Selected Publications

Complement in cancer: untangling an intricate relationship

September 18, 2017

Highlights:
    • This review summarizes our current understanding of complement-mediated effector functions in the tumour microenvironment, focusing on how complement activation can act as a negative or positive regulator of tumorigenesis.
    • This review offers insight into clinical aspects, including the feasibility of using complement biomarkers for cancer diagnosis and the use of complement inhibitors during cancer treatment.
Author and source information

Authors: Reis ES, Mastellos DC, Ricklin D, Mantovani A, Lambris JD.
Reference: Nat Rev Immunol. 2017 Sep 18. doi: 10.1038/nri.2017.97. [Epub ahead of print]
Source: www.ncbi.nlm.nih.gov

 
Safety and efficacy of the complement inhibitor AMY-101 in a natural model of periodontitis in non-human primates

September 15, 2017

Highlights:
    • This study was undertaken to determine the local safety of increasing doses of the drug as well as its efficacy when given at a reduced frequency or after systemic administration.
    • A local dose of AMY-101 (0.1 mg/site) that is free of local irritation and effective when given once every 3 weeks was determined.
    • A daily subcutaneous dose of AMY-101 (4 mg/kg bodyweight) was protective against NHP periodontitis.
    • Conclusion: AMY-101 appears to be a promising candidate drug for the adjunctive treatment of human periodontitis.
Author and source information

Authors: Kajikawa T, Briones RA, Resuello RRG, Tuplano JV, Reis ES, Hajishengallis E, Garcia CAG, Yancopoulou D, Lambris JD, Hajishengallis G.
Reference: Mol Ther Methods Clin Dev. 2017 Aug 18;6:207-215. doi: 10.1016/j.omtm.2017.08.001. eCollection 2017 Sep 15.
Source: www.ncbi.nlm.nih.gov

 
Local endothelial complement activation reverses endothelial quiescence, enabling t-cell homing, and tumor control during t-cell immunotherapy

June 8, 2017

Highlights:
    • This study shows that in the context of adoptive T cell therapy, antitumor T cells, delivered at high enough doses, can overcome the endothelial barrier and infiltrate tumors, a process that requires local production of C3, complement activation on tumor endothelium and release of C5a.
    • C5a acts on endothelial cells promoting the upregulation of adhesion molecules and T-cell homing.
    • A daily subcutaneous dose of AMY-101 (4 mg/kg bodyweight) was protective against NHP periodontitis.
    • Genetic deletion of C3 or the C5a receptor 1 (C5aR1), and pharmacological blockade of C5aR1, impaired the ability of T cells to overcome the endothelial barrier, infiltrate tumors, and control tumor progression in vivo, while genetic chimera mice demonstrated that C3 and C5aR1 expression by tumor stroma, and not leukocytes, governs T cell homing, acting on the local endothelium.
    • In vitro, endothelial C3 and C5a expressions were required for endothelial activation by type 1 cytokines.
    • Conclusion: Effective immunotherapy is a consequence of successful homing of T cells in response to local complement activation, which disrupts the tumor endothelial barrier.
Author and source information

Authors: Facciabene A, De Sanctis F, Pierini S, Reis ES, Balint K, Facciponte J, Rueter J, Kagabu M, Magotti P, Lanitis E, DeAngelis RA, Buckanovich RJ, Song WC, Lambris JD, Coukos G.
Reference: Oncoimmunology. 2017 Jun 8;6(9):e1326442. doi: 10.1080/2162402X.2017.1326442. eCollection 2017.
Source: www.ncbi.nlm.nih.gov

 
Alginate microbeads are coagulation compatible, while alginate microcapsules activate coagulation secondary to complement or directly through FXII

