Selected Publications

Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3

January 6, 2016

Highlights:
  • Human periodontitis is associated with overactivation of complement, which is triggered by different mechanisms converging on C3, the central hub of the system. This study assessed whether the C3 inhibitor Cp40 inhibits naturally-occurring periodontitis in non-human primates.
  • Non-human primates with chronic periodontitis were intra-gingivally injected with Cp40 either once (5 animals) or three times (10 animals) weekly for six weeks followed by a 6-week follow-up period.
  • Whether administered once or three times weekly, Cp40 caused a significant reduction in clinical indices that measure periodontal inflammation (gingival index and bleeding on probing), tissue destruction (probing pocket depth and clinical attachment level) or tooth mobility.
  • These clinical changes were associated with significantly reduced levels of pro-inflammatory mediators and decreased numbers of osteoclasts in bone biopsies. The protective effects of Cp40 persisted, albeit at reduced efficacy, for at least six weeks following drug discontinuation.
  • Conclusion: Cp40 inhibits pre-existing chronic periodontal inflammation and osteoclastogenesis in non-human primates, suggesting a novel adjunctive anti-inflammatory therapy for treating human periodontitis.
Author and source information

Authors: Maekawa T, Briones RA, Resuello RR, Tuplano JV, Hajishengallis E, Kajikawa T, Koutsogiannaki S, Garcia CA, Ricklin D, Lambris JD, Hajishengallis G.
Reference: J Clin Periodontol. 2016 Jan 5. doi: 10.1111/jcpe.12507. [Epub ahead of print]
Source: www.ncbi.nlm.nih.gov

 
Using an in vitro xenoantibody-mediated complement-dependent cytotoxicity model to evaluate the complement inhibitory activity of the peptidic C3 inhibitor Cp40

November 21, 2015

Highlights:
  • Simple and reliable methods for evaluating the inhibitory effects of drug candidates on complement activation are essential for preclinical development.
  • Using an immortalized porcine aortic endothelial cell line (iPEC) as target, this study evaluated the feasibility and effectiveness of an in vitro xenoantibody-mediated complement-dependent cytotoxicity (CDC) model for evaluating the complement inhibitory activity of Cp40, a potent analog of the peptidic C3 inhibitor compstatin.
  •  The binding of human xenoantibodies to iPECs led to serum dilution-dependent cell death.
  • Pretreatment of the human serum with Cp40 almost completely inhibited the deposition of C3 fragments and C5b-9 on the cells, resulting in a dose-dependent inhibition of CDC against the iPECs.
  • Using the same method to compare the effects of Cp40 on complement activation in humans, rhesus and cynomolgus monkeys, this study found that the inhibitory patterns were similar overall.
  • Conclusion: In vitro xenoantibody-mediated CDC assay may have considerable potential for future clinical use.
Author and source information

Authors:Wang J, Wang L, Xiang Y, Ricklin D, Lambris JD, Chen G.

Reference: Clin Immunol. 2015 Nov 6;162:37-44. doi: 10.1016/j.clim.2015.11.002. [Epub ahead of print]
Source: www.ncbi.nlm.nih.gov

 
Complement therapeutics in inflammatory diseases: promising drug candidates for C3-targeted intervention

October 7, 2015

Highlights:
    • Using the clinically developed compstatin family of C3 inhibitors and periodontitis as illustrative examples, this review highlights emerging therapeutic concepts and developments in the design of C3-targeted drug candidates as novel immunotherapeutics for oral and systemic inflammatory diseases.
Author and source information

Authors: Mastellos DC, Ricklin D, Hajishengallis E, Hajishengallis G, Lambris JD.
Reference: Mol Oral Microbiol. 2016 Feb;31(1):3-17. doi: 10.1111/omi.12129. Epub 2015 Oct 7.
Source: www.ncbi.nlm.nih.gov

 
Applying complement therapeutics to rare diseases

October 2, 2015

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 pipeline with potential to treat orphan diseases and discusses the molecular mechanisms triggered by complement involved with the disease pathogenesis.
Author and source information

Authors: Reis ES, Mastellos DC, Yancopoulou D, Risitano AM, Ricklin D, Lambris JD.
Reference: Clinical Immunology.2015 Dec;161(2):225-240. doi:10.1016/j.clim.2015.08.009. [Epub ahead of print].
Source: www.ncbi.nlm.nih.gov

