Highlights: As a key trigger of inflammatory processes, complement has been associated with a variety of diseases and has become an attractive therapeutic target for conditions involving inflammation. Clinical evidence shows the safety and efficacy of complement therapeutics This review provides an overview of the candidates currently in the pharmaceutical […]

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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.

Highlights: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. We hypothesized that by targeting C3 Cp40 would provide an effective treatment for C3G.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.

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.

Highlights: 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.

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.

Highlights: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.This study also showed that 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.

Authors: Mastellos DC, Yancopoulou D, Kokkinos P, Huber-Lang M, Hajishengallis G, Biglarnia AR, Lupu F, Nilsson B, Risitano AM, Ricklin D, Lambris JD.

Reference: Eur J Clin Invest. 2015 Feb 12. doi: 10.1111/eci.12419. [Epub ahead of print]

Authors: Reis ES, DeAngelis RA, Chen H, Resuello RR, Ricklin D, Lambris JD.

Ref: Immunobiology. 2014 Nov 3. pii: S0171-2985(14)00224-1. doi: 10.1016/j.imbio.2014.10.026. [Epub ahead of print]

Authors: Maekawa T, Abe T, Hajishengallis E, Hosur KB, DeAngelis RA, Ricklin D, Lambris JD, Hajishengallis G.

Ref: J Immunol. 2014 Jun 15;192(12):6020-7. doi: 10.4049/jimmunol.1400569. Epub 2014 May 7.

Authors: Risitano AM, Ricklin D, Huang Y, Reis ES, Chen H, Ricci P, Lin Z, Pascariello C, Raia M, Sica M, Del Vecchio L, Pane F, Lupu F, Notaro R, Resuello RR, DeAngelis RA, Lambris JD.

Ref: Blood. 2014 Mar 27;123(13):2094-101. doi: 10.1182/blood-2013-11-536573. Epub 2014 Feb 4.

Authors: Qu H, Ricklin D, Bai H, Chen H, Reis ES, Maciejewski M, Tzekou A, DeAngelis RA, Resuello RR, Lupu F, Barlow PN, Lambris JD.

Ref: Immunobiology. 2013 Apr;218(4):496-505. doi: 10.1016/j.imbio.2012.06.003. Epub 2012 Jun 17.

Authors: Knerr PJ, Tzekou A, Ricklin D, Qu H, Chen H, van der Donk WA, Lambris JD.

Ref:ACS Chem Biol. 2011 Jul 15;6(7):753-60. doi: 10.1021/cb2000378. Epub 2011 May 23.