[go: up one dir, main page]

WO2025217452A1 - Lipides cationiques ionisables contraints et nanoparticules lipidiques - Google Patents

Lipides cationiques ionisables contraints et nanoparticules lipidiques

Info

Publication number
WO2025217452A1
WO2025217452A1 PCT/US2025/024153 US2025024153W WO2025217452A1 WO 2025217452 A1 WO2025217452 A1 WO 2025217452A1 US 2025024153 W US2025024153 W US 2025024153W WO 2025217452 A1 WO2025217452 A1 WO 2025217452A1
Authority
WO
WIPO (PCT)
Prior art keywords
cicl
cationic lipid
ionizable cationic
lipid
formula
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
PCT/US2025/024153
Other languages
English (en)
Inventor
Priya Prakash Karmali
Steven Tanis
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.)
Capstan Therapeutics Inc
Original Assignee
Capstan Therapeutics 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 Capstan Therapeutics Inc filed Critical Capstan Therapeutics Inc
Publication of WO2025217452A1 publication Critical patent/WO2025217452A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/42—Oxygen atoms attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/08—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars

Definitions

  • Lipid nanoparticles comprising ionizable cationic lipids have been developed to address these issues to the extent that RNA-based products, such as the siRNA ONPATTRO ® and two mRNA-based SARS-CoV-2 vaccines, have received regulatory approval and entered the marketplace.
  • LNP administered intravenously are taken up primarily in the liver, lung, or spleen depending to a significant degree on net charge and particle size. It is possible to direct >90% of LNP to the liver by a combination of formulation and intravenous administration, for example. Intramuscular administration can provide a clinically useful level of local delivery and expression.
  • LNP can be redirected to other tissues or cell types by conjugating to the LNP a binding moiety with specificity for the target tissue or cell type, for example, conjugating an antibody to an LNP (see, e.g., Endsley and Ho, J. Acquir. Immune Defic.
  • this disclosure fulfills the needs for addressing issues of off-target delivery, poor efficiency of release of therapeutic agents and provides further related advantages.
  • this disclosure provides constrained ionizable cationic lipids having a structure of formula M6 set forth herein.
  • this disclosure provides constrained ionizable cationic lipids having a structure of formula M3 set forth herein.
  • this disclosure provides ionizable cationic lipids CICL-251, CICL-252, CICL-253, CICL-254, CICL-255, CICL-256, CICL-256, CICL-257, CICL-258, CICL- 259, CICL-260, CICl-261, CICL-262, CICL-263, CICL-264, CICL-265, CICL-266, CICL-267, CICL-268, CICL-269, CICL-270, CICL-271, CICL-272, CICL-273, CICL-274, CICL-275, CICL- 276, CICL-277, CICL-278, CICL-279, CICL-280, CICL-281, CICL-282,
  • this disclosure provides ionizable cationic lipids CICL-251- 154, CICL-251-155, CILC-251-157, CICL-251-159, CICL-251-160, CICL-251-167, CICL-253- 154, CICL-253-155, CILC-253-157, CICL-253-159, CICL-253-160, CICL-253-167, CICL-255- 154, CICL-255-155, CICL-255-157, CICL-255-159, CICL-255-160, CICL-255-167, CICL-258- 154, CICL-258-155, CICL-258-157, CICL-258-159, CICL-258-159, CICL-258-160, CICL-258-167, CICL-260- 154, CICL-260-155, CICL-260-157, CICL-260-159, CICL
  • this disclosure provides ionizable cationic lipids CICL-252- 164, CICL-254-164, CICL-256-164, CICL-257-164, CICL-259-164, CICL-262-164, CICL-263- 164, CICL-265-164, CICL-267-164, CICL-269-164, CICL-271-164, CICL-274-164, CICL-276- 164, CICL-277-164, CICL-279-164, CICL-282-164, CICL-283-164, CICL-285-164, CICL-287- 164, and CICL-289-164 set forth herein.
  • this disclosure provides methods of synthesizing ionizable cationic lipids as described herein, e.g., CICL-251, CICL-252, CICL-253, CICL-254, CICL-255, CICL-256, CICL-256, CICL-257, CICL-258, CICL-259, CICL-260, CICl-261, CICL-262, CICL- 263, CICL-264, CICL-265, CICL-266, CICL-267, CICL-268, CICL-269, CICL-270, CICL-271, CICL-272, CICL-273, CICL-274, CICL-275, CICL-276, CICL-277, CICL-278, CICL-279, CICL- 280, CICL-281, CICL-282, CICL-283, CICL-284, CICL-285, CICL-2
  • this disclosure provides methods of synthesizing ionizable cationic lipids as described herein, e.g., CICL-253-154, CICL-253-155, CILC-253-157, CICL- 253-159, CICL-253-160, CICL-253-167, CICL-255-154, CICL-255-155, CICL-255-157, CICL- 255-159, CICL-255-160, CICL-255-167, CICL-258-154, CICL-258-155, CICL-258-157, CICL- 258-159, CICL-258-160, CICL-258-167, CICL-260-154, CICL-260-155, CICL-260-157, CICL- 260-159, CICL-260-160, CICL-260-167, CICL-261-154, CICL-261-155, CICL-2
  • this disclosure provides methods of synthesizing ionizable cationic lipids as described herein, e.g., CICL-252-164, CICL-254-164, CICL-256-164, CICL- 257-164, CICL-259-164, CICL-262-164, CICL-263-164, CICL-265-164, CICL-267-164, CICL- 269-164, CICL-271-164, CICL-274-164, CICL-276-164, CICL-277-164, CICL-279-164, CICL- 282-164, CICL-283-164, CICL-285-164, CICL-287-164, and CICL-289-164.
  • this disclosure provides intermediates and methods of synthesizing such intermediates useful in the synthesis of the ionizable cationic lipids as described herein.
  • this disclosure provides lipid nanoparticles (LNPs) and targeted lipid nanoparticles (tLNPs) incorporating the ionizable cationic lipids disclosed herein.
  • this disclosure provides methods of preparing LNPs and tLNPs as described herein.
  • this disclosure provides methods of delivering biologically active payload (e.g., nucleic acid molecules encoding a therapeutic agent) into a cell (such as a T cell or hematopoietic stem cell) comprising contacting the cell with an LNP or tLNP of this disclosure.
  • biologically active payload e.g., nucleic acid molecules encoding a therapeutic agent
  • a cell such as a T cell or hematopoietic stem cell
  • FIGS. 1A-1C depict the transfection rate (percentage of cells expressing the mRNA) versus expression level (as molecules of equivalent soluble fluorochrome (MESF)) for two tLNP compositions with CICL-251 or CICL-1, as indicated.
  • the full lipid compositions are described in Table 6.
  • LNPs lipid nanoparticles
  • a biologically active payload e.g., nucleic acid molecules encoding a therapeutic agent
  • LNP compositions are also disclosed herein, including LNPs comprising a functionalized PEG-lipid to enable conjugation of a binding moiety to generate targeted LNPs (tLNPs); that is, LNPs containing a binding moiety that directs the tLNP to a desired tissue or cell type (e.g., immune cells such as T cells or stem cells such as hematopoietic stem cells (HSCs)).
  • tLNPs targeted LNPs
  • desired tissue or cell type e.g., immune cells such as T cells or stem cells such as hematopoietic stem cells (HSCs)
  • the LNP and tLNP of this disclosure can be used for in vivo, ex vivo, or extracorporeal transfection.
  • any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
  • any number range of this disclosure relating to any physical feature, such as polymer subunits, size, or thickness are to be understood to include any integer within the recited range, unless otherwise indicated.
  • “Derivative,” as used herein, refers to a chemically or biologically modified version of a compound that is structurally similar to a parent compound and (actually or theoretically) derivable from that parent compound.
  • a “derivative” differs from an “analogue” in that a parent compound can be the starting material to generate a “derivative,” whereas the parent compound is not necessarily used as the starting material to generate an “analogue.”
  • a derivative can have different chemical or physical properties than the parent compound. For example, a derivative can be more hydrophilic or hydrophobic, or it can have altered reactivity as compared to the parent compound.
  • a derivative can be obtained by physical (for example, biological or chemical) modification of the parent compound
  • a derivative can also be conceptually derived, for example, as when a protein sequence is designed based on one or more known sequences, an encoding nucleic acid is constructed, and the derived protein obtained by expression of the encoding nucleic acid.
  • extracorporeal is used with reference to cells, such as peripheral blood or bone marrow cells, harvested or extracted from the body and the manipulation or modification of those cells prior to their intended return (reinfusion).
  • Manipulation and modification of cells generally relates to cell separation and washing procedures and exposure to activation agents (e.g., biological response modifiers (BRMs)) and transfection agents (e.g., LNPs, tLNPs), over a time interval of several hours, for example, less than 6 hours, less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, or less than 1 hour; and in space to a single institution.
  • Extracorporeal is used in contradistinction to ex vivo which, as used herein, includes more extensive manipulation including extended periods of cell culture and expansion, and/or refrigerated or cryogenic storage or shipment, over several days or longer. [0037]
  • expansion refers to proliferation of cells increasing their number.
  • Activating agents can be used to stimulate proliferation (among other metabolic changes) but can also result in activation-induced death upon initial exposure so that there is no immediate expansion.
  • doubling time can be about 24 hours (which is fairly typical of mammalian cells in vitro generally); in vivo doubling time can be substantially shorter, depending on the presence and type of stimulation. Accordingly, during a limited time of extracorporeal manipulation, even when activating agents are used, such protocols will be effectively expansion-less.
  • an “exogenous protein” refers to a synthetic, recombinant, or other peptide or protein that is not produced by a wild-type cell of that type or is expressed at a lower level in a wild-type cell than in a cell containing the exogenous polypeptide, or that is administered to a subject rather than being produced inside the subject’s body.
  • an exogenous peptide is a peptide or protein encoded by a nucleic acid that was introduced into the cell, which nucleic acid is optionally not retained by the cell.
  • transfection refers to the introduction of nucleic acids into cells by non-viral methods. Transfection can be mediated by calcium phosphate, cationic polymers, magnetic beads, electroporation, and lipid-based reagents. In preferred embodiments disclosed herein transfection is mediated by solid lipid nanoparticles (LNP) including targeted LNP (tLNP) (which can also be used to deliver non-nucleic acid payloads into cells).
  • LNP solid lipid nanoparticles
  • tLNP targeted LNP
  • transfection is used in distinction to transduction – transfer of genetic material from cell to cell or virus to cell – and transformation – the uptake of extracellular genetic material by the natural processes of a cell.
  • phrases such as “delivering a nucleic acid into a cell” are synonymous with transfection.
  • “Reprogramming,” as used herein with respect to cells refers to changing the functionality of a cell. For example, reprogramming an immune cell can result in a change in antigenic specificity by causing expression of an exogenous T cell receptor (TCR), a chimeric antigen receptor (CAR), or an immune cell engager (“reprogramming agents”).
  • TCR T cell receptor
  • CAR chimeric antigen receptor
  • reprogramming agents an immune cell engager
  • T lymphocytes and natural killer (NK) cells can be reprogrammed with a TCR, a CAR, or an immune cell engager, while a CAR or an immune cell engager are typically used in reprogramming monocytes.
  • stem cells for example hematopoietic stem cells (HSC) or mesenchymal stem cells (MSC)
  • reprogramming refers to correction or amelioration of a genetic defect (for example, a hemoglobinopathy) so that the modified or corrected gene and gene product are the reprogramming agents. Reprogramming can be transient or durable depending on the nature of the engineering agent.
  • Engineerering agent refers to agents that confer the expression of a reprogramming agent by a cell, such as an immune cell, particularly a non-B lymphocyte or monocyte.
  • Engineering agents can include nucleic acid molecules, including mRNA, that encode a reprogramming agent.
  • Engineering agents can also include nucleic acid molecules that are or encode components of gene editing systems, such as RNA-guided nucleases, guide RNA, and nucleic acid templates for knocking-in a reprogramming agent or knocking- out an endogenous antigen receptor.
  • Gene editing systems comprise base-editors, prime- editors or gene-writers.
  • RNA-guided nucleases include CRISPR nucleases such as Cas9, Cas12, Cas13, Cas3, CasMINI, Cas7-11, and CasX.
  • CRISPR nucleases such as Cas9, Cas12, Cas13, Cas3, CasMINI, Cas7-11, and CasX.
  • an mRNA encoding the reprogramming agent can be used as the engineering agent.
  • the engineering agent can comprise mRNA-encoded RNA-directed nucleases, guide RNAs, nucleic acid templates, and other components of gene/genome editing systems.
  • Examples of gene editing components that are encoded by a nucleic acid molecule include an mRNA encoding an RNA-guided nuclease, a gene or base editing protein, a prime editing protein, a Gene Writer protein (e.g., a modified or modularized non-long terminal repeat (LTR) retrotransposon), a retrotransposase, an RNA writer, a zinc finger nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), a meganuclease, a transposase, a retrotransposon, a reverse transcriptase (e.g., M-MLV reverse transcriptase), a nickase or inactive nuclease (e.g., Cas9, nCas9, dCas9), a DNA recombinase, a CRISPR nuclease (e.g., Cas9, Cas12,
  • gRNA guide RNA
  • sgRNA single guide RNA
  • pegRNA prime editing guide RNA
  • CRISPR clustered regularly interspaced short palindromic repeat
  • tracrRNA trans-activating clustered regularly interspaced short palindromic repeat
  • DNA molecule to be inserted or serve as a template for double-strand break (DSB) repair at a specific genomic locus gRNA
  • sgRNA single guide RNA
  • pegRNA prime editing guide RNA
  • CRISPR clustered regularly interspaced short palindromic repeat
  • tracrRNA trans-activating clustered regularly interspaced short palindromic repeat
  • DSB double-strand break
  • Genome-, gene-, and base-editing technology are reviewed in Anzalone et al., Nature Biotechnology 38:824-844, 2020, Sakuma, Gene and Genome Editing 3-4:100017, 2022, and Zhou et al., MedComm 3(3):e155, 2022, each of which is incorporated by reference for all that they teach about the components and uses of this technology to the extent that it does not conflict with this disclosure.
  • Conditioning agent refers to a biological response modifier (BRM) that enhances the efficiency of engineering an immune cell, expands the number of immune cells available to be engineered or the number of engineered cells in a target tissue (for example, a tumor, fibrotic tissue, or tissue undergoing autoimmune attack), promotes activity of the engineered cell in a target tissue, or broadens the range of operative mechanisms contributing to a therapeutic immune reaction.
  • a conditioning agent can be provided by delivering an encoding nucleic acid in a LNP or tLNP.
  • Exemplary BRMs include cytokines, such as IL-7, IL-15, or IL-18.
  • Conditioning agents can be provided as the agent itself or, when the conditioning agent is a peptide or protein, as a nucleic acid molecule encoding the conditioning agent.
  • “Immune cell,” as used herein, can refer to any cell of the immune system. However, particular aspects can exclude polymorphonuclear leukocytes and/or B cells, or be limited to non-B lymphocytes such as T cell and/or NK cells, or to monocytes such as dendritic cells and/or macrophages in their various forms.
  • lipid nanoparticle means a solid particle, as distinct from a liposome having an aqueous lumen.
  • a “binding moiety” or “targeting moiety” refers to a protein, polypeptide, oligopeptide, peptide, carbohydrate, nucleic acid, or combination thereof that is capable of specifically binding to a target or multiple targets.
  • a binding domain includes any naturally occurring, synthetic, semi-synthetic, or recombinantly produced binding partner for a biological molecule or another target of interest.
  • Exemplary binding moieties of this disclosure include an antibody, a Fab ⁇ , F(ab ⁇ ) 2 , Fab, Fv, rIgG, scFv, hcAbs (heavy chain antibodies), a single domain antibody, VHH, VNAR, sdAbs, nanobody, receptor ectodomains or ligand- binding portions thereof, or ligands (e.g., cytokines, chemokines).
  • a “Fab” fragment antigen binding
  • a binding moiety comprises a ligand-binding domain of a receptor or a receptor ligand.
  • a binding moiety can have more than one specificity including, for example, bispecific or multispecific binders.
  • assays are known for identifying binding moieties of this disclosure that specifically bind a particular target, including Western blot, ELISA, and Biacore® analysis.
  • a binding moiety such as a binding moiety comprising immunoglobulin light and heavy chain variable domains (e.g., scFv), can be incorporated into a variety of protein scaffolds or structures as described herein, such as an antibody or an antigen binding fragment thereof, a scFv-Fc fusion protein, or a fusion protein comprising two or more of such immunoglobulin binding domains.
  • antibody refers to a protein comprising an immunoglobulin domain having hypervariable regions determining the specificity with which the antibody binds antigen; so-called complementarity determining regions (CDRs).
  • antibody can thus refer to intact or whole antibodies as well as antibody fragments and constructs comprising an antigen binding portion of a whole antibody. While the canonical natural antibody has a pair of heavy and light chains, camelids (camels, alpacas, llamas, etc.) produce antibodies with both the canonical structure and antibodies comprising only heavy chains. The variable region of the camelid heavy chain only antibody has a distinct structure with a lengthened CDR3 referred to as VHH or, when produced as a fragment, a nanobody.
  • Antigen binding fragments and constructs of antibodies include F(ab) 2 , F(ab), minibodies, Fv, single-chain Fv (scFv), diabodies, and VH.
  • Such elements can be combined to produce bi- and multi-specific reagents, such as T-cell engagers (for example, Bispecific T-Cell Engagers (BiTEs)) or other immune cell engagers.
  • T-cell engagers for example, Bispecific T-Cell Engagers (BiTEs)
  • BiTEs Bispecific T-Cell Engagers
  • Antibodies can be obtained through immunization, selection from a na ⁇ ve or immunized library (for example, by phage display), alteration of an isolated antibody- encoding sequence, or any combination thereof. Numerous antibodies that could be used as binding moieties are known in the art.
  • An antibody or other binding moiety “specifically binds” a target if it binds the target with an affinity or Ka (i.e., an equilibrium association constant of a particular binding interaction with units of 1/M) equal to or greater than 10 5 M -1 , while not significantly binding other components present in a test sample.
  • Binding domains (or fusion proteins thereof) can be classified as “high affinity” binding domains (or fusion proteins thereof) and “low affinity” binding domains (or fusion proteins thereof).
  • “High affinity” binding domains refer to those binding domains with a Ka of at least 10 8 M -1 , at least 10 9 M -1 , at least 10 10 M -1 , at least 10 11 M -1 , at least 10 12 M -1 , or at least 10 13 M -1 , preferably at least 10 8 M -1 or at least 10 9 M -1 .
  • “Low affinity” binding domains refer to those binding domains with a Ka of up to 10 8 M -1 , up to 10 7 M -1 , up to 10 6 M -1 , up to 10 5 M -1 .
  • affinity can be defined as an equilibrium dissociation constant (Kd) of a particular binding interaction with units of M (e.g., 10 -5 M to 10- 13 M).
  • binding domain polypeptides and fusion proteins can be readily determined using conventional techniques (see, e.g., Scatchard et al., 1949, Ann. N.Y. Acad. Sci.51:660; and U.S. Patent Nos.5,283,173, 5,468,614, or the equivalent).
  • payload refers to a negatively charged agent that can interact with cationic lipids, such as the ionizable cationic lipids of this disclosure, to become encapsulated within lipid nanoparticles comprising the cationic lipid.
  • the negatively charged agent can be a biologically active small organic molecule, or a macromolecule such as a nucleic acid molecule, a carbohydrate, a peptide, or a polypeptide.
  • a payload can be one or more nucleic acid molecules, such as RNA or DNA, including mRNA and guide RNA (gRNA) molecules.
  • gRNA guide RNA
  • a payload comprises an mRNA that encodes a biologically active molecule, such as a chimeric antigen receptor, a T cell receptor, an immune cell engager, or the like.
  • biologically active agent refers to any substance that affects a metabolic or physiologic response in a living organism, cells, or cultured cells thereof, including genetically reprograming, permanently or transiently, such organism or cells.
  • therapeutic agent is a substance, or a component of a combination of substances, the biological activity of which can potentially cure, ameliorate, stabilize, prevent, or otherwise beneficially impact a disease, pathological condition, or other disorder.
  • chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, and the like).
  • alkyl generally refers to a monovalent radical (e.g. CH 3 -CH 2 -)
  • a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH 2 -CH 2 -), which is equivalent to the term “alkylene.”
  • aryl refers to the corresponding divalent moiety, arylene.
  • All atoms are understood to have their normal number of valences for bond formation (i.e., 4 for carbon, 3 for nitrogen, 2 for oxygen, and 2, 4, or 6 for sulfur, depending on the oxidation state of the sulfur atom).
  • alkyl refers to saturated straight and branched chain aliphatic groups having from 1 to 12 carbon atoms. As such, “alkyl” encompasses C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 groups.
  • alkenyl as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms.
  • alkenyl encompasses C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 groups.
  • the hydrocarbon chain is unsubstituted.
  • one or more hydrogens of the alkyl or alkenyl group can be substituted with the same or different substituents.
  • Alkynoic refers to a carboxylic acid moiety comprising one or more carbon-carbon triple bonds.
  • hydrogens are unsubstituted.
  • one or more hydrogens of the alkynoic group can be substituted with the same or different substituents.
  • Amide refers to a carboxylic acid derivative comprising a carbonyl group of a carboxylic acid bonded to an amine moiety.
  • Head group refers to the hydrophilic or polar portion of a lipid.
  • Sterol refers to a subgroup of steroids that contain at least one hydroxyl (OH) group.
  • examples of sterols include, without limitation, cholesterol, ergosterol, ⁇ -sitosterol, stigmasterol, stigmastanol, 20-hydroxycholesterol, 22-hydroxycholesterol, and the like.
  • the bond represented as a solid wedge extends above the plane and the bond represented as a dashed wedge extends below the plane when depicting absolute stereochemistry, throughout.
  • a ring comprising a central branchpoint nitrogen atom connects the two branching tail groups to each other, reducing their freedom of movement.
  • constrained refers to this limited freedom of movement of the two tail groups extending from a ring comprising a nitrogen atom.
  • Each of the disclosed ionizable cationic lipids has two tail groups extending from the central branch point and each tail group branches again at its distal branch point.
  • the mobility of the two tail groups is constrained by the ring comprising the central branch point atom and the first one or two main chain atoms of each tail group.
  • a subscript has a value of “0”
  • the group is absent and the adjoining atoms are bonded to each other.
  • a 1 is (CH 2 ) 0
  • a 1 is absent.
  • a 1 through A 4 are such that there are only two main chain atoms between the ring nitrogen and each nearest ester oxygen in the nearest tail group.
  • each A 1 , A 2 , A 3 , and A 4 is independently (CH 2 ) 0 or (CH 2 ) 1 , provided that A 1 is (CH 2 ) 1 when A 3 is (CH 2 ) 0 ; A 1 is (CH 2 ) 0 when A 3 is (CH 2 ) 1 ; A 2 is (CH 2 ) 1 when A 4 is (CH 2 ) 0 ; and A 2 is (CH 2 ) 0 when A 4 is (CH 2 ) 1 .
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 1.
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 0
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 1 .
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • X is for example, in some embodiments of formula M6, X is [0075] In some embodiments of formula M6 as described herein, X is [0076] In some embodiments of formula M6 as described herein, X is [0077] In some embodiments of formula M6 as described herein, X is .In some embodiments X is [0078] In some embodiments of formula M6 as described herein, X is .
