Methods and compositions relating to P62 for the treatment and prophylaxis of cancer
Inventors
Shneider, Alexander • Venanzi, Franco • Sherman, Michael • Shifrin, Victor
Assignees
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Publication Number
US-10716837-B2
Publication Date
2020-07-21
Expiration Date
Abstract
Provided herein are novel p62 compositions for the prophylaxis and treatment of cancer and related methods. The invention also provides modified p62 compositions that increase the anti-cancer activity of p62.
Core Innovation
The invention concerns p62/SQSTM1-based compositions and methods that treat or inhibit progression of cancer by administering an agent comprising a p62/SQSTM1 polypeptide or a p62/SQSTM1 nucleic acid that encodes a polypeptide. The agent is designed to stimulate the immune defense mechanism to attack neoplastic cells in the subject. The cancer context includes metastatic cancer and can include breast cancer or ovarian cancer, and the methods also cover a veterinary subject limitation.
The described p62/SQSTM1 polypeptide or nucleic acid is characterized by sequence identity, for example at least 98% identical to SEQ ID NO: 2, and the invention includes nucleic acid formats such as DNA vaccination with plasmids or viral vectors. The compositions can also include fusion constructs and can involve domain deletions and post-translational modifications of p62/SQSTM1, including deletions and functional element variations related to PB1, ZZ, NLS1/NLS2, TB, NES, LIR, KIR, and UBA.
The invention further encompasses adjunct immune modulation, including the use of adjuvants and co-stimulatory components and blocking of negative regulatory immune mechanisms, for example by antibodies and other molecules such as anti-CTLA-4 antibody, anti-CD25 antibody, anti-CD4 antibody, and IL13Ra2-Fc. It also provides for combination with anticancer therapies, including chemotherapeutic agents, radiation, and anti-angiogenic agents, with described use in in vivo cancer models to support treatment, control, and reduction of metastases.
The background problem addressed by the invention is the need to treat or inhibit progression of cancer, including metastatic cancer, by engaging host immune defense to attack neoplastic cells. The described solution is to stimulate the immune defense mechanism through p62/SQSTM1 polypeptide or p62/SQSTM1 nucleic acid administration, producing immune activity associated with innate immunity markers, tumor necrosis, improved survival, and reduced metastases in the reported models.
Claims Coverage
The provided independent claims include three inventive method categories: metastasis treatment in a subject; cancer progression treatment in a subject where the cancer is breast or ovarian; and cancer treatment in a veterinary subject. Across these independent claims, the core inventive features are p62/SQSTM1 agent administration with a specified sequence identity threshold and immune-defense stimulation to attack neoplastic cells.
p62/SQSTM1 sequence-identical polypeptide or encoding nucleic acid with immune-defense stimulation for metastatic cancer
Administering to the subject an agent comprising a p62/SQSTM1 polypeptide at least 98% identical to SEQ ID NO. 2 or a p62/SQSTM1 nucleic acid that encodes a polypeptide at least 98% identical to SEQ ID NO. 2, and stimulating the immune defense mechanism to attack neoplastic cells, wherein the method treats or inhibits progression of metastasis of a cancer in the subject with metastatic cancer.
Breast or ovarian cancer treatment using p62/SQSTM1 sequence-identical polypeptide or encoding nucleic acid with immune-defense stimulation
Administering to the subject an agent comprising a p62/SQSTM1 polypeptide at least 98% identical to SEQ ID NO. 2 or a p62/SQSTM1 nucleic acid that encodes a polypeptide at least 98% identical to SEQ ID NO. 2, and stimulating the immune defense mechanism to attack neoplastic cells, wherein the cancer is breast cancer or ovarian cancer, to treat or inhibit progression of the cancer.
Veterinary cancer treatment using p62/SQSTM1 sequence-identical polypeptide or encoding nucleic acid with immune-defense stimulation
Administering to the subject, where the subject is a cat, a dog, or a horse, an agent comprising a p62/SQSTM1 polypeptide at least 98% identical to SEQ ID NO. 2 or a p62/SQSTM1 nucleic acid that encodes a polypeptide at least 98% identical to SEQ ID NO. 2, and stimulating the immune defense mechanism to attack neoplastic cells, to treat or inhibit progression of a cancer.
All provided independent claims require administration of a p62/SQSTM1 polypeptide or a p62/SQSTM1 nucleic acid encoding a polypeptide with at least 98% sequence identity to SEQ ID NO: 2 and stimulating the immune defense mechanism to attack neoplastic cells, with the primary variations being metastatic cancer scope, breast/ovarian cancer limitation, or veterinary subject limitation.
Stated Advantages
Treat or inhibit progression of metastasis of a cancer by stimulating the immune defense mechanism to attack neoplastic cells.
Treat or inhibit progression of cancer by stimulating the immune defense mechanism to attack neoplastic cells, including for breast cancer or ovarian cancer.
Provides in vivo outcomes including prevention/control of breast tumor growth, improved survival, promotion of innate immunity markers, and reduction of metastases in reported cancer models.
Documented Applications
In vivo DNA vaccination with p62 administration that prevents or controls breast tumor growth and improves survival in a T5 rat breast cancer model, including promotion of innate immunity markers (e.g., CD11b+ cells) and tumor necrosis.
In vivo p62 vaccination that reduces metastases in a Lewis lung carcinoma model.
Use of the methods for treating cancer progression in subjects with breast cancer or ovarian cancer.
Use of the methods for treating cancer progression in a veterinary context where the subject is a cat, a dog, or a horse.
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