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US-20260124315-A1 - CATALYST AUGMENTED TARGET SPECIFIC POLYPEPTIDE

US20260124315A1US 20260124315 A1US20260124315 A1US 20260124315A1US-20260124315-A1

Abstract

The present invention relates to an improved targeted transition metal catalyst (TMC) suitable for human therapy.

Inventors

  • Juri RAPPSILBER
  • Adam BELSOM
  • Ana PEREZ-LOPEZ

Assignees

  • TECHNISCHE UNIVERSITAT BERLIN

Dates

Publication Date
20260507
Application Date
20230803
Priority Date
20220818

Claims (14)

  1. 1 . A target-specific polypeptide molecule comprising: a catalytic unit of a Pd(II) and/or Pd(0) bioorthogonal transition metal which is in complex to a HRGDH peptide motif, wherein the peptide motif protects the catalyst from being deactivated by binding to biomolecules or from chemically reacting with biomolecules, and wherein the peptide motif is fused to a target-specific molecule.
  2. 2 . The target-specific polypeptide molecule according to claim 1 , wherein the peptide motif of the catalytic unit has a binding capacity (Kd) of at least 10 −6 M towards the metal ion.
  3. 3 . The target-specific polypeptide molecule according to claim 1 , wherein the peptide motif is elongated by sequences comprising at least 3-50 amino acids containing histidine, methionine, tryptophan, cysteine or tyrosine residues as binding sites (B), wherein two such binding sites are separated by 1-4 amino acids following the pattern B(X) n B, n=1-4.
  4. 4 . The target-specific polypeptide molecule according to claim 1 , wherein the polypeptide molecule is expressed from a nucleic acid sequence selected from the group consisting of cDNA and/or synthetic nucleic acid sequences.
  5. 5 . The target-specific polypeptide molecule according to claim 1 , wherein the peptide motif is directly or via a linker fused to a target specific molecule.
  6. 6 . The target-specific polypeptide molecule according to claim 5 , wherein the peptide motif is linked or fused to the target specific molecule by way of a spacer, and wherein the spacer is a G-rich spacer or is selected from the group of spacers with the amino acid sequence [GGGGS], [GGGS] or [GGGGG]n.
  7. 7 . The target-specific polypeptide molecule according to claim 1 , wherein the target-specific molecule is a peptide or polypeptide selected from the group of therapeutic antibodies, antigen-specific antibodies, tumour specific antibodies, antibody fragments, Fab, Fab2, F(ab′)2, scFv, diabodies, single domain antibodies, target peptide and nanobodies.
  8. 8 . The target-specific polypeptide molecule according to claim 7 , wherein the target-specific molecule is specifically targeting cell-specific surface structures or tumour antigen, and/or antigens selected from the group comprising HER2 (metastatic breast cancer), CD59 (B-cell chronic lymphocytic leukemia), PD-L1 (urothelial carcinoma, metastatic non-small cell lung cancer, metastatic Merkel cell carcinoma), VEGF (metastatic colorectal cancer, non-squamous non-small-cell lung carcinoma, glioblastoma, metastatic renal cell carcinoma, cervical cancer), CD19 (precursor B-cell acute lymphoblastic leukemia), CD30 (Hodgkin lymphoma, anaplastic large-cell lymphoma), EGFR (metastatic colorectal carcinoma, metastatic squamous non-small cell lung carcinoma), CD38 (multiple myeloma), GD2 (pediatric neuroblastoma), SLAMF7 (multiple myeloma), CD20 (B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, follicular lymphoma, diffuse large B-cell lymphoma), CTLA4 (metastatic melanoma), PD-1 (metastatic squamous non-small cell lung carcinoma, metastatic melanoma), VEGFR2 (gastric cancer), CD22 (precursor B-cell acute lymphoblastic leukemia), CD33 (acute myeloid leukemia).
  9. 9 . A method of generating the target-specific polypeptide molecule according to claim 1 , the method comprising the steps of amplifying the cDNA sequence containing the information of the peptide motif fused to a target specific molecule, optionally connected with a suitable spacer; purifying the polypeptide; exposing the purified polypeptide to a suitable amount of metal atoms in the form of a pharmaceutically-acceptable salt or soluble salt from Pd; incubating the purified polypeptide with the suitable metal salt in a pharmaceutically-acceptable buffer; and isolating the polypeptide now in complex with the metal atom after co-incubation.
  10. 10 . A pharmaceutical composition comprising the target-specific polypeptide molecule according to claim 1 , and a pharmaceutically acceptable carrier, diluent or excipient.
  11. 11 . A method of treating a soluble, solid, benign, malignant and/or metastatic tumour in a subject, wherein the tumour is selected from tumours with established target sites/antibody binding sites, the method comprising administering the target-specific polypeptide molecule according to claim 1 to the subject.
  12. 12 . A method of treating a disorder in a subject, wherein the disorder is connected with the existence or dominance of specific cell types for which established target sites/antibody binding sites have been identified, the method comprising administering the target-specific polypeptide molecule according to claim 1 to the subject.
  13. 13 . The method according to claim 11 , wherein the cancer therapy is co-administered with a cancer therapeutic agent, thermotherapy, plasmonic material and/or prodrug to a person in need thereof.
  14. 14 . The method according to claim 12 , wherein the cancer therapy is co-administered with a cancer therapeutic agent, thermotherapy, plasmonic material and/or prodrug to a person in need thereof.

