Anti-CD38 Antibody Formulation for Low-Viscosity Subcutaneous Delivery
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Solution Overview
Problem
Existing anti-CD38 antibodies are ineffective as single agents in inducing apoptosis in CD38+ cells and require combination with cytotoxic agents, and there is a need for formulations suitable for subcutaneous administration to treat CD38-expressing diseases.
Innovation Solution
Formulations of anti-CD38 antibodies with specific CDR sequences, pH 5.9-7.0, and viscosity up to 25 mPa·s, containing viscosity reducing agents like Arg-Cl or Lys-Ac, stabilizers like sucrose, and surfactants like Poloxamer 188 or Polysorbate 80, enabling subcutaneous administration by injection or infusion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If anti-CD38 antibodies are formulated at high concentration for subcutaneous administration, then the dosage efficiency is improved, but the viscosity increases making infusion difficult
Solution Approach 1:
The patent applies parameter changes by systematically optimizing formulation conditions including pH (5.5-7.0), temperature, ionic strength, and excipient concentrations to maintain low viscosity at high antibody concentrations (100-200 mg/mL), enabling subcutaneous administration without requiring dilution
Solution Approach 2:
The patent uses composite formulation strategies by combining antibody with multiple excipients including buffering agents (histidine, phosphate), surfactants (polysorbate 80, poloxamer 188), and stabilizers to create a composite system that maintains low viscosity and high stability at high antibody concentrations
2Device complexity
If existing anti-CD38 antibodies are used as single agents, then the treatment simplicity is improved, but the therapeutic effectiveness deteriorates as they fail to induce apoptosis
Solution Approach 1:
The patent introduces amino acid substitutions in the CDR regions of the anti-CD38 antibody (e.g., H310Y, H310F, H310W, H310Q, H310L mutations) to modify the antibody's functional properties, enabling it to induce apoptosis in CD38+ cells as a single agent without requiring combination with cytotoxic agents
3Ease of operation
If viscosity reducing agents are added to the formulation, then the viscosity is reduced for better infusion, but the formulation complexity increases
Solution Approach 1:
The patent optimizes the concentration ranges of viscosity reducing agents (arginine hydrochloride 0.1-1.0 M, lysine acetic acid 0.1-1.0 M) in combination with pH adjustment and other excipients to achieve the desired viscosity profile while maintaining formulation simplicity and manufacturability
Data Source
AI summary
Provided are formulations of anti-CD38 antibodies suitable for subcutaneous administration to a subject in need thereof. The formulations include a high concentration of antibody, a viscosity lowering agent, a stabilizing agent, a buffering agent and a surfactant. In certain embodiments, the viscosity of the solution is at most 25 mPa·s, and the pH of the solution is 5.9 to 7.0. In certain embodiments, the anti-CD38 antibody is isatuximab. The formulations will find use in treating CD38+ hematological malignancies, including multiple myeloma, as well as autoimmune and inflammatory diseases, in humans.