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EP4618983A2 - Peptidomimétiques de fusion mitochondriale - Google Patents

Peptidomimétiques de fusion mitochondriale

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Publication number
EP4618983A2
EP4618983A2 EP23892574.7A EP23892574A EP4618983A2 EP 4618983 A2 EP4618983 A2 EP 4618983A2 EP 23892574 A EP23892574 A EP 23892574A EP 4618983 A2 EP4618983 A2 EP 4618983A2
Authority
EP
European Patent Office
Prior art keywords
hsc
hscs
mfp
subject
transplantation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23892574.7A
Other languages
German (de)
English (en)
Inventor
Larry LUCHSINGER
Daniel K. JIN
Hans Willem SNOECK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
New York Blood Center Inc
Original Assignee
New York Blood Center Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by New York Blood Center Inc filed Critical New York Blood Center Inc
Publication of EP4618983A2 publication Critical patent/EP4618983A2/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0647—Haematopoietic stem cells; Uncommitted or multipotent progenitors

Definitions

  • This application contains a sequence listing having the filename 1958427- 00413_Sequence_Listing.xml, which is 4,000 bytes in size, and was created on November 16, 2023. The entire content of this sequence listing is incorporated herein by reference.
  • MFP mitofusion 2 fusion peptidomimetic
  • HSC hematopoietic stem cells
  • the HSC are cord blood HSCs. In some embodiments, the HSC are bone marrow HSCs.
  • the MFP comprises Compound A: In some embodiments, the MFP comprises Compound B:
  • the MFP comprises a peptide having the amino acid sequence of SEQ ID NO:1. In some embodiments, the MFP comprises a peptide having the amino acid sequence of SEQ ID NO:2. In some embodiments, the MFP comprises a peptide having the amino acid sequence of SEQ ID NO:3.
  • the cord blood HSCs have the phenotype CD45
  • the HSC cells suitable for transplantation, after culture with the MFP have the phenotype CD45 l0W Lin _ CD34 + .
  • the recovered HSCs do not exhibit HSC exhaustion when transplanted into the subject.
  • the malignant disorder is selected from the group consisting of multiple myeloma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), myelodysplastic dysplastic syndrome (MDS), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), myelofibrosis, essential thrombocytosis, and polycythemia vera.
  • AML acute myeloid leukemia
  • ALL acute lymphoid leukemia
  • MDS myelodysplastic dysplastic syndrome
  • CML chronic myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • myelofibrosis essential thrombocytosis
  • polycythemia vera polycythemia vera
  • the non-malignant disorder is selected from the group consisting of aplastic anemia, severe combined immune deficiency syndrome (SCID), a thalassemia, sickle cell disease, chronic granulomatous disease, leukocyte adhesion deficiency, Chediak-Higashi syndrome, Kostman syndrome, Fanconi anemia, Blackfan- Diamond anemia, and enzymatic disorders.
  • the non-malignant disorder is an autoimmune disease.
  • the autoimmune disease is selected from the group consisting of systemic sclerosis, systemic lupus erythematosus, neuromyelitis optica, and relapsing-remitting multiple sclerosis.
  • the HSCs are allogeneic to the subject. [0012] Also disclosed herein are methods of preventing HSC exhaustion in a subject receiving an HSC transplant, comprising culturing the HSC with a MFP according to a method disclosed herein before transplantation into the subject.
  • FIG. 1 depicts the effect of mitochondrial fusion on hematopoietic stem cell (HSC) expansion in culture.
  • FIG. 2A-F depicts the expression of Prdm16 (FIG. 2A), Mfn2 (FIG. 2B) , Mfn1 (FIG. 2C), Opal (FIG. 2D), Drp1 (FIG. 2E), and Fis1 (FIG, 2F) in cord blood (CB) HSCs.
  • HSPC hematopoietic stem and progenitor cells
  • MPP multipotent progenitors
  • Lin-CD34 + CD38' CD45RACD90 CD45RACD90
  • CMP common myeloid progenitors
  • FIG. 3 depicts exemplary mitochondrial peptidomimetics.
  • FIG. 4 depicts culture methodology with peptidomimetics and testing of expanded CB HSC for in vivo function.
  • FIG. 5A-C depicts increased mitochondrial fusion after mitofusin 2 fusion peptidomimetic (MFP) treatment with Compound A (FIG. 5A) or Compound B (FIG. 5B) and increased mitochondrial length (FIG. 5C) in phenotypic HSCs in vitro.
  • MFP mitofusin 2 fusion peptidomimetic
  • FIG. 6A-B depicts culture of MFP-treated cells.
  • FIG. 6B Seahorse extracellular flux analysis of mitochondrial respiration and ATP potential in 3-day cultures treated with vehicle, Compound A, or Compound B.
  • FIG. 7A-B depicts the effects of 7-day MFP treatment in expansion cultures (n>12 experiments) on frequency (FIG. 7A) and yield (FIG. 7B) of phenotypic HSCs.
  • FIG. 8A-B depicts significantly increased short-term (8 wk) human reconstitution in xenograft model of 7-day MFP-treated expansion cultures in two mice (FIG. 8A and 8B).
  • FIG. 9 depicts significantly increased long-term (15 wk) human reconstitution in xenograft model of 7-day MFP-treated expansion cultures.
  • FIG. 10 depicts long-term (17 wk) human reconstitution (chimerism) in a xenograft model.
  • FIG. 11A-B depicts 7-day MFP treatment of expansion cultures significantly increases long-term human reconstitution of phenotypic HSCs in recipient bone marrow and T cells in peripheral blood.