  • X is [0080] In some embodiments of formula M6 as described herein, X is [0081] In some embodiments of formula M6 as described herein, X is [0082] In some embodiments of formula M6 as described herein, X is [0083] In some embodiments of formula M6 as described herein, X is [0084] In some embodiments of formula M6 as described herein, X is [0085] In some embodiments of formula M6 as described herein, X is . [0086] In some embodiments of formula M6 as described herein, X is . [ 0087] In some embodiments of formula In some embodiments of formula M6, X is .
  • X is . [0088] In some embodiments of formula some e mbodiments of formula [0089] In some embodiments of formula M6, . In some embodiments of formula M6, X is . In some embodiments of formula M6, X is [ 0090] In some embodiments of formula some embodiments of formula some embodiments of formula M6, X is In some embodiments of formula M6, X is [ 0091] In some embodiments of formula some embodiments of formula M6, X is .
  • X is [ 0092] In some embodiments of formula some embodiments of formula M6, X is In some embodiments of formula M6, X is [0093] In some embodiments of formula some embodiments of formula M6, X is In some embodiments of formula M6, X is [ 0094] In some embodiments of formula some embodiments of formula M6, X is In some embodiments of formula M6, X is [ 0095] In some embodiments of formula M6, . In some embodiments of formula [ 0096] In some embodiments of formula some embodiments of formula [0097] As described above, in some embodiments of formula M6, Y can be selected from O, S, NH, or NCH 3 . In some embodiments of formula M6, Y is O.
  • Y is S. [0098] In some embodiments of formula M6, X is and Y is O. In some embodiments of formula [0099] As described above, Z can be selected from O, NH, or NCH 3 . In some embodiments, Z is O. [00100] In some embodiments of formula M6, X is and Z is O. In some embodiments of formula M6, X is and Z is O. In some embodiments of formula [00101] In some embodiments of formula some embodiments of formula [00102] In some embodiments of formula M6, and Z is O. In some embodiments of formula M6, and Z is O. In some embodiments of formula [00103] In some embodiments of formula some embodiments of formula M6, X is and Z is O.
  • X i and Z is O. In some embodiments of formula M6, X is [00104] In some embodiments of formula M6, X is and Z is O. In some embodiments of formula M6, X is and Z is O. In some embodiments of formula [00105] In some embodiments of formula M6, X is and Z is O. In some embodiments of formula M6, X is and Z is O. In some embodiments of formula [00106] In some embodiments of formula some embodiments of formula some embodiments of formula [00107] In some embodiments of formula some embodiments of formula some embodiments of formula [00108] In some embodiments of formula M6, X is and Z is O. In some embodiments of formula M6, X is Z is O.
  • each R 1 is independently C 7 -C 11 alkyl or C 7 - C 11 alkenyl. In some embodiments of formula M6, each R 1 is independently C 7 -C 11 alkyl, e.g., C 7 -C 10 alkyl, or C 7 -C 9 alkyl. In certain embodiments of formula M6, each R 1 is independently a linear C 7 -C 11 alkyl, e.g., a linear C 7 -C 10 alkyl, or a linear C 7 -C 9 alkyl.
  • each R 1 is independently (CH 2 ) 6-8 CH 3 . In some of these and other embodiments, R 1 is (CH 2 ) 7 CH 3 . In some embodiments of formula M6, each R 1 is independently a linear C 7 -C 11 alkenyl, e.g., a linear C 7 -C 10 alkenyl, or a linear C 7 -C 9 alkenyl. For example, in some embodiments of formula M6, each R 1 is a linear C 8 alkenyl.
  • each R 1 is independently a branched C 7 -C 11 alkyl, e.g., C 7 -C 10 alkyl, or C 7 -C 9 alkyl.
  • each R 1 is a branched C 8 alkyl.
  • each R 1 is independently a branched C 7 -C 11 alkenyl, e.g., C 7 -C 10 alkenyl, or C 7 -C 9 alkenyl.
  • each R 1 is a branched C 8 alkenyl.
  • each R 1 is the same.
  • each R 1 nearest a common branch point is the same, but those nearest a first common branch point differ from those nearest a second common branch point.
  • each R 1 nearest a common branch point is different but the pair of R 1 groups nearest a first common branch point is the same the pair nearest a second common branch point.
  • each W is independently CH or N.
  • each W is CH.
  • each W is N.
  • one W is CH and the other W is N.
  • the combination of a R 3 at a beta position of W being O and W being N is avoided.
  • at least one R 3 at a beta position of a W is O, that W is CH.
  • the constrained ionizable cationic lipids of this disclosure have a structure of formula M6-1, a stereoisomer thereof, or a mixture of such stereoisomers: M 6-1 wherein X, A 1 , A 2 , A 3 , A 4 , A 5 , and R 1 , are as otherwise described herein.
  • the constrained ionizable cationic lipids of this disclosure have a structure of formula M6-2A or formula M6-2B, a stereoisomer thereof, or a mixture of such stereoisomers:
  • the constrained ionizable cationic lipids of this disclosure have a structure of formula M6-3A or M6-3B, a stereoisomer thereof, or a mixture of such stereoisomers:
  • the constrained ionizable cationic lipids of this disclosure have a structure of formula M6-4A or formula M6-4B, a stereoisomer thereof, or a mixture of such stereoisomers:
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • a 5 is (CH 2 ) 1.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X, W, R 1 , R 2 , and R 3 are as described herein.
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • a 5 is (CH 2 ) 3.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X, W, R 1 , R 2 , and R 3 are as described herein.
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has a structure of formula M6, wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 1.
  • the ionizable cationic lipid has the structure: wherein X, W, R 1 , R 2 , and R 3 are as described herein.
  • the ionizable cationic lipid has a structure of formula M6, wherein A 1 is (CH 2 ) 1 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 0 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 0 .
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has a structure of formula M6, wherein A 1 is (CH 2 ) 1 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 0 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 1 .
  • the ionizable cationic lipid has the structure: wherein X, W, R 1 , R 2 , and R 3 are as described herein.
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 2.
  • the ionizable cationic lipid has the structure: wherein X, W, R 1 , R 2 , and R 3 are as described herein.
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • a 5 is (CH 2 ) 1.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X is as described herein. [00133] In certain embodiments of formula M6, X is , wherein Y is O. For example, in certain embodiments, the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X is as described herein. [00135] In certain embodiments of formula M6, X is , wherein Y is O. For example, in certain embodiments, the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein. [00137] In certain embodiments of formula M6, X is , wherein Y is O. For example, in certain embodiments, the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein. [00139] In certain embodiments of formula M6, X is , wherein Y is O. For example, in certain embodiments, the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein. [00143] In certain embodiments of formula M6, X is , wherein Y is O. For example, in certain embodiments, the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X, W, R 2 , and R 3 are as described herein.
  • the ionizable cationic lipid has the structure:
  • X is as described herein. - CH 3 Y (CH2)2 N
  • X is CH 3
  • Y is O
  • the ionizable cationic lipid has the structure: .
  • the ionizable cationic lipid has the structure:
  • X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: . . [00149]
  • the ionizable cationic lipid has the structure:
  • X is as described herein. - CH 3 Y (CH2)2 N
  • X is CH 3
  • Y is O
  • the ionizable cationic lipid has the structure: . . [00151]
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein. - CH 3 Y (CH2)2 N
  • X is CH 3 , wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • a 5 is (CH 2 ) 3.
  • the ionizable cationic lipid has the structure: wherein X, W, R 2 , and R 3 are as described herein.
  • the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • the ionizable cationic lipid has the structure:
  • X is as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure:
  • X is as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X, W, R 2 , and R 3 are as described herein.
  • the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X is as described herein. [00177] In certain embodiments of formula M6, X is wherein Y is O. For example, in certain embodiments, the ionizable cationic lipid has the structure: . [00178] For example, in certain embodiments of formula M6, the ionizable cationic lipid has the structure:
  • X is as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: . wherein X and W are as described herein. [00181] In certain embodiments of formula M6, X is wherein Y is O. For example, in certain embodiments, the ionizable cationic lipid has the structure: wherein W is as described herein. [00182] For example, in certain embodiments of formula M6, the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • CH is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • the ionizable cationic lipid has the structure:
  • X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid having the structure:
  • X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has a structure of formula M6, wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 1.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: . .
  • the ionizable cationic lipid has the structure:
  • X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein. [00211] In certain embodiments of formula M6, X is wherein Y is O. For example, in certain embodiments, the ionizable cationic lipid has the structure: wherein W is as described herein . [00212] For example, in certain embodiments of formula M6, the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • the ionizable cationic lipid has a structure of formula M6, wherein A 1 is (CH 2 ) 1 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 0 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 0 .
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has wherein X is as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: . .
  • the ionizable cationic lipid has the structure: wherein X is as described herein.
  • Y is O.
  • the ionizable cationic lipid has the structure: [00223]
  • the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein .
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • the ionizable cationic lipid has a structure of formula M6, wherein A 1 is (CH 2 ) 1 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 0 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 1 .
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X is as described herein. [00237] In certain embodiments of formula M6, X is wherein Y is O. For example, in certain embodiments, the ionizable cationic lipid has the structure: . . [00238] For example, in certain embodiments of formula M6, the ionizable cationic lipid has the structure:
  • X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: . .
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein. [00243] In certain embodiments of formula M6, X is , wherein Y is O. For example, in certain embodiments, the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 2.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: . .
  • the ionizable cationic lipid has the structure:
  • X is as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure:
  • X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein W is as described herein.
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X is as described herein. [0001] In certain embodiments of formula M6, X is wherein Y is O. For example, in certain embodiments, the ionizable cationic lipid has the structure: . . [00265] For example, in certain embodiments of formula M6, the ionizable cationic lipid has the structure:
  • X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure:
  • X is as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure: . . [00267]
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • X is wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein. [0006] In certain embodiments of formula M6, X is wherein Y is O. For example, in certain embodiments, the ionizable cationic lipid has the structure: wherein W is as described herein. [00270] For example, in certain embodiments of formula M6, the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the constrained ionizable cationic lipids of this disclosure have a structure of the formula M3, a stereoisomer thereof, or a mixture of such stereoisomers: wherein X
  • the position of X can be referred to as the central branch point and the position of each W can be referred to as a distal branch point.
  • Each of the disclosed ionizable cationic lipids has two tail groups extending from the central branch point and each tail group branches again at its distal branch point. The mobility of the two tail groups is constrained by the ring comprising the central branch point atom and the first one or two main chain atoms of each tail group.
  • a subscript has a value of “0”, the group is absent. For example, when A 1 is (CH 2 ) 0 , A 1 is absent.
  • each A 1 , A 2 , A 3 , and A 4 is independently (CH 2 ) 0 or (CH 2 ) 1 , provided that A 1 is (CH 2 ) 1 when A 3 is (CH 2 ) 0 ; A 1 is (CH 2 ) 0 when A 3 is (CH 2 ) 1 ; A 2 is (CH 2 ) 1 when A 4 is (CH 2 ) 0 ; and A 2 is (CH 2 ) 0 when A 4 is (CH 2 ) 1 .
  • a 1 through A 4 are such that there are only two main chain atoms between the ring nitrogen and each nearest ester oxygen in the nearest tail group.
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 1.
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 0
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 1 .
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • Different constituents for X, Y, Z, and R 1 allow for tuning of cLogD and c-pKa to achieve a desired value of measured pKa within a LNP or a tLNP.
  • the following head groups could be used - CH 3 Y (CH2)2 N [0009]
  • the following head groups could be used instead: , , [00280]
  • CH 2 groups in X will tend to increase basicity of the lipid which in turn will tend to increase measured pKa.
  • the addition of CH 2 groups in R 1 will tend to increase the lipophilicity (cLogD) of the lipid which in turn will tend to decrease measured pKa of the LNP or tLNP.
  • X is ( CH2)2-3 OCH 3 Y-(CH2)2-4 N ( CH2)2-3 OCH 3 .
  • X is .
  • X is .
  • X is . [0015] In some embodiments of formula M3 as described herein, X is . [0016] In some embodiments of formula M3 as described herein, X is . [0017] In some embodiments of formula M3 as described herein, X is . [0018] In some embodiments of formula M3 as described herein, X is . [0019] In some embodiments of formula M3 as described herein, is . [0020] In some embodiments of formula M3 as described herein, X is . [00283] In some embodiments of formula M3 as described herein, X is .
  • X is . In some embodiments of formula M3, X is . In some embodiments of formula M3, X is . In some embodiments of formula M3, X is . [00285] In some embodiments of formula some e mbodiments of formula [00286] In some embodiments of formula M3, . In some embodiments of formula M3, X is . In some embodiments of formula M3, X is [ 00287] In some embodiments of formula some embodiments of formula some embodiments of formula M3, X is In some embodiments of formula M3, X is [ 00288] In some embodiments of formula some embodiments of formula M3, X is .
  • X is [ 00289] In some embodiments of formula some embodiments of formula M3, X is In some embodiments of formula M3, X is [00290] In some embodiments of formula some embodiments of formula M3, X is In some embodiments of formula M3, X is [ 00291] In some embodiments of formula some embodiments of formula M3, X is In some embodiments of formula M3, X is [ 00292] In some embodiments of formula M3, . In some embodiments of formula [ 00293] In some embodiments of formula some embodiments of formula [00294] As described above, in various embodiments of formula M3, Y can be selected from O, S, NH, or NCH 3 .
  • Y is O. In some other embodiments, Y is S. [0021] In some embodiments, X is and Y is O. In some embodiments X [00295] As described above, Z can be selected from O, NH, or NCH 3 . In some embodiments, Z is O. [00296] In some embodiments of formula M3, X is and Z is O. In some embodiments of formula M3, X is and Z is O. In some embodiments of formula [00297] In some embodiments of formula some embodiments of formula [00298] In some embodiments of formula M3, X is and Z is O. In some embodiments of formula M3, X is and Z is O.
  • X is and Z is O. In some embodiments of formula some embodiments of formula M3, X is and Z is O. In some embodiments of formula M3, X is [00300] In some embodiments of formula M3, X is and Z is O. In some embodiments of formula M3, X is and Z is O. In some embodiments of formula [00301] In some embodiments of formula M3, X is and Z is O. In some embodiments of formula M3, X is and Z is O.
  • each R 1 is independently C 7 -C 11 alkyl or C 7 -C 11 alkene. In some embodiments of formula M3, each R 1 is independently C 7 -C 11 alkyl, e.g., C 7 -C 10 alkyl, or C 7 -C 9 alkyl.
  • each R 1 is independently a linear C 7 -C 11 alkyl, e.g., a linear C 7 -C 10 alkyl, or a linear C 7 -C 9 alkyl.
  • each R 1 is independently (CH 2 ) 6-8 CH 3 .
  • R1 is (CH 2 ) 7 CH 3 .
  • each R 1 is independently a linear C 7 -C 11 alkenyl, e.g., a linear C 7 -C 10 alkenyl, or a linear C 7 -C 9 alkenyl.
  • each R 1 is a linear C 8 alkenyl.
  • each R 1 is independently a branched C 7 -C 11 alkyl, e.g., C 7 -C 10 alkyl, or C 7 -C 9 alkyl.
  • each R 1 is a branched C 8 alkyl.
  • each R 1 is independently a branched C 7 -C 11 alkenyl, e.g., C 7 -C 10 alkenyl, or C 7 - C 9 alkenyl.
  • each R 1 is a branched C 8 alkenyl.
  • each R 1 is the same.
  • each R 1 nearest a common branch point is the same, but those nearest a first common branch point differ from those nearest a second common branch point.
  • each R 1 nearest a common branch point is different but the pair of R 1 groups nearest a first common branch point is the same the pair nearest a second common branch point.
  • W is CH or N. In certain embodiments, W is CH. In certain other embodiments, W is N.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein. [00311]
  • W is CH and the ionizable cationic lipid has the structure: wherein X is as described herein. In certain embodiments of formula M3, X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • W is N and the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • a 5 is (CH 2 ) 2.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein. [00314]
  • W is CH and the ionizable cationic lipid has the structure:
  • X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • W is N and the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • W is CH the ionizable cationic lipid has the structure: wherein X is as described herein. In certain embodiments of formula M3, X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • W is N
  • the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • a 5 is (CH 2 ) 4.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • W is CH and the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • W is N and the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • X and W are as described herein.
  • W is CH and the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • W is N and the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • the ionizable cationic lipid has a structure of formula M3, wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 1.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • W is CH and the ionizable cationic lipid has the structure: wherein X is as described herein .
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • W is N and the ionizable cationic lipid has the structure: CH wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • the ionizable cationic lipid has a structure of formula M3, wherein A 1 is (CH 2 ) 1 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 0 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 0 .
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • W is CH and the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • W is N and the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • W is N and the ionizable cationic lipid has the structure: .
  • the ionizable cationic lipid has a structure of formula M3, wherein A 1 is (CH 2 ) 1 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 0 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 1 .
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • W is CH and the ionizable cationic lipid has the structure:
  • X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • W is N and the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 2.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • W is CH and the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: .
  • W is N and the ionizable cationic lipid has the structure: Y wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: wherein X and W are as described herein.
  • W is CH and the ionizable cationic lipid has the structure: wherein X is as described herein. In certain embodiments of formula M3, X is , wherein Y is O.
  • the ionizable cationic lipid has the structure:
  • W is N and the ionizable cationic lipid has the structure: wherein X is as described herein.
  • X is , wherein Y is O.
  • the ionizable cationic lipid has the structure: . .
  • an ionizable cationic lipid of this disclosure is substantially enantiomerically pure (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% of one enantiomer).
  • an ionizable cationic lipid of this disclosure is a racemic mixture.
  • an ionizable cationic lipid of this disclosure is a mixture of two or more stereoisomers. In certain embodiments, at least two of the two or more stereoisomers are diastereomers.
  • Ionizable cationic lipids as described herein can be useful as a component of lipid nanoparticles for delivering nucleic acids, including DNA, mRNA, or siRNA into cells.
  • the ionizable cationic lipids can have a c-pKa (calculated pKa) in the range of from about 6, 7, or 8 to about 9, 10, or 11.
  • the ionizable cationic lipids have a c-pKa ranging from about 6 to about 10, about 7 to about 10, about 8 to about 10, about 8 to about 9, 6 to 10, 7 to 10, 8 to 10, or 8 to 9.
  • the ionizable cationic lipids have a c-pKa ranging from about 8.2 to about 9.0 or from 8.2 to 9.0.
  • the ionizable cationic lipids have a c-pKa ranging from about 8.4 to about 8.7 or from 8.4 to 8.7.
  • the ionizable cationic lipids as described herein can have cLogD ranging from about 9 to about 18, for example, ranging from about 10 to about 18, or about 10 to about 16, to about 10 to about 14, or about 11 to about 18, or about 11 to about 15, or about 11 to about 14, or about 12 to about 14.
  • the ionizable cationic lipids as described herein can have cLogD ranging from 9 to 18, for example, ranging from 10 to 18, or 10 to 16, to 10 to 14, or 11 to 18, or 11 to 15, or 11 to 14, or 12 to 14.
  • the ionizable cationic lipids have a cLogD ranging from about 13.6 to about 14.4 or from 13.6 to 14.4.
  • the ionizable cationic lipids as described herein can have a c-pKa ranging from about 8 to about 11 or from 8 to 11 and a cLogD ranging from about 9 to about 18 or from 9 to 18.
  • the ionizable cationic lipids have a c-pKa ranging from about 8.4 to about 8.7 or from 8.4 to 8.7 and cLogD ranging from about 13.6 to about 14.4 or from 13.6 to 14.4.
  • These ranges can lead to a measured pKa in the LNP ranging from about 6 to about 7 or from 6 to 7, which facilitates ionization in an endosome after delivery into a cell.
  • Ionizable cationic lipids of this disclosure have a branched structure to give the lipid a conical rather than cylindrical three-dimensional shape and such structure helps promote endosomolytic activity when incorporated into an LNP. The greater the endosomolytic activity, the more efficient is release of the biologically active payload (e.g., one or more species of nucleic acid molecule).
  • Another consideration in designing or selecting a particular ionizable cationic lipid for use in an LNP for delivering nucleic acids (or other negatively charged payloads) into cells is the type of cell and, for in vivo delivery, locus within the body targeted for delivery. This is also influenced by pKa. Zhang et al.
  • ionizable lipids with pKa across a wide range can be useful for delivery to various tissues. Of course, other factors can also impact what tissue or cells an LNP will deliver its payload to, including the use of a targeting moiety attached to the surface of the LNP. [00345] In some embodiments, somewhat greater basicity can be desirable and can be obtained from ionizable cationic lipids with c-pKa and cLogD in the ranges disclosed herein.
  • cLogD of ionizable cationic lipids of this disclosure is about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, or in a range bound by any pair of these values.
  • Lipid design also accounts for potential biodegradability pathways of target lipids, such as by way of esterases in plasma, liver and other tissues. Another consideration in lipid design is the fate of fragments of ionizable lipids resulting from degradation, such as after esterase cleavage(s). Preferably, the resulting fragments are rapidly cleared from the body without the need for hepatic oxidative metabolism.
  • cLogD is a calculated measure of lipophilicity that accounts for the state of ionization of the lipid molecule at a particular pH, which is a predictor of partitioning of the lipid between water and octanol as a function of pH. More specifically, cLogD is calculated at a specified pH based on cLogP and c-pKa. (LogP is the partition coefficient of a lipid molecule between aqueous (e.g., water) and lipophilic (e.g., octanol) phases). Numerous software packages are available to calculate cLogD values.
  • ionizable cationic lipids of this disclosure having a structure of formula M3 or M6, as R 1 increases from C 6 -C 10 , the increase overall lipophilicity of the ionizable cationic lipid will increase, as represented by cLogD.
  • Each of the ionizable cationic lipid species described herein have a cLogD and c-pKa values within the desired range(s), as described herein.
  • Specific cLogD and c-pKa values have been calculated using ACD Labs Structure Designer v 12.0 for ionic cationic lipids of the disclosure.
  • cLogP was calculated using ACD Labs Version B; cLogD was calculated at pH 7.4.
  • Table 1 shows cLogD and c-pKa for CICL-251 – CICL-290. Table 1.
  • the ionizable cationic lipid has the structure CICL-252:
  • CICL-252 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 , A 4 , and A 5 are CH 2 , W is CH, and the tail groups are symmetrically placed relative to the ring nitrogen in a cis configuration.
  • CICL-252 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • Other embodiments include diastereomers of this compound (e.g., CICL-253), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-253:
  • CICL-253 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, and A 3 , A 4 , and A 5 are CH 2 , W is CH, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • CICL-253 was synthesized as a racemate so that the structure drawn above indicates the relative stereochemistry for this lipid.
  • Other embodiments include the absolute stereochemistry drawn above, its enantiomer, and mixtures of the enantiomers with various ratios.
  • Other embodiments include diastereomers of these compounds (e.g., CICL-252), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-251:
  • CICL-251 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-153:
  • CICL-251-153 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-153 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-154: CICL-251-154 CICL-251-154 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-154 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-155:
  • CICL-251-155 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-155 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-156:
  • CICL-251-156 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-156 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-157: CICL-251-157 CICL-251-157 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-157 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-158:
  • CICL-251-158 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-158 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-159: CICL-251-159 CICL-251-159 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-159 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-160: CICL-251-160 CICL-251-160 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-160 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-161: CICL-251-161 CICL-251-161 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-161 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-162:
  • CICL-251-162 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-162 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-163:
  • CICL-251-163 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-163 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-164:
  • CICL-251-164 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-164 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-165: CICL-251-165 CICL-251-165 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-165 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-166:
  • CICL-251-166 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-166 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-167:
  • CICL-251-167 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-167 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-168: CICL-251-168 CICL-251-168 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-168 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-251-169:
  • CICL-251-169 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-251-169 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-254:
  • CICL-254 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a cis configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-254 (CICL- 256) and mixtures of the enantiomers (e.g., racemate, or other mixtures with various ratios).
