Methods of treating CART-T cell therapy-induced neuroinflammation using a GM-CSF antagonist
Inventors
DURRANT, Cameron • Chappell, Dale
Assignees
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Publication Number
US-11130805-B2
Publication Date
2021-09-28
Expiration Date
Abstract
Methods for reducing blood-brain barrier disruption in a subject treated with immunotherapy, the method comprising administering a recombinant GM-CSF antagonist to the subject. Methods for preserving blood-brain barrier integrity in a subject treated with immunotherapy, the method comprising administering a recombinant hGM-CSF antagonist to the subject. Methods for decreasing or preventing CAR-T cell therapy-induced neuroinflammation in a subject in need thereof, the method comprising administering a recombinant GM-CSF antagonist to the subject. Methods for preventing or reducing blood-brain barrier disruption in a subject treated with immunotherapy, the method comprising administering CAR-T cells having a GM-CSF gene knockout (GM-CSFk/o CAR-T cells) to the subject.
Core Innovation
The disclosure relates to decreasing or preventing CAR-T cell therapy-induced neuroinflammation in a subject in need thereof by administering a recombinant hGM-CSF antagonist, wherein the recombinant hGM-CSF antagonist is anti-hGM-CSF antibody lenzilumab. The approach targets GM-CSF activity associated with CAR-T cell therapy-induced neurotoxicity, neuroinflammation, cytokine release syndrome, and related inflammatory signaling in the subject.
The disclosure links GM-CSF activity to blood-brain barrier disruption during CAR-T cell therapy and describes preserving blood-brain barrier integrity by antagonizing hGM-CSF. It further characterizes impacts on peripheral and CSF cytokines/chemokines, clinical toxicity measures including CRS, NT, and CRES grades, and related biomarkers, including ANG1, ANG2, ANG2:ANG1 ratio, MCP-1, and genetic mutations associated with toxicity predisposition.
The disclosure also describes antibody binding and structural constraints for anti-hGM-CSF antibodies, including epitope relationships such as binding to the same epitope as a chimeric 19/2 antibody, CDR determinant constraints, and sequence identity thresholds for VH and V segments. It presents supportive evidence that GM-CSF neutralization with lenzilumab reduces CAR-T-related neuroinflammation/neurotoxicity and CRS severity while preserving or enhancing CAR-T function, expansion, and leukemia control.
Claims Coverage
The disclosure includes one independent claim directed to decreasing or preventing CAR-T cell therapy-induced neuroinflammation by administering a recombinant hGM-CSF antagonist, specifically anti-hGM-CSF antibody lenzilumab. Dependent claims further specify timing, binding and epitope specificity, quantified neuroinflammation reduction, blood-brain barrier-related effects, and antibody structural and sequence constraints.
Administering recombinant hGM-CSF antagonist to decrease CAR-T neuroinflammation
A method for decreasing or preventing CAR-T cell therapy-induced neuroinflammation in a subject in need thereof by administering a recombinant hGM-CSF antagonist, wherein the recombinant hGM-CSF antagonist is anti-hGM-CSF antibody lenzilumab.
Quantified reduction of CAR-T neuroinflammation
Decreasing neuro-inflammation in the subject by 75% to 95% compared to a subject treated with CAR-T cell therapy and a control antibody.
Blood-brain-barrier integrity by GM-CSF antagonism
Reducing disruption of the blood-brain barrier by administering the recombinant hGM-CSF antagonist.
Timing of anti-hGM-CSF antibody relative to CAR-T therapy
Administering an anti-hGM-CSF antibody before, during, or after CAR-T cell therapy, or administering it in combination with CAR-T cell therapy.
Epitope matching to chimeric 19/2
Performing the method such that the anti-hGM-CSF antibody binds to the same epitope as the chimeric 19/2 antibody.
Humaneered VH CDR3 determinant and sequence identity constraints
Providing an anti-hGM-CSF antibody whose VH region CDR3 contains the RQRFPY determinant (SEQ ID NO: 12) and wherein the J segment and V segment satisfy specified sequence identity constraints relative to stated human reference sequences.
Overall claim coverage centers on administering anti-hGM-CSF antibody lenzilumab as a recombinant hGM-CSF antagonist to decrease or prevent CAR-T cell therapy-induced neuroinflammation. Dependent refinements include quantified neuroinflammation reduction, blood-brain barrier-related effects, timing relative to CAR-T therapy, and antibody epitope and VH/CDR sequence identity constraints.
Stated Advantages
Decreases or prevents CAR-T cell therapy-induced neuroinflammation.
Reduces neuro-inflammation by 75% to 95% compared with CAR-T plus a control antibody.
Reduces disruption of the blood-brain barrier and helps maintain its integrity.
Reduces CAR-T-related neuroinflammation/neurotoxicity and CRS severity while preserving or enhancing CAR-T function/expansion and leukemia control.
Associated with reduced neuroinflammation while not reducing CAR-T efficacy, including no reduction or increased expansion.
Expected to impact clinical toxicity measures including CRS, NT, and CRES grades and related biomarkers.
Documented Applications
Reducing or preventing CAR-T cell therapy-induced neuroinflammation in a subject in need thereof.
Decreasing CAR-T-related neuroinflammation/neurotoxicity and CRS severity while preserving or enhancing CAR-T function/expansion and leukemia control.
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