Methods of treating inflammatory disorders with multivalent Fc compounds
Inventors
Block, David S. • Olsen, Henrik
Assignees
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Publication Number
US-11331372-B2
Publication Date
2022-05-17
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 disclosed invention provides a method of treating an inflammatory or autoimmune disease in a patient who is determined to have an inadequate response to a multi-Fc therapeutic. The determination is based on blood levels of inactivated C3b (iC3b) after administration with a starting dose, including cases where iC3b is lower than a predetermined threshold.
The method uses a cumulative escalated dosing approach in which a first cumulative escalated dose of the multi-Fc therapeutic is administered during a first dosing period. The first cumulative escalated dose is at least about 105% of the starting dose, and the patient is selected for additional treatment based on iC3b criteria from the first dosing period.
The disclosure further describes that multi-Fc therapies drive limited upstream complement activation followed by downstream inhibition, generating sustained anti-inflammatory iC3b. It correlates iC3b generation with therapeutic efficacy, including an example nephritis model, and describes complement split-product surrogates that can be correlated with iC3b levels.
Claims Coverage
Independent claim clm-00001 covers a decision-and-escalation method for treating an inflammatory or autoimmune disease with a multi-Fc therapeutic in patients determined to have an inadequate response, using iC3b level and/or iC3b change from baseline after a starting dose. The claim includes two iC3b-based inventive selection criteria tied to a first cumulative escalated dosing regimen, and it specifies structural aspects of the multi-Fc therapeutic.
Cumulative escalated dosing based on inadequate iC3b response
Administering a first cumulative escalated dose of the multi-Fc therapeutic at a dose of at least about 105% of a starting dose during a first dosing period, wherein the patient has been determined to have blood levels of iC3b lower than a predetermined threshold or a change percent of less than about 20%, less than about 30%, less than about 40% or less than about 50% from baseline.
Multi-Fc therapeutic multimer homodimer structural definition
The multi-Fc therapeutic comprises a multimer of a homodimer and the homodimer comprises a monomer comprising amino acids 21-264 of SEQ ID NO:4.
The claim coverage centers on selecting patients with inadequate iC3b response following a starting dose and administering a first cumulative escalated dose of a multi-Fc therapeutic, with the multi-Fc therapeutic structurally defined as a multimer of a homodimer including a monomer comprising amino acids 21-264 of SEQ ID NO:4.
Stated Advantages
Multi-Fc therapies drive limited upstream complement activation followed by downstream inhibition, generating sustained anti-inflammatory iC3b.
iC3b generation is correlated with therapeutic efficacy.
Complement split-product surrogates can be correlated with iC3b levels.
Documented Applications
Treatment of an inflammatory disease.
Treatment of an autoimmune disease.
An example nephritis model is described.
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