  • Other embodiments include diastereomers of this compound (e.g., CICL-255), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-255:
  • CICL-255 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-255 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-256:
  • CICL-256 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a cis configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-256 (CICL- 254) and mixtures of the enantiomers (e.g., racemate, or other mixtures with various ratios).
  • Other embodiments include diastereomers of this compound (e.g., CICL-255), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-257:
  • CICL-257 is an example of a lipid as disclosed herein in which A 3 , A 4 , and A 5 are absent, A 1 and A 2 are CH 2 , W is CH, and the tail groups are symmetrically placed relative to the ring nitrogen in a cis configuration .
  • CICL-257 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • Other embodiments include diastereomers of this compound (e.g., CICL-258), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-258:
  • CICL-258 CICL-258 is an example of a lipid as disclosed herein in which A 3 , A 4 , and A 5 are absent, A 1 and A 2 are CH 2 , W is CH, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-258 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • Other embodiments include diastereomers of these compounds (e.g., CICL-257), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-259:
  • CICL-259 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 are CH 2 , A 5 is CH 2 CH 2 , W is CH, and the tail groups are symmetrically placed relative to the ring nitrogen in a cis configuration.
  • CICL-259 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • Other embodiments include diastereomers of this compound (e.g., CICL-260), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-260:
  • CICL-260 is an example of a lipid as disclosed herein in A 1 and A 2 are absent, A 3 and A 4 are CH 2 , A 5 is CH 2 CH 2 , W is CH, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-260 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • Other embodiments include diastereomers of these compounds (e.g., CICL-259), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-261:
  • CICL-261 is an example of a lipid as disclosed herein in which A 1 , A 2 , and A 5 are CH 2 , and A 3 and A 4 are absent, W is CH, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-261 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-262:
  • CICL-262 is an example of a lipid as disclosed herein in which A 1 , A 2 , and A 5 are CH 2 , A 3 and A 4 are absent, W is CH, and the tail groups are symmetrically placed relative to the ring nitrogen in a cis configuration.
  • CICL-262 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • Other embodiments include diastereomers of this compound (e.g., CICL-261), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-263:
  • CICL-263 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 , are CH 2 , A 5 is CH 2 CH 2 CH 2 , W is CH, and the tail groups are symmetrically placed relative to the ring nitrogen in a cis configuration.
  • CICL-263 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • Other embodiments include diastereomers of this compound (e.g., CICL-264), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-264:
  • CICL-264 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 , are CH 2 , A 5 is CH 2 CH 2 CH 2 , W is CH, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • CICL-264 was synthesized as a racemate, so that the structure drawn above indicates the relative stereochemistry for this lipid.
  • Other embodiments include the absolute stereochemistry drawn above, its enantiomer, and mixtures of the enantiomers with various ratios.
  • Other embodiments include diastereomers of these compounds (e.g., CICL-263), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-265:
  • CICL-265 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • Other embodiments include diastereomers of this compound (e.g., CICL-266), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-266:
  • CICL-266 was synthesized as a racemate so that the structure drawn above indicates the relative stereochemistry for this lipid.
  • Other embodiments include the absolute stereochemistry drawn above, its enantiomer and mixtures of the enantiomers with various ratios.
  • Other embodiments include diastereomers of these compounds (e.g., CICL-265), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic structure has the structure CICL-267:
  • CICL-267 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 are CH 2 , A 5 is CH 2 CHCHCH 2 , W is CH, and the tail groups are symmetrically placed relative to the ring nitrogen in a cis configuration.
  • CICL-267 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • Other embodiments include diastereomers of this compound (e.g., CICL-268), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-268:
  • CICL-268 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 are CH 2 , A 5 is CH 2 CHCHCH 2 , W is CH, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • CICL-268 was synthesized as a racemate so the structure drawn above indicates the relative stereochemistry for this lipid.
  • Other embodiments include the absolute stereochemistry drawn above, its enantiomer, and mixtures of the enantiomers with various ratios.
  • the ionizable cationic lipid has the structure CICL-269:
  • CICL-269 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 are CH 2 , A 5 is CH 2 (CH 2 ) 2 CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a cis configuration.
  • CICL-269 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • the ionizable cationic lipid has the structure CICL-270:
  • CICL-270 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 are CH 2 , A 5 is CH 2 (CH 2 ) 2 CH 2 , W is CH, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • CICL-270 was synthesized as a racemate so the structure drawn above indicates the relative stereochemistry for this lipid.
  • the ionizable cationic lipid has the structure CICL-271:
  • CICL-271 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 , A 4 , and A 5 are CH 2 , W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a cis configuration.
  • CICL-271 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • Other embodiments include diastereomers of this compound (e.g., CICL-272), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-272:
  • CICL-272 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, and A 3 , A 4 , and A 5 are CH 2 , W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • the ionizable cationic lipid has the structure CICL-273:
  • CICL-273 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is N, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-273 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • Other embodiments include diastereomers of these compounds (e.g., CICL-274 and CICL-275), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-274:
  • CICL-274 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, A 2 , A 3 , and A 5 are CH 2 , W is N, and the tail groups are asymmetrically placed relative to the ring nitrogen in a cis configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-274 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-275: CICL-275 CICL-275 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, A 2 , A 3 , and A 5 are CH 2 , W is N, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • CICL-275 CICL- 273
  • mixtures of the enantiomers e.g., a racemate, or other mixtures with various ratios.
  • Other embodiments include diastereomers of these compounds (e.g., CICL-274 and CICL- 276), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-276:
  • CICL-276 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is N, and the tail groups are asymmetrically placed relative to the ring nitrogen in a cis configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-276 (CICL- 274) and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-277: CICL-277 CICL-277 is an example of a lipid as disclosed herein in which A 3 , A 4 , and A 5 are absent, A 1 and A 2 are CH 2 , W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a cis configuration . CICL-277 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • the ionizable cationic lipid has the structure CICL-278: CICL-278 CICL-278 is an example of a lipid as disclosed herein in which A 3 , A 4 , and A 5 are absent, A 1 and A 2 are CH 2 , W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • the ionizable cationic lipid has the structure CICL-279: CICL-279 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 are CH 2 , A 5 is CH 2 CH 2 , W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a cis configuration.
  • the ionizable cationic lipid has the structure CICL-280:
  • CICL-280 is an example of a lipid as disclosed herein in A 1 and A 2 are absent, A 3 and A 4 are CH 2 , A 5 is CH 2 CH 2 , W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • the ionizable cationic lipid has the structure of CICL-281:
  • CICL-281 is an example of a lipid as disclosed herein in which A 1 , A 2 , and A 5 are CH 2 , and A 3 and A 4 are absent, W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-281 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • Other embodiments include diastereomers of these compounds (e.g., CICL-282), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-282:
  • CICL-282 is an example of a lipid as disclosed herein in which A 1 , A 2 , and A 5 are CH 2 , A 3 and A 4 are absent, W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a cis configuration.
  • CICL-282 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • Other embodiments include diastereomers of this compound (e.g., CICL-281), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-283:
  • CICL-283 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 , are CH 2 , A 5 is CH 2 CH 2 CH 2 , W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a cis configuration.
  • CICL-283 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • Other embodiments include diastereomers of this compound (e.g., CICL-284), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-284:
  • CICL-284 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 , are CH 2 , A 5 is CH 2 CH 2 CH 2 , W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • CICL-284 was synthesized as a racemate so the structure drawn above indicates the relative stereochemistry for this lipid.
  • Other embodiments include the absolute stereochemistry drawn above, its enantiomer, and mixtures of the enantiomers with various ratios.
  • Other embodiments include diastereomers of these compounds (e.g., CICL-283), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-285:
  • CICL-285 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • Other embodiments include diastereomers of this compound (e.g., CICL-286), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-286:
  • CICL-286 was synthesized as a racemate so the structure drawn above indicates the relative stereochemistry for this lipid.
  • Other embodiments include the absolute stereochemistry drawn above, its enantiomer and mixtures of the enantiomers with various ratios.
  • the ionizable cationic lipid has the structure CICL-287:
  • CICL-287 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 are CH 2 , A 5 is CH 2 CHCHCH 2 , W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a cis configuration.
  • CICL-287 is symmetric with the two nominal cis configurations being superimposable, due to the tail groups being identical.
  • the ionizable cationic lipid has the structure CICL-288:
  • CICL-288 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 are CH 2 , A 5 is CH 2 CHCHCH 2 , W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • CICL-288 was synthesized as a racemate so the structure drawn above indicates the relative stereochemistry for this lipid.
  • the ionizable cationic lipid has the structure CICL-289:
  • CICL-289 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 are CH 2 , A 5 is CH 2 (CH 2 ) 2 CH 2 , W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a cis configuration.
  • the ionizable cationic lipid has the structure CICL-290:
  • CICL-290 is an example of a lipid as disclosed herein in which A 1 and A 2 are absent, A 3 and A 4 are CH 2 , A 5 is CH 2 (CH 2 ) 2 CH 2 , W is N, and the tail groups are symmetrically placed relative to the ring nitrogen in a trans configuration.
  • CICL-290 was synthesized as a racemate so the structure drawn above indicates the relative stereochemistry for this lipid.
  • Other embodiments include the absolute stereochemistry drawn above, its enantiomer, and mixtures of the enantiomers with various ratios.
  • Other embodiments include diastereomers of these compounds (e.g., CICL-289), as well as mixtures including two or more of the various stereoisomers.
  • the ionizable cationic lipid has the structure CICL-304:
  • CICL-304 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • the ionizable cationic lipid has the structure CICL-305:
  • CICL-305 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the first tail group i.e., the 2S tail group
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-305 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-306:
  • CICL-306 CICL-306 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the second tail group i.e., the 4R tail group
  • the ionizable cationic lipid has the structure CICL-307:
  • CICL-307 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-307 and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-308:
  • CICL-308 is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the second tail group i.e., the 4R tail group
  • the ionizable cationic lipid has the structure CICL-308a: CICL-308a CICL-308a is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • Other embodiments include the enantiomer of CICL-308a and mixtures of the enantiomers (e.g., a racemate, or other mixtures with various ratios).
  • the ionizable cationic lipid has the structure CICL-308b:
  • CICL-308b is an example of a lipid as disclosed herein in which A 1 and A 4 are absent, and A 2 , A 3 , and A 5 are CH 2 , W is CH, and the tail groups are asymmetrically placed relative to the ring nitrogen in a trans configuration.
  • first tail group i.e., the 2S tail group
  • second tail group i.e., the 4R tail group
  • the structure drawn above indicates the absolute stereochemistry for this lipid.
  • the ionizable cationic lipid has the structure of the following:
  • the ionizable cationic lipid has the structure of the following: [00413]
  • R 4 is H.
  • R 4 is a protecting group (i.e., PG 1 ).
  • PG 1 can be selected from base labile or acid labile protecting groups as known in the art.
  • R 4 is an acid labile protecting group such as t-butoxycarbonyl (BOC) or benzyloxycarbonyl (Cbz).
  • R 4 is a base labile protecting group such as a trimethylsilylethoxycarbonyl moiety.
  • R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , A 4 , and A 5 are as otherwise described here.
  • a 1 through A 4 are such that there are only two main chain atoms between the ring nitrogen and each nearest ester oxygen in the nearest tail group.
  • each A 1 , A 2 , A 3 , and A 4 is independently (CH 2 ) 0 or (CH 2 ) 1 , provided that A 1 is (CH 2 ) 1 when A 3 is (CH 2 ) 0 ; A 1 is (CH 2 ) 0 when A 3 is (CH 2 ) 1 ; A 2 is (CH 2 ) 1 when A 4 is (CH 2 ) 0 ; and A 2 is (CH 2 ) 0 when A 4 is (CH 2 ) 1 .
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 1.
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 0
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 1 .
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • the lipid (e.g., intermediate lipid) of this disclosure have a structure of formula M6-6, a stereoisomer thereof, or a mixture of such stereoisomers:
  • R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , A 4 , and A 5 are as otherwise described here.
  • a 1 through A 4 are such that there are only two main chain atoms between the ring nitrogen and each nearest ester oxygen in the nearest tail group.
  • each A 1 , A 2 , A 3 , and A 4 is independently (CH 2 ) 0 or (CH 2 ) 1 , provided that A 1 is (CH 2 ) 1 when A 3 is (CH 2 ) 0 ; A 1 is (CH 2 ) 0 when A 3 is (CH 2 ) 1 ; A 2 is (CH 2 ) 1 when A 4 is (CH 2 ) 0 ; and A 2 is (CH 2 ) 0 when A 4 is (CH 2 ) 1 .
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 1.
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 0
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 1 .
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • R 4 is a protecting group (i.e., PG 1 ).
  • PG 1 can be selected from base labile or acid labile protecting groups as known in the art.
  • R 4 is an acid labile protecting group such as t-butoxycarbonyl (BOC) or benzyloxycarbonyl (Cbz).
  • R 4 is a base labile protecting group such as a trimethylsilylethoxycarbonyl moiety.
  • R 1 , A 1 , A 2 , A 3 , A 4 , and A 5 are as otherwise described here.
  • a 1 through A 4 are such that there are only two main chain atoms between the ring nitrogen and each nearest ester oxygen in the nearest tail group.
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 1.
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 0 .
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 1
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 1 through A 4 are such that there are only two main chain atoms between the ring nitrogen and each nearest ester oxygen in the nearest tail group.
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 0
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 1
  • a 1 is (CH 2 ) 0
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 1
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 1.
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 0 .
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • a 5 is (CH 2 ) 1
  • a 1 is (CH 2 ) 1
  • a 2 is (CH 2 ) 1
  • a 3 is (CH 2 ) 0
  • a 4 is (CH 2 ) 0
  • the fatty acid tails are designed to comprise esters in a position that minimizes steric hindrance of ester cleavage.
  • the fatty acid tails can also move through less energetically favorable positions.
  • one of the tails can extend toward the carbonyl and sterically hinders cleavage of the ester.
  • the ester carbonyl of a tail group there is at least one carbon atom between the ester carbonyl of a tail group and the branch point (i.e., W, as described herein). In certain embodiments, there are at least two atoms between the ester carbonyl of a tail group and the branch point (i.e., W, as described herein).
  • W branch point
  • esters i.e., the esters nearest to the central branchpoint nitrogen atom
  • the transesterification would be a simple intramolecular ester exchange and no piece of the molecule would be released. Accordingly, to promote biodegradation, it is advantageous for a methylene to be at an alpha position of W.
  • An advantage of ionizable cationic lipids of this disclosure is that, at least in part, the toxicity associated with quaternary ammonium cationic lipids can be avoided.
  • the use of ionizable cationic lipids of this disclosure in an LNP obviates the need for quaternary ammonium cationic lipids and, thereby, can mitigate or avoid potential LNP toxicity.
  • use of an LNP or tLNP of this disclosure causes no detectable toxicity to cells or in a subject.
  • use of an LNP or tLNP of this disclosure causes no more than mild toxicity to cells or in a subject that is asymptomatic or induces only mild symptoms that do not require intervention. In certain embodiments, use of an LNP or tLNP of this disclosure causes no more than moderate toxicity to cells or in a subject which may impair activities of daily living that requires only minimal, local, or non-invasive interventions.
  • the relationship between the efficacy and toxicity of a drug is generally expressed in terms of therapeutic window and therapeutic index. Therapeutic window is the dose range from the lowest dose that exhibits a detectable therapeutic effect up to the maximum tolerated dose (MTD); the highest dose that will the desired therapeutic effect without producing unacceptable toxicity.
  • MTD maximum tolerated dose
  • therapeutic index is calculated as the ratio of LD 50 :ED 50 when based on animal studies and TD 50 :ED 50 when based on studies in humans (though this calculation could also be derived from animal studies and is sometimes called the protective index), where LD 50 , TD 50 , and ED 50 are the doses that are lethal, toxic, and effective in 50% of the tested population, respectively.
  • LD 50 , TD 50 , and ED 50 are the doses that are lethal, toxic, and effective in 50% of the tested population, respectively.
  • Toxicities and adverse events can be graded according to a 5-point scale. A grade 1 or mild toxicity is asymptomatic or induces only mild symptoms; may be characterized by clinical or diagnostic observations only; and intervention is not indicated.
  • a grade 2 or moderate toxicity may impair activities of daily living (such as preparing meals, shopping, managing money, using the telephone, etc.) but only minimal, local, or non-invasive interventions are indicated.
  • Grade 3 toxicities are medically significant but not immediately life- threatening; hospitalization or prolongation of hospitalization is indicated; activities of daily living related to self-care (such as bathing, dressing and undressing, feeding oneself, using the toilet, taking medications, and not being bedridden) may be impaired.
  • Grade 4 toxicities are life-threatening and urgent intervention is indicated.
  • Grade 5 toxicity produces an adverse event-related death.
  • a toxicity is confined to grade 2 or less, grade 1 or less, or produces no observed toxicity.
  • LNPs deliver primarily to the liver. Liver toxicity has been the major dose-limiting parameter observed with LNP-containing pharmaceuticals.
  • ONPATTRO® comprising the ionizable lipid MC3
  • NOAEL no observed adverse effect level
  • a benchmark LNP comprising the ionizable cationic lipid ALC-0315, used in the SARS-CoV-2 vaccine COMIRNATY®, caused elevated levels of liver enzymes and acute phase proteins at single doses of ⁇ 1 mg/kg in the rat.
  • this disclosure provides methods for synthesizing an ionizable cationic lipid of formula M6 (e.g., CICL-304, CICL-305, CICL-306, CICL-307, CICL-308, CICL- XX1, and CICL-XX2).
  • an ionizable cationic lipid of formula M6 e.g., CICL-304, CICL-305, CICL-306, CICL-307, CICL-308, CICL- XX1, and CICL-XX2.
  • this disclosure provides methods for synthesizing an ionizable cationic lipid of formula M3 (e.g., CICL-251, CICL-252, CICL-253, CICL-254, CICL-255, CICL- 256, CICL-256, CICL-257, CICL-258, CICL-259, CICL-260, CICl-261, CICL-262, CICL-263, CICL-264, CICL-265, CICL-266, CICL-267, CICL-268, CICL-269, CICL-270, CICL-271, CICL- 272, CICL-273, CICL-274, CICL-275, CICL-276, CICL-277, CICL-278, CICL-279, CICL-280, CICL-281, CICL-282, CICL-283, CICL-284, CICL-285, CICL-2
  • this disclosure provides methods for synthesizing an ionizable cationic lipid of formula M6 comprising the synthesis step as shown in Scheme M6, A- is an anion of an acid AH, and the rest of the substituents are defined the same as in formula M6.
  • the method further comprises the synthesis step shown in Scheme 4-A.
  • a particular stereoisomer of the ionizable cationic lipid of formula M6 can be prepared according to the synthesis method disclosed herein with starting materials and/or intermediates having the same stereochemistry.
  • Formula M6 allows for the esters constituted by R 2 and R 3 to be oriented in either direction in various combinations among the 4 positions within the lipid where the R 2 /R 3 esters occur.
  • the tails containing the R 2 /R 3 esters attach to the ring at equivalent or non-equivalent positions depending on the particular species to be synthesized. More detailed synthetic schemes leading to each of the tail configurations encompassed by Formula M6 are set out in Schemes M3, M6-1, M6-2, M6-3, and M-4. [00458]
  • the lipid preparations, described in Schemes M6, M3, M6-1, M6-2, M6-3, and M- 4 utilize the coupling of a mono-acid 2-A, 2-B, 2-C, or 2-D with a protected (PG 1 ) diol 4-A.
  • a 1 , A 2 , A 3 , A 4 , and A 5 sections of 4-A when combined with the stereochemistry of the -A 3 -OH and -A 4 -OH moieties will result in the individual hydroxyl moieties either being identical/symmetric or regioisomeric/stereoisomeric.
  • the coupling of 4-A with an excess (> 2 eq.) of 2-A, 2-B, 2-C, or 2-D will afford bis-esters 5.
  • Lipid synthesis is completed upon removal of an acid-labile protecting group (PG1) with an acid HA, to give an amine salt, followed by a reaction with carbonyldiimidazole (CDI), giving imidazolecarboxyamides 7.
  • PG1 acid-labile protecting group
  • CDI carbonyldiimidazole
  • this disclosure provides methods for synthesizing an ionizable cationic lipid of formula M3 comprising the synthesis step as shown in Scheme M3, A- is an anion of an acid AH, and the rest of the substituents are defined the same as in formula M3.
  • the method further comprises the synthesis step shown in Scheme 4-A.
  • a particular stereoisomer of the ionizable cationic lipid of formula M3 can be prepared according to the synthesis method disclosed herein with starting materials and/or intermediates having the same stereochemistry.
  • this disclosure provides methods for synthesizing an ionizable cationic lipid of formula M6-1 comprising the synthesis steps as shown in Scheme M6-1, A- is an anion of an acid AH, and the rest of the substituents are defined the same as in formula M3.
  • the method further comprises the synthesis step shown in Scheme 4-A.
  • a particular stereoisomer of the ionizable cationic lipid of formula M6- 1 can be prepared according to the synthesis method disclosed herein with starting materials and/or intermediates having the same stereochemistry.
  • the method can further comprise synthesis of the diester- amine 6-B, 6-A, and/or 6-C comprising deprotecting a protected diester-amine 5-B, 5-A, and/or 5-C to provide the unprotected diester-amine 6-B, 6-A, and/or 6-C.
  • the deprotection can be carried out under reductive (hydrogen and a catalyst), acidic or basic conditions, depending on the protecting group (PG 1 ).
  • the deprotection step can be carried out under an acidic condition (e.g., in the presence of an acid HA, such as trifluoroacetic acid, TFA, when the protecting groups is an acid labile protecting group, e.g., t-butoxycarbonyl (BOC)) in an organic solution (e.g., CH 2 Cl 2 ) as illustrated in Schemes M6, M3, and M6-1.
  • an acidic condition e.g., in the presence of an acid HA, such as trifluoroacetic acid, TFA, when the protecting groups is an acid labile protecting group, e.g., t-butoxycarbonyl (BOC)
  • an organic solution e.g., CH 2 Cl 2
  • the method further comprises synthesis of the protected diester-amine 5-B, 5-A, and/or 5-C comprising coupling an unprotected diester-acid 2-B, 2-A, and/or 2-C with a desired diol-amine protected by a protecting group (PG 1 ) (diol-protected amine 4-A) to form protected diester-amine 5-B, 5-A, and/or 5-C.
  • PG 1 protecting group
  • the coupling reaction is carried out in an organic solvent (e.g., acetonitrile) in the presence of a nucleophilic catalyst (e.g., DMAP) and an acidic catalyst (e.g., 1-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC-HCl)).
  • a nucleophilic catalyst e.g., DMAP
  • an acidic catalyst e.g., 1-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC-HCl)
  • PG 1 can be a be a benzyloxycarbonyl (Cbz) that can be removed in the presence of hydrogen and a Pd/C catalyst.
  • Cbz benzyloxycarbonyl
  • a base labile PG 1 such as trimethylsilylethoxycarbonyl moiety, can also be used and be removed with nBuNH 4 or HF- pyridine.
