Engineered Lymphocytes With Bispecific Engagers for CLL-1 Targeting
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Solution Overview
Problem
Current chemotherapy regimens for acute myeloid leukemia (AML) are ineffective due to the difficulty in specifically targeting leukemic myeloblasts while sparing normal tissue, leading to a low cure rate and unchanged mortality rate over two decades.
Innovation Solution
Engineered lymphocytes, such as T cells, are developed to secrete bispecific engager molecules that bind to CLL-1 positive leukemic cells and activate native T cells, while sparing CLL-1 negative cells like myeloid progenitor cells, using a polypeptide construct with an antigen-recognition domain for CLL-1 and an activation domain for CD3.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemotherapy regimens are used to treat AML, then some leukemic cells are killed, but normal tissue is also damaged and cure rate remains low
Solution Approach 1:
The invention segments the target population into two distinct groups based on CLL-1 expression: CLL-1 positive leukemic cells (target) and CLL-1 negative normal cells (spared). The engineered lymphocytes are designed to specifically recognize and attack only the CLL-1 positive population, achieving segmentation of therapeutic effect. This is implemented through the antigen-recognition domain that binds specifically to CLL-1 on leukemic cells while ignoring CLL-1 negative normal tissue.
Solution Approach 2:
The invention introduces an intermediary molecule - the bispecific engager - that mediates between the engineered lymphocytes and the target leukemic cells. This engager molecule contains an antigen-recognition domain that binds CLL-1 on leukemic cells and an activation domain that triggers T cell activation. The intermediary enables selective targeting without direct contact between lymphocytes and all cells, providing specificity and reducing harm to normal tissue.
2Manufacturing precision
If standard chemotherapy is administered, then leukemic myeloblasts are targeted, but specificity is insufficient and normal cells are affected
Solution Approach 1:
The invention applies local quality by endowing engineered lymphocytes with a specific property (CLL-1 recognition capability) that is localized to their surface receptors. The antigen-recognition domain on the lymphocytes provides local specificity at the cell surface, enabling these cells to distinguish leukemic targets from normal cells based on the presence or absence of CLL-1 expression. This localized quality enhancement achieves precise targeting without affecting other cell types.
3Productivity
If T cells are activated to kill leukemic cells, then treatment efficacy improves, but selectivity between leukemic and normal cells must be maintained
Solution Approach 1:
The invention merges two distinct functions into a single engineered lymphocyte: (1) the ability to recognize leukemic cells through the antigen-recognition domain binding CLL-1, and (2) the ability to activate T cells through the activation domain. This merging ensures that T cell activation (productivity) occurs only when both recognition and activation conditions are met at the leukemic cell surface, thereby maintaining selectivity while enhancing treatment efficacy.
Solution Approach 2:
The bispecific engager acts as an intermediary that bridges the recognition function and activation function. The antigen-recognition domain binds CLL-1 on leukemic cells, and the activation domain subsequently triggers T cell activation. This intermediary mechanism ensures that activation (productivity) is coupled to recognition (selectivity), as the engager must first bind the specific target before initiating the activation cascade.
Data Source
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AI summary
Provided here are compositions comprising engineered lymphocytes that secrete bispecific engager molecules, thereby activating T cells in the local environment to kill target cells. In particular embodiments, engineered lymphocytes selectively target CLL-1 positive leukemic cells, both directly and through activation of a subject's own T cells, while sparing CLL-1 negative cells, such as myeloid progenitor cells. In particular embodiments, engineered lymphocytes selectively target CD123 and CLL-1 positive leukemic cells, both directly and through activation of native T cells.