The goal of this project is to generate pathway-specific therapeutic inhibitors for the study and treatment of complement-related diseases. Complement has been shown to play a role in various disorders ranging from inflammatory (e.g., periodontitis), immune, and degenerative, diseases to sepsis. Also, complement-related complications can be detrimental in biomaterial applications (e.g., hemodialysis) and transplant rejection. While the potential of inhibiting complement has long been recognized, therapeutic options are still limited, costly, do not include specific inhibitors of initiation and amplification steps, and are not readily available for research. Hence, extension and diversification of the inhibitory arsenal is desired both for therapy and as tools to dissect disease mechanisms. Starting from a panel of potent inhibitors discovered by our group or publicly disclosed, this project aims at generating a """"""""complement inhibitor toolbox"""""""" with broad use in the studies of this P01. The C3 inhibitor compstatin, which blocks initiation, amplification, and effector pathways, has shown clinical promise in many disease models, including transplantation, hemodialysis, and periodontitis, yet its pharmacokinetic (PK) profile and limited administration options render the use of this compound challenging in certain applications. We will therefore optimize the PK parameters of compstatin and evaluate its oral and subcutaneous administration in non-human primates. While inhibition of C3 has advantages, we will also develop inhibitors that specifically block the classical and alternative pathways. For the former, we will focus on a potent CIs-binding protein from leeches, which appears to bind both the catalytic and a potential exosite on CIs. By characterizing the activity of this protein and derived peptides, we will generate and optimize novel inhibitors for CIs. Based on factor H (FH) as a major host regulator of the alternative pathway, we rationally engineered a streamlined inhibitor with unique targeting properties toward diseased host cells and a potency that surpasses the parent protein FH. Terminal pathway inhibition will focus on anti- C5 antibodies and peptidomimetics available to this group, and the """"""""toolbox"""""""" will be completed by inhibitors Of the lectin pathway, the clinically used regulator C1-INH, and anaphylatoxin receptor antagonists. Finally, we explore novel strategies to direct complement inhibitors to foreign or diseased surfaces, where complement activation mainly occurs. For this purpose, we will modify compstatin and a newly discovered FHbinding peptide with anchors that allow attachment to cell membranes, self-cell surfaces, or biomaterials. All inhibitors and targeting options will be characterized for efficacy and specificity, and selected compounds will be subjected to production in Core B and evaluation in Projects 2 &3. Our integrated inhibitor development based on modular synthesis, potent lead structures and established techniques has high potential to pave the way to new clinical complement inhibitors and will be of great use for the study of complement diseases.

Public Health Relevance

The purpose of this study is to develop compounds for the selective inhibition of the complement system. We will optimize promising candidate drugs and develop novel compounds that act at distinct stages of the complement cascade, thereby contributing to preclinical research and therapeutic applications. Optimized compounds will be evaluated in disease models to arrive at potent and specific inhibitors with clinical potential.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI068730-06
Application #
8627395
Study Section
Special Emphasis Panel (ZAI1-ESB-I (S1))
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$473,384
Indirect Cost
$177,519
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Schmidt, Christoph Q; Harder, Markus J; Nichols, Eva-Maria et al. (2016) Selectivity of C3-opsonin targeted complement inhibitors: A distinct advantage in the protection of erythrocytes from paroxysmal nocturnal hemoglobinuria patients. Immunobiology 221:503-11
Blatt, Adam Z; Saggu, Gurpanna; Kulkarni, Koustubh V et al. (2016) Properdin-Mediated C5a Production Enhances Stable Binding of Platelets to Granulocytes in Human Whole Blood. J Immunol 196:4671-80
Mastellos, Dimitrios C; Reis, Edimara S; Yancopoulou, Despina et al. (2016) From orphan drugs to adopted therapies: Advancing C3-targeted intervention to the clinical stage. Immunobiology 221:1046-57
Hajishengallis, George; Lambris, John D (2016) More than complementing Tolls: complement-Toll-like receptor synergy and crosstalk in innate immunity and inflammation. Immunol Rev 274:233-244
Lindorfer, Margaret A; Cook, Erika M; Reis, Edimara S et al. (2016) Compstatin Cp40 blocks hematin-mediated deposition of C3b fragments on erythrocytes: Implications for treatment of malarial anemia. Clin Immunol 171:32-35
Maekawa, Tomoki; Briones, Ruel A; Resuello, Ranillo R G et al. (2016) Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3. J Clin Periodontol 43:238-49
Hajishengallis, George; Hajishengallis, Evlambia; Kajikawa, Tetsuhiro et al. (2016) Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application. Semin Immunol 28:285-91
Ricklin, Daniel; Reis, Edimara S; Lambris, John D (2016) Complement in disease: a defence system turning offensive. Nat Rev Nephrol 12:383-401
Hajishengallis, George; Moutsopoulos, Niki M (2016) Role of bacteria in leukocyte adhesion deficiency-associated periodontitis. Microb Pathog 94:21-6
Wang, Junxiang; Wang, Lu; Xiang, Ying et al. (2016) Using an in vitro xenoantibody-mediated complement-dependent cytotoxicity model to evaluate the complement inhibitory activity of the peptidic C3 inhibitor Cp40. Clin Immunol 162:37-44

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