  • reductive and basic removal can be done in a manner to avoid undesired reaction paths and side products.
  • this disclosure provides methods for synthesizing an ionizable cationic lipid of formula M6-2 comprising the synthesis steps as shown in Scheme M6-2,
  • the use of ca.1 equivalent of 2-D in an initial reaction with 4-A results in the formation of mono-ester isomers 8-D and 9-D if the nature of 4A is such that OH groups appended to A 3 and A 4 are non-equivalent/non-symmetrical.
  • the method further comprises the synthesis step shown in Scheme 4-A.
  • Particular regioisomeric/stereoisomeric forms of the ionizable cationic lipids of formula M6-2A and M6- 2B can be prepared according to the synthesis method disclosed herein with starting materials and/or intermediates having the same stereochemistry.
  • this disclosure provides methods for synthesizing an ionizable cationic lipid of formula M6-3 comprising the synthesis steps as shown in Scheme M6-3,
  • the use of ca.1 equivalent of 2-A in an initial reaction with 4-A results in the formation of mono-ester isomers 8-A and 9-A if the nature of 4A is such that OH groups appended to A 3 and A 4 are non-equivalent/non-symmetrical.
  • the method further comprises the synthesis step shown in Scheme 4-A.
  • Particular regioisomeric/stereoisomeric forms of the ionizable cationic lipids of formula M6-3A and M6- 3B can be prepared according to the synthesis method disclosed herein with starting materials and/or intermediates having the same stereochemistry.
  • the method further comprises the synthesis step shown in Scheme 4-A.
  • Particular regioisomeric/stereoisomeric forms of the ionizable cationic lipids of formula M6-4A and M6- 4B can be prepared according to the synthesis method disclosed herein with starting materials and/or intermediates having the same stereochemistry.
  • 8-A and 9- A would be identical, resulting in the production of a single ionizable cationic lipid M6-4 as M6- 4A and M6-4B would be identical.
  • the synthesis steps shown in Schemes M6-2, M6-3, and M6-4 comprises reacting protected amines 5-DC/5-CD, 5-AC/5-CA, and 5-AD/5-DA respectively, with an acid HA followed by a reaction with CDI to provide imidazolecarboxyamides 7-DC/7-CD, 7-AC/7- CA, and 7-AD/7-DA respectively, which are then reacted with MeOTf to give activated imidazolecarboxyamides which are coupled with a desired alcohol/thiol/amine to provide corresponding carbamates/thiocarbamates/ureas having the structures M6-2A/M6-2B, M6- 3A/M6-3B, and M6-4A/M6-4B respectively.
  • the imidazolecarboxyamide 7-B, 7-A, 7-C, 7-DC/7-CD, 7- AC/7-CA, and/or 7-AD/7-DA synthesis is carried out in an organic solvent (e.g., without limitation, CH 2 Cl 2 ) in the presence of a basic catalyst (e.g., without limitation, trimethylamine).
  • an organic solvent e.g., without limitation, CH 2 Cl 2
  • a basic catalyst e.g., without limitation, trimethylamine
  • the carbamate/thiocarbamate/urea synthesis can comprise first reacting the imidazolecarboxyamide 7-B, 7-A, 7-C, 7-DC/7-CD, 7-AC/7-CA, and/or 7-AD/7- DA with methyl trifluoromethanesulfonate, then reacting with the desired alcohol/thiol/amine (HX) in the presence of a base (e.g., trimethylamine).
  • a base e.g., trimethylamine
  • the reaction can be carried out in an organic solvent (e.g., acetonitrile).
  • HX is an alcohol, wherein X is as described herein.
  • HX is a thiol, wherein X is as described herein.
  • HX is an amine, wherein X is as described herein.
  • HX is an alcohol/thiol/amine that provides that desired X group to the lipids of formula M6 and M3.
  • HX is selected from the group
  • HX is O, NH, NCH 3 .
  • the various HX compounds disclosed herein are commercially available, are known in the scientific literature, or can be made using procedures familiar to the person of ordinary skill in the art, provided from commercial sources, or the general procedures described in the Examples below.
  • HX is selected from any one of , , , , , , [00469]
  • the method further comprises synthesis of the diol- protected amine 4-A as shown in Scheme 4-A, comprising reacting a benzyl diol-amine 3-A with a dicarbonate (e.g., (PG 1 ) 2 O such as di-tert-butyl dicarbonate (BOC 2 O)) in the presence of a catalyst (e.g., Pd(OH) 2 ) and hydrogen to provide the diol-protected amine 4-A.
  • a dicarbonate e.g., (PG 1 ) 2 O such as di-tert-butyl dicarbonate (BOC 2 O)
  • a catalyst e.g., Pd(OH) 2
  • THF can be substituted, for example, without limitation, by DMF, diethyl ether, methyl t-butyl ether, dioxane, or 2-methyl THF.
  • Ethyl acetate can be substituted by, for example, without limitation, isopropyl acetate, THF, 2-methyl THF, dioxane, or methyl t-butyl ether.
  • Dichloromethane can be substituted by, for example, without limitation, ethyl acetate, isopropyl acetate, THF, methyl t-butyl ether, 2-methyl THF, dioxane, or heptane.
  • Methanol can be substituted by, for example, without limitation, ethanol, iso-propanol, or aqueous THF.
  • Acetonitrile can be substituted by, for example, THF, 2-methyl THF, dichloromethane, ethyl acetate, isopropyl acetate, methyl t-butyl ether, or toluene.
  • any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins.
  • the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Still, Kahn, Mitra, J. Org. Chem.1978, 43, 2923-292, Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, ed E. Stahl, Springer-Verlag, New York, 1969. [00474] During any of the processes for preparation of the subject compounds, it can be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned.
  • compounds of structural formula M3 can be prepared according to Scheme M3, Scheme 4A, general procedures (see the Examples below), and/or analogous synthetic procedures.
  • One of skill in the art can adapt the reaction sequences of Schemes M6, M3, and 4A, general procedures, and Examples described to fit the desired target molecule.
  • one of skill in the art will use different reagents to affect one or more of the individual steps or to use protected versions of certain of the substituents.
  • compounds of the disclosure can be synthesized using different routes altogether.
  • LNPs Lipid Nanoparticles
  • tLNPs Targeted LNPs
  • this disclosure provides an LNP comprising an ionizable cationic lipid of formula M3 and/or M6.
  • an LNP comprises an ionizable cationic lipid of formula M3 and/or M6 and a phospholipid, a sterol, a co-lipid, a PEGylated lipid, or a combination thereof.
  • the PEG-lipids are not functionalized PEG- lipids.
  • the PEG-lipids are functionalized PEG-Lipids.
  • the LNP comprises at least one PEG-lipid that is functionalized and at least PEG-lipid that is not functionalized.
  • this disclosure provides a targeted lipid nanoparticle (tLNP) comprising an ionizable cationic lipid of formula M3 and/or M6.
  • the aforementioned tLNP can further comprise one or more of a phospholipid, a sterol, a co-lipid, and a PEG-lipid, or a combination thereof, and a functionalized PEG-lipid.
  • “functionalized PEG-lipid” refers to a PEG-lipid in which the PEG moiety has been derivatized with a chemically reactive group that can be used for conjugating a targeting moiety to the PEG-lipid.
  • the functionalized PEG-lipid can be reacted with a binding moiety (e.g., an antibody or Fab) after the LNP is formed, so that the binding moiety is conjugated to the PEG portion of the lipid.
  • the conjugated binding moiety can thus serve as a targeting moiety for the tLNP.
  • a binding moiety of a LNP or tLNP comprises an antigen binding domain, an antigen, a ligand-binding domain of a receptor, or a receptor ligand.
  • a binding moiety comprises a complete antibody, an F(ab) 2 , an Fab, a minibody, a single-chain Fv (scFv), a diabody, a VH domain, or a nanobody, such as a VHH or single domain antibody.
  • the receptor ligand is a carbohydrate, for example, a carbohydrate comprising terminal galactose or N-acetylgalactosamine units, which are bound by the asialoglycoprotein receptor.
  • These binding moieties constitute means for LNP targeting. Some embodiments specifically include one or more of these binding moieties. Other embodiments specifically exclude one or more of these binding moieties.
  • LNP and tLNP Compositions [00479] The LNP composition contributes to the formation of stable LNPs and tLNPs, efficient encapsulation of a payload, protection of a payload from degradation until it is delivered into a cell, and promotion of endosomal escape of a payload into the cytoplasm.
  • LNP and tLNP compositions are generally disclosed in PCT/US2024/032141, filed 31 May 2024, published as WO2024/249954, and entitled Lipid Nanoparticle Formulations and Compositions, which is incorporated by reference for all that it teaches about the design, formation, characterization, properties, and use of LNPs and tLNPs.
  • the LNPs and/or tLNPs can include the various components in amounts sufficient to provide a nanoparticle with a desired shape, fluidity, and bio-acceptability as described herein.
  • the LNPs comprises at least one ionizable cationic lipid as described herein in an amount in the range of from about 35 to about 65 mol%, e.g., in an amount of from about 40 to about 65 mol%, about 40 to about 60 mol%.
  • the LNP or tLNP comprises about 58 mol% or 62 mol% ionizable cationic lipid.
  • is the LNP (or tLNP) comprises a phospholipid in an amount in the range of from about 7 to about 30 mol%, e.g., in an amount of from about 13 to about 30 mol%.
  • the LNP or tLNP comprises about 10 mol% phospholipid.
  • the LNP (or tLNP) comprises a sterol in an amount in the range of from about 20 to about 50 mol%, e.g., in an amount in the rage of from about 20 to about 45 mol%, or about 30 to about 50 mol%, or about 30 to about 45 mol%.
  • the LNP or tLNP comprises about 30.5, 26.5, or 23.5 mol% sterol.
  • the LNP (or tLNP) comprises at least one co-lipid in an amount in the range of from about 1 to about 30 mol%.
  • the LNP (or tLNP) comprises at least one unfunctionalized PEG-lipid in an amount of from 0 to about 5 mol%, e.g., in the range of amount 0 to about 3 mol%, or about 0.1 to about 5 mol%, or about 0.5 to about 5 mol%, or about 0.5 to about 3 mol%. In some embodiments, the LNP or tLNP comprises about 1.4 mol% unfunctionalized PEG-lipid. In some embodiments, the LNP or tLNP comprises at least one functionalized PEG-lipid in an amount in the range of from about 0.1 to about 5 mol%, e.g., in the range of from about 0.1 to 0.3 mol%.
  • the LNP or tLNP comprises about 0.1 mol% functionalized PEG-lipid.
  • the functionalized PEG-lipid is conjugated to a binding moiety.
  • this disclosure provides an LNP or tLNP, wherein the LNP or tLNP comprises about 35 mol% to about 65 mol% of an ionizable cationic lipid, about 0.5 mol% to about 3 mol% of a PEG-lipid (including non-functionalized PEG-lipid and optionally a functionalized PEG-lipid), about 7 mol% to about 13 mol% of a phospholipid, and about 30 mol% to about 50 mol% of a sterol.
  • an LNP or tLNP comprises a payload with a net negative charge for example, a peptide, a polypeptide, a protein, a small molecule, or a nucleic acid molecule, and combinations thereof.
  • a payload is generally encompassed by or in the interior of an LNP or tLNP.
  • dosages always refer to the amount of payload being provided.
  • a payload comprises one or more species of nucleic acid molecule.
  • tLNP encapsulating mRNA dosages are typically in the range of 0.05 to 5 mg/kg without regard for recipient species. In some embodiments, the dosage is in the range of 0.1 to 1 mg/kg.
  • the ratio of total lipid to nucleic acid is about 10:1 to about 50:1 on a weight basis. In some embodiments, the ratio of total lipid to nucleic acid is about 10:1, about 20:1, about 30:1, or about 40:1 to about 50:1, or 10:1 to 20:1, 30:1, 40:1 or 50:1, or any range bound by a pair of these ratios.
  • the N/P ratio is from about 3 to about 9, about 3 to about 7, about 3 to about 6, about 4 to about 6, about 5 to about 6, or about 6. In some instances, the N/P ratio is from 3 to 9, 3 to 7, 3 to 6, 4 to 6, 5 to 6, or 6.
  • an LNP or tLNP comprises about 40 mol% to about 62 mol% ionizable cationic lipid. In some embodiments, an LNP or tLNP comprises about 1 mol% to about 2 mol% total PEG-lipid.
  • an LNP or tLNP comprises about 0.1 mol% to about 0.3 mol%, for example about 0.1 mol%, about 0.2 mol%, or about 0.3 mol% functionalized PEG- lipid.
  • a binding moiety is conjugated to functionalized PEG-lipid.
  • a tLNP is an LNP that further comprises an antibody (for example, a whole IgG) as the binding moiety which is present at an antibody:mRNA ratio (w/w) of about 0.3 to about 1.0 w/w.
  • the LNP or tLNP has a hydrodynamic diameter of 50 to 150 nm and in some embodiments the hydrodynamic diameter is ⁇ 120, ⁇ 110, ⁇ 100, or ⁇ 90 nm. Uniformity of particle size is also desirable with a polydispersity index (PDI) of ⁇ 0.2 (on a scale of 0 to 1) being acceptable. Both hydrodynamic diameter and polydispersity index are determined by dynamic light scattering (DLS). Particle diameter as assessed from cryo-transmission electron microscopy (Cryo-TEM) can be smaller than the DLS-determined value.
  • Phospholipids [00484] As would be understood by the person or ordinary skill in the art, phospholipids are amphiphilic molecules.
  • phospholipids include a hydrophilic head group, including a functionalized phosphate group, and two hydrophobic tail groups derived from fatty acids.
  • the phospholipids include a phosphate group functionalized with ethanolamine, choline, glycerol, serine, or inositol.
  • the phospholipid includes two hydrophobic tail groups derived from fatty acids. These hydrophobic tail groups can be derived from unsaturated or saturated fatty acids.
  • a phospholipid comprises dioleoylphosphatidyl ethanolamine (DOPE), dimyristoylphosphatidyl choline (DMPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidyl glycerol (DMPG), dipalmitoyl phosphatidylcholine (DPPC), or 1,2-diarachidoyl-sn-glycero-3- phosphocholine (DAPC), or a combination thereof.
  • DOPE dioleoylphosphatidyl ethanolamine
  • DMPC dimyristoylphosphatidyl choline
  • DSPC distearoylphosphatidylcholine
  • DMPG dimyristoylphosphatidyl glycerol
  • DPPC dipalmitoyl phosphatidylcholine
  • DAPC 1,2-diarachidoyl-sn-glycero-3- phosphocholine
  • the phospholipid is selected from the group comprising dioleoylphosphatidyl ethanolamine (DOPE), dimyristoylphosphatidyl choline (DMPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidyl glycerol (DMPG), dipalmitoyl phosphatidylcholine (DPPC), or 1,2- diarachidoyl-sn-glycero-3-phosphocholine (DAPC).
  • DOPE dioleoylphosphatidyl ethanolamine
  • DMPC dimyristoylphosphatidyl choline
  • DSPC distearoylphosphatidylcholine
  • DMPG dimyristoylphosphatidyl glycerol
  • DPPC dipalmitoyl phosphatidylcholine
  • DAPC 1,2- diarachidoyl-sn-glycero-3-phosphocholine
  • the phospholipid is diste
  • Phospholipids can contribute to formation of a membrane, whether monolayer, bilayer, or multi-layer, surrounding the core of the LNP or tLNP. Additionally, phospholipids such as DSPC, DMPC, DPPC, DAPC impart stability and rigidity to membrane structure. Phospholipids, such as DOPE, impart fusogenicity. Further phospholipids, such as DMPG, which attains negative charge at physiologic pH, facilitates charge modulation. Thus, phospholipids constitute means for facilitating membrane formation, means for imparting membrane stability and rigidity, means for imparting fusogenicity, and means for charge modulation.
  • an LNP or tLNP has about 7 mol% to about 13 mol% phospholipid, about 7 mol% to about 10 mol% phospholipid, or about 10 mol% to about 13 mol% phospholipid. In certain embodiments, an LNP has about 7 mol%, about 10 mol%, or about 13 mol% phospholipid. In certain instances, the phospholipid is DSPC. In certain instances, the phospholipid is DAPC.
  • Sterols [00487] The disclosed LNP and tLNP comprise a sterol. Sterol refers to a subgroup of steroids that contain at least one hydroxyl (OH) group.
  • sterols include, without limitation, cholesterol, ergosterol, ⁇ -sitosterol, stigmasterol, stigmastanol, 20- hydroxycholesterol, 22-hydroxycholesterol, and the like.
  • a sterol is cholesterol, 20-hydroxycholesterol, 22- hydroxycholesterol, or a phytosterol.
  • the phytosterol comprises campesterol, sitosterol, or stigmasterol, or combinations thereof.
  • the cholesterol is not animal-sourced but is obtained by synthesis using a plant sterol as a starting point.
  • LNPs incorporating C-24 alkyl (such as methyl or ethyl) phytosterols have been reported to provide enhanced gene transfection.
  • the length of the alkyl tail, the flexibility of the sterol ring, and polarity related to a retain C-3 -OH group are important to obtaining high transfection efficiency. While ⁇ -sitosterol and stigmasterol performed well, vitamin D2, D3 and calcipotriol, (analogs lacking intact body of cholesterol) and betulin, lupeol ursolic acid and olenolic acid (comprising a 5 th ring) should be avoided.
  • Sterols serve to fill space between other lipids in the LNP or tLNP and influence LNP or tLNP shape. Sterols also control fluidity of lipid compositions, reducing temperature dependence. Thus, sterols such as cholesterol, 20-hydroxycholesterol, 22-hydroxycholesterol, campesterol, fucosterol, ⁇ -sitosterol, and stigmasterol constitute means for controlling LNP shape and fluidity or sterol means for increasing transfection efficiency. In designing a lipid composition for a LNP or tLNP, in some embodiments, sterol content can be chosen to compensate for different amounts of other types of lipids, for example, ionizable cationic lipid or phospholipid.
  • an LNP or tLNP has about 27 mol% or about 30 mol% to about 50 mol% sterol, or about 30 mol% to about 38 mol% sterol. In certain embodiments, an LNP or tLNP has about 30.5 mol%, about 33.5 mol%, or about 37.5 mol% sterol. In certain instances, the sterol is cholesterol. In certain embodiments, the sterol is a mixture of sterols, for example, cholesterol and ⁇ -sitosterol or cholesterol and 20-hydroxycholesterol. In some instances, the sterol is about 25 mol% 20-hydroxycholesterol and about 75 mol% cholesterol.
  • the sterol is about 25 mol% ⁇ -sitosterol and about 75 mol% cholesterol. In some instances, the sterol is about 50 mol% ⁇ -sitosterol and about 50 mol% cholesterol. In certain embodiments, an LNP or tLNP has 27 mol% or 30 mol% to 50 mol% sterol or 30 mol% to 38 mol% sterol. In further embodiments, an LNP or tLNP has 30.5 mol%, 33.5 mol%, or 37.5 mol% sterol. In certain instances, a sterol is cholesterol.
  • a sterol is a mixture of sterols, for example, cholesterol and ⁇ -sitosterol or cholesterol and 20- hydroxycholesterol. In some instances, a sterol is 25 mol% 20-hydroxycholesterol and 75 mol% cholesterol. In further instances, a sterol is 25 mol% ⁇ -sitosterol and 75 mol% cholesterol. In still further instances, a sterol is 50 mol% ⁇ -sitosterol and 50 mol% cholesterol. [00489] With respect to LNPs or tLNPs of this disclosure, in some embodiments, a co-lipid is absent or comprises an ionizable lipid, anionic or cationic.
  • a co-lipid can be used to adjust various properties of an LNP or tLNP, such as surface charge, fluidity, rigidity, size, stability, and the like properties.
  • a co-lipid is an ionizable lipid, such as cholesterol hemisuccinate (CHEMS) or an ionizable lipid of this disclosure.
  • CHEMS cholesterol hemisuccinate
  • a co-lipid is a charged lipid, such as a quaternary ammonium head group containing lipid.
  • a quaternary ammonium head group containing lipid comprises 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), N-(1-(2,3-dioleyloxy)propyl)- N,N,N-trimethylammonium (DOTMA), or 3 ⁇ -(N-(N’,N’- Dimethylaminoethane)carbamoyl)cholesterol (DC-Chol), or combinations thereof.
  • these compounds a chloride, bromide, mesylate, or tosylate salt.
  • the co-lipid is a quaternary ammonium head group containing lipid
  • the quaternary ammonium head group containing lipid makes up no more than 50 mol% of the total cationic lipid, for example, from 5 to 50% of the total cationic lipid.
  • an LNP or tLNP were to have cationic lipid content of 70 mol% and 5 to 50 mol% of the total cationic lipid as quaternary ammonium lipid, the LNP or tlNP would have from 3.5 mol% quaternary ammonium lipid and 66.5 mol% ionizable cationic lipid to 35 mol% each of quaternary ammonium lipid and ionizable cationic lipid.
  • the disclosed ionizable lipids of formula M3 and/or M6 have a measured pKa ranging from about 6 to about 7 or from 6 to 7, they can contribute substantial endosomal release activity to an LNP or tLNP containing the ionizable lipid. More acidic or basic ionizable lipids of formula M3 and/or M6 can contribute surface charge and thus serve as a co-lipid as described immediately above. In such cases, it can be advantageous to incorporate another lipid with fusogenic activity into an LNP or tLNP of this disclosure.
  • a PEG-lipid is a lipid conjugated to a polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • the PEG-lipid is a C 14 -C 20 lipid conjugated with a PEG.
  • the PEG-lipid is a C 14 -C 20 lipid conjugated with a PEG, or a C 14 -C 18 lipid conjugated with a PEG, or a C 14 -C 16 lipid conjugated with a PEG.
  • the PEG-lipid is a fatty acid conjugated with a PEG.
  • the fatty acid of the PEG-lipid can have a variety of chain lengths.
  • the PEG-lipid is a fatty acid conjugated with PEG, wherein the fatty acid chain length is in the range of C 14 -C 20 (e.g., in the range of C 14 -C 18 , or C 14 -C 16 ).
  • PEG-lipids with fatty acid chain lengths less than C 14 are too rapidly lost from the LNP or tLNP while those with chain lengths greater than C 20 are prone to difficulties with formulation.
  • the LNP comprises one or more PEG-lipids and/or functionalized PEG-lipids; when both a functionalized and unfunctionalized PEG-lipid, the PEG-lipid present they can be the same or different; and one or more ionizable cationic lipids; the LNP can further comprise a phospholipid, a sterol, a co-lipid, or any combination thereof.
  • the term “functionalized PEG-lipid” refers to a PEG-lipid in which the PEG moiety has been derivatized with a chemically reactive group that can be used for conjugating a targeting moiety to the PEG-lipid.
  • the functionalized PEG-lipid can be reacted with a binding moiety so that the binding moiety is conjugated to the PEG portion of the lipid.
  • the conjugated binding moiety can thus serve as a targeting moiety for the LNP to constitute a tLNP.
  • the binding moiety is conjugated to the functionalized PEG-lipid after an LNP comprising the functionalized PEG-lipid is formed.
  • the binding moiety is conjugated to the PEG-lipid and then the conjugate is inserted into a previously formed LNP.
  • the LNP is a tLNP comprising one or more functionalized PEG-lipids that has been conjugated to a binding moiety.
  • the tLNP also comprises PEG-lipids not functionalized or conjugated with a binding moiety.
