Anti-C3d antibody conjugates and methods of detecting complement activation
Inventors
Tomlinson, Stephen • Holers, V. Michael • Engel, Pablo
Assignees
Universitat de Barcelona UB • MUSC Foundation for Research and Development • US Department of Veterans Affairs • University of Colorado Denver
Publication Number
US-11191851-B2
Publication Date
2021-12-07
Expiration Date
2033-08-16
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Abstract
Provided herein, inter alia, are compositions and methods of using the same for detecting complement activation.
Core Innovation
The invention provides antibody conjugates including an antibody, or antigen binding fragment thereof, and a detectable moiety for detecting complement activation. Methods of detecting complement-mediated inflammation in an individual are disclosed that comprise administering to the individual an effective amount of an anti-C3d antibody conjugate, allowing the anti-C3d antibody conjugate to bind to a complement C3 protein fragment within the individual, and detecting the resulting complex in the individual. Similar methods are provided for detecting complement activation in biological samples such as tissue, blood, serum, or cells.
The problem being addressed is the difficulty and risks involved in diagnosing complement-mediated inflammation. Complement activation and deposition of processed protein fragments derived from complement component C3 are key markers of tissue inflammation in many autoimmune, inflammatory, and ischemic diseases. Existing diagnostic methods such as tissue biopsy and immunostaining have limitations including sample error and risk of complications like internal bleeding. Non-invasive methods to detect or monitor complement-mediated inflammation would provide significant clinical value.
Claims Coverage
The claims include one independent claim directed to an isolated peptide and its nucleic acid encoding sequence with various embodiments relating to detectable moieties and compositions. Key inventive features cover aspects of the isolated peptide and its use in diagnostic and therapeutic applications.
Isolated peptide comprising amino acids 1-275 of SEQ ID NO:32
An isolated peptide consisting of the amino acid sequence of residues 1 through 275 of SEQ ID NO:32, optionally including the full SEQ ID NO:32 sequence.
Peptide conjugated to detectable moiety
The isolated peptide conjugated to a detectable moiety such as fluorescent dyes, paramagnetic nanoparticles, radionuclides, antibodies, or other imaging agents or contrast agents.
Nucleic acid encoding the isolated peptide
An isolated nucleic acid molecule encoding the isolated peptide comprising amino acids 1 through 275 of SEQ ID NO:32, optionally further encoding a detectable moiety.
Pharmaceutical composition comprising the peptide or nucleic acid
Compositions comprising the isolated peptide and/or nucleic acid molecules encoding the peptide for use in diagnostic or therapeutic applications.
The claims broadly cover the isolated peptide of SEQ ID NO:32, nucleic acid molecules encoding it, conjugation with diverse detectable moieties, and compositions comprising such peptides or nucleic acids for diagnostic or therapeutic use.
Stated Advantages
Provides non-invasive detection of complement-mediated inflammation, improving diagnosis and monitoring of inflammatory diseases.
Targets diagnostic agents specifically to C3d and other processed complement fragments covalently fixed at sites of complement activation, enhancing localization and sensitivity.
Enables imaging of complement activation and tissue inflammation using modalities such as MRI, fluorescence, PET, and ultrasound.
Antibodies have high affinity and specificity for activated forms of C3 fragments (iC3b, C3dg, and C3d) over intact C3, reducing background signal from circulating complement.
Allows repeated monitoring without the risks associated with invasive biopsy procedures.
Documented Applications
Non-invasive detection and monitoring of complement-mediated inflammation in autoimmune, inflammatory and ischemic diseases including systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, transplant rejection, ischemia/reperfusion injury, and age-related macular degeneration.
Diagnostic imaging of complement deposition in tissues such as kidney, retina, and choroid in disease models and patients.
Targeted delivery of therapeutic and diagnostic agents (nano-sized contrast agents, radionuclides, fluorescent tags) to sites of complement activation for molecular imaging and therapy.
Monitoring treatment response and disease progression in conditions associated with alternative complement pathway activation.
Use in biological samples such as biopsies, blood, serum, and cells to detect complement activation and inflammation ex vivo.
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