May 30, 2017

Highlights:
    • This study uses a lepirudin based human whole blood model to investigate the coagulation potentials of alginate-based microspheres: alginate microbestemic administration (Ca/Ba Beads), alginate poly-l-lysine microcapsules (APA and AP microcapsules) and sodium alginate-sodium cellulose sulfate-poly(methylene-co-cyanoguanidine) microcapsules (PMCG microcapsules).
    • Coagulation activation measured by prothrombin fragments 1+2 (PTF1.2) was rapidly and markedly induced by the PMCG microcapsules, delayed and lower induced by the APA and AP microcapsules, and not induced by the Ca/Ba Beads.
    • Monocytes tissue factor (TF) expression was similarly activated by the microcapsules, whereas not by the Ca/Ba Beads. PMCG microcapsules-induced PTF1.2 was abolished by FXII inhibition (corn trypsin inhibitor), thus pointing to activation through the contact pathway.
    • PTF1.2 induced by the AP and APA microcapsules was inhibited by anti-TF antibody, pointing to a TF driven coagulation.
    • The TF induced coagulation was inhibited by the complement inhibitors compstatin (C3 inhibition) and eculizumab (C5 inhibition), revealing a complement-coagulation cross-talk.
    • Conclusion: This is the first study on the coagulation potentials of alginate microspheres, and identifies differences in activation potential, pathways and possible intervention points.
Author and source information

Authors: Gravastrand C, Hamad S, Fure H, Steinkjer B, Ryan L, Oberholzer J, Lambris JD, Lacík I, Mollnes TE, Espevik T, Brekke OL, Rokstad AM.
Reference: Acta Biomater. 2017 Aug;58:158-167. doi: 10.1016/j.actbio.2017.05.052. Epub 2017 May 30.
Source: https://proxy.library.upenn.edu

 
Iron oxide nanoparticles induce cytokine secretion in a complement-dependent manner in a human whole blood model

May 23, 2017

Highlights:
    • The IONPs activated complement, as measured by C3a, C5a and sC5b-9, and induced the production of pro-inflammatory cytokines in a particle-dose dependent manner, with the strongest response at 10 µg/mL IONPs. Complement inhibitors at C3 (compstatin analog Cp40) and C5 (eculizumab) levels completely inhibited complement activation and secretion of inflammatory mediators induced by the IONPs.
    • Blockade of complement receptors C3aR and C5aR1 significantly reduced the levels of various cytokines, indicating that the particle-induced secretion of inflammatory mediators is mainly C5a and C3a mediated.
    • The IONPs did not induce cell death or reactive oxygen species, which further suggests that complement activation alone was responsible for most of the particle-induced cytokines.
    • Conclusion: These data suggest that the lepirudin anti-coagulated human whole blood model is a valuable ex vivo system to study the inflammatory potential of IONPs. We conclude that IONPs induce complement-mediated cytokine secretion in human whole blood.
Author and source information

Authors: Wolf-Grosse S, Rokstad AM, Ali S, Lambris JD, Mollnes TE, Nilsen AM, Stenvik J.
Reference: MInt J Nanomedicine. 2017 May 23;12:3927-3940. doi: 10.2147/IJN.S136453. eCollection 2017.
Source: https://proxy.library.upenn.edu

 
Complement C3-targeted therapy: replacing long-held assertions with evidence-based discovery

April 14, 2017

Highlights:
    • Complement dysregulation underlies several inflammatory disorders, and terminal complement inhibition has thus far afforded significant clinical gains.
    • Emerging pathologies, fueled by complement imbalance and therapy-skewing genetic variance, underscore the need for more comprehensive, disease-tailored interventions.
    • Modulation at the level of C3, a multifaceted orchestrator of the complement cascade, opens up prospects for broader therapeutic efficacy by targeting multiple pathogenic pathways modulated by C3-triggered proinflammatory crosstalk.
    • Notably, C3 intervention is emerging as a viable therapeutic strategy for renal disorders with predominantly complement-driven etiology, such as C3 glomerulopathy (C3G).
    • Conclusion: Using C3G as a paradigm, we argue that concerns about the feasibility of long-term C3 intervention need to be placed into perspective and weighed against actual therapeutic outcomes in prospective clinical trials.
Author and source information

Authors: Mastellos DC, Reis ES, Ricklin D, Smith RJ, Lambris JD.
Reference: Trends Immunol. 2017 Jun;38(6):383-394. doi: 10.1016/j.it.2017.03.003. Epub 2017 Apr 14.
Source: www.ncbi.nlm.nih.gov/pubmed

 
Complement inhibition enables tumor delivery of LCMV glycoprotein pseudotyped viruses in the presence of antiviral antibodies