  • the functionalization is a maleimide.
  • the functionalization is a bromomaleimide or bromomaleimide amide, alkynylamide, or alkynylimide moiety at the terminal hydroxyl end of the PEG moiety.
  • the binding moiety comprises an antibody or antigen binding portion thereof.
  • the binding moiety is a polypeptide comprising a binding domain and an N- or C-terminal extension comprising an accessible thiol group.
  • the conjugation linkage comprises a reaction product of a thiol in the binding moiety with a functionalized PEG-lipid.
  • the functionalization is a maleimide, azide, alkyne, dibenzocyclooctyne (DBCO), bromomaleimide or bromomaleimide amide, alkynylamide, or alkynylimide.
  • the binding moiety comprises an antibody or antigen binding portion thereof.
  • the binding moiety is a polypeptide comprising a binding domain and an N- or C-terminal extension comprising an accessible thiol group.
  • n ⁇ 22 to 113 is used to represent PEG-lipids incorporating PEG moieties in the range of PEG-1000 to PEG-5000 such as PEG-1000, PEG-1500, PEG-2000, PEG-2500, PEG-3000, PEG-3500, PEG-4000, PEG-4500, and PEG-5000, although some molecules from preparations at the average molecular weight boundaries will have an n outside that range.
  • n ⁇ 22 is used to represent PEG-lipids incorporating PEG moieties from PEG-1000
  • n ⁇ 45 is used to represent PEG-lipids incorporating PEG moieties from PEG-2000
  • n ⁇ 67 is used to represent PEG-lipids incorporating PEG moieties from PEG- 3000
  • n ⁇ 90 is used to represent PEG-lipids incorporating PEG moieties from PEG-4000
  • n ⁇ 113 is used to represent PEG-lipids incorporating PEG moieties from PEG-5000.
  • a PEG is of 500-5000 or 1000-5000 Da molecular weight (MW).
  • the PEG of the PEG-lipid has a molecular weight in the range of 1500-5000 Da or 2000-5000 Da.
  • the PEG-lipid has a molecular weight in the range of 500-4000 Da, or 500-3000 Da, or 1000-4000 Da, or 1000-3000, or 1000-2500, or 1500-4000, or 1500-3000, or 1500-2500 Da.
  • the PEG unit has a MW of 2000 Da (sometime abbreviated as PEG(2k)).
  • PEG moieties of PEG-1000, PEG-2000, or PEG-5000 comprise a DSG- PEG, for example, DSG-PEG-2000.
  • Certain embodiments comprise a DSPE-PEG, for example, DSPE-PEG-2000.
  • Certain embodiments comprise both DSG-PEG-2000 and/or DSPE-PEG2000.
  • the PEG moiety is PEG-500 to PEG-5000 such as PEG- 500, PEG-1000, PEG-1500, PEG-2000, PEG-2500, PEG-3000, PEG-3500, PEG-4000, PEG- 4500, and PEG-5000.
  • the PEG moiety is PEG-2000.
  • the PEG unit has a MW of 2000 Da.
  • Common PEG-lipids fall into two classes diacyl glycerols and diacyl phospholipids.
  • diacyl glycerol PEG-lipids include DMG-PEG (1,2-dimyristoyl-glycero-3- methoxypolyethylene glycol), DPG-PEG (1,2-dipalmitoyl-glycero-3-methoxypolyethylene glycol), DSG-PEG (1,2-distearoyl-glycero-3-methoxypolyethylene glycol), and DOG-PEG (1,2-dioleoyl-glycero-3-methoxypolyethylene glycol).
  • diacyl phospholipids examples include DMPE-PEG (1,2-dimyristoyl-glycero-3-phosphoethanolamine-3-methoxypolyethylene glycol), DPPE-PEG (1,2-dipalmitoyl-glycero-3-phosphoethanolamine-3-methoxypolyethylene glycol), DSPE-PEG (1,2-distearoyl-glycero-3-phosphoethanolamine-3-methoxypolyethylene glycol), and DOPE-PEG (1,2-dioleoyl-glycero-3-phosphoethanolamine-3- methoxypolyethylene glycol).
  • the MW2000 PEG-lipid (e.g., a PEG-lipid comprising a PEG of a molecular weight of 2000 Da) comprises DMG-PEG2000 (1,2-dimyristoyl-glycero-3- methoxypolyethylene glycol-2000), DPG-PEG2000 (1,2-dipalmitoyl-glycero-3- methoxypolyethylene glycol-2000), DSG-PEG2000 (1,2-distearoyl-glycero-3- methoxypolyethylene glycol-2000), DOG-PEG2000 (1,2-dioleoyl-glycero-3- methoxypolyethylene glycol-2000), DMPE-PEG200 (1,2-dimyristoyl-glycero-3- phosphoethanolamine-3-methoxypolyethylene glycol-2000), DPPE-PEG2000 (1,2- dipalmitoyl-glycero-3-phosphoethanolamine-3-methoxypolyethylene glycol-2000), DPPE-
  • the PEG unit has a MW of 2000 Da.
  • the MW2000 PEG-lipid comprises DMrG- PEG2000 (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000), DPrG-PEG2000 (1,2-dipalmitoyl-rac-glycero-3-methoxypolyethylene glycol-2000), DSrG-PEG2000 (1,2- distearoyl-rac-glycero-3-methoxypolyethylene glycol-2000), DorG-PEG2000 (1,2-dioleoyl- glycero-3-methoxypolyethylene-rac-glycol-2000), DMPEr-PEG200 (1,2-dimyristoyl-rac- glycero-3-phosphoethanolamine-3-methoxypolyethylene glycol-2000), DPPEr-PEG2000 (1,2-dipalmitoyl-rac-glycero-3-phosphoethanolamine-3-methoxypolyethylene glyco
  • the glycerol in these lipids is chiral.
  • the PEG-lipid is racemic.
  • optically pure antipodes of the glycerol portion can be employed, that is, the glycerol portion is homochiral.
  • optically pure means ⁇ 95% of a single enantiomer (D or L).
  • the enantiomeric excess is ⁇ 98%.
  • the enantiomeric excess is ⁇ 99%.
  • PEG-lipids including achiral PEG-lipids built on a symmetric dihydroxyacetone scaffold, a symmetric 2- (hydroxymethyl)butane-1,4-diol, or a symmetric glycerol scaffold, are disclosed in U.S. Provisional Application No.63/362,502, filed on April 5, 2022, and PCT/US2023/017648 filed on April 5, 2023 (WO 2023/196445), both entitled PEG-Lipids and Lipid Nanoparticles, which are incorporated by reference in their entirety. [00498] The above examples are presented as methoxypolyethylene glycols, but the terminus need not necessarily be methoxyl.
  • the PEG moiety of the PEG lipids can terminate with a methoxyl, a benzyloxyl, a 4-methoxybenzyloxyl, or a hydroxyl group (that is, an alcohol).
  • the terminal hydroxyl facilitates functionalization.
  • the methoxyl, benzyloxyl, and 4-methoxybenzyloxyl groups are advantageously provided for PEG-lipid that will be used without functionalization as a component of the LNP. However, all four of these alternatives are useful as the (non-functionalized) PEG-lipid component of LNPs.
  • the 4- methoxybenzyloxyl group is readily removed to generate the corresponding hydroxyl group.
  • the 4- methoxybenzyloxyl group offers a convenient path to the alcohol when it is not synthesized directly.
  • the alcohol is useful for being functionalized, prior to incorporation of the PEG-lipid into an LNP, so that a binding moiety can be conjugated to it as a targeting moiety for the LNP (making it a tLNP).
  • the terminus of the PEG moiety and similar constructions, refers to the end of the PEG moiety that is not attached to the lipid.
  • a PEG-moiety provides a hydrophilic surface on the LNP, inhibiting aggregation or merging of LNP, thus contributing to their stability and reducing polydispersity, i.e. reducing the heterogeneity of a dispersion of LNPs. Additionally, a PEG moiety can impede binding by the LNP, including binding to plasma proteins. These plasma proteins include apoE which is understood to mediate uptake of LNP by the liver so that inhibition of binding can lead to an increase in the proportion of LNP reaching other tissues. These plasma proteins also include opsonins so that inhibition of binding reduces recognition by the reticuloendothelial system.
  • the PEG-moiety can also be functionalized to serve as an attachment point for a targeting moiety. Conjugating a cell- or tissue-specific binding moiety to the PEG-moiety enables a tLNP to avoid the liver and bind to its target tissue or cell type, greatly increasing the proportion of LNP that reaches the targeted tissue or cell type. PEG-lipid can thus serve as means for inhibiting LNP binding, and PEG-lipid conjugated to a binding moiety can serve as means for LNP-targeting. [00500] As used herein, the term “functionalized PEG-lipid” and similar constructions refer generally to both the unreacted and reacted entities.
  • lipid composition of a LNP can be described referencing the reactive species even after conjugation has taken place (forming a tLNP).
  • a lipid composition can be described as comprising DSPE-PEG- maleimide and can be said to further comprise a binding moiety without explicitly noting that upon reaction to form the conjugate the maleimide will have been converted to a succinimide (or hydrolyzed succinimide).
  • the reactive group is bromomaleimide, after conjugation it will be maleimide.
  • Certain embodiments comprise a functionalized DSPE-PEG, for example, functionalized DSPE-PEG-2000. Certain embodiments comprise both DSG-PEG-2000 and functionalized DSPE-PEG-2000.
  • the functionalized PEG-lipid is functionalized with a maleimide moiety, for example, DSPE-PEG-2000-MAL.
  • DSG-PEG serves as the functionalized or functionalized and non-functionalized PEG-lipid.
  • the PEG-lipid and/or functionalized PEG-lipid comprises a scaffold selected from Formula S1, Formula S2, Formula S3, or Formula S4: wherein represents the points of ester connection with a fatty acid, and represents the point of ester (S1) or ether (S2, S3, and S4) formation with the PEG moiety.
  • the fatty acid esters are C 14 -C 20 straight-chain alkyl fatty acids.
  • the PEG moiety is functionalized and the fatty acid esters are C 16 -C 20 straight- chain alkyl fatty acids.
  • the straight-chain alkyl fatty acid is C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , or C 20 .
  • the fatty acid esters are C 14 -C 20 symmetric branched-chain alkyl fatty acids.
  • the branched-chain alkyl fatty acid is C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , or C 20 .
  • symmetric it is meant that each alkyl branch has the same number of carbons.
  • the branch is at the 3, 4, 5, 6, or 7 position of the fatty acid ester.
  • PEG-lipids built on scaffolds S1-S4 are disclosed in WO2023/196445A1 which is incorporated by reference for all that it teaches about PEG-lipids and their use.
  • Some embodiments of the disclosed ionizable cationic lipids have head groups with small ( ⁇ 250 Da) PEG moieties. These lipids are not what is meant by the term PEG-lipid as used herein. These small PEG moieties are generally too small to impede binding to a similar extent as the larger PEG moieties of the PEG-lipids disclosed above, though they will impact the lipophilicity of ionizable cationic lipid.
  • a functionalized PEG-lipid of a LNP or tLNP of this disclosure comprises one or more fatty acid tails, each of which is no shorter than C 16 nor longer than C 20 for straight-chain fatty acids. For branched chain fatty acids, tails no shorter than C 14 fatty acids nor longer than C 20 are acceptable. In some embodiments, fatty acid tails are C 16 . In some embodiments, the fatty acid tails are C 18 . In some embodiments, the functionalized PEG-lipid comprises a dipalmitoyl lipid.
  • the functionalized PEG-lipid comprises a distearoyl lipid.
  • the fatty acid tails serve as means to anchor the PEG-lipid in the tLNP to reduce or eliminate shedding of the PEG-lipid from the tLNP. This is a useful property for the PEG-lipid whether or not it is functionalized but has greater significance for the functionalized PEG-lipid as it will have a targeting moiety attached to it and the targeting function could be impaired if the PEG-lipid (with the conjugated binding moiety, such as an antibody) were shed from the tLNP.
  • an LNP or tLNP comprises about 0.5 mol% to about 3 mol% or 0.5 mol% to 3 mol% PEG-lipid comprising functionalized and non-functionalized PEG-lipid.
  • an LNP or tLNP comprises DSG-PEG.
  • an LNP or tLNP comprises DMG-PEG or DPG-PEG.
  • an LNP or tLNP comprises DSPE-PEG.
  • the functionalized and non-functionalized PEG-lipids are not the same PEG-lipid, for example, the non-functionalized PEG-lipid can be a diacylglycerol and the functionalized PEG-lipid a diacyl phospholipid.
  • tLNP with such mixtures have reduced expression in the liver, possibly due to reduced uptake.
  • the functionalized PEG-lipid is DSPE-PEG and the non-functionalized PEG-lipid is DSG-PEG.
  • an LNP or tLNP comprises about 0.4 mol% to about 2.9 mol% or about 0.9 mol% to about 1.4 mol% non-functionalized PEG lipid.
  • an LNP or tLNP comprises about 1.4 mol% or 1.4 mol% non-functionalized PEG lipid. In some embodiments, an LNP or tLNP comprises about 0.1 mol% to about 0.3 mol% or 0.1 mol% to 0.3 mol% functionalized lipid. In some instances, the functionalized lipid is DSPE-PEG. In certain instances, an LNP or tLNP comprises about 0.1 mol%, about 0.2 mol%, or about 0.3 mol% DSPE-PEG. In certain instances, an LNP or tLNP comprises 0.1 mol%, 0.2 mol%, or 0.3 mol% DSPE-PEG.
  • the functionalized PEG-lipid is conjugated to a binding moiety.
  • the phrase “is conjugated to” and similar constructions are meant to convey a state of being, that is, a structure, and not a process, unless context dictates otherwise.
  • Conjugation Any suitable chemistry can be used to conjugate the binding moiety to the PEG of the PEG-lipid, including maleimide (see Parhiz et al., J. Controlled Release 291:106, 2018) and click (see Kolb et al., Angewandte Chemie International Edition 40(11):2004, 2001; and Evans, Australian J. Chem.60(6):384, 2007) chemistries.
  • Reagents for such reactions include lipid-PEG-maleimide, lipid-PEG-cysteine, lipid-PEG-alkyne, lipid, PEG- dibenzocyclooctyne (DBCO), and lipid-PEG-azide. Further conjugations reactions make use of lipid-PEG-bromo maleimide, lipid-PEG-alkylnoic amide, PEG-alkynoic imide, and lipid-PEG-alkyne reactions, as disclosed in U.S. Provisional Application No.
  • the binding moiety e.g., an antibody
  • SATA N-succinimidyl S-acetylthioacetate
  • SATA is then deprotected, for example, using 0.5 M hydroxylamine followed by removal of the unreacted components by G-25 Sephadex Quick Spin Protein columns (Roche Applied Science, Indianapolis, IN).
  • the reactive sulfhydryl group on the binding moiety is then conjugated to maleimide moieties on LNPs of the disclosure using thioether conjugation chemistry.
  • an alkyne can be added to a sulfhydryl or an epsilon amino of a lysine to participate in a click chemistry reaction.
  • Purification can be performed using Sepharose CL-4B gel filtration columns (Sigma-Aldrich).
  • tLNPs LNPs conjugated with a targeting antibody
  • Others have conjugated antibody to free functionalized PEG-lipid and then incorporated the conjugated lipid into pre-formed LNP. However, it was found that this procedure is more controllable and produces more consistent results.
  • C-terminal extensions of native or artificial sequences containing a particularly accessible cysteine residue are commonly used. Partial reduction of cysteine bonds in an antibody, for example, with tris(2-carboxy)phosphine (TCEP), can also generate thiol groups for conjugation which can be site-specific under defined conditions with an amenable antibody fragment.
  • TCEP tris(2-carboxy)phosphine
  • the C-terminal extension can contain a sortase A substrate sequence, LPXTG (SEQ ID NO: 1) which can then be functionalized in a reaction catalyzed by sortase A and conjugated to the PEG-lipid, including through click chemistry reactions (see, for example, Moliner-Morro et al., Biomolecules 10(12):1661, 2020 which is incorporated by reference herein for all that it teaches about antibody conjugations mediated by the sortase A reaction and/or click chemistry).
  • LPXTG SEQ ID NO: 1
  • AJICAP reagents are modified affinity peptides that bind to specific loci on the Fc and react with an adjacent lysine residue to form an affinity peptide conjugate of the antibody. The peptide is then cleaved with base to leave behind a thiol-functionalized lysine residue which can then undergo conjugation through maleimide or haloamide reactions, for example).
  • the binding moiety is conjugated to the PEG moiety of the PEG-lipid through a thiol modified lysine residue.
  • the conjugation is through a cysteine residue in a native or added antibody sequence.
  • the tLNP of the various disclosed aspects comprise a binding moiety, such as an antibody or antigen binding domain thereof or a cell surface receptor ligand.
  • a “binding moiety” or “targeting moiety” refers to a protein, polypeptide, oligopeptide or peptide, carbohydrate, nucleic acid, or combinations thereof capable of specifically binding to a target or multiple targets.
  • a binding domain includes any naturally occurring, synthetic, semi- synthetic, or recombinantly produced binding partner for a biological molecule or another target of interest.
  • Exemplary binding moieties of this disclosure include an antibody, a Fab ⁇ , F(ab ⁇ ) 2 , Fab, Fv, rIgG, scFv, hcAb (heavy chain antibody), a single domain antibody, VHH, VNAR, sdAb, nanobody, receptor ectodomain or ligand-binding portions thereof, or ligand (e.g., cytokines, chemokines).
  • Fab antigen binding fragment
  • a binding moiety comprises a ligand-binding domain of a receptor or a receptor ligand.
  • a binding moiety can have more than one specificity including, for example, bispecific or multispecific binders.
  • assays are known for identifying binding moieties of this disclosure that specifically bind a particular target, including Western blot, ELISA, biolayer interferometry, and surface plasmon resonance.
  • a binding moiety such as a binding moiety comprising immunoglobulin light and heavy chain variable domains (e.g., scFv), can be incorporated into a variety of protein scaffolds or structures as described herein, such as an antibody or an antigen binding fragment thereof, a scFv-Fc fusion protein, or a fusion protein comprising two or more of such immunoglobulin binding domains.
  • scFv immunoglobulin light and heavy chain variable domains
  • a binding moiety can be an antibody or an antigen-binding portion thereof; an antigen; a ligand-binding domain of a receptor; or a receptor ligand. In some embodiments, a binding moiety can have more than one specificity including, for example, bispecific or multispecific binders. [00513] In some embodiments, a binding moiety comprises an antibody or an antigen- binding portion thereof.
  • antibody refers to a protein comprising an immunoglobulin domain having hypervariable regions determining the specificity with which the antibody binds antigen, termed complementarity determining regions (CDRs).
  • antibody can thus refer to intact or whole antibodies as well as antibody fragments and constructs comprising an antigen binding portion of a whole antibody. While the canonical natural antibody has a pair of heavy and light chains, camelids (from camels, alpacas, llamas, etc.) produce antibodies with both the canonical structure and antibodies comprising only heavy chains.
  • the variable region of the camelid heavy chain-only antibody has a distinct structure with a lengthened CDR3 referred to as VHH or, when produced as a fragment, a nanobody.
  • Antigen binding fragments and constructs of antibodies include F(ab) 2 , F(ab), minibodies, Fv, single-chain Fv (scFv), diabodies, and VH.
  • Such elements can be combined to produce bi- and multi-specific reagents, including various immune cell engagers, such as BiTEs (bi-specific T-cell engagers).
  • various immune cell engagers such as BiTEs (bi-specific T-cell engagers).
  • Antibodies can be obtained through immunization, selection from a na ⁇ ve or immunized library (for example, by phage display), alteration of an isolated antibody-encoding sequence, or any combination thereof. Numerous antibodies that can be used as binding moieties are known in the art.
  • WO2024040195A1 is also a source of sequence and other information for a wide range of antibodies with specificity for various cell surface antigens of immune system cells and cancer cells and is incorporated herein by reference for all that it teaches about individual antibodies and the antigens they bind.
  • An antibody or other binding moiety “specifically binds” a target if it binds the target with an affinity or Ka (i.e., an equilibrium association constant of a particular binding interaction with units of 1/Molar or 1/M) equal to or greater than 10 5 M -1 , while not significantly binding other components present in a test sample.
  • Ka i.e., an equilibrium association constant of a particular binding interaction with units of 1/Molar or 1/M
  • Binding domains can be classified as “high affinity” binding domains (or fusion proteins thereof) and “low affinity” binding domains (or fusion proteins thereof).
  • “High affinity” binding domains refer to those binding domains with a Ka of at least 10 8 M -1 , at least 10 9 M -1 , at least 10 10 M -1 , at least 10 11 M -1 , at least 10 12 M -1 , or at least 10 13 M -1 , preferably at least 10 8 M -1 or at least 10 9 M -1 .
  • “Low affinity” binding domains refer to those binding domains with a Ka of up to 10 8 M -1 , up to 10 7 M -1 , up to 10 6 M -1 , up to 10 5 M -1 .
  • affinity can be defined as an equilibrium dissociation constant (Kd) of a particular binding interaction with units of M (e.g., 10 -5 M to 10 -13 M).
  • Kd equilibrium dissociation constant
  • Affinities of binding domain polypeptides and fusion proteins according to this disclosure can be readily determined using conventional techniques (see, e.g., Scatchard et al., 1949, Ann. N.Y. Acad. Sci.51:660; and U.S. Patent Nos.5,283,173, 5,468,614, or the equivalent).
  • a diabody is a type of scFv dimer in which each chain consists of the V H and V L regions connected by a small peptide linker that is too short to allow pairing between the two domains of the same chain.
  • a BiTE is a fusion protein having two scFvs of different antibodies, usually an antibody for a tumor-associated antigen and antibody for CD3, on a single peptide chain, thus forming a cytolytic synapse between T cells and target antigen-bearing cells.
  • the term "antigen-binding portion" can refer to a portion of an antibody as described that possesses the ability to specifically recognize, associate, unite, or combine with a target molecule.
  • An antigen-binding portion includes any naturally occurring, synthetic, semi-synthetic, or recombinantly produced binding partner for a specific antigen.
  • antibodies and antigen-binding portions thereof constitute means for binding to the surface molecule on a cell.
  • the cell can be an immune cell, a leukocyte, a lymphocyte, a monocyte, a stem cell, an HSC or an MSC, according to the specificity of the antibody.
  • the antibody or antigen-binding portion thereof can be derived from a mammalian species, for example, mice, rats, or human.
  • Antibody variable regions can be those arising from one species, or they can be chimeric, containing segments of multiple species possibly further altered to optimize characteristics such as binding affinity or low immunogenicity. For human applications, it is desirable that the antibody has a human sequence.
  • the antibody or antigen-binding portion thereof can be humanized to reduce immunogenicity in a human subject.
  • the non-human antibody can be humanized, e.g., through CDR grafting, in which the CDRs from the non- human antibody are placed into the respective positions in a framework of a compatible human antibody.
  • an antibody in which only the constant region of the non-human antibody is replaced with human sequence are commonly referred to as chimeric antibodies in distinction to humanized antibodies.
  • the antibody or antigen-binding portion thereof is non- immunogenic.
  • the antibody can be modified in its Fc region to reduce or eliminate secondary functions, such as FcR engagement, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and/or complement- dependent cytotoxicity (CDC); this is often referred to as an Fc silenced antibody.
  • a binding moiety density on the LNP (or tLNP) can be defined according to the ratio of antibody (binder) to mRNA (w/w) either based on the amount of antibody input in the conjugation reaction or as measured in the LNP or (tLNP) after conjugation.
