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Publication Number
US-12345712-B2
Publication Date
2025-07-01
Expiration Date
Abstract
The presently disclosed subject matter provides methods and compositions for treating myeloid disorders (e.g., acute myeloid leukemia (AML)). It relates to immunoresponsive cells bearing antigen recognizing receptors (e.g., chimeric antigen receptors (CARs)) targeting AML-specific antigens.
Core Innovation
The invention relates to a method for producing an antigen-specific immunoresponsive cell for acute myeloid leukemia (AML) or other myeloid disorders. It introduces an antigen recognizing receptor that binds EMR2, where binding of the antigen recognizing receptor to EMR2 is capable of activating the immunoresponsive cell, and a chimeric co-stimulating receptor (CCR) that binds CLEC12A, where binding of the CCR to CLEC12A is capable of stimulating the immunoresponsive cell.
The method is characterized by a binding-affinity relationship in which the antigen recognizing receptor binds EMR2 with a binding affinity lower than the binding affinity with which the CCR binds to CLEC12A. This affinity asymmetry is used in combinatorial engagement to address a suboptimal primary recognition response while enabling dual-antigen engagement for enhanced cytolytic activity.
The described approach includes selection criteria intended to avoid on-target/off-tumor toxicity and emphasizes antigen expression patterns on normal tissues. It includes immunoresponsive cells selected from T cells, Natural Killer (NK) cells, cytolytic T lymphocytes (CTL), tumor infiltrating lymphocytes (TIL), and regulatory T cells (Rv-Tregs), and discusses use of chimeric antigen receptors (CAR) and CCR pairing to stimulate or costimulate the immunoresponsive cell.
Claims Coverage
The claim coverage centers on producing an antigen-specific immunoresponsive cell by introducing dual receptor nucleic acids for EMR2 and CLEC12A, with an explicit binding-affinity ordering. Dependent claims further constrain receptor binding parameters, CCR standalone signaling behavior, and selected receptor architecture constraints.
Lower affinity EMR2 antigen recognition with higher affinity CLEC12A co-stimulation
Introducing into an immunoresponsive cell a first nucleic acid encoding an antigen recognizing receptor that binds EMR2 to activate the immunoresponsive cell and a second nucleic acid encoding a chimeric co-stimulating receptor (CCR) that binds CLEC12A to stimulate the immunoresponsive cell, wherein the antigen recognizing receptor binds EMR2 with a binding affinity lower than the binding affinity with which the CCR binds to CLEC12A.
Dual Kd constraints for EMR2 and CLEC12A binding
The antigen recognizing receptor binds EMR2 with a Kd within a specified range, and the CCR binds CLEC12A with a Kd within a specified range.
CCR stimulates without alone delivering an activation signal
The CCR does not alone deliver an activation signal to the cell.
Antigen recognizing receptor as a chimeric antigen receptor (CAR)
The antigen recognizing receptor is a chimeric antigen receptor (CAR).
CCR intracellular signaling excludes CD3Q polypeptide
The CCR intracellular signaling domain does not include a CD3Q polypeptide.
Overall, the claim set coverage centers on producing an antigen-specific immunoresponsive cell by introducing dual receptor constructs for EMR2 and CLEC12A, with an explicit binding-affinity ordering, plus dependent limitations on receptor binding parameters, CCR standalone signaling behavior, and selected receptor architecture constraints.
Stated Advantages
Greater cytolytic activity against dual-antigen positive cells compared to single-antigen targeting.
Reduced off-tumor risk by biasing activation to dual-positive tumor cells using a low binding affinity or low binding avidity antigen recognition receptor relative to the CCR.
Avoiding on-target/off-tumor toxicity by using selection criteria related to antigen expression on normal tissues.
Rescuing suboptimal primary recognition using dual-antigen engagement and enhanced cytolytic activity.
Documented Applications
Engineering and using dual-antigen targeting immunoresponsive cells for antigen-specific targeting involving EMR2 and CLEC12A, including applications described with myeloid/AML surface antigens such as EMR2 and CLEC12A.
Treating or preventing myeloid disorders including acute myeloid leukemia (AML).
Reducing tumor burden.
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