CLL-1 CAR T Cells Targeting Leukemia Specificity
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Solution Overview
Problem
Current therapies are inadequate in effectively targeting and eliminating cells expressing C-type lectin-like-1 (CLL-1), which are associated with various leukemias and myeloid disorders, due to limited specificity and efficacy of existing treatments.
Innovation Solution
Development of a chimeric antigen receptor (CAR) engineered immune effector cells, such as T cells and NK cells, equipped with a CAR comprising a human anti-CLL-1 binding domain, a transmembrane domain, and an intracellular signaling domain, specifically designed to recognize and target CLL-1 positive cells, enhancing cellular immunity against CLL-1 expressing malignancies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapies are used to treat CLL-1 associated leukemias and myeloid disorders, then treatment can be administered with existing methods, but the therapy lacks sufficient specificity and efficacy to effectively target and eliminate CLL-1 expressing cells
Solution Approach 1:
The patent introduces a chimeric antigen receptor (CAR) as an intermediary component that bridges the immune system and CLL-1 expressing cells. The CAR comprises an anti-CLL-1 binding domain (antibody portion) that specifically recognizes CLL-1 on target cells, coupled with signaling domains that activate immune cells. This intermediary structure enables precise targeting of leukemia cells while sparing normal cells, resolving the contradiction between efficacy and treatment complexity by providing a targeted approach rather than broad-spectrum therapy.
Solution Approach 2:
The patent modifies the parameters of immune cells by engineering them to express the CAR receptor. This changes the specificity, affinity, and functional response of the immune cells from their natural state to a state optimized for recognizing and eliminating CLL-1 expressing cells. The parameter changes include: (1) introducing new binding specificity through the anti-CLL-1 antibody domain, (2) enhancing signaling capacity through costimulatory domains, and (3) improving persistence and functionality through selective expansion of CAR-expressing cells.
2Reliability
If conventional therapies are used, then treatment administration is simpler, but the specificity to target CLL-1 positive cells is insufficient leading to inadequate elimination of malignant cells
Solution Approach 1:
The anti-CLL-1 binding domain within the CAR acts as a specific intermediary that mediates recognition between the immune system and CLL-1 expressing cells. This antibody-based binding domain provides high specificity for CLL-1, enabling the immune cell to distinguish target cells from normal cells. The intermediary nature of the CAR allows for precise molecular recognition while maintaining the natural killing mechanisms of the immune cell, thereby achieving high specificity without requiring complex targeted delivery systems.
3Productivity
If existing treatments are applied, then the treatment protocol is straightforward, but the ability to recognize and eliminate CLL-1 expressing cells is limited
Solution Approach 1:
The CAR construct combines multiple functions into a single engineered component on the immune cell surface: (1) antigen recognition through the anti-CLL-1 binding domain, (2) signal transduction through the signaling domain, and (3) costimulation through the costimulatory domain. This multi-functional design enables a single cell type (immune effector cell) to perform all necessary functions for effective target cell elimination, achieving high productivity without requiring multiple different therapeutic agents or complex treatment protocols.
Data Source
AI summary
The invention provides compositions and methods for treating diseases associated with expression of CLL-1. The invention also relates to chimeric antigen receptor (CAR) specific to CLL-1, vectors encoding the same, and recombinant cells comprising the CLL-1 CAR. The invention also includes methods of administering a genetically modified cell expressing a CAR that comprises a CLL-1 binding domain.