  • preferred ratios are about 0.3 to about 1.0, about 0.3 to about 0.7, about 0.3 to about 0.5, about 0.5 to about 1.0, and about 0.5 to about 0.7 for either the input or final measured binder ratio.
  • a LNP or tLNP has an antibody ratio of 0.3 to 1.0, 0.3 to 0.7, 0.3 to 0.5, 0.5 to 1.0, and 0.5 to 0.7 for either the input or final measured binder ratio.
  • a LNP or tLNP comprise a binding moiety that is a F(ab’) or F(ab’) analog.
  • F(ab’) and F(ab’)-like formats offer certain advantages as targeting moieties for a tLNP.
  • F(ab’) analog has been adopted herein to refer to engineered sequences comprising amino acid substitutions and/or that have been truncated and to distinguish them from the paradigmatic natural sequence.
  • F(ab’) are smaller than whole antibodies which can be advantageous in manufacturing.
  • targeting moiety on a tLNP their antigen binding domain is further from the LNP surface than, for example, a scFv, which can facilitate interaction with the target cell surface.
  • F(ab’) molecules have cysteine residues in the partial hinge region that can be readily conjugated to a functionalized PEG-lipid (for example, a maleimide-functionalized PEG-lipid).
  • a functionalized PEG-lipid for example, a maleimide-functionalized PEG-lipid
  • the F(ab’) can be engineered so that there is unique accessible cysteine enabling for site-specific conjugation which is desirable for product consistency. This can be accomplished with recombinant DNA technology by truncating the hinge region of the F(ab’) or by changing cysteine residues to another amino acid, such as serine, or both.
  • the hinge region cysteines can form a cystine with another F(ab’) molecule forming an F(ab’) 2 which would make the cysteine unavailable for conjugation to an LNP (more specifically, a functionalized lipid thereof).
  • This can be prevented by processing the F(ab’) under mildly reducing conditions, however, this poses a risk of disrupting the interchain disulfide bond between CL and CH1. That risk can be obviated by relocating the interchain bond to a less accessible region in the molecule.
  • Some aspects combine constant regions of an F(ab’) or F(ab’) analog with a humanized immunoglobulin antigen binding domain derived from the anti-CD8 ⁇ antibody CT8 as disclosed herein.
  • Humanized anti-CD8 antigen binding domains and antibodies and F(ab’) analog design useful as LNP targeting moieties are disclosed, for example, in International Patent Application No. PCT/US2024/060426, filed December 16, 2024, which is incorporated for reference for all that it teaches about anti-CD8 antigen binding domains and antibodies and F(ab’) analog designs.
  • Some aspects combine constant regions of an F(ab’) analog with the antigen binding domain of an anti-CD8 antibody.
  • the anti-CD8 antigen binding domain recognizes the CT8 epitope.
  • the anti-CD8 antigen binding domain is derived from YTC182.20, TRX2, or CT8.
  • the anti-CD8 antigen binding domain comprises a humanized immunoglobulin antigen binding domain derived from the anti-CD8 ⁇ antibody CT8 as disclosed herein.
  • an F(ab’) analog engineered as disclosed herein is conjugated to an LNP but is generic with respect to the variable domains of the F(ab’) analog and its specificity.
  • an F(ab’) or F(ab’) analog constant regions are combined with the antigen binding domain of an anti-CD8 antibody which is conjugated to an LNP.
  • the anti-CD8 antigen binding domain recognizes the CT8 epitope.
  • the anti-CD8 antigen binding domain is derived from YTC182.20, TRX2, or CT8.
  • the anti-CD8 antigen binding domain comprises a humanized immunoglobulin antigen binding domain derived from the anti-CD8 ⁇ antibody CT8 as disclosed herein.
  • the F(ab’) analog comprises a relocated interchain disulfide bond, for example, a C ⁇ S162C substitution paired with an IgG1 or IgG4 CH1 F174C substitution.
  • a LNP or tLNP comprises a binding moiety derived from an anti-CD40* antibody, an anti-LRRC15 ⁇ antibody, an anti-CTSK antibody, an anti- ADAM12 antibody, an anti-ITGA11 antibody, an anti-FAP* ⁇ antibody, an anti-NOX4 antibody, an anti-SGCD antibody, an anti-SYNDIG1 antibody, an anti-CDH11 antibody, an anti-PLPP4 antibody, an anti-SLC24A2 antibody, an anti-PDGFRB* antibody, an anti-THY1 antibody, an anti-ANTXR1 antibody, an anti-GAS1 antibody, an anti-CALHM5 antibody, an anti-SDC1* antibody, an anti-HER2* ⁇ antibody, an anti-
  • a LNP comprises a binding moiety specific for an immune cell antigen selected from CD1, CD2* ⁇ , CD3* ⁇ , CD4* ⁇ , CD5 ⁇ , CD7 ⁇ , CD8 ⁇ , CD11b, CD14 ⁇ , CD16, CD25 ⁇ , CD26*, CD27* ⁇ , CD28* ⁇ , CD30* ⁇ , CD32*, CD38* ⁇ , CD39, CD40* ⁇ , CD40L (CD154)* ⁇ , CD44*, CD45 ⁇ , CD64*, CD62 ⁇ , CD68, CD69, CD73 ⁇ , CD80*, CD83, CD86*, CD95, CD103, CD119, CD126, CD137 (41BB) ⁇ , CD150, CD153, CD161, CD166, CD183 (CXCR3), CD183 (CXCR5), CD223 (LAG-3)* ⁇ ,
  • a tLNP comprises a binding moiety specific for an HSC surface molecule selected from CD117 ⁇ , CD34*, CD44*, CD90 (Thy1) , CD105, CD133, BMPR2, and Sca-1; or specific for an MSC surface molecules selected from CD70*, CD105, CD73, Stro-1, SSEA-3, SSEA-4, CD271, CD146, GD2* ⁇ , SUSD2, Stro-4, MSCA-1, CD56, CD200* ⁇ , PODXL, CD13, CD29*, CD44*, and CD10.
  • a binding moiety is an antibody or antigen-binding portion thereof.
  • WO2024040195A1 filed August 17, 2023, each of which is incorporated herein by reference for all that it teaches about individual antibodies and the antigens they bind.
  • the following paragraphs provide non-exhaustive examples of known antibodies that bind to cell surface markers/antigens on immune cells (lymphocytes and monocytes) and stem cells (HSC and MSC). These antibodies or the antigen binding domains thereof can be used as binding moieties to target the disclosed LNP. Similarly, these antibodies can contribute their antigen binding domains to immune cell reprogramming agents such as CARs and ICEs.
  • an immune cell reprogramming agent While typically an immune cell reprogramming agent is expressed in an immune cell, one call also express a biological response modifier (conditioning agent) or an immune cell reprogramming agent, such as an ICE, in a tumor cell.
  • a biological response modifier conditioning agent
  • an immune cell reprogramming agent such as an ICE
  • the immune and stem cell surface markers that can serve as a targeted antigen of a tLNP can also usefully be a target of an immune cell reprogramming agent when the cell expressing that antigen has a role in the pathology of some disease or condition.
  • Collectively these antibodies and polypeptides comprising the antigen binding domains thereof constitute means for binding cell surface markers or means for binding immune and stem cells.
  • CD2 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD2 antibody.
  • CD2 contains three well- characterized epitopes (T11.1, T11.2, and T11.3/CD2R).
  • T11.3/CD2R are membrane proximal and exposure is increased upon T cell activation and CD2 clustering.
  • the anti-CD2 antigen binding domain is derived from, RPA-2.10; OKT11, UMCD2, 0.1, and 3T4-8B5 (T11.1 epitope); 9.6 and 1OLD2-4C1 (T11.2 epitope); 1Mono2A6 (T11.3 epitope), siplizumab (T11.2/T11.3 epitope), HuMCD2, TS2/18, TS1/8, AB75, LT-2, T6.3, MEM-65, OTI4E4, or an antigen-binding portion thereof.
  • CD2 can be used as a CD2 binding moiety as can alefacept, a CD58- Fc fusion.
  • CD3 constitutes a means for binding CD2 (Li et al., 1996, J Mol Biol. 263:209-26; Binder et al., 2020, Front Immunol.9:11:1090).
  • CD3 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD3 antibody.
  • the antigen binding domain is derived from muromonab-CD3 (OKT3), teplizumab, otelixizumab, visilizumab, cevostamab, teclistamab, elranatamab pavurutamab, vibecotamab, odronextamab, or an antigen-binding portion thereof.
  • CD4 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD4 antibody.
  • the antigen binding domain is derived from ibalizumab, inezetamab, semzuvolimab, zanolimumab, tregalizumab, UB-421, priliximab, MTRX1011A, cedelizumab, clenoliximab, keliximab, M-T413, TRX1, hB-F5, MAX.16H5, IT208, or an antigen-binding portion thereof.
  • CD5 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD5 antibody.
  • the antigen binding domain is derived from 5D7, UCHT2, L17F12, H65, HE3, OKT1, MAT304, as well as those disclosed in WO1989006968, WO2008121160, US8,679,500, WO2010022737, WO2019108863, WO2022040608, or WO2022127844, each of which is incorporated by reference for all that they teach about anti-CD5 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD5.
  • CD7 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD7 antibody.
  • the antigen binding domain is derived from TH-69, 3A1E, 3A1F, Huly-m2, WT1, YTH3.2.6, T3-3A1, grisnilimab, as well as those disclosed in US10,106,609, WO2017213979, WO2018098306, US11447548, WO2022136888, WO2020212710, WO2021160267, WO2022095802, WO2022095803, WO2022151851, or WO2022257835 each of which is incorporated by reference for all that they teach about anti-CD7 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD7.
  • CD8 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD8 antibody.
  • the antigen binding domain is derived from crefmirlimab (IAB22M), 3B5, SP- 16, LT8, 17D8, MEM-31, MEM-87, RIV11, UCHT4, YTC182.20, RPA-T8, OKT8, SK1, 51.1, TRX2, MT807-R1, HIT8 ⁇ , C8/144B, RAVB3, SIDI8BEE, BU88, EPR26538-16, 2ST8.5H7, as well as those disclosed in US10,414,820, WO2015184203, WO2017134306, WO2019032661, WO2020060924, US10,730,944, WO2019033043, WO2021046159, WO2021127088, WO2022081516, US11,535,869, or
  • humanized anti-CD8 antibodies are described in U.S. Provisional Patent Application Number 63/610,917, filed on December 15, 2023, and U.S. Provisional Patent Application Number 63/654,930, filed on May 31, 2024, .S. Provisional Patent Application Number 63/708,461, filed on October 17, 2024, and International Patent Application Number PCT/US2024/060426, filed on December 16, 2024, each of which is incorporated by reference for all that it teaches about these humanized anti- CD8 antibodies and their properties, or an antigen-binding portion thereof.
  • Each of the foregoing anti-CD8 antibodies constitutes a means for binding CD8.
  • a tLNP is targeted to CD10 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD10 antibody.
  • the antigen binding domain is derived from the one produced by the hybridoma represented by Accession No. NITE BP-02489 (disclosed in WO2018235247 which is incorporated by reference for all that they teach about anti-CD10 antibodies and their properties), FR4D11, or REA877, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD10.
  • CD11b is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD11b antibody.
  • the antigen binding domain is derived from ASD141 or MAB107 as well as those disclosed in US20150337039, US10,738,121, WO2016197974, US10,919,967, or WO2022147338 each of which is incorporated by reference for all that they teach about anti- CD11b antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD11b.
  • CD13 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD13 antibody.
  • CD13 is also known as aminopeptidase N (APN).
  • the antigen binding domain is derived from MT95-4 or Nbl57 (disclosed in WO2021072312 which is incorporated by reference for all that they teach about anti-CD13 antibodies and their properties), as well as those disclosed in WO2023037015 which is incorporated by reference for all that it teaches about anti-CD13 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD13.
  • CD14 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD14 antibody.
  • the antigen binding domain is derived from atibuclimab or r18D11 as well as those disclosed in WO2018191786 or WO2015140591 each of which is incorporated by reference for all that they teach about anti-CD14 antibodies and their properties, or an antigen- binding portion thereof. Each of these constitutes a means for binding CD14.
  • CD16a is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD16a antibody.
  • the antigen binding domain is derived from AFM13, sdA1, sdA2, or hu3G8-5.1-N297Q as well as those disclosed in US11535672, WO2018158349, WO2007009065, US10385137, WO2017064221, US10,758,625, WO2018039626, WO2018152516, WO2021076564, WO2022161314, or WO2023274183 each of which is incorporated by reference for all that they teach about anti-CD16A antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD16a.
  • CD25 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD25 antibody.
  • the antigen binding domain is derived from daclizumab, basiliximab, camidanlumab, tesirine, inolimomab, RO7296682, HuMax-TAC, CYT-91000, STI-003, RTX- 003, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD25.
  • CD28 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD28 antibody.
  • the antigen binding domain is derived from GN1412, acazicolcept, lulizumab, prezalumab, theralizumab, FR104CD, and davoceticept, as well as those disclosed in US8,454,959, US8,785,604, US11,548,947, US11,530,268, US11,453,721, US11,591,401, WO2002030459, WO2002047721, US20170335016, US20200181260, US11608376, WO2020127618, WO2021155071, or WO2022056199 each of which is incorporated by reference for all that they teach about anti-CD28 antibodies and their properties, or an antigen- binding portion thereof.
  • CD29 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD29 antibody. Accordingly, in some such embodiments, the antigen binding domain is derived from OS2966, 6D276, 12G10, REA1060, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD29.
  • CD32A is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD32A antibody.
  • the antigen binding domain is derived from VIB9600, humanized IV.3, humanized AT-10, or MDE-8 as well as those disclosed in US9,688,755, US9,284,375, US9,382,321, US11306145, or WO2022067394 each of which is incorporated by reference for all that they teach about anti-CD32A antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD32A.
  • CD34 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD34 antibody.
  • the antigen binding domain is derived from h4C8, 9C5, 2E10, 5B12, REA1164, C5B12, C2e10, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD34.
  • CD40 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD40 antibody.
  • the antigen binding domain is derived from cifurtilimab, sotigalimab, iscalimab, dacetuzumab, selicrelumab, bleselumab, lucatumumab, or mitazalimab as well as those disclosed in US10633444, each of which is incorporated by reference for all that they teach about anti-CD40 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD40.
  • CD44 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD44 antibody.
  • the antigen binding domain is derived from RO5429083, VB6-008, PF- 03475952, or RG7356, as well as those disclosed in WO2008144890, US8,383,117, WO2008079246, US20100040540, WO2015076425, US9,220,772, US20140308301, WO2020159754, WO2021160269, WO2021178896, WO2022022749, WO2022022720, or WO2022243838, each of which is incorporated by reference for all that they teach about anti- CD44 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD44.
  • CD45 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD45 antibody.
  • the antigen binding domain is derived from apamistamab, BC8-B10, as well as those disclosed in WO2023183927, WO2023235772, US7,825,222, WO2017009473, WO2021186056, US9,701,756, US9,701,756, WO2020092654, WO2022040088, WO2022040577, WO2022064191, WO2022063853, or WO2024064771, each of which is incorporated by reference for all that they teach about anti-CD45 antibodies and their properties, or an antigen-binding portion thereof.
  • CD56 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD56 antibody.
  • the antigen binding domain is derived from lorvotuzumab, adcitmer, or promiximab, as well as those disclosed in WO2012138537, US10,548,987, US10,730,941, or US20230144142, each of which is incorporated by reference for all that they teach about anti- CD56 antibodies and their properties, or an antigen-binding portion thereof.
  • Each of these constitutes a means for binding CD56.
  • CD64 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD64 antibody.
  • the antigen binding domain is derived from HuMAb 611 or H22 as well as those disclosed in US7,378,504, WO2014083379, US20170166638, or WO2022155608 each of which is incorporated by reference for all that they teach about anti-CD64 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD64.
  • CD68 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD68 antibody.
  • the antigen binding domain is derived from Ki-M7, PG-M1, 514H12, ABM53F5, 3F7C6, 3F7D3, Y1/82A, EPR20545, CDLA68-1, LAMP4-824, or an antigen- binding portion thereof. Each of these constitutes a means for binding CD68.
  • CD70 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD70 antibody.
  • the antigen binding domain is derived from cusatuzumab, vorsetuzumab, MDX-1203, MDX-1411, AMG-172, SGN-CD70A, ARX305, PRO1160, as well as those disclosed in US9,765,148, US8,124,738, IS10,266,604, WO2021138264, US9,701,752, US10,108,123, WO2014158821, US10,689,456, WO2017062271, US11,046,775, US11,377,500, WO2021055437, WO2021245603, WO2022002019, WO2022078344, WO2022105914, WO2022143951, WO2023278520, WO2022226317, WO2022262101, US11,613,584, or WO2023072307, each of which is incorporated by reference for all that they teach about anti-CD70 antibodies and their properties, or an antigen-binding portion
  • CD73 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD73 antibody.
  • the antigen binding domain is derived from oleclumab, uliledlimab, mupadolimab, AK119, IBI325, BMS-986179, NZV930, JAB-BX102, Sym024, TB19, TB38, HBM1007, 3F7, mAb19, Hu001-MMAE, IPH5301, or INCA00186, as well as those disclosed in US9,938,356, US10,584,169, WO2022083723, WO2022037531, WO2021213466, WO2022083049, US10,822,426, WO2021259199, US10,100,129, US11,312,783, US11,174,319, US11,634,500,
  • CD90 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD90 antibody. Accordingly, in some such embodiments, the antigen binding domain is derived from REA897, OX7, 5E10, K117, L127, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD90.
  • CD105 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD105 antibody.
  • the antigen binding domain is derived from carotuximab, TRC205, or huRH105, as well as those disclosed in US8,221,753, US9,926,375, WO2010039873, WO2010032059, WO2012149412, WO2015118031, WO2021118955, US20220233591, or US20230075244, each of which is incorporated by reference for all that they teach about anti- CD105 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD105.
  • CD117 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD117 antibody.
  • the antigen binding domain is derived from briquilimab, barzolvolimab, CDX-0158, LOP628, MGTA-117, NN2101, CK6, JSP191, Ab85, 104D2, or SR1, as well as those disclosed in US7,915,391, WO2022159737, US9540443, WO2015050959, US9,789,203, US8,552,157, US10,406,179, US9,932,410, WO2019084067, WO2020219770, US10,611,838, WO2020076105, WO2021107566, US11,208,482, WO2021044008, WO2021099418, WO2022187050, or WO2023026791, WO2021188590, each of which is incorporated by reference for all that they teach about anti-CD117 antibodies and their properties, or an antigen-binding portion thereof.
  • CD133 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD133 antibody.
  • the antigen binding domain is derived from AC133, 293C3, CMab-43, or RW03, as well as those disclosed in WO2018045880, US8,722,858, US9,249,225, WO2014128185, US10,711,068, US10,106,623, WO2018072025, or WO2022022718, each of which is incorporated by reference for all that they teach about anti-CD133 antibodies and their properties, or an antigen-binding portion thereof.
  • CD137 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD137 antibody.
  • CD137 is also known as 4-1BB.
  • the antigen binding domain is derived from YH004, urelumab (BMS-663513), utomilumab (PF-05082566), ADG106, LVGN6051, PRS-343, as well as those disclosed in WO2005035584, WO2012032433, WO2017123650, US11,203,643, US11,242,395, US11,555,077, US20230067770, US11,535,678, US11,440,966, WO2019092451, US10,174,122, US11,242,385, US10,716,851, WO2020011966, WO2020011964, or US11,447,558, each of which is incorporated by reference
  • CD146 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD146 antibody.
  • the antigen binding domain is derived from imaprelimab, ABX-MA1, huAA98, M2H, or IM1-24-3, as well as those disclosed in US10,407,506, US10,414,825, US6,924,360, US9,447,190, WO2014000338, US9,782,500, WO2018220467, US11,427,648, WO2019133639, WO2019137309, WO2020132190, or WO2022082073, each of which is incorporated by reference for all that they teach about CD146 antibodies and their properties, or an antigen-binding portion thereof.
  • CD166 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD166 antibody.
  • the antigen binding domain is derived from praluzatamab, AZN-L50, REA442, or AT002, as well as those disclosed in US10,745,481, US11,220,544, or WO2008117049, each of which is incorporated by reference for all that they teach about CD166 antibodies and their properties, or an antigen-binding portion thereof.
  • Each of these constitutes a means for binding CD166.
  • CD200 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD200 antibody.
  • the antigen binding domain is derived from samalizumab, OX-104, REA1067, B7V3V2, HPAB-0260-YJ, or TTI-CD200, as well as those disclosed in WO2007084321 or WO2019126536, each of which is incorporated by reference for all that they teach about CD200 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD200.
  • CD205 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD205 antibody.
  • CD205 is also known as DEC205.
  • the antibody comprises 3G9-2D2 (a component of CDX-1401) or LY75_A1 (a component of MEN1309) as well as those disclosed in US8,236,318, US10,081,682, or US11,365,258, each of which is incorporated by reference for all that they teach about anti-CD205 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD205.
  • CD271 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CD271 antibody.
  • the antigen binding domain is derived from REA844 or REAL709 as well as those disclosed in WO2022166802 which is incorporated by reference for all that it teaches about anti-CD271 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding CD271.
  • BMPR2 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-BMPR2 antibody.
  • the antigen binding domain is derived from TAB-071CL (Creative Biolabs catalog no.) as well as those disclosed in US11,292,846 or WO2021174198, each of which is incorporated by reference for all that they teach about anti-BMPR2 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding BMPR2.
  • claudin 18.2 (CLDN 18.2) is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-claudin 18.2 antibody.
  • the antigen binding domain is derived from zolbetuximab, osemitamab, RC118, IBI-343, AZD0901, M108, SYSA1801, TORL-2-307-ADC, LM-302, ASKB589, gresonitamab, SPX-101, SKB315, Q-1802, GIVASTOMIG, LCAR-C18S, SOT102, CT041 as well as those disclosed in WO2013167259, WO2021032157, WO2021254481, WO2022007808, WO2021008463, WO2022111616, WO2018006882, WO2020147321, WO2019219089, US20200040101, WO2020025792, WO2020139956, WO2020135201, US20240228610, WO2021218874, WO2021027850, WO2021129765, WO2022068854, WO2021111003, each of
  • CTLA-4 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-CTLA-4 antibody.
  • the antigen binding domain is derived from botensilimab, ipilimumab, nurulimab, quavonlimab, tremelimumab, zalifrelimab, ADG116, ADG126, ADU- 1604, AGEN1181, BCD-145, BMS-986218, BMS-986249, BT-007, CS1002, GIGA-564, HBM4003, IBI310 JK08, JMW-3B3, JS007, KD6001, KN044, ONC-392, REGN4659, TG6050, XTX101, YH001, or an antigen-binding portion thereof.
  • GD2 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-GD2 antibody.
  • the antigen binding domain is derived from dinutuximab, ganglidiximab, naxitamab, nivatrotamab, EMD 273063, hu14.18k322A, MORAb-028, 3F8BiAb, BCD-245, KM666, ATL301, Ektomab, as well as those disclosed in US9,777,068, US9,315,585, WO2004055056, US9,617,349, US9,493,740, US20210002384, US8507657, WO2001023573, WO2012071216, WO2018010846, US8,951,524, WO2023280880, US9,856,324, WO2015132604,
  • GITR is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-GITR antibody.
