Methods of treating inflammatory disorders with multivalent Fc compounds
Inventors
Block, David S. • Olsen, Henrik
Assignees
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Publication Number
US-12337026-B2
Publication Date
2025-06-24
Expiration Date
Abstract
The present invention provides methods for the identification of patients with an inflammatory or autoimmune disease that demonstrate an inadequate response to treatment with a multi-Fc therapeutic, and the determination of an optimal dose of a multi-Fc therapeutic for said patient based on the patient's circulating levels of inactivated C3b (iC3b) and/or additional complement components that may be employed as a surrogate for iC3b based on an analogous response to multi-Fc therapeutics. The present invention further provides for improvements in the use of such multi-Fc therapeutics in the treatment of autoimmune and inflammatory diseases.
Core Innovation
The described invention provides methods for determining an effective dose of a multi-Fc therapeutic in a subject in need thereof. The approach administers a starting dose and determines a blood iC3b level after administration. A need for a first cumulative escalated dose is determined when the blood iC3b level is lower than a predetermined threshold or when the blood iC3b level shows a change percent meeting specified low-change ranges from baseline.
The method includes administering a first cumulative escalated dose when the subject is determined to require escalation based on the measured blood iC3b level behavior. The multi-Fc therapeutic is described as comprising multimers of a homodimer, where the homodimer includes a monomer comprising amino acids 21-264 of SEQ ID NO:4. The document further links the use of circulating inactivated C3b (iC3b) and/or iC3b surrogate complement markers to therapeutic effectiveness.
The described framework also encompasses measurement approaches for iC3b and surrogate markers, including immunoassays such as ELISA and western blot, as well as flow cytometry, and uses surrogate complement split products. The selection of surrogate markers for iC3b is described from enumerated markers such as iC3b1, iC3b2, C3a, C3a desArg, C4a, C4a desArg, and others, with predetermined thresholds applied to determine whether escalation is required.
Claims Coverage
The partial content identifies one independent claim (clm-00001). The independent claim contains a multi-step inventive scheme centered on using blood iC3b level or iC3b-surrogate complement markers after a starting dose to decide whether to administer a first cumulative escalated dose, including defined therapeutic composition constraints.
Determine an effective multi-Fc dose using blood iC3b thresholding
Administer the multi-Fc therapeutic at a starting dose to a subject, determine the blood iC3b level, determine that the subject requires a first cumulative escalated dose if the blood iC3b level is lower than a predetermined threshold or shows a specified low change percent from baseline, and administer the first cumulative escalated dose when escalation criteria are met.
Multi-Fc therapeutic as homodimer multimers with a monomer defined by SEQ ID NO:4
Provide the multi-Fc therapeutic as multimers of a homodimer, where the homodimer comprises a monomer comprising amino acids 21-264 of SEQ ID NO:4 in the dosing method that includes escalation based on blood iC3b level.
Across the independent claim, the core coverage is directed to determining escalation to an effective dose of a multi-Fc therapeutic by measuring blood iC3b level against a predetermined threshold or low change percent from baseline, while the multi-Fc therapeutic is specified as multimers of a homodimer with a monomer comprising amino acids 21-264 of SEQ ID NO:4.
Stated Advantages
Allows determination of an effective dose of a multi-Fc therapeutic based on measured blood iC3b level behavior and predetermined thresholds.
Supports selecting an escalated dose when iC3b levels are below threshold or remain within specified low-change ranges from baseline.
Documented Applications
Autoimmune/inflammatory diseases and complement-mediated conditions suitable for treatment, including ITP, RA, SLE, CIDP, Guillain-Barre, myasthenia gravis, and Kawasaki disease.
A nephritis model (Thy-1 model of nephritis) in which iC3b generation and correlation with effective dose are described.
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