pHLIP® peptide-mediated epitope tethering at cell surfaces

Abstract

The invention features methods and compositions for eliciting an anti-tumor response in a subject comprising administering to the subject a pHLIP® construct comprising an antibody recruiting molecule linked to one or more pHLIP® peptides by a non-cleavable linker compound. The construct increases the amount of the antibody recruiting molecule on the surface of a diseased cell.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62 / 797,899, filed Jan. 28, 2019, the entire contents of which is incorporated herein by reference in its entirety.STATEMENT AS TO FEDERALLY SPONSORED RESEARCH[0002]This invention was made with government support under R01 GM073857 awarded by the National Institute of General Medical Sciences of the National Institutes of Health. The government has certain rights in the invention.INCORPORATION BY REFERENCE OF SEQUENCE LISTING[0003]The contents of the sequence listing text file named “040984-512001WO_SL.txt”, which was created on Jan. 28, 2020 and is 222 kilobytes in size, is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0004]The present invention relates to immunotherapy.BACKGROUND[0005]Antibody therapies are based on the alteration of signaling, promotion of apoptosis, sequestration of growth factors, activation of the immun...

AI Technical Summary

Benefits of technology

[0006]The invention provides a solution to the limitations of existing therapeutic approaches by utilizing a strategy in which a desired epitope is positioned on cell surfaces in diseased tissues, such as tumors or inflamed tissues. Positioning the epitope on the cell surface, (e.g., preferentially in diseased tissues), is a great advantage and enhances the recruitment of cells of the immune system or endogenous antibodies, and enhances the use of developed monoclonal antibodies such as trastuzumab (Herceptin), antibody-drug conjugates, and antibodies generated in the course of vaccination. The invention further provides compositions and methods to augment any amount of particular epitopes at cell surfaces for immunoregulation and efficient binding of immune cells, antibodies and ADCs.

[0007]Provided herein are compositions and methods for the decoration of target cells with epitopes, e.g., a protein, a peptide, or a small molecule epitope, that can (1) recruit immune cells (or exogenous engineered T-cells and NK-cells), (2) recruit endogenous antibodies, (3) enhance the use of the exogenous antibodies or ADCs administrated into body, and (4) enhance the use of antibodies, which are produced (generated) in the course of vaccination leading to cell death.

[0010]By binding (linking and / or conjugating) a pHLIP®, or pHLIP® equivalent, to an epitope, it is possible to specifically target the cell and decorate a tumor cell or cells in inflamed tissues with epitopes to recognize or recruit endogenous (natural) immune cells or antibodies circulating in the blood, promote and enhance binding of exogenous engineered T-cells and NK-cells or antibodies or ADCs administrated into body, or antibodies, which are generated in the course of vaccination and thereby promote cell killing. A significant advantage of this approach is that the pHLIP® constructs described herein are associated with few to no side effects for the patient due to the targeted delivery of epitopes to the cell surfaces. The epitope may be of mammalian origin, viral origin, or bacterial origin.

[0061]Furthermore, provided herein are methods of treating a diseased tissue with a naturally acidic extracellular environment or a tissue with an artificially induced acidic extracellular environment relative to normal physiological pH in a subject. For example, the diseased tissue includes a cancerous tissue or a tumor. As described above, the composition recruits the subject's immune cells, endogenous antibodies and proteins to induce an immune response, and thereby treats the diseased tissue in the subject. The immune response can include, for example, initiation of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), or the release of cytokines or inflammatory mediators to promote T-cell or NK-cell responses. The immune response can include, for example, homing of T-cells and NK-cells and their activation. Also as described above, the composition promotes binding of antibody-drug conjugates to the cells in targeted tissue, and thus promotes cell killing.

[0067]The composition preferentially targets a diseased tissue compared to a healthy tissue, thereby minimizing damage to the healthy tissue. For example, the composition selectively promotes cell killing in the diseased tissue, e.g., the tumor cell.

Problems solved by technology

However, their use is limited by (1) the lack of adequate amounts (or any amounts) of accessible epitopes in many cancers, and (2) the emergence of resistance by selection of expression mutants not presenting proper epitopes.

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