  • the antigen binding domain is derived from ragifilimab, TRX518, MK-4166, AMG 228, MEDI1873, BMS-986156, REGN6569, ASP1951, MK-1248, FRA154, GWN323, JNJ-64164711, ATOR-1144, or an antigen-binding portion thereof.
  • the antigen binding domain is derived from ragifilimab, TRX518, MK-4166, AMG 228, MEDI1873, BMS-986156, REGN6569, ASP1951, MK-1248, FRA154, GWN323, JNJ-64164711, ATOR-1144, or an antigen-binding portion thereof.
  • Each of these constitutes a means for binding GITR.
  • a low affinity IL-2 receptor is a targeted cell surface antigen (CD122 and/or CD132) and a binding moiety comprises the antigen binding domain of an anti- IL-2 receptor antibody.
  • the antiCD122 antibody comprises ANV419, FB102, MiK-Beta-1 and the anti CD122 antibodies disclosed in WO2011127324, WO2017021540, WO2022212848, WO2022221409, WO2023078113, US20230272090, WO2024073723, or an antigen-binding portion thereof.
  • the anti-CD132 antibody comprises REGN7257 and the anti-CD132 antibodies disclosed in WO2020160242, WO2017021540, WO2022212848, WO2023078113, US20230272089, or an antigen-binding portion thereof.
  • Each of these constitutes a means for binding the low affinity IL-2 receptor (CD122 or CD132, as appropriate)
  • a high affinity IL-2 receptor is a targeted cell surface antigen (CD25) and a binding moiety comprises the antigen binding domain of an anti-IL-2 receptor antibody.
  • the antigen binding domain is derived from daclizumab, basiliximab, camidanlumab, vopitug, inolimomab, HuMAx-TAC, Xenopax, STI- 003, RA8, RTX-003, and the anti-CD25 antibodies disclosed in WO2023031403, WO2006108670, WO2019175223, WO2019175215, WO2019175226, WO2004045512, WO2022104009, WO2020102591, or an antigen-binding portion thereof. Each of these constitutes a means for binding the high affinity IL-2 receptor (CD25).
  • IL-7 receptor is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-IL-7 receptor antibody.
  • the antigen binding domain is derived from PF- 06342674, GSK2618960, OSE-127, lusvertikimab, bempikibart, and the anti-CD127 antibodies disclosed in WO2011104687, WO2011094259, WO2013056984, WO2015189302, WO2017062748, WO2020154293, WO2020254827, WO2021222227, WO2023201316, or an antigen-binding portion thereof.
  • IL-12 receptor is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-IL-12 receptor antibody. Accordingly, in some such embodiments, the antigen binding domain is derived from CBYY- I0413, REA333, or an antigen-binding portion thereof. Each of these constitutes a means for binding the IL-12 receptor.
  • IL-15 receptor ⁇ is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-IL-15 receptor ⁇ antibody.
  • the antigen binding domain is derived from MAB1472-100, MAB5511, JM7A4, 5E3E1, JM7A4, 2639B, or an antigen-binding portion thereof. Each of these constitutes a means for binding the IL-15 receptor ⁇ .
  • IL-18 receptor ⁇ is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-IL-18 receptor ⁇ antibody.
  • the antigen binding domain is derived from H44, or an antigen-binding portion thereof. Each of these constitutes a means for binding the IL-18 receptor ⁇ .
  • IL-21 receptor is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-IL-21 receptor antibody.
  • the antigen binding domain is derived from 1D1C2, 19F5, 18A5, REA233, or an antigen-binding portion thereof. Each of these constitutes a means for binding the IL-21 receptor ⁇ .
  • LAG-3 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-LAG-3 antibody.
  • the antigen binding domain is derived from relatlimab, tebotelimab, bootszelimab, fianlimab, miptenalimab, HLX26, ieramilimab, GSK2831781, INCAGN2385, RO7247669, encelimab, FS118, SHR-1802, Sym022, IBI110, IBI323, bavunalimab, EMB-02, ABL501, INCA32459, AK129, or an antigen-binding portion thereof. Each of these constitutes a means for binding LAG-3.
  • MSCA-1 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti- MSCA-1 antibody. Accordingly, in some such embodiments, the antigen binding domain is derived from REAL219, W8B2, X9C3, or an antigen-binding portion thereof. Each of these constitutes a means for binding MSCA-1.
  • OX40 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-OX40 antibody.
  • the antigen binding domain is derived from MEDI6469, ivuxolimab, rocatinlimab, GSK3174998, BMS-986178, vonlerizumab, INCAGN1949, tavolimab, BGB- A445, INBRX-106, BAT6026, telazorlimab, ATOR-1015, MEDI6383, cudarolimab, FS120, HFB301001, EMB-09, HLX51, Hu222, ABM193, or an antigen-binding portion thereof.
  • Each of these constitutes a means for binding OX40.
  • PD-1 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-PD-1 antibody.
  • the antigen binding domain is derived from nivolumab, pembrolizumab, camrelizumab, torpalimab, sintilimab, tislelizumab, cemiplimab, spartalizumab, serplulimab, cadonilimab, penpulimab, dostarlimab, zimberelimab, retifanlimab, pucotenlimab, pidilizumab, pidilizumab, balstilimab, ezabenlimab, AK112, geptanolimab, cetrelimab, prolgolimab, tebotelimab, sasanlimab, SG001, vudalimab, MEDI
  • PODXL is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-PODXL antibody. Accordingly, in some such embodiments, the antigen binding domain is derived from MAI1738, HPAB- 3334LY, HPAB-MO612-YC, REA246, REA157, or an antigen-binding portion thereof. Each of these constitutes a means for binding PODXL.
  • Sca-1 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-Sca-1 antibody.
  • the antigen binding domain is derived from CPP324-1-18, 2D4-C9-F1, AMM22070N, or an antigen-binding portion thereof. Each of these constitutes a means for binding SCA-1.
  • SSEA-3 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-SSEA-3 antibody.
  • the antigen binding domain is derived from MC631, 2A9, 8A7, ND- 742, 3H420, as well as those disclosed in US11,643,456 or WO2021138378, each of which is incorporated by reference for all that they teach about anti-SSEA-3 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding SSEA-3.
  • SSEA-4 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-SSEA-4 antibody.
  • the antigen binding domain is derived from ch28/11, REA101, MC- 813-70, ND-942-80, as well as those disclosed in US11,446,379, US10,273,295, US11,643,456, WO2019190952, or WO2021044039, each of which is incorporated by reference for all that they teach about anti-SSEA-4 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding SSEA-4.
  • Stro-1 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-Stro-1 antibody.
  • the antigen binding domain is derived from STRO-1, TUSP-2, as well as those disclosed in US20130122022, which is incorporated by reference for all that it teaches about anti-Stro-1 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding Stro-1.
  • Stro-4 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-Stro-4 antibody.
  • the antigen binding domain is derived from STRO-4, efungumab, 4C5, as well as those disclosed in US7,722,869, US20110280881, US9,115,192, US10,273,294, US10,457,726, WO2023091148, each of which is incorporated by reference for all that they teach about anti-Stro-4 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding Stro-4 (also known as heat shock protein-90).
  • SUSD2 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-SUSD2 antibody.
  • the antigen binding domain is derived from REA795, CBXS-3571, CBXS-1650, CBXS-1989, CBXS-1671, CBXS1990, CBXS-3676, 1279B, EPR8913(2), W5C5, or an antigen-binding portion thereof.
  • TIM-3 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-TIM-3 antibody.
  • the antigen binding domain is derived from TQB2618, sabatolimab, cobolimab, RO7121661, INCAGN02390, AZD7789, surzebiclimab, LY3321367, Sym023, BMS-986258, SHR-1702, LY3415244, LB1410, or an antigen-binding portion thereof. Each of these constitutes a means for binding TIM-3.
  • TREM2 is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-TREM2 antibody.
  • the antigen binding domain is derived from PI37012 as well as those disclosed in US10,508,148, US10,676,525, WO2017058866, US11,186,636, US11,124,567, WO2020055975, US11,492,402, WO2020121195, WO2023012802, WO2021101823, WO2023047100, WO2022032293, WO2022241082, WO2023039450, or WO2023039612, each of which is incorporated by reference for all that they teach about anti-TREM2 antibodies and their properties, or an antigen-binding portion thereof. Each of these constitutes a means for binding TREM2.
  • G protein-coupled receptor, class C, group 5, member D is a targeted cell surface antigen and a binding moiety comprises the antigen binding domain of an anti-GPRC5D antibody.
  • the antigen binding domain of an anti-GPRC5D antibody is derived from talquetamab, forimtamig, BMS-986393, IBI-3003, QLS32015, SIM0500, or EPR28376-41, or is disclosed in WO2018017786, WO2016090329, WO2022174813, WO2023236889, WO2018147245, WO2024079015, WO2019154890, WO2021018859, WO2021018925, WO2020092854, WO2024031091, WO2020148677, WO2022175255, WO2022222910, WO2022247804, WO2022247756, WO2023078382, WO20
  • FCRL5 (CD307E) is a targeted cell surface antigen and binding moiety comprises the antigen binding domain of an anti-FCRL5 antibody.
  • the antigen binding domain of an anti-FCRL5 antibody is derived from cevostamab, 2A10H7, 307307, 2A10D6, EPR27365-87, EPR26948-19, or EPR26948- 67, or is disclosed in WO2016090337, WO2017096120, WO2022263855, or WO2024047558 each of which is incorporated by reference for all that they teach about anti-FCRL5 antibodies and their properties, or an antigen-binding portion thereof.
  • LRRC15 is a targeted cell surface antigen and binding moiety comprises the antigen binding domain of an anti-LRRC15 antibody.
  • the antigen binding domain of an anti-LRRC15 antibody is derived from samrotamab or DUNP19 or is disclosed in WO2005037999, WO2021022304, WO2024081729, WO2021102332, WO2021202642, WO2022157094, or WO2024158047, each of which is incorporated by reference for all that they teach about anti-LRRC15 antibodies and their properties, or an antigen-binding portion thereof.
  • a tLNP is targeted to a tumor cell.
  • the tumor cell expresses one of the antigens described above and the tLNP is targeted to antigen expressing tumors using the same means as described above.
  • the tLNP is targeted to some other tumor antigen, such as those enumerated in U.S. Provisional Application No. 63/371,742, filed on August 17, 2022, entitled CONDITIONING FOR IN VIVO IMMUNE CELL ENGINEERING which is incorporated by reference for all that it teaches about the delivery of nucleic acids into tumor cells using tLNP that is not inconsistent with this disclosure.
  • the disclosed LNP and tLNP comprise a payload comprising or consisting of one or more nucleic acid species.
  • the LNP or tLNP payload comprises only one nucleic acid species while in other embodiments the LNP or tLNP payload comprises multiple nucleic acid species, for example, 2, 3, or 4 nucleic acid species.
  • the payload can comprise or consist of 1) a single nucleic acid species encoding a single species of CAR or ICE, 2) a single nucleic acid species encoding 2 or more species of CAR or ICE (or a mixture of CAR and ICE) such as a bicistronic or multicistronic mRNA in which each CAR and/or ICE has specificity for a same target antigen, 3) a single nucleic acid species encoding 2 or more species of CAR or ICE (or a mixture of CAR and ICE) such as a bicistronic or multicistronic mRNA in which at least one CAR and/or ICE has specificity for a different target antigen than the other(s), 4) two or more nucleic acid species encoding 2 or more species of CAR or ICE (or a mixture of CAR and ICE) in which each C
  • the nucleic acid can be RNA or DNA.
  • the nucleic acid can be multicistronic, for example, bicistronic.
  • LNPs or tLNPs of this disclosure further comprise a nucleic acid payload.
  • a nucleic acid is an mRNA, a self-replicating RNA (also known as self-amplifying RNA), a circular RNA, a siRNA, a miRNA, DNA, a gene editing component (for example, a guide RNA, a tracr RNA, an sgRNA), a gene writing component, an mRNA encoding a gene or base editing protein, a zinc-finger nuclease, a TALEN, a CRISPR nuclease, such as Cas9, a DNA molecule to be inserted or serve as a template for repair), and the like, or a combination thereof.
  • a gene editing component for example, a guide RNA, a tracr RNA, an sgRNA
  • a gene writing component for example, a guide RNA, a tracr RNA, an sgRNA
  • a gene writing component for example, a guide RNA, a tracr RNA, an sgRNA
  • the nucleic acid comprises small interfering RNA (siRNA), microRNA (miRNA), antisense oligonucleotide (ASO).
  • the nucleic acid comprises a self-replicating RNA or a circular RNA.
  • the mRNA encodes a reprogramming agent or comprises or encodes a conditioning agent.
  • the RNA linear mRNA, circular, or self- replicating
  • an mRNA encodes a chimeric antigen receptor (CAR).
  • an mRNA encodes a gene-editing or base-editing or gene writing protein.
  • a nucleic acid is a guide RNA.
  • an LNP or tLNP comprises both a gene- or base-editing or gene writing protein-encoding mRNA and one or more guide RNAs.
  • CRISPR nucleases can have altered activity, for example, modifying the nuclease so that it is a nickase instead of making double- strand cuts or so that it binds the sequence specified by the guide RNA but has no enzymatic activity.
  • Base-editing proteins are often fusion proteins comprising a deaminase domain and a sequence-specific DNA binding domain (such as an inactive CRISPR nuclease).
  • the reprogramming agent comprises an immune receptor (for example, a chimeric antigen receptor or a T cell receptor) or an immune cell engager (for example, a bispecific T cell engager (BiTE), a bispecific killer cell engager (BiKE), a trispecific kill cell engager (TriKE), a dual affinity retargeting antibody (DART), a TRIDENT (linking two DART units or a DART unit and a Fab domain), a macrophage engager (e.g., BiME), an innate cell engager, and the like).
  • the nucleic acid is an RNA, for example, mRNA, and the RNA comprises at least one modified nucleoside.
  • the modified nucleoside is pseudouridine, N 1 -methylpseudouridine, 5-methylcytosine, 5-methyluridine, N 6 - methyladenosine, 2’-O-methyluridine, or 2-thiouridine.
  • all of the uridines are substituted with a modified nucleoside. Further disclosure of modified nucleosides and their use can be found in U.S. Patent No. 8,278,036 which is incorporated herein by reference for those teachings.
  • the reprogramming agent encodes or is a gene/genome editing component.
  • the gene/genome editing component is a guide RNA for an RNA-directed nuclease or other nucleic acid editing enzyme, clustered regularly interspaced short palindromic repeat RNA (crisprRNA), a trans-activating clustered regularly interspaced short palindromic repeat RNA (tracrRNA).
  • crisprRNA clustered regularly interspaced short palindromic repeat RNA
  • tracrRNA trans-activating clustered regularly interspaced short palindromic repeat RNA
  • the gene/genome editing component is a nucleic acid-encoded enzyme, such as RNA-guided nuclease, a gene or base editing protein, a zinc finger nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), a meganuclease, a transposase, or a CRISPR nuclease (e.g., Cas9 or Cas 12, etc.).
  • the gene/genome editing component is DNA to be inserted or that serves as a template in gene or genome editing for example a template for repair of a double-strand break.
  • the nucleic acid can be multicistronic. In other embodiments comprising multiple agents or components, each agent or component is encoded or contained is a separate nucleic acid species. In some embodiments involving multiple payload nucleic acid species, two or more nucleic acid species are packaged together in a single LNP species. In other embodiments, a subset of the payload nucleic acid species to be delivered, (e.g., a single nucleic acid species) is packaged in one LNP or tLNP species while another subset of the nucleic acid species is packaged in another LNP or tLNP species. The different (t)LNP species can differ by only the payload they contain.
  • this disclosure provides a method of making a LNP or tLNP comprising mixing of an aqueous solution of a nucleic acid (or other negatively charged payload) and an alcoholic solution of the lipids in proportions disclosed herein. In particular embodiments, the mixing is rapid.
  • the aqueous solution is buffered at pH of about 3 to about 5, for example, without limitation, with citrate or acetate.
  • the alcohol can be ethanol, isopropanol, t-butanol, or a combination thereof.
  • rapid mixing is accomplished by pumping the two solutions through a T-junction or with an impinging jet mixer.
  • Microfluidic mixing through a staggered herringbone mixer (SHM) or a hydrodynamic mixer (microfluidic hydrodynamic focusing), microfluidic bifurcating mixers, and microfluidic baffle mixers can also be used.
  • SHM staggered herringbone mixer
  • hydrodynamic mixer microfluidic hydrodynamic focusing
  • microfluidic bifurcating mixers microfluidic bifurcating mixers
  • microfluidic baffle mixers can also be used.
  • buffer for example phosphate, HEPES, or Tris
  • the diluted LNPs are purified either by dialysis or ultrafiltration or diafiltration using tangential flow filtration (TFF) against a buffer in a pH range of 6 to 8.5 (for example, phosphate, HEPES, or Tris) to remove the alcohol. Alternatively, one can use size exclusion chromatography. Once the alcohol is completely removed the buffer is exchanged with like buffer containing a cryoprotectant (for example, glycerol or a sugar such as sucrose, trehalose, or mannose).
  • a cryoprotectant for example, glycerol or a sugar such as sucrose, trehalose, or mannose.
  • the LNPs are concentrated to a desired concentrated, followed by 0.2 ⁇ m filtration through, for example, a polyethersulfone (PES) or modified PES filter and filled into glass vials, stoppered, capped, and stored frozen.
  • PES polyethersulfone
  • a lyoprotectant is used and the LNP lyophilized for storage instead of as a frozen liquid.
  • Further methodologies for making LNP can be found, for example, in U.S. Patent Application Publication Nos. US 2020/0297634, US 2013/0115274, and International Patent Application Publication No. WO 2017/048770, each of which is incorporated by reference for all that they teach about the production of LNP.
  • Some aspects are a method of making a tLNP comprising rapid mixing of an aqueous solution of a nucleic acid (or other negatively charged payload) and an alcoholic solution of the lipids as disclosed for LNP.
  • the lipid mixture includes functionalized PEG-lipid, for later conjugation to a targeting moiety.
  • functionalized PEG-lipid refers to a PEG-lipid in which the PEG moiety has been derivatized with a chemically reactive group (such as, maleimide, N-hydroxysuccinimide (NHS) ester, Cys, azide, alkyne, and the like) that can be used for conjugating a targeting moiety to the PEG- lipid, and thus, to the LNP comprising the PEG-lipid.
  • a chemically reactive group such as, maleimide, N-hydroxysuccinimide (NHS) ester, Cys, azide, alkyne, and the like
  • the functionalized PEG-lipid is inserted into an LNP subsequent to initial formation of an LNP from other components.
  • the targeting moiety is conjugated to functionalized PEG-lipid after the functionalized PEG-lipid containing LNP is formed.
  • Protocols for conjugation can be found, for example, in Parhiz et al., 2018, J. Controlled Release 291:106- 115 and Tombacz et al., 2021, Molecular Therapy 29(11):3293-3304, each of which is incorporated by reference for all that it teaches about conjugation of PEG-lipids to binding moieties.
  • the targeting moiety can be conjugated to the PEG-lipid prior to insertion into pre-formed LNP.
  • the method comprises: i).
  • the method comprises: i).
  • the method comprises: i). forming one or more conjugated functionalized PEG-lipids by conjugating the one or more functionalized PEG-lipids with the one or more targeting moieties; and ii).
  • the method comprises: i). forming one or more conjugated functionalized PEG-lipids by conjugating the one or more functionalized PEG-lipids with the one or more targeting moieties; ii). forming an LNP by mixing all components of the tLNP, except the one or more conjugated functionalized PEG-lipids; and iii). forming the tLNP by mixing the initial LNP with the one or more conjugated functionalized PEG-lipids.
  • the tLNPs are purified by dialysis, tangential flow filtration, or size exclusion chromatography, and stored, as disclosed above for LNPs.
  • the encapsulation efficiency of the nucleic acid by the LNP or tLNP is typically determined with a nucleic acid binding fluorescent dye added to intact and lysed aliquots of the final LNP or tLNP preparation to determine the amounts of unencapsulated and total nucleic acid, respectively. Encapsulation efficiency is typically expressed as a percentage and calculated as 100 x (T-U)/T where T is the total amount of nucleic acid and U is the amount of unencapsulated nucleic acid.
  • the encapsulation efficiency is ⁇ 80%, ⁇ 85%, ⁇ 90%, or ⁇ 95%.
  • Methods of Delivering a Payload into a Cell comprising contacting the cell with LNP or tLNP of as disclosed herein. Accordingly, each of the herein disclosed genera, subgenera, and or species of LNP or tLNP disclosed herein including those based on the inclusion or exclusion of particular lipids, particular lipid compositions, particular payloads, and/or particular targeting moieties can be used in defining the scope of the methods of delivering a payload to a cell.
  • the contacting takes place ex vivo. In some embodiments, the contacting takes place extracorporeally. In some embodiments, the contacting takes place in vivo. In various embodiments, contacting in vivo can be accomplished through any appropriate route of administration.
  • an LNP or tLNP is contacted with target cells in vivo, by systemic or local administration.
  • the in vivo contacting comprises intravenous, intramuscular, subcutaneous, intralesional, intranodal or intralymphatic administration. In further instances, transfection of hepatocytes is reduced as compared to tLNPs comprising a conventional, prior art ionizable cationic lipid, such as ALC-0315.
  • an LNP or tLNP is administered 1-3 times a week for 1, 2, 3, or 4 weeks.
  • toxicity is confined (or largely confined) to grades of 0 or 1 or 2, as discussed above.
  • Advantageous compact administration regimens for tLNPs for example, comprising one or more cycles of 2 or 3 administrations at 72-hour intervals, are described in U.S. Provisional Patent Application Number 63/556,735, filed February 22, 2024, U.S. Provisional Patent Application Number 63/708,513, filed October 17, 2024, U.S. Provisional Patent Application Number 63/721,154, filed November 15, 2024, and PCT patent application No.
  • LNP and tLNP compositions and formulations have reduced toxicity as compared to widely used prior LNP compositions such as those containing ALC-0315.
  • the toxicity can be described as an observable toxicity, a substantial toxicity, a severe toxicity, or an acceptable toxicity, or a dose-limiting toxicity (such as but not limited to a maximum tolerated dose (MTD)).
  • MTD maximum tolerated dose
  • an observable toxicity it is meant that while a change is observed the effect is negligible or mild.
  • substantial toxicity it is meant that there is a negative impact on the patient’s overall health or quality of life.
  • a substantial toxicity can be mitigated or resolved with other ongoing medical intervention.
  • a severe toxicity it is meant that the effect requires acute medical intervention and/or dose reduction or suspension of treatment.
  • the acceptability of a toxicity will be influenced by the particular disease being treated and its severity and the availability of mitigating medical intervention.
  • toxicity is confined (or largely confined) to an observable toxicity.
  • toxicity is confined (or largely confined) to grades of 0 or 1 or 2.
  • the payload is a nucleic acid and the method of delivering is a method of transfecting.
  • the nucleic acid payload comprises an mRNA, circular RNA, self-amplifying RNA, or guide RNA.
  • Nucleic acid structures and especially mRNA structures, as well as individual RNA molecules encoding particular polypeptides, that are well-adapted to delivery by LNP or tLNP are disclosed in U.S. Provisional Patent Application Number.63/595,753 filed November 2, 2023, U.S. Provisional Patent Application Number. 63/611,092 filed December 15, 2023, U.S. Provisional Patent Application Number 63/654,928 (Attorney Docket Number 23-1871-US-PRO3), filed May 31, 2024, and International Patent Application No.
