Method of increasing the efficacy of CAR-T immunotherapy using lenzilumab
Inventors
DURRANT, Cameron • Chappell, Dale
Assignees
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Publication Number
US-11673962-B2
Publication Date
2023-06-13
Expiration Date
Abstract
Methods of inhibiting or reducing the incidence or the severity of immunotherapy-related toxicity in a subject, the method comprising a step of administering a recombinant hGMCSF antagonist to the subject, wherein said administering inhibits or reduces the incidence or the severity of immunotherapy-related toxicity in said subject, are provided. An hGMCSF antagonist for use in methods of inhibiting or reducing the incidence or the severity of immunotherapy-related toxicity in a subject also are provided.
Core Innovation
The invention relates to methods to inhibit or reduce immunotherapy-related toxicity in a subject receiving CAR-T immunotherapy, including CAR-T related neurotoxicity and cytokine release syndrome. The methods administer a recombinant hGM-CSF antagonist, specifically an anti-hGM-CSF antibody lenzilumab, in a way intended to mitigate toxicity while increasing the efficacy of CAR-T immunotherapy in the subject.
GM-CSF blockade is described as increasing CAR-T efficacy and as being associated with increased CAR-T cell expansion and reduced myeloid-derived suppressor cells (MDSC). The disclosed efficacy improvements also include synergy with a checkpoint inhibitor, and the context includes preservation of CAR-T killing and proliferation while GM-CSF blockade is applied.
The disclosed compositions include anti-hGM-CSF antibodies and embodiments described with antibody sequence features. Examples emphasize VH and VL CDR3 binding specificity determinants and related sequence information, including motifs such as RQRFPY or RDRFPY and QQFNKSPLT along with SEQ ID references.
Claims Coverage
The claim set centers on an independent method claim to increase CAR-T efficacy by administering a recombinant hGM-CSF antagonist, with dependent claims refining administration timing, efficacy components, and antibody specificity. Overall coverage includes six inventive features.
Recombinant hGM-CSF antagonist for increasing CAR-T efficacy
Administering a recombinant hGM-CSF antagonist to increase the efficacy of CAR-T immunotherapy in a subject, wherein the recombinant hGM-CSF antagonist is anti-hGM-CSF antibody lenzilumab.
Timing relative to CAR-T immunotherapy
Administering the recombinant hGM-CSF antagonist before, during, or after CAR-T immunotherapy or a combination thereof.
Efficacy including expansion, MDSC reduction, checkpoint inhibitor synergy
Increasing efficacy comprising one or more of increased CAR-T cell expansion, reduced myeloid-derived suppressor cells (MDSC), synergy with a checkpoint inhibitor, or any combination thereof.
Quantitative CAR-T cell expansion threshold
Increasing CAR-T cell expansion by at least a 50% increase versus a control.
CD19 CAR-T immunotherapy
Using CAR-T immunotherapy comprising CD19 CAR-T cells.
VH/VL CDR3 binding specificity determinants
Using an anti-hGM-CSF antibody whose VH and VL regions have specific CDR3 binding specificity determinants and sequences, including VH CDR3 determinants RQRFPY or RDRFPY and a VL CDR3 motif QQFNKSPLT.
Across the independent claim and its refinements, the inventive coverage is directed to increasing CAR-T immunotherapy efficacy via administering anti-hGM-CSF antibody lenzilumab, with further claim coverage for timing, specific efficacy manifestations including expansion and MDSC reduction, a quantitative expansion threshold, CD19 CAR-T cells, and antibody binding specificity defined by VH and VL CDR3 determinants.
Stated Advantages
Increases the efficacy of CAR-T immunotherapy in the subject.
Mitigates or reduces immunotherapy-related toxicity, including CAR-T related neurotoxicity and cytokine release syndrome.
Increases CAR-T cell expansion.
Reduces myeloid-derived suppressor cells (MDSC).
May provide synergy with a checkpoint inhibitor.
Documented Applications
Methods to inhibit or reduce CAR-T related neurotoxicity and cytokine release syndrome in subjects receiving CAR-T immunotherapy, by administering a recombinant hGM-CSF antagonist.
Increasing the efficacy of CAR-T immunotherapy in a subject by administering anti-hGM-CSF antibody lenzilumab.
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