Inhibiting Alternative Pathway Complement Activation by Targeting the Factor D Exosite

Katschke, Kenneth J.; Wu, Ping; Ganesan, Rajkumar; Kelley, Robert F.; Mathieu, Mary; Hass, Philip E.; Murray, J.M.; Kirchhofer, Daniel; Wiesmann, Christian; Campagne, Menno van Lookeren

doi:10.1074/jbc.m112.345082

Cited by 75 publications

(65 citation statements)

References 38 publications

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“…Antigen retrieval was done using pronase E digestion for 40 minutes at 37°C (C1q, C3c) or cooking for 2, 5 min in target retrieval solution pH 6 (DAKO Deutschland). After blocking of endogenous peroxidase using 3% H 2 O 2 and Avidin-Biotin block (Vector laboratories, Burlingame, CA, USA), normal goat serum and blotto (1:5) sections were incubated over night at 4°C using the following antibodies diluted in 1%BSA in 50 mM Tris pH 7, 4: C1q, a rabbit polyclonal antibody against human C1q (A0126; DAKO Deutschland, Hamburg, Germany); C3c, a rabbit polyclonal antibody against human C3c (A0062; DAKO Deutschland); C3d, a mouse monoclonal antibody against human C3d (Quidel, Athens, OH, USA); C9, a mouse monoclonal antibody against human C9 (Quidel, Athens, OH, USA); CFD, a mouse monoclonal antibody directed against active human complement factor D (Clone 8E2, provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland [19]); MASP-2, a rabbit polyclonal directed against human Mannan-binding lectin serine peptidase 2 (Sigma Aldrich, Taufkirchen, Germany); Collectin-11, a rabbit polyclonal antibody against Collectin-11 (Sigma Aldrich). After washing with 50 mM Tris pH 7, 4, sections were incubated with biotinylated secondary goat anti-rabbit IgG (BA-1000; Vector laboratories) or horse anti-mouse IgG (BA-2001, Vector laboratories).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Is Early Complement Activation in Renal Transplantation Associated with Later Graft Outcome?

Bobka

Ebert

Koertvely

et al. 2018

Kidney Blood Press Res

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Background/Aims: Complement activation is important in post-transplantation renal injury, but data on its role as predictor of transplant outcome/complications when assessed in donor kidneys are lacking. Methods: In human renal transplant biopsies with delayed graft function (DGF, n=12), antibody mediated rejection (ABMR, n=8), T-cell mediated rejection (TCMR, n=11), 1 year protocol biopsies (control, n=10) and corresponding zero-biopsies we performed immunohistochemical analyses of 6 complement factors using FFPE sections and correlated the findings with kidney function, as assessed by serum creatinine, and morphological changes including interstitial fibrosis and tubular atrophy (IF/TA). Results: In DGF, TCMR and ABMR significant complement deposition was observed, which was less pronounced in corresponding zero-biopsies. Zero-biopsies with subsequent ABMR showed glomerular complement factor D and C3c expression. Moreover, glomerular C3c and C9 and tubular MASP-2 and Collectin-11 expression in zero-biopsies significantly correlated with serum creatinine at diagnosis of DGF, TCMR or ABMR. Glomerular C1q was significantly increased in ABMR, but not in DGF and TCMR. In contrast, peritubular C1q was significantly enhanced in DGF and TCMR compared to zero-biopsies. Using C3d as a surrogate marker for complement activity we could confirm that stained complement factors are frequently associated with complement activity. Conclusion: Complement deposition strongly correlated with histopathological changes observed in renal transplants. All 3 complement pathways were operational in biopsies with DGF, TCMR and ABMR albeit with differential abundance and localization. Since complement deposition in zero-biopsies correlated with graft function and morphological changes, early specific complement inhibition in renal transplantation may be a new therapeutic option to prevent graft loss.

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Section: Immunohistochemistrymentioning

confidence: 99%

Is Early Complement Activation in Renal Transplantation Associated with Later Graft Outcome?

Bobka

Ebert

Koertvely

et al. 2018

Kidney Blood Press Res

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“…Genentech subsequently developed a humanized IgG murine anti-FD antibody (FCFD4514S) and showed that it could block the formation of the alternative pathway, C3 convertase [85]. The FD antibody was named lampalizumab.…”

Section: Complement As a Therapeutic Target In Amdmentioning

confidence: 99%

Age-Related Macular Degeneration: A Complementopathy?

Kijlstra¹,

Berendschot²

2015

Ophthalmic Res

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Age-related macular degeneration (AMD) is a progressive eye disease affecting many elderly individuals. It has a multifactorial pathogenesis and is associated with numerous environmental (e.g. smoking, light and nutrition) and genetic risk factors. A breakthrough in the mechanisms causing AMD is emerging; the involvement of the alternative pathway of the complement system appears to play a pivotal role. This has led to the statement that AMD is a disease caused by a hyperactive complement system, allowing the term ‘complementopathy' to define it more precisely. Abundant evidence includes: the identification of drusen components as activators of complement, immunohistochemical data showing the presence of many species of the complement system in the retinal pigment epithelium-Bruch's membrane-choroidocapillary region of AMD eyes, a strong association of AMD with certain genetic complement protein variants, raised complement levels in blood from AMD patients and the preliminary successful treatments of geographic atrophy with complement factor D (FD) inhibitors. FD is the rate-limiting enzyme of the alternative complement pathway, and is produced by adipose tissue. Recent findings suggest that nutrition may play a role in controlling the level of FD in the circulation. Addressing modifiable risk factors such as smoking and nutrition may thus offer opportunities for the prevention of AMD.

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“…The earliest clues that controlling FD might affect retinal disease came from a mouse model where it was shown that photoreceptors were protected from light induced damage in FD knockout animals [84]. Based on these promising findings, Genentech, Inc. (San Francisco, CA) has developed a humanized IgG Fab murine anti-factor D antibody (FCFD4514S) [85]. In vitro studies showed that this monoclonal antibody blocked the FD mediated proteolytic activation of its C3bB substrate [85].…”

Section: Successful Targeting Of Factor D In Amd?mentioning

confidence: 99%

Lutein and Factor D: Two intriguing players in the field of age-related macular degeneration

Tian

Kijlstra

Webers

et al. 2015

Archives of Biochemistry and Biophysics

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Age-related macular degeneration (AMD) is a progressive eye disease that impairs central vision among elderly populations in Western, industrialized countries. In this review we will focus on the role of factor D (FD) and lutein in AMD. FD is a rate-limiting enzyme of the alternative complement activation pathway that may play an important role in the development of AMD. Several independent studies have shown a significant increase in the level of a number of complement factors of the alternative pathway, including factor D in the blood of AMD patients as compared to healthy individuals, which suggests a systemic involvement in the pathogenesis of AMD. FD, also called adipsin, is mainly produced by adipose tissue. Besides playing a role in the activation of the alternative pathway, FD is also known to regulate the immune system. Of interest is our preliminary finding that lutein supplementation of early AMD cases was shown to lower the level of systemic FD. If confirmed, these findings provide further support for the application of anti-factor D intervention as a new approach to control the development of this disease.

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Inhibiting Alternative Pathway Complement Activation by Targeting the Factor D Exosite

Cited by 75 publications

References 38 publications

Is Early Complement Activation in Renal Transplantation Associated with Later Graft Outcome?

Is Early Complement Activation in Renal Transplantation Associated with Later Graft Outcome?

Age-Related Macular Degeneration: A Complementopathy?

Lutein and Factor D: Two intriguing players in the field of age-related macular degeneration

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