Description

SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on Jan. 7, 2026, is named 50322-009001_Sequence_Listing_1_7_26.xml and is 13,371 bytes in size. The present invention relates to an improved targeted transition metal catalyst (TMC) for human therapy. After the development of chemotherapeutic anticancer treatments based on cisplatin or its analogues in the late 1990's the knowledge around cytotoxicity, usefulness, effectiveness of transition metal based anticancer agents has increased dramatically and led—iter alia—to the rise of the field of bioorthogonal chemistry (van de L'Isle et al., 2021, Current Opinion in Chemical Biology, 61: 32-42). Remarkable developments and advances of transition metal catalysts (TMCs) as bioorthogonal tools have helped to explore, elicit and tune therapeutic approaches by medicinal chemistry. Commonly the term “bioorthogonal” refers to artificial synthetic chemistry using highly chemospecific reactive partners conducted in a biological environment without causing adverse biological effects. In the context of the present application “bioorthogonal” is further used to describe compounds modified by synthetic chemistry and medicinal chemistry to make them applicable into a biological environment and suitable for human therapy. TMCs (transition metal catalysts) are typical representatives for bioorthogonal chemistry. TMCs comprising platinum, so called platinum complexes, are known to target DNA and are predisclosed as successful antitumor drugs. In contrast, it has been found that palladium complexes, even if from a chemical perspective significantly similar and thus promising, do so far not prove as valuable. Abu-Surrah et al., 2008, (Cancer therapy Vol. 6, pp 1-10) review the numerous palladium complexes with promising activity against cancer that have been synthesised. A key factor that might explain why palladium complexes are less useful, depends on their fast hydrolysis and ligand-exchange kinetic, which is about 105 times faster than for platinum complexes. Such rapid dissociation in solution is leading to highly reactive, i.e. species too reactive to remain functionally able to reach the intended pharmacological target in a living subject. It is thus a need in the prior art to provide further bioorthogonal catalysts that are protected from immediate reactivity when administered to a biological environment. It is thus an objective of the present invention to provide alternative approaches to design TMC complexes suitable for therapeutic intervention in a subject in need thereof and/or suitable or favourable as therapeutic or diagnostic agents. The object of the present application has been solved by the newly developed target-specific polypeptide molecule comprising a catalytic unit complexing a transition metal atom with a peptide motif according to claim 1. Dependent claims are directed to further embodiments or suitable applications of the claimed catalytic unit. For this the inventors provided a catalytic unit comprising a bioorthogonal transition metal catalyst complexing an abiotic transition metal atom, which has the potential to catalyse chemical reactions and is advantageous in that the unit protects the catalyst from chemically reacting with biomolecules and thereby from being quickly deactivated by biomolecules. Bioorthogonal chemistry represents a class of high-yielding chemical reactions that proceed rapidly and selectively in biological environments, largely without affecting biomolecules or interfering with biochemical processes. According to the invention, the term “catalytic unit” defines primarily a chemical unit or i.e. a complex comprising an abiotic transition metal atom which is interacting with a peptide motif. In chemistry, the terminology “transition metal” is—iter alia—used for defining different groups of metals in the periodic table. According to the IUPAC definition the term “transition metal” is primarily understood as any element in the d-block of the periodic table, which includes the atoms of the elements having between 0 and 10 d-electrons. However, not all 40 elements of the d-block are relevant or suitable for the present invention and consequently the present invention, whenever using the term “transition metal” understands this as referring to the elements of the group 4d-5d, which due to their ability to form different oxidation states and their utilisation of 4d or 5d electrons in changing the activation energy in neighbouring chemical reaction often are referred to as catalysts. Not all 20 elements of the group 4d and 5d are relevant or suitable for the present invention and consequently the present invention distinguishes between biotic and abiotic transition metal atoms and provides catalytic units with abiotic transition metal catalysts (TMC), only. Often transition metal catalyse