A (SR-A) and macrophage receptor with collagenous domain (MARCO), are expressed on macrophages and are associated with macrophage function. The goal of this study is to examine the role of macrophage scavenger receptors in immune cell recruitment and the formation of CNV. METHODS.Laser photocoagulation was performed in wild-type and knockout mice with deletion of SR-A (SR-A À/À ), MARCO (MARCO À/À ), or both SR-A and MARCO double knockout (DKO). Immune cell recruitment at different time points and CNV lesions at 14 days after laser treatment were evaluated through immunostaining and confocal microscopy. Microarray analysis was performed in eyes 1 day after laser injury. RESULTS.Wild-type eyes showed higher chemokine/receptor expression compared with knockout eyes after laser injury. Scavenger receptor deficiency markedly impaired the recruitment of neutrophils and macrophages to CNV lesions at 1-and 3-days post laser injury, respectively. Significantly reduced CNV volumes were found in the eyes from scavenger receptor knockout mice compared with wild-type mice.CONCLUSIONS. The deficiency of scavenger receptors impairs the formation of CNV and immune cell recruitment. Our findings suggest a potential role for scavenger receptors in contributing to CNV formation and inflammation in AMD.Keywords: AMD, CNV, macrophages, scavenger receptors A ge-related macular degeneration is the leading cause of irreversible central blindness in the elderly, worldwide. It is clinically characterized by degenerative changes in the macula, the region of the retina that permits fine central vision. One of the key pathologic features of AMD is the development of large drusen, extracellular deposits located in Bruch's membrane beneath the RPE. Their presence is a harbinger of further retinal change, the major risk factor for the development of advanced AMD, which can be classified into two subtypes: geographic atrophy (dry) and neovascular/exudative (wet). 1 In wet AMD, new vessels from the choroid breach Bruch's membrane and grow into the subretinal space and retina. This process is also called choroidal neovascularization (CNV). It represents only 10% of all cases of advanced AMD, but about 90% of AMD patients experience severe vision loss resulting from this subtype. Various animal models attempt to mimic the clinical manifestations of AMD. Among them, a laser-induced murine CNV model is widely used to mimic the wet form of AMD by compromising Bruch's membrane to induce CNV formation in the subretinal region. This model allows for visualization and evaluation of the morphologic changes of experimental CNV and has been a valuable tool to study the diverse components of complex CNV lesions. 2The exact mechanisms that cause AMD are not clear. Recent information suggests that immune mechanisms play...

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“…Anti-mouse CCL2 and CCL12 (a murine CCL2 ortholog) and IgG2a control Abs were delivered i.p. at 50 mg/kg every 3 days (37,38). Harvest and pleural lavage are described elsewhere (25,26,38,47,48).…”

Section: Methodsmentioning

confidence: 99%

Mast cells mediate malignant pleural effusion formation

et al. 2015

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Generation, characterization and biological activity of CCL2 (MCP-1/JE) and CCL12 (MCP-5) specific antibodies

Cited by 30 publications

References 30 publications

Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8⁺ Cells

Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8⁺ Cells

The Role of Macrophage Class A Scavenger Receptors in a Laser-Induced Murine Choroidal Neovascularization Model

Mast cells mediate malignant pleural effusion formation

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Generation, characterization and biological activity of CCL2 (MCP-1/JE) and CCL12 (MCP-5) specific antibodies

Cited by 30 publications

References 30 publications

Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8+ Cells

Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8+ Cells

The Role of Macrophage Class A Scavenger Receptors in a Laser-Induced Murine Choroidal Neovascularization Model

Mast cells mediate malignant pleural effusion formation

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Product

Resources

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Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8⁺ Cells

Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8⁺ Cells