  • FIG. 11 B depicts 7-day MFP treatment of expansion cultures significantly increases long-term human reconstitution of phenotypic HSCs in recipient bone marrow.
  • FIG. 12A-D depicts a schematic diagram describing primary and secondary xenograft transplant models.
  • FIG. 12B-C depicts primary xenograft results 30 weeks post-transplantation of cord blood CD90 + HSC cultures expanded with mitofusion agonist small molecules (FIG. 12B) or mitofusion agonist peptides (FIG. 12C).
  • FIG. 12D depicts secondary xenograft results 30 weeks post-transplantation of primary xenograft bone marrow samples.
  • FIG. 13A-D depict RNA sequence analysis of re-sorted CD90 + HSCs after 7 days of expansion with mitofusion agonists. Principal component analysis (FIG. 13A) and differential gene expression (FIG. 13B) demonstrated differences between control (DMSO) and Compound B-treated CD90 + HSCs.
  • FIG. 13C-D depict gene ontology (GO) pathway analysis of differentially expressed genes showing upregulation of autophagy (FIG. 13C), ribosomal and stress granule (KEGG) pathways (FIG. 13D) after Compound B treatment.
  • FIG. 14A-F depicts results of OP-Puromycin protein rate synthesis assay showing representative flow cytometry plot and quantification (FIG. 14A and B), lysosome quantity (FIG. 14C), autophagosome formation (FIG. 14D), and transcription factor EP-green fluorescent protein (TFEB-GFP nuclear localization assay (FIG. 14F) from CD90 + HSC cultures treated with DMSO or Compound B for 3 days.
  • FIG. 15 depicts the results of an immunoprecipitation assay using 293 cells transfected with His/Myc-tagged Mfn2 for 48 h.
  • FIG. 16 depicts a model for mitochondrial fusion agonist mechanism of action.
  • Mfn2 increases buffering of Cai 2+ , an effect mediated through its ER-mitochondria tethering activity, thereby negatively regulating nuclear translocation and transcriptional activity of Nuclear Factor of Activated T cells (NFAT).
  • NFAT inhibition rescues the effects of Mfn2 deletion in HSCs, demonstrating that negative regulation of NFAT is the prime downstream mechanism of Mfn2 in the maintenance of HSCs with extensive lymphoid potential. Mitochondria therefore play an important role in HSCs.
  • HSCT hematopoietic stem cell transplantation
  • CMT2A Charcot Marie Tooth disease type 2A
  • Prdm16 is a 140 kDa zinc finger protein that is a physiologic regulator of HSCs. Prdm16 exists in two isoforms arising from distinct transcription start sites, full length (fl) and short (s) Prdm16, which lacks the N-terminal PR-domain. Only sPrdm16, but not flPrdm16, activated a Mfn2 promoter luciferase reporter, and induced Mfn2 mRNA in Prdm16 ⁇ /_ mouse embryonic fibroblasts (MEFs).
  • Mfn2 promoter luciferase reporter activated a Mfn2 promoter luciferase reporter
  • Mfn2 mRNA induced Mfn2 mRNA in Prdm16 ⁇ /_ mouse embryonic fibroblasts (MEFs).
  • chromatin immunoprecipitation in MEFs using FLAG-tagged isoforms of Prdm16 showed binding of sPrdm16, but not of flPrdm16, to the Mfn2 promoter. Mfn2 is therefore a direct target of sPrdm16.
  • Prdm 16-deletion did not affect Mfn1
  • transduction of sPrdm16 did increase Mfn1 mRNA expression.
  • Mfn1 is therefore susceptible to regulation by sPrdm16, but with a higher and likely non-physiological threshold.
  • HSCs display clonal heterogeneity in their differentiation potential ranging from rare lymphoid-biased HSCs, to balanced myeloid/lymphoid and myeloid-dominant HSCs with low lymphoid potential. Myeloid-dominant HSCs are enriched in the CD150 hi , while HSCs with extensive lymphoid potential are enriched in the CD150 10 fraction. HSCs expressed more Mfn2 mRNA and protein than more mature populations. Within the HSC compartment, CD15O 10 HSCs expressed more Mfn2 mRNA and protein than did CD150 hi HSCs.
  • Mfn1 did not show HSC-selective expression, and its expression in CD15O 10 HSCs was tenfold lower than that of Mfn2.
  • sPrdm16 was the predominant Prdm16 isoform in CD15O 10 but not in CD150 hi HSCs.
  • mice expressing a mitochondrially- targeted Dendra2 fluorescent protein Pham mice
  • HSCs expanded according to the disclosed methods retain their long-term hematopoietic potentiality and self renewal characteristics after transplantation in contrast to untreated HSCs which undergo HSC exhaustion.
  • the term “functional” when used regarding HSCs refers to HSCs which maintain their hematopoietic potentiality and do not undergo HSC exhaustion after transplantation into a subject.
  • FIG. 3 Peptidomimetic compounds (FIG. 3) have been described to induce mitochondrial fusion via Mfn2 proteins (Pelay-Gimeno et al. Angew Chem Int Ed Engl. 54:8896-927, 2015). Supplementation by mitochondrial fusion peptidomimetics in CB HSC cultures may improve engraftment of expanded CB HSC cultures in immunocompromised xenotransplantation models of human hematopoiesis. Addition of mitofusin 2 fusion peptidomimetics (MFPs) significantly improves the function of 7-day CB HSC expansion cultures in vivo using NSG (NOD-Pr ⁇ dc 86 ' ⁇ TM ⁇ '') recipient mice. This could constitute a significant advancement in the technology available to reliably expand functional HSCs in vitro for clinical and cell therapy use. Mfn2 fusion peptidomimetics
  • Class B modified peptides/foldamers
  • peptides with various backbone and side chain alterations including foldamers
