Selected Publications

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

May 7, 2014

  • 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.


Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria

March 27, 2014

  • For effect of the peptidic C3 inhibitor, compstatin Cp40, and its long-acting form (polyethylene glycol [PEG]-Cp40) on hemolysis and opsonization of PNH erythrocytes in an established in vitro system:
    1. Both compounds demonstrate dose-dependent inhibition of hemolysis with IC50 ∼4 µM and full inhibition at 6 µM.
    2. Protective levels of either Cp40 or PEG-Cp40 efficiently prevent deposition of C3 fragments on PNH erythrocytes.
  • For potential of both inhibitors for systemic administration and performed pharmacokinetic evaluation in nonhuman primates:
    1. A single intravenous injection of PEG-Cp40 results in a prolonged elimination half-life of >5 days but may potentially affect the plasma levels of C3.
    2. Despite faster elimination kinetics, saturating inhibitor concentration could be reached with unmodified Cp40 through repetitive subcutaneous administration.
  • Conclusion: Peptide inhibitors of C3 activation effectively prevent hemolysis and C3 opsonization of PNH erythrocytes, and are excellent, and potentially cost-effective, candidates for further clinical investigation.
Author and source information

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


New analogs of the clinical complement inhibitor compstatin with with subnanomolar affinity and enhanced pharmacokinetic properties

June 17, 2012

  • This study reports improvements in both the inhibitory potency and pharmacokinetic parameters of compstatin that broaden its clinical applications.
  • Selective modification of the compstatin N-terminus with non-proteinogenic amino acids resulted in the first analogue with subnanomolar binding affinity (KD=0.5nM) and other similarly potent derivatives with improved solubility in clinically relevant solvents.
  • Detailed structure-activity relationship studies based on biophysical and computational methods revealed key structural determinants for the observed improvements.
  • Importantly, pharmacokinetic evaluation in non-human primates revealed target-driven elimination kinetics with plasma half-life values exceeding expectations for peptidic drugs (close to 12h).
  • Conclusion: This successful optimization strategy is expected to pave the way for systemic administration of compstatin in a range of clinical conditions.
Author and source information

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


Synthesis and activity of thioether-containing analogues of the complement inhibitor compstatin

May 23, 2011

  • This study applies substitution of a disulfide bond with a reduction-resistant cystathionine bridge to the therapeutic complement inhibitor compstatin in an effort to maintain its potent activity while improving its biological stability.
  • Thioether-containing compstatin analogues were produced via solid-phase peptide synthesis utilizing orthogonally protected cystathionine amino acid building blocks and solid-supported peptide cyclization.
  • Overall, the affinity of these analogues for their biological target and potent inhibition of complement activation were largely maintained when compared to those of the parent disulfide-containing peptides.
  • Conclusion: The improved stability to reduction conferred by the thioether bond makes this new class of compstatin peptides a promising alternative for therapeutic applications, and the versatility of this synthesis allows for exploration of disulfide-to-thioether substitution in a variety of other therapeutic peptides.
Author and source information

Authors: Knerr PJ, Tzekou A, Ricklin D, Qu H, Chen H, van der Donk WA, Lambris JD.
Reference: ACS Chem Biol. 2011 Jul 15;6(7):753-60. doi: 10.1021/cb2000378. Epub 2011 May 23.


Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency

November 9, 2010

  • To obtain more potent compstatin analogues, an N-methylation scan of the peptide backbone and amino acid substitutions at position 13 was performed.
  • One analogue (Ac-I[CVW(Me)QDW-Sar-AHRC](NMe)I-NH(2)) displayed a 1000-fold increase in both potency (IC(50) = 62 nM) and binding affinity for C3b (K(D) = 2.3 nM) over that of the original compstatin.
  • Biophysical analysis using surface plasmon resonance and isothermal titration calorimetry suggests that the improved binding originates from more favorable free conformation and stronger hydrophobic interactions.
  • Conclusion: This study provides a series of significantly improved drug leads for therapeutic applications in complement-related diseases, and offers new insights into the structure-activity relationships of compstatin analogues.
Author and source information

Authors: Qu H, Magotti P, Ricklin D, Wu EL, Kourtzelis I, Wu YQ, Kaznessis YN, Lambris JD.
Reference: Mol Immunol. 2011 Jan;48(4):481-9. doi: 10.1016/j.molimm.2010.10.004. Epub 2010 Nov 9.