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US-20260125418-A1 - A COMPOUND AND ITS USE FOR DETECTING A DISEASE IN THE EXHALED BREATH OF A SUBJECT

US20260125418A1US 20260125418 A1US20260125418 A1US 20260125418A1US-20260125418-A1

Abstract

The invention relates to a compound of the formula X m —(Y-L-T) n and a method for the detection or prognosis of a disease in the exhaled breath of a subject. X, when present is a moiety operable to target the compound to a site of interest in vivo; m is (or at least 1, Y is a cleavable group; L is a self-immolative linker, T is a terminating moiety, and n is 1 when m is 0 or n is at least 1 when m is at least 1, L is a self-immolative linker. The terminating moiety, T, may comprise an isotopically labelled reporter molecule or a precursor thereof. The reporter molecule is operable to be released upon cleavage of the cleavable group, Y; and the reporter molecule, upon release, is a volatile compound.

Inventors

  • Bryan Wittmann
  • Matthew Hart
  • Max Allsworth
  • Marc van der Schee
  • Christiaan Labuschagne

Assignees

  • OWLSTONE MEDICAL LIMITED

Dates

Publication Date
20260507
Application Date
20231003
Priority Date
20221003

Claims (20)

  1. 1 . A compound of the formula X m —(Y-L-T) n , wherein X, when present is a moiety operable to target the compound to a site of interest in vivo; m is 0 or at least 1; Y is a cleavable group; L is a self-immolative linker; T is a terminating moiety; and n is 1 when m is 0 or n is at least 1 when m is at least 1; wherein at least one of the self-immolative linker, L, and terminating moiety, T, comprise an isotopically labelled reporter molecule or a precursor thereof; wherein the reporter molecule is operable to be released upon cleavage of the cleavable group, Y; and wherein the reporter molecule, upon release, is a volatile compound.
  2. 2 . The compound according to claim 1 , wherein m is at least 1 and n is at least 1.
  3. 3 . The compound according to any preceding claim , wherein m is 1 and n is 1.
  4. 4 . The compound according to any preceding claim , wherein X comprises an antigen-binding moiety, a ligand for a cell surface receptor, a pHLIP, and/or a nanoparticle.
  5. 5 . The compound according to claim 4 , wherein X is an antigen-binding moiety.
  6. 6 . The compound according to claim 5 , wherein the antigen-binding moiety comprises an antibody and/or an antibody mimetic, for example a cyclic peptide, a cysteine knot and/or an anticalin.
  7. 7 . The compound according to claim 6 , wherein X is cyclic peptide, for example a bicyclic peptide.
  8. 8 . The compound according to claim 7 , wherein X is a peptide comprising at least three cysteine residues, separated by at least two loop sequences, and a molecular scaffold which forms covalent bonds with the cysteine residues of the polypeptide such that at least two polypeptide loops are formed on the molecular scaffold, wherein the peptide ligand comprises an amino acid sequence of formula: -C-X 1 -U/O-X 3 -X 4 -G-C-E-D-F-Y-X 10 -X 11 -C- (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof; wherein X represents any amino acid residue; U represents a polar, uncharged amino acid residue selected from the group consisting of N, C, Q, M, S and T; and O represents a non-polar aliphatic amino acid residue selected from the group consisting of G, A, I, L, P and V.
  9. 9 . The compound according to claim 8 , wherein X 1 is selected from Y, M, F or V, for example Y.
  10. 10 . The compound according to any of claim 8 or 9 , wherein U/O is a U, for example N.
  11. 11 . The compound according to any of claim 8 or 9 , wherein U/O is an O, for example G.
  12. 12 . The compound according to any of claims 8-11 , wherein X 3 is selected from N, C, Q, M, S, T, D or E, for example Q or E.
  13. 13 . The compound according to any of claims 8-12 , wherein X 4 is selected from F, W or Y.
  14. 14 . The compound according to any of claims 8-13 , wherein X 10 is selected from D or E, for example D.
  15. 15 . The compound according to any of claims 8-14 , wherein X 11 is selected from G, A, I, L, P or V, for example I.
  16. 16 . The compound according to claim 4 , wherein X comprises a ligand for a cell-surface receptor.
  17. 17 . The compound according to claim 16 , wherein the ligand comprises folic acid, folate, and/or a peptide hormone.
  18. 18 . The compound according to claim 17 , wherein the peptide hormone comprises a somatostatin and/or a somatostatin analogue.
  19. 19 . The compound according to any preceding claim , wherein the self-immolative linker, L, comprises a methylene carbamate group, an aminobenzyl carbamate group, an aminobenzyl carbonate group, an aminobenzyl ether group, a dithiobenzyl carbamate group, a dithiobenzyl carbonate group and/or a dithiobenzyl ether group.
  20. 20 . The compound according to claim 19 , wherein the self-immolative linker, L, comprises an aminobenzyl carbamate group and/or an aminobenzyl carbonate group, for example a p-aminobenzyl carbamate group and/or a p-aminobenzyl carbonate group.

