Selective cleavage of human IgG by the matrix metalloproteinases, matrilysin and stromelysin

Gearing, A. J. H.; Thorpe, Susan J.; Miller, Karen; Mangan, Matthew; Varley, Paul; Dudgeon, T.J.; Ward, George A.; Turner, Christina; Thorpe, Robin

doi:10.1016/s0165-2478(01)00333-9

Cited by 73 publications

(69 citation statements)

References 28 publications

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“…26 Immunoevasion due to MMP-7 would be related to FASL cleavage 16,17 or to IgG degradation. 27 Matrilysin has been found overexpressed in a variety of tumors such as CRC. 28 There is substantial evidence that overexpression of MMP-7 in CRC primary tumors, taking into account the measurement of both activated and pro forms, is related to a more aggressive phenotype of tumor cells and a poorer prognosis.…”

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confidence: 99%

Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients

Maurel

Nadal

García-Albéniz

et al. 2007

Intl Journal of Cancer

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Metalloproteinase 7 (MMP-7) plays an important role in tumor growth, invasion and dissemination, and is secreted to the media. Because of the close implication of MMP-7 in cancer biology, we sought to define the prognostic significance of serum levels of MMP-7 in metastatic colorectal cancer (CRC) and explore its possible impact in the daily clinical practice. MMP-7 expression was determined by enzyme-linked immunoabsorbent assay. We assessed serum MMP-7 levels in 87 healthy controls, 96 patients with nonmetastatic CRC and 120 patients with advanced CRC. Clinical information was gathered from patient files. Cox proportional hazards model was used to assess survival. MMP-7 and the variables associated with prognosis were entered and a backward elimination method was employed to adjust the model. Inclusion criteria was p 0.05 and exclusion criteria was p 0.10. Advanced CRC patients have a significant higher mean serum MMP-7 levels (13.4 ng/ml) than those in nonmetastatic CRC (5.5 ng/ml; p < 0.001) and healthy controls (4.2 ng/ml; p < 0.001). In metastatic patients, after adjusting for other prognostic variables, MMP-7 (entered as a continuous variable) is associated with decreased survival (HR 1.016, IC 95% 1.002-1.031). Serum MMP-7 levels are significantly elevated in patients with advanced CRC. In conclusion, MMP-7 is an independent prognostic factor for survival in advanced CRC. In our sample, the risk of death associated to MMP-7 increase is much higher than the risk of death associated to lactate dehydrogenase elevation. ' 2007 Wiley-Liss, Inc.Key words: colorectal cancer; prognosis; matrix metalloproteinases Widely accepted prognostic factors in advanced colorectal cancer (CRC) are performance status (PS), serum lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) levels. 1-4 Despite of it, novel markers and useful prognostic indexes are needed to better classify these patients for clinical practice.Matrylisin (MMP-7) is a proteolytic enzyme belonging to Matrix Metalloproteinase (MMPs) family. [5][6][7] It is constitutively expressed in the ductal and glandular epithelium of many tissues. 8 In the lung and intestine it plays a role activating antibacterial peptides such as prodefensins. 9 MMP-7 is synthesized and secreted by tumor epithelial cells as a 28-KDa proenzyme that can be activated through proteolytic removal of a 9-KDa prodomain from the N-terminus. The soluble activated form binds to the tumor epithelial cell surface. Both active forms, the soluble and the membranebounded, have proteolytic activity. Its expression is regulated by transcription factors such as AP-1, PEA3 and b-catenin/ tcf4 complex. [10][11][12] By degrading elastin, laminin, proteoglycans, osteopontin, fibronectin and type IV collagen, MMP-7 gains the capacity to invade. Matrilysin can also promote tumor invasion by activating other MMPs (MMP-2 and MMP-9), through ectodomain shedding of E-cadherin. 13 and receptor activator of nuclear factor-kappa B ligand (RANKL) 14 or through cleavage of adhesion molecules, such as integri...

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confidence: 99%

Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients

Maurel

Nadal

García-Albéniz

et al. 2007

Intl Journal of Cancer

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“…3 Since no loss of Fc or other structural elements was associated with the scission of one peptide bond, it was at first presumed that this type of breakage would leave IgG functions intact. Surprisingly, scIgGs were found to be functionally incapacitated to the same degree as F(ab′) 22 s in both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays (Figures 2(a,b), respectively).…”

Section: A Single Peptide Bond Scission In the Hinge Disables Igg Effmentioning

confidence: 99%

“…These observations raised the possibility of localized antibody dysfunction and immune evasion in tumors. 3,51,52 Hypothetically, the restoration of proteinase-damaged IgG functions could provide a valuable supplement to existing anti-tumor therapies in these immunosuppressive environments. Complicating factors will surely include the actual identities of proteinases with hinge cleaving properties for different IgG isotypes, and the timing and amounts of enzyme expression over time throughout the heterogeneous tumor environment.…”

Section: Cancer Investigationsmentioning

confidence: 99%

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Proteinase-nicked IgGs: an unanticipated target for tumor immunotherapy

et al. 2018

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The host immune system adopts multiple mechanisms involving antibodies to confront cancer cells. Accordingly, anti-tumor mAbs have become mainstays in cancer treatment. However, neither host immunity nor mAb therapies appear capable of controlling tumor growth in all cases. Structural instability of IgG was overlooked as a factor contributing to immunosuppression in the tumor microenvironment. Recently, physiological proteinases were identified that disable IgG immune effector functions. Evidence shows that these proteinases cause localized IgG impairment by selective cleavage of a single IgG peptide bond in the hinge-region. The recognition of IgG cleavage in the tumor microenvironment provides alternatives for tumor immunotherapy.

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“…GluV8 of Staphylococcus aureus and IdeS of Streptococcus pyogenes) and invasive cancers (e.g. the matrix metalloproteinases (MMPs)) (22)(23)(24). Cleavage within the lower hinge of IgG1 occurs in a two-step process where first one heavy chain is cleaved, resulting in a singly cleaved intermediate (8,22,23,25).…”

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confidence: 99%

Engineered Protease-resistant Antibodies with Selectable Cell-killing Functions

Kinder

Greenplate

Grugan

et al. 2013

Journal of Biological Chemistry

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Background: Proteases can cleave human IgG1 antibodies, resulting in loss of cell-killing functions. Results: Mutation of the lower hinge of IgG1 confers protease resistance but disrupts Fc effector functions. Conclusion: Compensating mutations in the C H 2 domain can selectively restore Fc effector functions on a protease-resistant backbone. Significance: Protease-resistant antibodies may be desirable for microenvironments with high protease content and/or when selected cell-killing functions are needed.

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Selective cleavage of human IgG by the matrix metalloproteinases, matrilysin and stromelysin

Cited by 73 publications

References 28 publications

Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients

Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients

Proteinase-nicked IgGs: an unanticipated target for tumor immunotherapy

Engineered Protease-resistant Antibodies with Selectable Cell-killing Functions

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