January 15, 2017

Highlights:
    • This study provides experimental evidence that antibodies generated against the lymphocytic choriomeningitis virus glycoprotein mediate robust complement-dependent viral neutralization via activation of the classical pathway.
    • We show that this phenotype can be capitalized upon to deliver maraba virus pseudotyped with the lymphocytic choriomeningitis virus glycoprotein in a Fischer rat model in the face of neutralizing antibody through the use of complement modulators.
    • High-fat diet induces complement activation and generation of C5a, which in turn induces the production of proinflammatory cytokines and expression of proto-oncogenes.
    • This finding changes the understanding of the humoral immune response to arenaviruses, and also describes methodology to deliver viral vectors to their therapeutic sites of action without the interference of neutralizing antibody.
Author and source information

Authors: Evgin L, Ilkow CS, Bourgeois-Daigneault MC, de Souza CT, Stubbert L, Huh MS, Jennings VA, Marguerie M, Acuna SA, Keller BA, Lefebvre C, Falls T, Le Boeuf F, Auer RA, Lambris JD, McCart JA, Stojdl DF, Bell JC.
Reference: Mol Ther Oncolytics. 2016 Nov 16;3:16027. eCollection 2016.
Source: www.ncbi.nlm.nih.gov

 
High-fat diet-induced complement activation mediates intestinal inflammation and neoplasia, independent of obesity

October 14, 2016

Highlights:
    • Using a mouse model of intestinal neoplasia and strains that are susceptible or resistant to diet-induced obesity, this study demonstrates that high-fat diet-induced inflammation, rather than obesity or metabolic status, is associated with increased intestinal neoplasia.
    • The complement fragment C5a acts as the trigger for inflammation and intestinal tumorigenesis.
    • High-fat diet induces complement activation and generation of C5a, which in turn induces the production of proinflammatory cytokines and expression of proto-oncogenes.
    • Pharmacological and genetic targeting of the C5a receptor reduced both inflammation and intestinal polyposis, suggesting the use of complement inhibitors for preventing diet-induced neoplasia.
Author and source information

Authors: Doerner SK, Reis ES, Leung ES, Ko JS, Heaney JD, Berger NA, Lambris JD, Nadeau JH.
Reference: Mol Cancer Res. 2016 Oct;14(10):953-965. Epub 2016 Aug 17.
Source: www.ncbi.nlm.nih.gov

 
From orphan drugs to adopted therapies: Advancing C3-targeted intervention to the clinical stage

June 16, 2016

Highlights:
    • This review highlights recent developments in the field of complement therapeutics, focusing on C3-directed inhibitors and alternative pathway (AP) regulator-based approaches.
    • Translational perspectives and considerations are discussed, particularly with regard to the structure-guided drug optimization and clinical advancement of a new generation of C3-targeted peptidic inhibitors.
Author and source information

Authors: Mastellos DC, Reis ES, Yancopoulou D, Hajishengallis G, Ricklin D, Lambris JD.
Reference: Immunobiology. 2016 Oct;221(10):1046-57. doi: 10.1016/j.imbio.2016.06.013. Epub 2016 Jun 16
Source: www.ncbi.nlm.nih.gov/pubmed

 
Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application

March 29, 2016

Highlights:
  • Current therapies for periodontitis are not always effective and this prevalent oral disease continues to be a significant health and economic burden.
  • Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss.
  • This review discusses these mechanistic advances and moreover focuses on the compstatin family of C3 inhibitors as a novel approach to treat periodontitis.
  • In this regard, local application of the current lead analog Cp40 was recently shown to block both inducible and naturally occurring periodontitis in non-human primates.
  • These promising results from non-human primate studies and the parallel development of Cp40 for clinical use highlight the feasibility for developing an adjunctive, C3-targeted therapy for human periodontitis.
Author and source information

Authors: George Hajishengallis, Evlambia Hajishengallis, Tetsuhiro Kajikawa, Baomei Wang, Despina Yancopoulou, Daniel Ricklin, John D. Lambris.
Reference: Seminars in Immunology. 2016 Mar 26. doi:10.1016/j.smim.2016.03.006.
Source: http://linkinghub.elsevier.com