CD38 Fusion Protein Formulation for Long-Term Lyophilized Stability
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Solution Overview
Problem
Existing compositions of CD38-binding fusion proteins, particularly those containing anti-CD38 antibodies fused to interferon alpha-2b, face stability and activity issues during storage, which affect their efficacy in treating CD38-expressing cancers.
Innovation Solution
A composition comprising a CD38-binding fusion protein with an anti-CD38 antibody fused to an attenuated interferon alpha-2b, along with a buffer (histidine/histidine-HCl), tonicity agent (arginine-HCl), stabilizer (sucrose), and surfactant (polysorbate 80), formulated to maintain stability and activity over extended periods, typically months to years, with a pH range of 6.0-7.0 and specific concentrations of the components.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the CD38-binding fusion protein is formulated with multiple excipients (buffer, tonicity agent, stabilizer, surfactant), then the stability and activity of the protein during storage is improved, but the complexity of the formulation increases
Solution Approach 1:
The patent optimizes specific parameters of multiple excipients including pH (6.0-7.0), ionic strength, and concentrations of each component (sucrose 2-10%, polysorbate 80 0.01-0.1%, arginine-HCl 10-100 mM, histidine 10-50 mM) to achieve stable protein formulation. This systematic parameter optimization resolves the contradiction by finding the precise balance point where multiple components work synergistically to protect the protein without excessive complexity
Solution Approach 2:
The formulation uses a composite approach combining multiple excipients (buffer system, tonicity agent, stabilizer, surfactant) with the fusion protein. Each component serves a specific protective function: histidine buffer maintains pH, arginine-HCl provides tonicity and stability, sucrose prevents aggregation, and polysorbate 80 reduces surface adsorption. This composite formulation strategy addresses the stability-complexity contradiction by integrating multiple specialized components that collectively protect the protein
2Duration of action of stationary object
If the fusion protein is stored for extended periods (months to years), then the therapeutic effectiveness is maintained, but the protein may degrade or lose activity
Solution Approach 1:
The formulation incorporates excipients that preemptively protect the protein against degradation mechanisms before storage begins. The stabilizer (sucrose) pre-establishes a protective environment that prevents aggregation, the surfactant (polysorbate 80) pre-coats potential aggregation surfaces, and the buffer system (histidine/arginine-HCl) pre-establishes optimal pH conditions. This preliminary protective action enables long-term storage while maintaining protein activity
Solution Approach 2:
The formulation provides beforehand cushioning against various degradation pathways through multiple excipients. Sucrose cushions against aggregation by preferential exclusion, polysorbate 80 cushions against surface-induced denaturation, and the buffer system cushions against pH shifts. This multi-layer protective cushioning strategy enables the protein to withstand extended storage conditions while maintaining therapeutic activity
Data Source
AI summary
Disclosed herein are compositions comprising a CD38-binding fusion protein, a buffer (e.g., a histidine/histidine-HCl buffer), a tonicity agent (e.g., arginine-HCl), a stabilizer (e.g., sucrose), and a surfactant (e.g., polysorbate such as polysorbate 80). In some aspects, the compositions described herein provide for stable storage of the CD38-binding fusion protein when lyophilized. Methods of treating cancer (e.g., CD38 positive cancer) using the composition described herein are also provided.