Mutant CALR Antibodies for Detecting Cleaved Neoepitopes
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing antibodies fail to correctly detect mutant CALR proteins caused by frameshift mutations in myeloproliferative neoplasms due to cleavage, leading to inadequate detection and therapeutic challenges.
Innovation Solution
Development of antibodies that specifically recognize a short amino acid sequence at the amino-terminal side of the cleavage site in mutant CALR proteins, enhancing detection sensitivity and therapeutic efficacy by targeting both full-length and cleaved forms of the protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If an antibody recognizes a sequence (neo-antigen) specific to the mutant CALR protein appearing by the frameshift mutation, then the mutant CALR protein can be detected, but the detection sensitivity is reduced due to cleavage of the mutant protein
Solution Approach 1:
The antibody specifically targets the amino-terminal sequence of the mutant CALR protein that remains intact after cleavage, while the carboxyl-terminal sequence is removed. This segmentation approach allows the antibody to recognize and bind to the remaining N-terminal portion, maintaining detection capability despite the cleavage event that would otherwise eliminate the neo-antigen.
Solution Approach 2:
Instead of targeting the carboxyl-terminal sequence that is cleaved off (which would result in loss of detection), the invention inverts the approach by targeting the amino-terminal sequence that survives cleavage. This inversion of the targeting strategy ensures continuous detection sensitivity while accommodating the cleavage modification.
2Quantity of substance
If a frameshift mutation occurs in the CALR gene, then a mutant CALR protein is produced with oncogenicity, but the protein is cleaved leading to loss of therapeutic target sequences
Solution Approach 1:
The invention extracts and targets the specific amino-terminal sequence that remains after cleavage, separating the useful diagnostic/therapeutic target from the cleaved-off carboxyl-terminal portion. This extraction allows maintenance of therapeutic effectiveness by focusing on the surviving N-terminal sequence that retains oncogenic relevance.
Solution Approach 2:
The invention changes the parameter of antibody targeting from the carboxyl-terminal sequence (which is lost upon cleavage) to the amino-terminal sequence (which is preserved). This parameter change in the targeting location maintains the quantity of detectable and treatable mutant protein despite the cleavage event.
3Productivity
If cleavage of the mutant CALR protein is allowed to occur, then protein processing is completed, but detection sensitivity and therapeutic effectiveness are reduced
Solution Approach 1:
The invention converts the harmful effect of cleavage (which removes neo-antigen sequences) into a beneficial situation by targeting the remaining N-terminal sequence. The cleavage event, rather than eliminating the target, actually defines the specific epitope that the antibody recognizes, thereby maintaining detection sensitivity and therapeutic effectiveness.
Data Source
AI summary
A diagnostic, preventive, or therapeutic agent may be used for a myeloproliferative neoplasm. An antibody or a functional fragment thereof that binds to a cleaved mutant CALR protein, may include an antigen-recognition site in (a) a polypeptide chain having an amino acid sequence set forth in SEQ ID NO: 1 or (b) a polypeptide chain having an amino acid sequence having deletion, substitution, or addition of one to several amino acids in SEQ ID NO: 1; and a diagnostic, preventive, or therapeutic agent for a myeloproliferative neoplasm containing the antibody.