Compstatin analog Cp40 inhibits complement dysregulation in vitro in C3 glomerulopathy
Ref: Immunobiology. 2015 Aug;220(8):993-8. doi: 10.1016/j.imbio.2015.04.001. Epub 2015 May 5. Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov’t
Authors: Zhang Y, Shao D, Ricklin D, Hilkin BM, Nester CM, Lambris JD, Smith RJ.
- C3 glomerulopathy (C3G) defines a group of untreatable ultra-rare renal diseases caused by uncontrolled activation of the alternative complement pathway. Nearly half of patients progress to end stage renal failure within 10 years.
- This study shows that Cp40 prevents complement-mediated lysis of sheep erythrocytes in sera from C3G patients, prevents complement dysregulation in the presence of patient-derived autoantibodies to the C3 and C5 convertases, and prevents complement dysregulation associated with disease-causing genetic mutations.
- In aggregate, these data suggest that Cp40 may offer a novel and promising therapeutic option to C3G patients as a disease-specific, targeted therapy.
Complement C3dg-mediated erythrophagocytosis: implications for paroxysmal nocturnal hemoglobinuria
Ref: Blood. 2015 Aug 13;126(7):891-4. doi: 10.1182/blood-2015-02-625871. Epub 2015 Jun 16.
Authors: Lin Z, Schmidt CQ, Koutsogiannaki S, Ricci P, Risitano AM, Lambris JD, Ricklin D.
- Because the current treatment for PNH only prevents C5-induced lysis but not upstream C3 activation, it has been speculated that ongoing opsonization with C3 fragments leads to recognition and phagocytosis of PNH erythrocytes by immune cells.
- For the first time, this study provides experimental evidence for such extravascular hemolysis and demonstrates that PNH erythrocytes from anti-C5-treated patients are phagocytosed by activated monocytes in vitro.
- This uptake can be mediated by the end-stage opsonin C3dg, which is not traditionally considered a phagocytic marker, via interaction with complement receptor 3 (CR3). Interaction studies confirmed that C3dg itself can act as a ligand for the binding domain of CR3.
- The degree of C3dg-mediated erythrophagocytosis in samples from different PNH patients correlated well with the individual level of C3dg opsonization.
Inhibition of the alternative complement pathway preserves photoreceptors after retinal injury
Ref: Sci Transl Med. 2015 Jul 22;7(297):297ra116. doi: 10.1126/scitranslmed.aab1482.
Authors: Sweigard JH, Matsumoto H, Smith KE, Kim LA, Paschalis EI, Okonuki Y, Castillejos A, Kataoka K, Hasegawa E, Yanai R, Husain D, Lambris JD, Vavvas D, Miller JW, Connor KM.
- This study analyzed innate immune system regulators in the vitreous of human patients with retinal detachment and correlated the results with findings in a mouse model of retinal detachment.
- The study identified the alternative complement pathway as promoting early photoreceptor cell death during retinal detachment.
- Photoreceptors down-regulate membrane-bound inhibitors of complement, allowing for selective targeting by the alternative complement pathway.
- When photoreceptors in the detached retina were removed from the primary source of oxygen and nutrients (choroidal vascular bed), the retina became hypoxic, leading to an up-regulation of complement factor B, a key mediator of the alternative pathway.
- Inhibition of the alternative complement pathway in knockout mice or through pharmacological means ameliorated photoreceptor cell death during retinal detachment.
Complement inhibition prevents oncolytic vaccinia virus neutralization in immune humans and cynomolgus macaques
Ref: Mol Ther. 2015 Jun;23(6):1066-76. doi: 10.1038/mt.2015.49. Epub 2015 Mar 25.
Authors: Evgin L, Acuna SA, Tanese de Souza C, Marguerie M, Lemay CG, Ilkow CS, Findlay CS, Falls T, Parato KA, Hanwell D, Goldstein A, Lopez R, Lafrance S, Breitbach CJ, Kirn D, Atkins H, Auer RC, Thurman JM, Stahl GL, Lambris JD, Bell JC, McCart JA.
- This study demonstrates that for a prototype of the clinical vaccinia virus based product Pexa-Vec, the neutralizing activity of antibodies elicited by smallpox vaccination, as well as the anamnestic response in hyperimmune virus treated cancer patients, is strictly dependent on the activation of complement.
- In immunized rats, complement depletion stabilized vaccinia virus in the blood and led to improved delivery to tumors.
- Complement depletion also enhanced tumor infection when virus was directly injected into tumors in immunized animals. The feasibility and safety of using a complement inhibitor, CP40, in combination with vaccinia virus was tested in cynomolgus macaques.
- CP40 pretreatment elicited an average 10-fold increase in infectious titer in the blood early after the infusion and prolonged the time during which infectious virus was detectable in the blood of animals with preexisting immunity.
Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters
Ref: Immunobiology. 2015 Apr;220(4):476-82. doi: 10.1016/j.imbio.2014.10.026. Epub 2014 Nov 3. Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov’t.
Authors: Reis ES, DeAngelis RA, Chen H, Resuello RR, Ricklin D, Lambris JD.
- This study used a refined pre-clinical model of hemodialysis in cynomolgus monkeys to confirm that even modern, polymer-based hemodialysis filters activate complement and to evaluate the potential of Cp40, a peptidic C3 inhibitor, to attenuate hemodialysis-induced complement activation.
- The data show marked induction of complement activation even after only a single session of hemodialysis. Importantly, complete inhibition of complement activation was achieved in response to two distinct Cp40 treatment regimens.
- The application of Cp40 during hemodialysis resulted in increased levels of the anti-inflammatory cytokine IL-10, indicating that Cp40 may be a potent and cost-effective treatment option for attenuating chronic inflammatory conditions in dialysis-dependent patients.
Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention
Ref: Eur J Clin Invest. 2015 Feb 12. doi: 10.1111/eci.12419. [Epub ahead of print]
Authors: Mastellos DC, Yancopoulou D, Kokkinos P, Huber-Lang M, Hajishengallis G, Biglarnia AR, Lupu F, Nilsson B, Risitano AM, Ricklin D, Lambris JD.
- This review provides an up-to-date survey of the drug design effort placed on the compstatin family of C3 inhibitors.
- It highlights the most promising drug candidates.
- It discusses translational challenges in complement drug discovery and peptide drug development.
- It reviews concerns related to systemic C3 interception.
PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer
Ref: Cell. 2015 Feb 12;160(4):700-714.
- PTX3 deficiency unleashes Complement-dependent tumor-promoting inflammation.
- Tumors developed in a PTX3-deficient context have higher frequency of mutated Trp53.
- PTX3 expression is epigenetically repressed in selected human tumors.
- Complement is an essential component of tumor-promoting inflammation.
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