 
Compstatin analog Cp40 inhibits complement dysregulation in vitro in C3 glomerulopathy

August 25, 2015

Highlights:
  • C3 glomerulopathy (C3G) defines a group of untreatable ultra-rare renal diseases caused by uncontrolled activation of the alternativecomplement 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.
  • Conclusion: Cp40 may offer a novel and promising therapeutic option to C3G patients as a disease-specific, targeted therapy.
  • Author and source information

    Authors: Zhang Y, Shao D, Ricklin D, Hilkin BM, Nester CM, Lambris JD, Smith RJ.
    Reference: Immunobiology. 2015 Aug;220(8):993-8. doi: 10.1016/j.imbio.2015.04.001. Epub 2015 May 5.
    Source: www.ncbi.nlm.nih.gov

     

     
    Complement inhibition prevents oncolytic vaccinia virus neutralization in immune humans and cynomolgus macaques

    June 1, 2015

    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.
      • Conclusion: Capitalizing on the complement dependence of antivaccinia antibody with adjunct complement inhibitors may increase the infectious dose of oncolytic vaccinia virus delivered to tumors in virus in immune hosts.
    Author and source information

    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.
    Reference: Mol Ther. 2015 Jun;23(6):1066-76. doi: 10.1038/mt.2015.49. Epub 2015 Mar 25.
    Source: www.ncbi.nlm.nih.gov

     
    Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters

    April 1, 2015

    Highlights:

    • This study uses 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.
    • Conclusion: Cp40 may be a potent and cost-effective treatment option for attenuating chronic inflammatory conditions in dialysis-dependent patients.
    Author and source information

    Authors: Reis ES, DeAngelis RA, Chen H, Resuello RR, Ricklin D, Lambris JD.
    Reference:Immunobiology. 2015 Apr;220(4):476-82. doi: 10.1016/j.imbio.2014.10.026. Epub 2014 Nov 3.
    Source:www.ncbi.nlm.nih.gov

     
    Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention

    February 12, 2015

    Highlights:
    • This review provides an up-to-date survey of the drug design effort placed on the compstatin family of C3 inhibitors, highlighting 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.
    Author and source information

    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 Apr;45(4):423-40. doi: 10.1111/eci.12419. Epub 2015 Mar 9.
    Source: www.ncbi.nlm.nih.gov

     

     
    Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters

    October 26, 2014

    Highlights:
    • This study uses 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.
    • Complete inhibition of complement activation is achieved in response to two distinct Cp40 treatment regimens.
    • Application of Cp40 during hemodialysis results in increased levels of the anti-inflammatory cytokine IL-10.
    • Conclusion: Cp40 may be a potent and cost-effective treatment option for attenuating chronic inflammatory conditions in dialysis-dependent patients.
    Author and source information

    Authors: Reis ES, DeAngelis RA, Chen H, Resuello RR, Ricklin D, Lambris JD.
    Reference: Immunobiology. 2015 Apr;220(4):476-82. doi: 10.1016/j.imbio.2014.10.026. Epub 2014 Nov 3.
    Source: www.ncbi.nlm.nih.gov

     

     
    Genetic and intervention studies implicating complement C3 as a major target for the treatment of periodontitis

    May 7, 2014

    Highlights:
    • In mice, C3 is required for maximal periodontal inflammation and bone loss, and for the sustenance of the dysbiotic microbiota.
    • C3 is required  for induction of bone loss in distinct models, including Porphyromonas gingivalis–induced periodontitis, ligature-induced periodontitis, and aging-associated periodontitis.
    • Local treatment of non-human primates (NHPs) with Cp40 inhibits ligature-induced periodontal inflammation and bone loss, which correlates with lower gingival crevicular fluid levels of proinflammatory mediators and decreased osteoclastogenesis in bone biopsy specimens, as compared with control treatment.
    • Conclusion: This study’s findings strongly support the feasibility of C3-targeted intervention for the treatment of human periodontitis. 
    Author and source information

    Authors: Maekawa T, Abe T, Hajishengallis E, Hosur KB, DeAngelis RA, Ricklin D, Lambris JD, Hajishengallis G.
    Reference: J Immunol. 2014 Jun 15;192(12):6020-7. doi: 10.4049/jimmunol.1400569. Epub 2014 May 7.
    Source: www.ncbi.nlm.nih.gov