Methods and compositions for decreasing soluble immune receptor CD28
Inventors
HAKIM, MOTTI • ALISHEKEVITZ, DROR • HAVES ZIV, Dana • MEILIN, Edna • Sapir, Yair • Shulman, Avidor • Ben-Moshe, Tehila • Mandel, Ilana
Assignees
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Publication Number
US-12139534-B2
Publication Date
2024-11-12
Expiration Date
Abstract
Methods of treating cancer and improving immunotherapies comprising decreasing soluble immune receptor levels are provided. Agents that bind membranal immune receptor and inhibit proteolytic cleavage of the receptor and agents that bind soluble immune receptor and that are neither receptor agonists nor antagonists are also provided, as are methods of producing these agents.
Core Innovation
The invention relates to an immunotherapy strategy targeting the soluble CD28 (sCD28) immunosuppressive axis in cancer. It identifies a relationship in which high sCD28 levels in many cancer patients are linked to inhibition of PD-1/PD-L1 therapy, and seeks to improve PD-1/PD-L1 based immunotherapy by decreasing sCD28 levels in a subject suffering from cancer.
To decrease sCD28, the invention proposes anti-cleavage agents and anti-cleavage strategies that bind membrane CD28 (mCD28) stalk and inhibit ADAM10/ADAM17-mediated shedding. The invention also proposes sweeping agents that bind sCD28 without acting as CD28 agonists/antagonists, to promote degradation and clearance, including lysosome, endosome, and proteasome clearance.
The disclosed strategy is grounded in reported examples showing that ADAM10/ADAM17 inhibition reduces sCD28 generation during chronic T-cell activation, and that recombinant sCD28 suppresses IFNγ and alters cytokine profiles including IL-6 and IL-10. The disclosure further reports that sCD28 abrogates anti-PD-1 effects in vitro and that elevated sCD28 impairs anti-PD-1 tumor control in a mouse model when human recombinant sCD28 is administered.
Claims Coverage
The claim coverage centers on decreasing soluble CD28 (sCD28) to improve PD-1/PD-L1 based immunotherapy, with dependent claims adding subject selection constraints and biological conditions. The inventive features across the claim set focus on decreasing sCD28 and preserving membrane CD28 (mCD28) and mCD28-mediated immune cell activation.
Decreasing soluble CD28 to improve PD-1/PD-L1 immunotherapy
A method of improving PD-1/PD-L1 based immunotherapy in a subject suffering from cancer, comprising decreasing soluble CD28 (sCD28) levels in the subject; thereby improving PD-1/PD-L1 based immunotherapy.
Baseline blood sCD28 threshold prior to decreasing
The method wherein, before the decreasing step, the subject’s blood contains at least 5 ng/ml of sCD28.
Selecting non-responders or low responders
The method wherein the subject is selected who does not respond or responds lowly to PD-1 and/or PD-L1 based immunotherapy.
Preserving mCD28 and mCD28-mediated immune cell activation
The method characterized by not degrading mCD28 or decreasing mCD28-mediated immune cell activation.
Using a PD-1 or PD-L1 blocking antibody as the checkpoint inhibitor
The method wherein the PD-1/PD-L1 checkpoint inhibitor is a PD-1 or PD-L1 blocking antibody.
Restricting the subject population to specific cancer types
The method wherein the subject has cancer selected from melanoma, head and neck cancer, non-small cell lung cancer, ovarian cancer, kidney cancer, gastric cancer, and colorectal cancer.
Overall, the claim coverage centers on decreasing sCD28 to improve PD-1/PD-L1 immunotherapy, with dependent claim refinements that specify when to apply the method, who to treat, how to preserve biology, and that the checkpoint inhibitor can be a PD-1 or PD-L1 blocking antibody.
Stated Advantages
Improves PD-1/PD-L1 based immunotherapy in a subject suffering from cancer by decreasing sCD28 levels.
Documented Applications
Use for improving PD-1/PD-L1 based immunotherapy in subjects suffering from cancer, including melanoma, head and neck cancer, non-small cell lung cancer, ovarian cancer, kidney cancer, gastric cancer, and colorectal cancer.
Patient suitability determination and selection using a baseline blood sCD28 level criterion prior to decreasing sCD28.
Treatment context focused on subjects who do not respond or respond lowly to PD-1 and/or PD-L1 based immunotherapy.
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