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Combination cancer therapy involving chemical activation of integrin and targeted cellular immunotherapy

A technology of integrin and therapy, applied in the treatment of cancer including solid tumors and hematological malignancies, increasing the phagocytosis of cancer cells

Pending Publication Date: 2022-05-13
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, while monoclonal antibodies are now of great clinical importance in the treatment of cancer, especially leukemia, there is still a considerable need for improved treatments

Method used

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  • Combination cancer therapy involving chemical activation of integrin and targeted cellular immunotherapy
  • Combination cancer therapy involving chemical activation of integrin and targeted cellular immunotherapy
  • Combination cancer therapy involving chemical activation of integrin and targeted cellular immunotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Additional Experimental Procedures

[0100] cell culture

[0101] RAW264.7 macrophages were provided by ATCC and certified Mycoplasma-free. Cells were incubated with 1x Penicillin-Streptomycin-Glutamine (Corning, Cat. No. 30-009Cl), 1 mM Sodium Pyruvate (Gibco, Cat. No. 11360-070) and 10% heat-inactivated fetal calf serum (Atlanta Biologicals , Cat. No. S11150H) in DMEM (Gibco, Cat. No. 11965-092). To keep variation to a minimum, cells were discarded after 20 passages. L1210 cells were also obtained from ATCC.

[0102] J774A.1 macrophages were provided by the UCSF Cell Culture Facility. J774A.1 and 293T cells were tested for Mycoplasma using the Lonza MycoAlert Detection Kit (Lonza, Cat. No. LT07-318) and a control group (Lonza, Cat. No. LT07-518).

[0103] Bone marrow-derived macrophages (BMDM) from C57BL / 6J mice in the hip and long bones.

[0104] Constructs and Antibodies

[0105] exist Figure 9 All relevant information on the constructs and antibodies ...

Embodiment 2

[0149] CD47 inhibits IgG and phosphatidylserine "eat me" signaling

[0150] This example describes the results of experiments performed to demonstrate that CD47-SIRPA signaling inhibits IgG and phosphatidylserine "eat me" signaling. To study the mechanisms underlying the integration of "eat me" and "don't eat me" signals during phagocytosis, develop and use methods such as figure 1 Reconstituted phagocytosis targets shown in A. Silica beads were coated in a supported lipid bilayer to mimic the surface of cancer cells. To activate phagocytosis, IgG was introduced synergistically with CD47 blockade (a well-defined "eat me" signal) to promote cancer cell clearance. IgG is recognized by the Fcγ family of receptors (FcRs), which activate downstream signaling and phagocytosis (Freeman and Grinstein, 2014). To activate SIRPA, the CD47 extracellular domain was treated at a surface density chosen to mimic the CD47 density on cancer cells (approximately 600 molecules / μm 2 , figu...

Embodiment 3

[0154] CD47 linkage relocates SIRPA to phagocytic synapses

[0155] This example describes the results of experiments performed to demonstrate that CD47 linkage relocalizes SIRPA to phagocytic synapses. These experiments were performed to determine the mechanism by which CD47 linkage regulates SIRPA activity. SIRPA localization during phagocytosis of IgG-coated beads was first examined. When not bound to CD47, SIRPA dissociates from phagocytic cups encapsulated on IgG-coated beads ( image 3 A). Similarly, SIRPA was depleted at the center of the immune synapse between macrophages and a supporting lipid bilayer containing phosphatidylserine ( Figure 4 A- Figure 4 F). In contrast, SIRPA is retained in the phagocytic cup in the presence of CD47 ( image 3 A). These data demonstrate that unlinked SIRPA is excluded from phagocytic synapses, whereas CD47-bound SIRPA is retained in phagocytic synapses.

[0156] Additional experiments were performed to address the mechanis...

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PUM

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Abstract

The present disclosure generally relates to novel methods of activating integrin signaling to overcome CD47 checkpoint inhibition and to promote the macrophage phagocytic signaling pathway. The present disclosure also provides methods and compositions for treating cancers, including solid tumors and hematological malignancies, by promoting macrophage-mediated phagocytosis of cancer cells. Also provided is the use of integrin activation in combination with adoptive metastasis of engineered macrophages for increasing phagocytosis to cancer cells.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62 / 887,978, filed August 16, 2019. The disclosures of the above-referenced applications are expressly incorporated herein by reference in their entirety, including any drawings. technical field [0003] The present disclosure generally relates to novel methods of activating integrin signaling to overcome CD47 checkpoint inhibition. The present disclosure also provides methods of treating cancer, including solid tumors and hematological malignancies, by promoting macrophage-mediated phagocytosis of cancer cells. Also disclosed is the use of integrin activation in combination with targeted cancer therapy, such as adoptive transfer of engineered macrophages, to increase phagocytosis of cancer cells. Background technique [0004] The success of cancer immunotherapy has fueled increasing interest in identifying novel immunoth...

Claims

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Application Information

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IPC IPC(8): A61K39/00A61K45/06C07K14/725
CPCA61K45/06A61K39/001129A61K2039/505A61K39/0011A61K33/32A61K31/427A61K38/1709C07K14/7051A61P35/00C07K2319/03C07K14/70546A61K39/4614A61K39/4622A61K39/464429A61K2300/00A61K35/15A61K39/3955
Inventor R·D·韦尔M·A·莫里西
Owner RGT UNIV OF CALIFORNIA
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