Dosing strategy that mitigates cytokine release syndrome for therapeutic antibodies
AssigneeRegeneron Pharmaceuticals, Inc.
InventorsCarrie Brownstein, Israel Lowy, Lieve Lucille Adriaens
Life of this patent
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Abstract
Administration regimens for therapeutic proteins (e.g., T cell-activating bispecific antibodies) that mitigate cytokine release syndrome and infusion-related reaction are disclosed. The methods employ initial fractional dosing with optional administration of additional agents such as steroids or cytokine antagonists that are discontinued with maximal weekly dosing over the course of the dosing regimen.
Claims53
A method of administering a therapeutic protein to a subject in a dosing regimen to mitigate adverse effects of cytokine release syndrome (CRS) or infusion-related reaction (IRR) in the treatment of a CD20-expressing B-cell malignancy, comprising:
- administering fractions of a primary dose (D1) of the therapeutic protein in week 1 of the dosing regimen, wherein the primary dose comprises no more than 10 mg of the therapeutic protein, a first dose fraction (F1D1) comprises 40% to 60% of the total primary dose and is administered to the subject on day 1 of week 1, and a second dose fraction (F2D1) comprises the remaining 40% to 60% of the total primary dose and is administered to the subject from 12 to 96 hours following administration of the F1D1;
- administering fractions of a secondary dose (D2) of the therapeutic protein in week 2 of the dosing regimen, wherein the secondary dose is greater than the primary dose and no more than one-half of a maximum weekly dose of the therapeutic protein, a first dose fraction (F1D2) comprises 40 to 60% of the total secondary dose, a second dose fraction (F2D2) comprises the remaining 40% to 60% of the total secondary dose, and the F2D2 is administered to the subject from 12 to 96 hours following administration of the F1D2 during week 2 of the dosing regimen;
- and
- administering the maximum weekly dose of the therapeutic protein to the subject as a single dose in a subsequent week of the dosing regimen,
- wherein the administration of the therapeutic protein to the subject in the dosing regimen reduces the prevalence or severity, or both the prevalence and severity, of CRR or IRR compared to a dosing regimen not including split administration of the primary dose and the secondary dose, and
- wherein the therapeutic protein is a bispecific antibody or antigen-binding fragment thereof comprising a first antigen-binding arm that binds human CD3 and comprises complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 comprising the amino acid sequences, respectively, of SEQ ID NOs:
- 19-20-21-22-23-24, and a second antigen-binding arm that binds human CD20 and comprises complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 comprising the amino acid sequences, respectively, of SEQ ID NOs:
- 16-17-18-22-23-24.
Dependencies are inferred from the claim text.