pH-triggered membrane peptide-mediated epitope tethering at cell surfaces
Inventors
Reshetnyak, Yana K. • Andreev, Oleg A. • Moshnikova, Anna • Engelman, Donald M.
Assignees
Yale University • Rhode Island University
Publication Number
US-12285462-B2
Publication Date
2025-04-29
Expiration Date
2040-01-28
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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.
Core Innovation
The invention provides compositions and methods for eliciting an anti-tumor immune response by administering a pH-triggered membrane peptide (pHLIP®) construct comprising an antibody or immune cell recruiting molecule (epitope) linked via a non-cleavable linker to one or more pHLIP® peptides. The pHLIP® component specifically targets and inserts into cell membranes at acidic pH, characteristic of tumor and inflamed tissues, thereby positioning the epitope selectively on diseased cell surfaces.
This strategy addresses the limitations of current antibody therapies, which are often hindered by the lack or inadequate amounts of accessible epitopes on certain cancer cells and the emergence of resistance due to loss of epitope expression. By decorating diseased cell surfaces with epitopes, the invention enhances the recruitment and binding of endogenous antibodies, exogenous antibodies, immune cells (including engineered T-cells and NK-cells), and antibody-drug conjugates (ADCs), leading to targeted immune-mediated cell killing or cytotoxicity.
The invention encompasses a broad range of constructs, including those with peptide, protein, or small molecule epitopes, which can be selectively targeted to the surface of tumor or inflamed cells using pHLIP® peptides. This allows for precise immune modulation and can augment immune cell recruitment, antibody binding, and ADC delivery, providing a platform for improved immunoregulatory strategies and anti-tumor therapies.
Claims Coverage
The patent claims cover two main inventive features relating to compositions of epitopes linked to pH-triggered peptides and their specific configurations.
Composition comprising an epitope linked to a pH-triggered peptide by a non-cleavable linker
A composition where an epitope (antibody recruiting molecule or immune cell recruiting molecule) is linked, via a linker or extension, to one or more pH-triggered peptides. The peptide comprises the sequence AXDDQNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 18) or AXDQDNPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 495), where X is any amino acid or Azido-containing amino acid. The epitope is specifically a hemagglutinin peptide (HA peptide) of less than 50 amino acids.
Composition comprising two antibody recruiting molecules linked to a pH-triggered peptide
A composition where two antibody recruiting molecules are linked to a pH-triggered peptide using PEG linkers. The peptide sequence is selected from Ac-AKQNDDQNKPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 511), Ac-AKQNDNDNKPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 535), ACQNDDQNCPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 536), or ACQNDNDNCPWRAYLDLLFPTDTLLLDLLWA (SEQ ID NO: 505). One or both antibody recruiting molecules can be a HA peptide of less than 50 amino acids, or selected from specific peptide sequences including QVSHWVSGLAEGSFG (SEQ ID NO: 1), LSHTSGRVEGSVSLL (SEQ ID NO: 2), QMWAPQWGPD (SEQ ID NO: 3), MASMTGGQQMG (SEQ ID NO: 4), and others.
The inventive features encompass specific constructs of pH-sensitive peptide-epitope conjugates, including single and dual epitope configurations, defined amino acid sequences for the pH-triggered peptide, and specified epitope types and lengths for targeted immune cell or antibody recruitment.
Stated Advantages
Enhances recruitment of immune cells and binding of antibodies on the surface of diseased cells, leading to robust immune responses and efficient cell killing.
Specifically targets diseased (acidic) tissues such as tumors, reducing or minimizing damage to healthy tissue.
Expands and augments the effectiveness of antibody-based therapies and antibody-drug conjugates by providing accessible epitopes on tumor cells.
The approach is associated with few to no side effects for the patient due to targeted delivery of epitopes to diseased tissues.
Documented Applications
Treatment of cancer, including but not limited to solid tumors such as colon, prostate, breast, bladder, lung, skin, liver, bone, ovarian, stomach, pancreatic, testicular, and brain cancers.
Treatment of diseases associated with inflammation by targeting inflamed tissue.
Eliciting or augmenting immune responses (including by recruiting immune cells or antibodies) for immunoregulation and targeted cell killing.
Enhancing delivery and effectiveness of antibody-drug conjugates for inducing cell killing in diseased tissue.
Targeted recruitment of both endogenous and exogenous antibodies, as well as immune cells, to diseased tissue surfaces.
Administration formulations for intravenous, subcutaneous, intraarterial, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intracardiac, intracavernous, intraosseous, intraocular, intravitreal, intramuscular, intradermal, transdermal, transmucosal, intralesional, topical, epicutaneous, extra-amniotic, intravaginal, intravesical, nasal, or oral administration; including direct injection into diseased tissue.
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