Humanized Anti-CD38 Monoclonal Antibody for Tumor Killing
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Solution Overview
Problem
Current treatments for multiple myeloma, particularly those targeting the CD38 antigen, face challenges such as high clinical adverse reactions, long administration times, variable patient responses, and limited efficacy in non-human primates due to lack of recognition by existing monoclonal antibodies like Daratumumab.
Innovation Solution
Development of a novel anti-CD38 monoclonal antibody with a distinct antigen-binding site/epitope, capable of binding both human and monkey CD38 antigens, and its corresponding DNA molecule, pharmaceutical composition, and preparation method, including derivatives like Fab fragments and single-chain antibodies, to enhance bioactivity and safety.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing monoclonal antibodies like Daratumumab are used to target CD38 antigen, then tumor cells with high CD38 expression can be killed, but the treatment causes high clinical adverse reactions and has long administration times
Solution Approach 1:
The patent modifies the constant region of the monoclonal antibody from murine to human sequences, changing the immunological parameters of the antibody. This humanization reduces the immunogenicity and adverse reactions while maintaining the antigen-binding capability through preserved variable regions, thus resolving the contradiction between efficacy and safety
2Reliability
If existing monoclonal antibodies are used, then human CD38 antigen can be bound, but the antibodies fail to recognize monkey CD38 antigen due to sequence differences
Solution Approach 1:
The patent applies local quality by differentiating the function of different regions of the antibody: the variable region (specifically CDRs) is optimized for human CD38 binding, while the constant region is humanized to reduce immunogenicity. This localized optimization allows the antibody to maintain high affinity for human CD38 while the human constant region structure inadvertently provides better cross-reactivity with monkey CD38 due to structural homology
3Measurement precision
If traditional monoclonal antibody development methods are used, then specific antigen binding can be achieved, but the development process is time-consuming and has variable patient responses
Solution Approach 1:
The patent employs preliminary action by pre-selecting and humanizing the constant region sequences before completing the full antibody development process. This advance preparation of the constant region framework allows for faster subsequent optimization of the variable regions and accelerates the overall development timeline while maintaining binding specificity
Data Source
AI summary
A monoclonal antibody specifically binding to human and monkey CD38 antigens or a derivative thereof includes: antigen complementarity-determining regions CDR1, CDR2 and CDR3 of an antibody light chain variable region having amino acid sequences as set forth in SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 5, respectively; and antigen complementarity-determining regions CDR1, CDR2 and CDR3 of an antibody heavy chain variable region having amino acid sequences as set forth in SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, respectively. The monoclonal antibody or derivative thereof can be used as a component of a pharmaceutical composition or prepared into a suitable pharmaceutical preparation, administered alone or combined with other therapeutic means such as chemotherapy drugs, for treating tumors with positive CD38 expression, such as human myeloma and human lymphoma.