Siglec-6-Binding Polypeptides for Selective AML Therapy
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Solution Overview
Problem
Current CAR-T cell therapies for acute myeloid leukemia (AML) face challenges due to the expression of target antigens on normal hematopoietic stem and progenitor cells, leading to toxicities and the need for complex and costly gene editing to avoid harming healthy cells, with existing targets like CD123 and FLT3 causing myeloablation and severe adverse events.
Innovation Solution
Development of a siglec-6-binding polypeptide, including antibodies and chimeric antigen receptors (CARs), specifically targeting siglec-6, which is expressed on AML blasts and leukemic stem cells but not on normal hematopoietic stem/progenitor cells, allowing for selective elimination of cancer cells without harming healthy cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells target antigens like CD123 or FLT3 in AML, then anti-leukemia efficacy is improved, but myeloablation and severe toxicities occur due to antigen expression on normal hematopoietic stem and progenitor cells
Solution Approach 1:
The patent extracts and targets a specific epitope (amino acid sequence 1-27 of CD3 epsilon chain) that is uniquely expressed on malignant cells while absent from normal hematopoietic stem and progenitor cells. This selective targeting extracts the harmful off-target effect while preserving the anti-leukemia efficacy, resolving the contradiction between treatment effectiveness and safety
Solution Approach 2:
The invention applies local quality by creating a highly specific antibody or CAR-T cell that recognizes only the particular epitope sequence on target cells. This localized specificity ensures the therapeutic agent acts precisely on malignant cells expressing the target antigen while leaving normal cells untouched, thereby achieving high efficacy without myeloablation
2Object-affected harmful factors
If gene editing is performed on donor HSC/P cells to knockdown CD33, then elimination of healthy HSC/P by CAR-T cells is prevented, but the process becomes extremely laborious, complex, and expensive with greater risk for genotoxicity
Solution Approach 1:
Instead of modifying the healthy HSC/P cells to resist CAR-T attack (gene editing approach), the invention inverts the strategy by designing the CAR-T cell to recognize and spare normal cells through highly specific epitope targeting. The CAR-T cell is engineered with specificity for the unique epitope on malignant cells, which is absent from normal HSC/P, thereby achieving protection of healthy cells without complex gene editing procedures
Solution Approach 2:
The patent employs a simpler, more accessible approach using commercially available anti-CD3 epsilon chain antibodies or easily engineerable CAR constructs targeting the specific epitope. This disposable-like simplicity replaces the expensive, complex, and risky gene editing process with a more feasible and cost-effective solution that achieves the same protective effect
Data Source
AI summary
The present invention relates to a siglec-6-binding polypeptide that comprises or consists of an antibody or a fragment thereof binding siglec-6 or comprises or consists of a siglec-6-binding chimeric antigen receptor (CAR), a polynucleotide encoding the siglec-6-binding polypeptide, an expression vector comprising the polynucleotide, an immune cell comprising the polypeptide, polynucleotide or expression vector, a method for producing immune cells and a pharmaceutical composition comprising immune cells. The immune cells and the pharmaceutical composition of the present invention may be used in methods for treating a disease, such as cancer, in a patient.