  • Class D (mechanistic mimetics) - molecules that mimic the mode of action of a peptide without a direct link to its side chains.
  • Non-limiting examples of Class D small molecule MFPs include but are not limited to Compounds A and B (below and FIG. 3).
  • Class B modified peptide MFPs include, but are not limited to, G, S, and D peptides depicted below and in FIG. 3.
  • Hematopoietic stem cells can be isolated from numerous sources including, but not limited to, peripheral blood, bone marrow, umbilical cord blood, and embryonic stem cells. In some embodiments, the hematopoietic stem cells are isolated from cord blood.
  • the HSCs are cultured under standard culture conditions with the inclusion of a mitofusion 2 fusion peptidomimetic (MFP).
  • MFP is a small molecule such as, but not limited to, Compound A or Compound B disclosed herein.
  • the small molecule MFP is included in the culture at a concentration of 1 nM to 10 nM. In some embodiments, the concentration is 2.5 nM to 5 nM. In some embodiments, the concentration of small molecule MFP is 5 nM. In some embodiments, the small molecule MFP is Compound B.
  • the MFP is a peptide such as, but not limited to Peptide S, Peptide D, or Peptide G disclosed herein.
  • the peptide MFP is included in the culture at a concentration of 0.5-1.0 pM.
  • the peptide MFP is Peptide S.
  • the MFP is present in the culture medium for 3-14 days.
  • the HSCs are cultured with the MFP for 7-10 days.
  • the HSCs generated by culture with MFPs as disclosed herein are suitable for transplantation into subjects with a variety of conditions.
  • the HSCs produced by the methods disclosed herein can be used to treat malignant and non-malignant conditions.
  • the malignant condition includes, but is not limited to, multiple myeloma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), myelodysplastic dyndrome (MDS), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), myelofibrosis, essential thrombocytosis, and polycythemia vera.
  • AML acute myeloid leukemia
  • ALL acute lymphoid leukemia
  • MDS myelodysplastic dyndrome
  • CML chronic myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • cord blood units are cryopreserved after collection and expansion of HSCs is performed on previously cropreserved cells.
  • the HSCs are expanded in the presence of an MFP as disclosed herein and then cryopreserved prior to administration to a subject.
  • the HSCs are expanded in culture in the presence of an MFP as disclosed herein and administered to a subject after the desired number of days in culture without cryopreservation.
  • a bank of expanded HSCs is generated by culturing HSC from individual CB units with an MFP as disclosed herein, and the HSCs cryopreserved as an off-the-shelf HSC preparation.
  • Phenotypic CB HSC population (CD45 low Lin _ CD34 + CD38'CD45RA'CD90 + ) were isolated to initiate cultures and standard tissue culture materials were used to expand HSCs (StemSpan from SCT® + standard human recombinant cytokines) and treated with either mitofusin 2 fusion peptidomimetics (MFPs; Compound A or Compound B) or vehicle control (DMSO).
  • MFPs mitofusin 2 fusion peptidomimetics
  • DMSO vehicle control
  • the MFP-expanded HSC were evaluated in primary and secondary xenografts transplant models as depicted in FIG. 12A.
  • Two small molecule MFPs (Compounds A and B; FIG. 12C) and three peptide MFPs (Peptides G, D, and S; FIG. 12D) were evaluated in the primary xenograft model 30 weeks post-transplantation of cord blood CD90 + HSC cultures expanded with the MFPs.
  • Compound B was also evaluated in the secondary xenograft model 30 weeks post-transplantation of primary xenograft bone marrow cells from primary NSG recipients (FIG. 12E).
  • FOG. 13A Principal component analysis
  • FIG. 13B differential gene expression
  • FIG. 13C-D Gene Ontology pathway analysis of differentially expressed genes showing upregulation of autophagy, ribosomal and stress granule pathways with Compound B treatment. Heatmaps calling out specific genes of interest in the GO pathway analysis were also performed.
  • Mfn2 and MTORC1 mimmalian target of rapamycin complex 1 proteins was then evaluated (FIG. 15).
  • 293 cells were transfected with his/Myc-tagged Mfn2 for 24 hr followed by treatment with Compound B or vehicle for an additional 24 hr.
  • the cells were lysed and incubated with Ni/NTA beads and imidazole-eluted extracts were analyzed by SDS-PAGE.
  • Immunoblotting with anti-Mfn2 or anti-MTORC1 demonstrated a positive association between the Mfn2 and MTORC1 protein, which increased in the presence of mitofusion agonist Compound B.
  • FIG. 16 depicts a model for the mitochondrial fusion agonist mechanism of action.
  • HSCs Under tissue culture conditions, high nutrient availability and proliferative demand force HSCs to activate anabolic MTORC1 signaling pathways, including high protein synthesis and low autophagy, which have been previously shown to induce HSC exhaustion.
  • Mitofusion agonist Compound B induced the open conformation of Mfn2, which leads to direct interaction with MTORC1 and negative regulation of MTORC1 activity, increased autophagy and reduced protein synthesis. These pathways converge to maintain repopulating HSCs during in vitro expansion and the observed increase in xenograft transplants without a substantial increase in the yield of phenotypic HSCs in vitro.