Description

FIELD OF THE INVENTION The invention relates to compounds, compositions and kits that may be used in methods for the detection of prognosis of a disease. INTRODUCTION Early diagnosis of cancer remains an important goal in any treatment plan. Cancer that is diagnosed at an early stage is more likely to be treated successfully. If the cancer spreads, effective treatment becomes more difficult, and generally a person's chances of surviving are much lower. Examples of the benefits of early detection apply to lung cancer, breast cancer, ovarian cancer and bowel cancer. For example, more than 80% of lung cancer patients will survive for at least a year if diagnosed at the earliest stage compared to around 15% for people diagnosed with the most advanced stage of disease. As a further example, more than 90% of women diagnosed with breast cancer at the earliest stage survive their disease for at least 5 years compared to around 15% for women diagnosed with the most advanced stage of disease. Whilst early detection of cancer is paramount, there are few non-invasive test methods available which enable a reliable diagnosis whilst increasing patient compliance due to the convenient testing methods. Moreover, there is also a need for monitoring the progression of cancer in a reliable and non-invasive way to determine treatment options. Tumor cells are characterized by metabolic changes during the earliest stages of their development. Measuring the biochemicals related to these metabolic changes can therefore provide diagnostic biomarkers with a potential utility for the early detection of cancer (Muthu & Nordstrom, 2019). These biomarkers can be detected in bodily fluids such as breath, urine and blood. An attractive matrix for detection of these metabolites is breath as it can be accessed fully non-invasively at point of care, therefore lowering the threshold for participation in screening (Hakim et al., 2012). Recently, the Exogenous Volatile Organic Compound (EVOC) Probe approach has been pioneered which enables active investigation of disease specific pathways. In this approach exogenous metabolic probe compounds are administered to patients which are metabolized by disease specific pathways resulting in a volatile product released in the patient breath (Gaude et al., 2018). There is a need to develop EVOC probes that can be used during non-invasive point of care. There is also a need for reliable non-invasive screening methods for early detection of cancer. SUMMARY OF THE INVENTION In a first aspect, the invention relates to a compound of the formula Xm—(Y-L-T)n, wherein X, when present, is an antigen-biding moiety, a ligand for a cell-surface receptor and/or a pH low insertion peptide (pHLIP); m is 0 or at least 1; Y is a cleavable group; L is a self-immolative linker; T is a terminating moiety; and n is 1 when m is 0 or n is at least 1 when m is at least 1; wherein at least one of the self-immolative linker, L, and terminating moiety, T, comprise an isotopically labelled reporter molecule or a precursor thereof; wherein the reporter molecule is operable to be released upon cleavage of the cleavable group, Y; and wherein the reporter molecule, upon release, is a volatile compound. In a second aspect, the invention relates to a composition comprising the compound according to the first aspect of the invention. In a third aspect, the invention relates to a method for the detection or prognosis of a disease comprising administering a compound according to the first aspect of the invention or a composition according to the second aspect of the invention to a subject and detecting the presence or absence of the released reporter molecule in the exhaled breath of the subject. In a fourth aspect, the invention relates to a kit comprising the compound according to the first aspect of the invention and/or the composition according to the second aspect of the invention and a device for capturing a breath sample from a patient. In a fifth aspect, the invention relates to the use of a compound according to the first aspect of the invention, a composition according to the second aspect of the invention and/or the kit according to the fourth aspect of the invention in a method according to third aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous. Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, pathology, oncology, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well-