Use of TLR agonist and anti-CD47 agent to enhance phagocytosis of cancer cells
Inventors
Weissman, Irving L. • FENG, Mingye • Volkmer, Jens-Peter
Assignees
Leland Stanford Junior University
Publication Number
US-12318448-B2
Publication Date
2025-06-03
Expiration Date
2036-01-21
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Therapeutic and diagnostic methods are provided, which methods relate to the induction of expression of calreticulin on phagocytic cells. Specifically, the methods relate to macrophage-mediated programmed cell removal (PrCR), the methods comprising increasing PrCR by contacting a phagocytic cell with a toll-like receptor (TLR) agonist; or down-regulating PrCR by contacting a phagocytic cell with an inhibitor of Bruton's tyrosine kinase (BTK). In some embodiments, an activator of TLR signaling or a BTK agonist is provided in combination with CD47 blockade.
Core Innovation
The invention provides therapeutic and diagnostic methods related to macrophage-mediated programmed cell removal (PrCR). It demonstrates that phagocytic cells, such as macrophages, upregulate expression of calreticulin (CRT) on their cell surface in response to toll-like receptor (TLR) signaling. CRT present on the phagocyte surface interacts with target cells, including cancer cells, to initiate PrCR. The upregulation of CRT by phagocytic cells involves a Bruton's tyrosine kinase (BTK) signaling pathway, with BTK activation promoting CRT expression and BTK inhibition reducing CRT levels and subsequently decreasing PrCR.
The invention addresses the problem that some tumor cells are able to evade recognition and destruction by the immune system, particularly through mechanisms that prevent effective phagocytosis by monocytes and macrophages. This immune evasion impairs the body’s ability to clear cancer cells. The present methods aim to overcome these immune evasion strategies by enhancing the ability of phagocytic cells to recognize and remove tumor cells.
The methods of the invention include increasing PrCR by contacting phagocytic cells with TLR agonists or BTK agonists, or downregulating PrCR using BTK inhibitors. Activation of TLR signaling or administration of a BTK agonist, when combined with CD47 blockade, results in a synergistic increase in PrCR relative to either agent alone. These interventions can be applied both in vitro, to prime phagocytic cells, and in vivo, for direct therapeutic treatment. Measurement of CRT expression on phagocyte surfaces is used as a biomarker for determining their phagocytic capacity.
Claims Coverage
There is a single independent claim in this patent, featuring two main inventive features.
Enhancing programmed cell removal of solid tumor cells with TLR agonist and anti-CD47 antibody
This method comprises: - Contacting a population of phagocytic cells with a Bruton's tyrosine kinase (Btk) activating TLR agonist in a dose effective to increase expression of calreticulin on the phagocytic cell surface. - Contacting the same population of phagocytic cells with an anti-CD47 antibody that blocks binding of CD47 to SIRPa, in a dose effective to increase programmed cell removal of the solid cells, wherein the antibody is a humanized IgG4 antibody. - The combination of the TLR agonist and the anti-CD47 antibody enhances programmed cell removal of solid tumor cells by the phagocytic cells.
The inventive feature is focused on a method for enhancing programmed cell removal of solid tumor cells by combining a Btk-activating TLR agonist and a humanized IgG4 anti-CD47 antibody to increase calreticulin expression and phagocytosis.
Stated Advantages
The described methods synergistically increase programmed cell removal beyond what is achieved by monotherapies with TLR agonists or anti-CD47 agents alone.
Increased expression of calreticulin on the surface of phagocytic cells serves as a biomarker for assessing and determining the phagocytic capability of these cells.
Phagocytic cell priming and combination therapy enhance the efficacy of tumor cell clearance and can improve therapeutic outcomes in vivo.
Documented Applications
Treatment of cancer, including solid tumors such as lymphoma, prostate cancer, and breast cancer, by enhancing macrophage-mediated phagocytosis in vivo or ex vivo.
Diagnosing and monitoring the phagocytic capability of macrophages by measuring CRT surface expression.
Use of BTK inhibitors to downregulate programmed cell removal for conditions involving excessive or undesirable phagocytosis, including myelodysplastic syndrome, autoimmune hemolytic anemia, and immune thrombocytopenic purpura.
Interested in licensing this patent?