Methods to eliminate cancer stem cells by targeting CD47
Inventors
Roberts, David D. • Kaur, Sukhbir • Liu, Chengyu
Assignees
US Department of Health and Human Services
Publication Number
US-11053314-B2
Publication Date
2021-07-06
Expiration Date
2035-10-09
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Abstract
Described herein is the discovery that cancer stem cells (CSCs) can be induced to differentiate by altering CD47 signaling. Provided herein are methods and compositions for inducing differentiation of cancer stem cells, for instance irreversible differentiation, including methods of treating subjects with cancer such as breast cancer, colon cancer, lung cancer, ovarian cancer, or melanoma, and including metastatic as well as primary cancer. Also provided are methods for treating subjects with triple negative breast cancers involving forcing differentiation of bCSCs of the subjects through targeting of CD47.
Core Innovation
The invention provides methods and compositions for selectively eliminating cancer stem cells (CSCs) by altering CD47 signaling to induce their differentiation, including irreversible differentiation. This approach is exemplified with breast cancer stem cells (bCSCs), with the discovery that agents such as anti-CD47 antibodies (including the monoclonal antibody B6H12 and humanized versions), peptide 7N3, and CD47-targeted CRISPR constructs can induce differentiation of CSCs in various cancers including breast, colon, lung, ovarian cancer, and melanoma, encompassing both primary and metastatic tumors.
The problem addressed stems from conventional cancer therapies' inability to effectively target and kill cancer stem cells, which possess properties like self-renewal and asymmetric division and are responsible for tumor initiation and metastasis. These CSCs often overexpress CD47, which is believed primarily to protect them from immune clearance by macrophages through a “don't eat me” signal. However, existing therapies targeting CD47 have mainly focused on facilitating macrophage-mediated phagocytosis without considering direct effects on CSC differentiation or proliferation.
This invention challenges the existing paradigm by demonstrating that targeting CD47 signaling not only promotes macrophage clearance but also directly induces CSC differentiation and inhibits their proliferation independently of SIRPα-mediated phagocytic pathways. In particular, the anti-CD47 antibody B6H12 exhibits unique direct signaling effects on CSCs, including suppression of asymmetric cell division, inhibition of EGFR signaling via reduced EGFR expression and phosphorylation, and upregulation of tumor suppressor and apoptotic genes, thereby decreasing CSC maintenance and tumor growth potential.
Claims Coverage
The patent contains multiple independent claims focused on methods to induce differentiation of cancer stem cells by targeting CD47 using various agents.
Use of anti-CD47 antibody B6H12 or peptide SEQ ID NO: 1 to induce CSC differentiation
A method comprising contacting breast, lung, prostate, or melanoma cancer stem cells with the anti-CD47 monoclonal antibody B6H12, its humanized form, or a peptide consisting of SEQ ID NO: 1 for at least 3 days in a subject, thereby inducing macrophage SIRPα-independent terminal differentiation of CSCs.
Treatment of subjects having tumors or metastatic cancer cells
Where the subject has a primary tumor, tumor in regression, metastatic tumor, or suspected metastatic tumor, and is treated by administering relevant anti-CD47 agents inducing CSC differentiation.
Combination therapy with anti-cancer treatments
Methods further comprising administering a therapeutically effective amount of an anti-cancer treatment before, concurrent with, or after treatment with an agent that alters CD47 signaling to induce CSC differentiation.
Extended treatment durations for CSC differentiation
Contacting cancer stem cells with the anti-CD47 monoclonal antibody B6H12, humanized antibody B6H12, or peptide SEQ ID NO: 1 for at least 10 days.
In vitro induction of CSC differentiation using CD47-targeted agents
Methods for inducing SIRPα-independent terminal differentiation of CSCs by contacting them in vitro with anti-CD47 monoclonal antibody B6H12, its humanized form, or peptide SEQ ID NO: 1 for at least 3 days.
Use of CD47-targeted CRISPR constructs to induce differentiation
Methods involving administering a CD47-targeted CRISPR construct using SEQ ID NO: 2 to a subject with cancer or contacting CSCs in vitro, inducing macrophage SIRPα-independent terminal differentiation of CSCs.
The independent claims cover methods for inducing macrophage SIRPα-independent terminal differentiation of cancer stem cells by targeting CD47 with specific agents including monoclonal antibody B6H12, its humanized forms, peptide SEQ ID NO: 1, and CD47-targeted CRISPR constructs. These methods apply both in vivo to subjects with various cancers and in vitro to isolated CSCs, optionally combined with other anti-cancer treatments and covering varied treatment durations.
Stated Advantages
Therapeutic antibodies targeting CD47 can selectively benefit patients with triple negative breast cancers by forcing differentiation of breast cancer stem cells.
Certain CD47 antibodies exhibit direct tumor suppressive activity independent of macrophage-mediated clearance, acting through induction of CSC differentiation and inhibition of proliferation.
The anti-CD47 antibody B6H12 inhibits EGFR signaling and asymmetric cell division in CSCs, leading to reduced tumor growth potential.
The discovery of a direct signaling role for CD47 on CSCs provides novel mechanisms for cancer therapy beyond immune clearance, potentially improving treatment of metastatic and primary cancers.
Documented Applications
Treating subjects with cancer such as breast cancer (including triple negative breast cancers), colon cancer, lung cancer, ovarian cancer, or melanoma, including metastatic and primary tumors.
Inducing differentiation or irreversible differentiation of CSCs in vitro and in vivo.
Combination therapies involving agents that alter CD47 signaling concomitant with standard anti-cancer treatments such as chemotherapy or radiation therapy.
Use in experimental and clinical treatment contexts targeting breast cancer stem cells or other CSCs identified by characteristic markers.
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