Anti-CD38 Antibodies Stabilized by Amino Acid Substitutions
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for CD38-expressing diseases, including multiple myeloma, face challenges in achieving effective cytotoxicity and stability, with existing anti-CD38 antibodies often having lower than expected isoelectric points and thermal stability issues, which can impact their efficacy and commercial production.
Innovation Solution
Development of anti-CD38 antibodies with specific light and heavy chain amino acid sequences, formulated with sucrose, L-histidine, and polysorbate 80, which exhibit superior antibody-dependent cellular cytotoxicity and phagocytosis, and are stabilized for human administration despite lower isoelectric points and thermal instability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-CD38 antibodies are used, then they can bind to CD38 antigen, but they exhibit lower than expected isoelectric points and thermal stability issues
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequences of both light and heavy chains of the anti-CD38 antibody. Specific substitutions including L238Q, S244N, T250E, and others in the heavy chain, and Q49R, S52P, T58E, and others in the light chain are designed to alter the isoelectric point and improve thermal stability while maintaining antigen binding capability
Solution Approach 2:
The patent creates a composite antibody structure by combining modified light and heavy chains with specific amino acid sequences. The engineered antibody comprises a light chain with sequences containing specific mutations and a heavy chain with sequences containing specific mutations, forming a composite protein structure that achieves both stability and functionality
2Productivity
If antibody sequences are optimized for cytotoxicity, then superior ADCC and ADCP activity is achieved, but stability under thermal stress may be compromised
Solution Approach 1:
The patent simultaneously optimizes multiple parameters including cytotoxic activity and thermal stability through coordinated amino acid substitutions in both light and heavy chains. The modifications are designed to enhance ADCC and ADCP activity while maintaining or improving thermal stability, resolving the trade-off between potency and stability
Solution Approach 2:
The patent applies local quality changes by making specific amino acid substitutions at particular positions in the antibody sequence. Each substitution is strategically placed to affect specific properties: some positions are modified to enhance cytotoxic activity while others are modified to improve thermal stability, allowing simultaneous optimization of multiple functions
3Adaptability or versatility
If isoelectric point is lower than expected, then the antibody may have improved binding characteristics, but commercial production and stability are impacted
Solution Approach 1:
The patent deliberately modifies the isoelectric point parameter through specific amino acid substitutions in the light and heavy chains. The changes are designed to achieve an optimized isoelectric point that balances binding characteristics with manufacturability, improving both clinical efficacy and commercial production feasibility
Data Source
AI summary
Provided herein are antibodies that specifically bind human CD38, formulations and unit dosage forms comprising the antibodies, methods of preparing the antibodies and methods of using the antibodies.