New therapeutic and diagnostic opportunities for injured tissue-specific targeting of complement inhibitors and imaging modalities.
Despite substantial opportunity and commercial interest in developing drugs that modulate the complement system in a broad range of non-orphan indications, several obstacles remain to be overcome. Among these issues is the biophysical nature of complement proteins, whose circulating levels are typically very high and whose turnover rates are relatively rapid, especially in the setting of chronic inflammatory conditions. This situation necessitates the use of very high levels of therapeutic compounds in order to achieve both multi-pathway and multiple effector mechanism inhibition. In addition, one must avoid infectious complications or the systemic impairment of the other important physiological functions of complement. Herein we focus on the development of a novel therapeutic strategy based on injured tissue-specific targeting of complement inhibitors using the antigen-combining domains of a small subset of natural IgM antibodies, which as endogenous antibodies specifically recognize sites of local damage across a broad range of tissues and locally activate complement C3, resulting in C3 fragment covalent fixation. Because the use of such recombinant tissue-targeting inhibitors precludes the utility of measuring systemic levels of complement biomarkers or function, since a goal of this targeting strategy is to leave those processes intact and unimpeded, we also briefly describe a new method designed to quantitatively measure using imaging modalities the inhibition of generation of fixed C3 fragments at sites of inflammation/injury. In addition to the ability to determine whether complement activation is locally constrained with the use of inhibitors, there is also a broader application of this imaging approach to inflammatory and autoimmune diseases characterized by local complement activation.
Departments of Medicine and Immunology, University of Colorado School of Medicine, Aurora, CO, United States. Electronic address: Michael.Holers@ucdenver.edu.
V Michael
VM
Holers
Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, United States; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States.
Stephen
S
Tomlinson
Departments of Medicine and Immunology, University of Colorado School of Medicine, Aurora, CO, United States.
Liudmila
L
Kulik
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States; Department of Surgery, Transplant Immunobiology Laboratory, Medical University of South Carolina, Charleston, SC, United States.
Carl
C
Atkinson
Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, United States; Department of Ophthalmology, Medical University of South Carolina, Charleston, SC, United States.
Bärbel
B
Rohrer
Departments of Medicine and Immunology, University of Colorado School of Medicine, Aurora, CO, United States.
Nirmal
N
Banda
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States.
Joshua M
JM
Thurman
D000818:Animals; D015551:Autoimmunity; D003167:Complement Activation; D051056:Complement Inactivating Agents / Q000627:therapeutic use*; D003165:Complement System Proteins / Q000378:metabolism*; D003952:Diagnostic Imaging; D006801:Humans; D007249:Inflammation / Q000175:diagnosis* / Q000628:therapy*; D058990:Molecular Targeted Therapy; D009928:Organ Specificity
D051056:Complement Inactivating Agents; D003165:Complement System Proteins
Cell injury; Imaging; Natural antibodies; Neoepitopes; Targeting; Therapeutics