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Abstract

L'invention concerne des procédés de préparation de cellules hématopoïétiques fonctionnelles appropriées pour une transplantation chez un receveur comprenant l'obtention de cellules souches hématopoïétiques (HSC), la culture des HSC avec un peptidomimétique de fusion de mitofusine 2, et la récupération de cellules hématopoïétiques appropriées pour une transplantation dans un destinataire. L'invention concerne également des procédés de traitement de maladies et de prévention de l'épuisement des HSC à l'aide des HSC produites par un procédé de l'invention.
EP23892574.7A 2022-11-16 2023-11-16 Peptidomimétiques de fusion mitochondriale Pending EP4618983A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263425989P 2022-11-16 2022-11-16
PCT/US2023/080066 WO2024107988A2 (fr) 2022-11-16 2023-11-16 Peptidomimétiques de fusion mitochondriale

Publications (1)

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EP4618983A2 true EP4618983A2 (fr) 2025-09-24

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EP23892574.7A Pending EP4618983A2 (fr) 2022-11-16 2023-11-16 Peptidomimétiques de fusion mitochondriale

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EP (1) EP4618983A2 (fr)
AU (1) AU2023379680A1 (fr)
WO (1) WO2024107988A2 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2868348A1 (fr) * 2013-11-04 2015-05-06 Universität Zürich Composés à libération de monoxide de carbone et leurs formulations utiles pour induire la biogenèse mitochondriale et la réparation tissulaire
WO2018200323A1 (fr) * 2017-04-23 2018-11-01 Washington University Régulateurs de type petite molécule de fusion mitochondriale et procédés d'utilisation de ceux-ci
US11813268B2 (en) * 2017-10-17 2023-11-14 Albert Einstein College Of Medicine Mitofusin activators and uses thereof

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WO2024107988A3 (fr) 2024-06-20
AU2023379680A1 (en) 2025-06-26
WO2024107988A2 (fr) 2024-05-23

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