  • the payload comprises a nucleic acid encoding an immune receptor or immune cell engager and the method of delivering is also a method of reprogramming an immune cell.
  • the payload comprises a nucleic acid that encodes, or is, a BRM and the method of delivering is also a method of providing a conditioning agent.
  • the BRM or conditioning agent is a gamma chain receptor cytokine such as IL-2, IL-7, IL-15, IL-15/15Ralpha, IL-21; an immune modulating (also known as pan activating) cytokine such as IL-12, IL-18; an immune checkpoint inhibitor such as an antagonist of cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), program cell death ligand 1 (PD-L1), T-cell immunoglobulin and mucin- domain-containing-3 (Tim-3), lymphocyte activation gene 3 (LAG-3) or indoleamine 2,3- dioxygenase (IDO) or agonists of 4-immunoglobulin and BB cell surface glycoprotein (4-1BB), OX40 or inducible costimulator (ICOS); a chemokine such as RANTES, IP10, MIG; or another BRM such as Flt3, GM-CSF, and G-CSF.
  • CTLA-4
  • the payload comprises a nucleic acid encoding a gene/genome editing enzyme and/or a guide RNA or other component of a gene/genome editing system and the method of delivering is also a method of reprogramming a cell.
  • the cell is an immune cell.
  • the cell is an HSC.
  • the cell is an MSC.
  • the binding moiety binds to a lymphocyte surface molecule or a monocyte surface molecule.
  • Lymphocyte surface molecules include CD2, CD3, CD4, CD5, CD7, CD8, CD28, 4-1BB (CD137), CD166, CTLA-4, OX40, PD-1, GITR, LAG-3, TIM-3, CD25, low affinity IL-2 receptor, IL-7 receptor, IL-12 receptor, IL-15 receptor, IL-18 receptor, and IL-21 receptor.
  • Monocyte surface molecules include CD5, CD14, CD16a, CD32, CD40, CD11b (Mac-1), CD64, DEC205, CD68, and TREM2.
  • Exemplary antibodies that can provide antigen binding domains to bind these surface molecules are disclosed herein. Such antibodies, individually and collectively, constitute means for binding to an immune cell (or leukocyte) – or to a lymphocyte or monocyte, as indicated.
  • the binding moiety binds to a HSC surface molecule or a MSC surface molecule.
  • HSC surface molecules include CD117, CD34, CD44, CD90 (Thy1), CD105, CD133, BMPR2, and Sca-1.
  • MSC surface molecules include CD70, CD105, CD73, Stro-1, SSEA-4, CD271, CD146, GD2, SSEA-3, SUSD2, Stro-4, MSCA-1, CD56, CD200, PODXL, CD13, CD29, CD44, and CD10.
  • Exemplary antibodies that can provide antigen binding domains to bind these surface molecules are disclosed herein above.
  • this disclosure provides methods of treating a disease or disorder comprising administering a tLNP (or LNP) of this disclosure to a subject in need thereof.
  • a tLNP or LNP
  • Each of the herein disclosed genera, subgenera, and or species of LNP or tLNP disclosed herein including those based on the inclusion or exclusion of particular lipids, particular lipid compositions, particular payloads, and/or particular targeting moieties can be used in defining the scope of the methods of treatment.
  • a subject is a human.
  • a tLNP is administered systemically.
  • a tLNP is administered by intravenous or subcutaneous infusion or injection. In some embodiments, a tLNP is administered locally. In some embodiments, a tLNP is administered by intraperitoneal or intralesional infusion injection. [00615] In further embodiments, a tLNP can be administered in combination with the standard of care for a particular indication, such as corticosteroids (e.g., prednisone) for management of myositis or lupus nephritis.
  • corticosteroids e.g., prednisone
  • myositis is also treated with methotrexate, which can be combined with immunosuppressive agents (e.g., azathioprine, mycophenolate mofetil, tacrolimus), which are usually required in addition to corticosteroids.
  • immunosuppressive agents e.g., azathioprine, mycophenolate mofetil, tacrolimus
  • cyclical steroids and cyclophosphamide might be used in combination with tLNPs of this disclosure.
  • an anti-IL-6 such as tocilizumab
  • the disease or disorder is an autoimmune disease.
  • autoimmune disease examples include, without limitation, myocarditis, acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, fibrosing alveolitis, multiple sclerosis, rheumatic fever, polyglandular syndromes, agranulocytosis, autoimmune hemolytic anemias, bullous pemphigoid, Wegener's granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, pernicious anemia, rapidly progressive glomerulonephritis, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, allergic responses, insulin-resistant diabetes, ps
  • the autoimmune disease is a T cell-mediated autoimmunity or a B cell-mediated autoimmunity.
  • the B cell-mediated autoimmune disease is myositis (such as anti-synthetase myositis), lupus nephritis, membranous nephropathy, systemic lupus erythematosus, anti-neutrophilic cytoplasmic antibody (ANCA) vasculitis, neuromyelitis optica spectrum disorder (NMOSD), myasthenia gravis, pemphigus vulgaris, rheumatoid arthritis, dermatomyositis, immune mediated necrotizing myopathy (IMNM), anti-synthetase syndrome, polymyositis, systemic sclerosis, diffuse cutaneous systemic sclerosis, limited cutaneous systemic sclerosis, anti-synthetase syndrome (idiopathic inflammatory myopathy
  • myositis such as anti-
  • the B cell-mediated autoimmune disease is myositis, lupus nephritis, membranous neuropathy, scleroderma, systemic lupus erythematosus, myasthenia gravis, ANCA vasculitis, multiple sclerosis, or pemphigus vulgaris.
  • the B cell-mediated autoimmune disease is myositis, lupus nephritis, membranous neuropathy, or scleroderma.
  • the B cell-mediated autoimmune disease is myositis. In some instances, the myositis is anti-synthetase myositis.
  • the B cell- mediated autoimmune disease is systemic lupus erythematosus, myasthenia gravis, ANCA vasculitis, multiple sclerosis, or pemphigus vulgaris.
  • the disease or disorder is rejection of an allogeneic organ or tissue graft.
  • Pre-existing antibodies and/or B cells, in their role as antigen presenting cells, can facilitate rapid immune rejection through known mechanisms hence depleting a large number of B cells can help prevent allograft rejection.
  • B cell depletion can be used in the management of graft-versus-host disease.
  • the disease or disorder is a graft-versus-host disease.
  • the disease or disorder is a cancer.
  • cancers include, without limitation, carcinomas, sarcomas, and hematologic cancers.
  • the hematologic cancer is a lymphoma, leukemia, or myeloma.
  • the hematologic cancer is a B lineage or T lineage cancer.
  • the B lineage cancer is multiple myeloma, diffuse large B cell lymphoma, acute myeloid leukemia, Mantle Cell lymphoma, follicular lymphoma, B acute lymphoblastic leukemia, chronic lymphocytic leukemia, or myelodysplastic syndrome.
  • the cancer is a sarcoma.
  • the cancer is a carcinoma, such as breast cancer, colon cancer, ovarian cancer, lung cancer, testicular cancer, or pancreatic cancer.
  • the cancer is melanoma.
  • Some embodiments are methods of B cell depletion utilizing a CAR or other reprogramming agent with specificity for a B cell antigen.
  • the term “B cell antigen” can refer to any antigen expressed by cell in the B cell lineage from pro-B cells through plasma cells.
  • Exemplary B cell antigens include CD19, CD20, CD22, BCMA, GPRC5D, and FCRL5, as well as antigens noted to be associated with hematologic cancers of the B cell lineage.
  • B cell-mediated autoimmunity, allotransplant rejection, GVHD, and the like as disclosed above B cell depletion blunt induction of anti-drug antibodies as an additional feature of such treatments or as an adjunct to other therapies.
  • the disease or disorder is a genetic disease or disorder such as a monogenic genetic disease.
  • the genetic disease or disorder is a hemoglobinopathy, for example, sickle cell disease or ⁇ -thalassemia.
  • the disease or disorder is a fibrotic disease or disorder.
  • a tLNP of this disclosure comprises a nucleic acid encoding a chimeric antigen receptor (CAR).
  • the receptors are chimeric because they combine both antigen-binding and T cell activating functions into a single receptor.
  • a nucleic acid encoding a CAR refers to one or more nucleic acid species encoding one or more CARs; for example, a single or multiple species of nucleic acid encoding a single CAR species, or multiple species of nucleic acid encoding multiple CAR species. In some instances, these multiple CAR species have a same specificity while in other instances they have multiple specificities.
  • a CAR of this disclosure is multispecific, for example, bispecific, comprising multiple antigen binding moieties each specific for separate antigens.
  • the CAR in LCAR-AIO targets three antigens — CD19, CD20 and CD22 (see, Blood (2021) 138 (Supplement 1): 1700).
  • a CAR can comprise an extracellular binding domain that specifically binds a target antigen, a transmembrane domain, and one or more intracellular signaling domains.
  • a CAR can further comprise one or more additional elements, including one or more signal peptides, one or more extracellular hinge domains, or one or more intracellular costimulatory domains. Domains can be directly adjacent to one another, or there can be one or more amino acids linking the domains.
  • the signal peptide can be derived from an antibody, a TCR, CD8 or other type 1 membrane proteins, preferably a protein expressed in a T or other immune cell.
  • the transmembrane domain can be one associated with any of the potential intracellular domains or from another type 1 membrane protein, such as TCR alpha, beta, or zeta chain, CD3 epsilon, CD4, CD8, or CD28, amongst other possibilities known in the art.
  • the transmembrane domain can further comprise a hinge domain located between the extracellular binding domain and the hydrophobic membrane-spanning region of the transmembrane domain.
  • the hinge domain and transmembrane domain are contiguous sequences in the same source protein.
  • the hinge and membrane-spanning domains are derived from CD28. In other instances, the hinge and membrane-spanning domains are derived from CD8 ⁇ .
  • the intracellular signaling domain can be derived from the CD3 zeta chain, DAP10, DAP12, Fc ⁇ RIII, FcsRI, or an immunoreceptor tyrosine-based activation motif (ITAM) bearing cytoplasmic domain, amongst other possibilities known in the art.
  • ITAM immunoreceptor tyrosine-based activation motif
  • the intracellular costimulatory domain can be derived from CD27, CD28, 4-1BB, OX40, or ICOS, amongst other possibilities known in the art.
  • CARs are used to treat a disease or condition associated with a target cell that expresses the antigen targeted by the CAR.
  • an anti-CD19 or anti-CD20 CAR can be used to target and treat B cell-mediated pathologies such as B cell malignancies or B cell-mediated autoimmune conditions or diseases (e.g., having an immune cell targeting moiety, such as an anti-CD8 antibody).
  • B cell-mediated pathologies such as B cell malignancies or B cell-mediated autoimmune conditions or diseases (e.g., having an immune cell targeting moiety, such as an anti-CD8 antibody).
  • an anti-FAP CAR can be used to target and treat solid tumors or fibrosis (e.g., cardiac fibrosis, cancer-associated fibroblasts), which can also have an immune cell targeting moiety, such as an anti-CD8 antibody.
  • CARs that can be used in accordance with the embodiments described herein include to those disclosed in US 7,446,190, US 9,328,156, US 11,248,058, US20190321404, WO2019119822, WO2019159193, WO2020011706, WO2022125837, and WO2024086190 (anti-CD19), US 10,287,35 (anti-CD19), US 10,442,867 and US2021/0363245 (anti-CD19 and anti-CD20), US 10,543,263 (anti-CD22), WO2016149578 (anti-CD19 and anti-CD22), US 10,316,101, US 11,623,961 WO2015052538, WO2016166630, WO2017130223, WO2017173256, WO2019085102, WO2019241426, WO2020065330, WO2020038146, WO2020190737, WO2021091945 (anti-BCMA), WO2016130598 (anti-BCMA and syndecan- 1), US 7,
  • Each CAR constitutes means for targeting an immune cell, for example, a T cell, to the indicated antigen.
  • Exemplary target antigens against which a CAR, TCR, or ICE can have specificity FAP* ⁇ , FOLH1, FOLR1* ⁇ , GD2* ⁇ , GPC3* ⁇ , GPNMB* , IL1RAP ⁇ , IL3RA* , IL13RA2* , (mesothelin)* ⁇ , SDC1)* , CD319 (SLAMF7)* ⁇ , CD248 (TEM1) , ULBP1, ULBP2, and G-protein coupled receptor family C group 5 member D (GPRC5D) ⁇ (associated with leukemias); CD319 (SLAMF7)* ⁇ , CD38* ⁇ , CD138 ⁇ , GPRC5D ⁇ , CD267 (TACI) , and BCMA ⁇ (associated with myelomas); and GD
  • Well-known TCR targets include NYESO-1, SSX2, PRAME, lineage specific antigens tyrosinase, PSMA, and Melan A/MART-1, and cancer testes antigens MAGE, GAGE, and LAGE.
  • * indicates that exemplary antibodies with the indicated specificity from which a binding moiety could be derived can be found in US Patent 11,326,182B2 Table 9 or 10.
  • ⁇ indicates that exemplary antibodies with the indicated specificity from which a binding moiety could be derived can be found in Wilkinson & Hale, 2022. Both references cited and incorporated by reference above.
  • the extracellular binding domain of the CAR comprises a ligand of a receptor expressed on the target cell.
  • the extracellular binding domain of the CAR comprises a ligand binding domain of a receptor for a ligand expressed on the target cell.
  • the advantages of the aspects and embodiments disclosed herein are independent of the specificity of the binding moiety. As such, the disclosed aspects and embodiments are generally agnostic to binding specificity. In certain embodiments, a particular binding specificity can be required.
  • the tLNP comprises a nucleic acid encoding an anti-CD19 chimeric antigen receptor (CAR).
  • the nucleic acid comprises mRNA. Examples of anti-CD19 CARs include those incorporating a CD19 binding moiety derived from the human antibody 47G4 or the mouse antibody FMC63.
  • the anti-CD19 CAR is the CAR found in tisagenlecleucel, lisocabtagene maraleucel, axicabtagene ciloleucel, or brexucabtagene autoleucel.
  • Each of these CARs constitutes means for targeting an immune cell, for example, a T cell, to CD19.
  • the entire contents of each of foregoing references in this paragraph are incorporated by reference for all that they teach about the design, structure, and activity of anti-CD19 CARs.
  • certain embodiments include tLNPs encapsulating a CD19 CAR payload encoded by RNA and having a T cell targeting moiety, such as an anti-CD8 antibody.
  • the tLNP comprises a nucleic acid encoding an anti-CD20 chimeric antigen receptor (CAR).
  • CD20 is an antigen found on the surface of B cells as early as the pro-B phase and progressively at increasing levels until B cell maturity, as well as on the cells of most B-cell neoplasms. CD20 positive cells are also sometimes found in cases of Hodgkin's disease, myeloma, and thymoma.
  • the nucleic acid comprises mRNA.
  • anti-CD20 CARs include those incorporating a CD20 binding moiety derived from an antibody specific to CD20, including, for example, Leu16, IF5, 1.5.3, rituximab, obinutuzumab, ibritumomab, ofatumumab, tositumumab, odronextamab, veltuzumab, ublituximab, and ocrelizumab.
  • the anti-CD20 CAR is derived from a CAR specific to CD20, including, for example, MB-106 (Fred Hutchinson Cancer Research Center, see Shadman et al., Blood 134(Suppl.1):3235 (2019)) UCART20 (Cellectis, www.cellbiomedgroup.com), or C-CAR066 (Cellular Biomedicine Group, see Liang et al., J. Clin. Oncol. 39(15) suppl:2508 (2021)).
  • the extracellular binding domain of the anti-CD20 CAR comprises an scFv derived from the Leu16 monoclonal antibody, which comprises the heavy chain variable region (V H ) and the light chain variable region (V L ) of Leu16 connected by a linker.
  • V H heavy chain variable region
  • V L light chain variable region
  • certain embodiments include tLNPs encapsulating a CD20 CAR payload encoded by RNA and having a T cell targeting moiety, such as an anti-CD8 antibody.
  • the tLNP comprises a nucleic acid encoding an anti-BCMA chimeric antigen receptor (CAR).
  • CAR anti-BCMA chimeric antigen receptor
  • BCMA is a tumor necrosis family receptor (TNFR) member expressed on cells of the B cell lineage, with the highest expression on terminally differentiated B cells or mature B lymphocytes. BCMA is involved in mediating the survival of plasma cells for maintaining long-term humoral immunity.
  • the expression of BCMA has been recently linked to a number of cancers, such as multiple myeloma, Hodgkin's and non-Hodgkin's lymphoma, various leukemias, and glioblastoma.
  • the nucleic acid comprises mRNA.
  • anti-BCMA CARs include those incorporating a BCMA binding moiety derived from C11D5.3, a Mouse monoclonal antibody as described in Carpenter et al., Clin. Cancer Res. 19(8):2048-2060 (2013). See also PCT Application Publication No. WO 2010/104949.
  • the extracellular binding domain of the BCMA CAR comprises an scFv derived from another Mouse monoclonal antibody, C12A3.2, as described in Carpenter et al., Clin. Cancer Res.19(8):2048-2060 (2013) and PCT Application Publication No. WO2010104949.
  • the extracellular binding domain of the BCMA CAR comprises an scFv derived from a Mouse monoclonal antibody with high specificity to human BCMA, referred to as BB2121 in Friedman et al., Hum. Gene Ther. 29(5):585-601 (2016). See also, PCT Application Publication No. WO2012163805.
  • the extracellular binding domain of the BCMA CAR comprises single variable fragments of two heavy chains (VHH) that can bind to two epitopes of BCMA as described in Zhao et al., J. Hematol. Oncol.11(1):141 (2016), also referred to as LCAR-B38M. See also, PCT Application Publication No. WO 2018/028647.
  • the extracellular binding domain of the BCMA CAR comprises a fully human heavy-chain variable domain (FHVH) as described in Lam et al., Nat. Commun. 11(1):283 (2020), also referred to as FHVH33. See also, PCT Application Publication No. WO 2019/006072.
  • the extracellular binding domain of the BCMA CAR comprises an scFv derived from CT103A (or CAR0085) as described in U.S. Patent No.11,026,975 B2.
  • Further anti-BCMA CARs are disclosed in U.S. Application Publication Nos. 2020/0246381 and 2020/0339699. Further anti-BCMA CARs include Allo-605 (described in U.S. Patent Publication No.20200261503), CT053 (described in U.S. Patent No. US11,525,006), Descartes-08 (described in U.S. Patent No.10,934,337), LCAR-B38M (described in U.S. Patent No.
  • EMB-06 (described with other anti-BCMA antibodies in U.S. Patent Publication No. US20230002489), HPN217(described in U.S. Patent No. 11,136,403), MEDI2228 (described in U.S. Patent No. 10,988,546), REGN5459 (described in U.S. Patent No.11,384,153), SAR445514 (described in U.S. Patent Publication No. 20240034816), SEA-BCMA (described in U.S. Patent No. 11,078,291), TNB-383B (described in U.S. Patent No. 11,505,606), TQB2934 (described in U.S.
  • Patent Publication No.20230193292 WV078 (described in U.S. Patent No.11,492,409), alnuctamab (described in U.S. Patent No. 10,683,369), belantamab (described in U.S. Patent No. 9,273,141), elranatamab (described in U.S. Patent No.11,814,435), ispectamab (described in U.S. Patent Publication No. 20210130483), linvoseltamab (described in U.S. Patent No. 11,919,965), pavurutamab (described in U.S.
  • Patent No.11,419,933), and teclistamab (described in U.S. Patent No.10,072,088).
  • the entire contents of each of foregoing references in this paragraph are incorporated by reference for all that they teach about the design, structure, and activity of anti-BCMA CARs and anti-BCMA antibodies that can provide an antigen binding domain for a CAR or immune cell engager.
  • certain embodiments include tLNPs encapsulating a BCMA CAR payload encoded by RNA and having a T cell targeting moiety, such as an anti-CD8 antibody.
  • the tLNP comprises a nucleic acid encoding an anti- GPRC5D chimeric antigen receptor (CAR).
  • CAR GPRC5D chimeric antigen receptor
  • GPRC5D is a G protein-coupled receptor without known ligands and of unclear function in human tissue. However, this receptor is expressed in myeloma cell lines and in bone marrow plasma cells from patients with multiple myeloma. GPRC5D has been identified as an immunotherapeutic target in multiple myeloma and Hodgkin lymphomas.
  • anti-GPRC5D CARs include those incorporating a GPRC5D binding moiety such as MCARH109 (Mailankody et al., N Engl J Med.
  • anti-GPRC5D CARs include those incorporating a GPRC5D binding moiety derived from an antibody specific to GPRC5D, for example, talquetamab (Pillarisetti et al., Blood 135:1232-43 (2020)), or forimtamig.
  • the extracellular binding domain of the anti-GPRC5D CAR comprises an scFv derived from a 6D9 Mouse antibody with specificity to human GPRC5D (see creative-biolabs.com/car-t/anti- gprc5d-6d9-h-41bb-cd3-car-pcdcar1-26380.htm).
  • the extracellular binding domain of the GPRC5D CAR comprises an scFv of anti-GPRC5D antibody linked to 4-1BB or CD28 costimulatory domain and CD3 ⁇ signaling domain as described in Mailankody et al., N Engl J Med.387(13): 1196-1206 (2022); creative-biolabs.com/car-t/anti-gprc5d-6d9- h-41bb-cd3-car-pcdcar1-26380.htm; and Rodriguez-Otero et al., Blood Cancer J. 14(1): 24 (2024).
  • tLNPs encapsulating an anti-GPRC5D CAR payload encoded by RNA and having a T cell targeting moiety, such as an anti-CD8 antibody.
  • the tLNP comprises a nucleic acid encoding an anti-FCRL5 chimeric antigen receptor (CAR).
  • FCRL5 Fc receptor-like 5
  • FCRH5 Fc receptor-like 5
  • BXMAS1, CD307, CD307E, and IRTA2 is a protein marker expressed on the surface of plasma cells in patients with multiple myeloma. Furthermore, contact with FCRL5 stimulates B-cell proliferation; thus, FCRL5 has been identified as an immunotherapeutic target for this disease.
  • anti-FCRL5 CARS include those incorporating an FCRL5 binding moiety, such as those described in WO2016090337, WO2017096120, WO2022263855, and WO2024047558.
  • the extracellular binding domain of the anti-FCRL5 CAR comprises an scFv with specificity to FCRL5, such as ET200-31, ET200-39, ET200-69, ET200-104, ET200-105, ET200-109, or ET200-117.
  • the extracellular binding domain of the anti-FCRL5 CAR comprises an scFv derived from a mouse antibody with specificity to human FCRL5.
  • Such antibodies include 7D11, F25, F56, and F119, as described in Polson et al., Int. Immunol., 18(9): 1363-1373 (2006); Franco et al., J. Immunol.
  • the extracellular binding domain of the anti-FCRL5 CAR comprises a binding moiety derived from the antigen binding domain of an anti-FCRL5 antibody or nanobody, including cevostamab, 2A10H7, 307307, 2A10D6, 13G9, 10A8, 509f6, EPR27365-87, EPR26948-19, or EPR26948-67, or as disclosed in WO2016090337, WO2017096120, WO2022263855, or WO2024047558.
  • the extracellular binding domain of the anti-FCRL5 CAR comprises a binding moiety derived from an antibody-drug conjugate targeting FCRL5, such as those described in Elkins et al., Mol.
  • the extracellular binding domain of the anti-FCRL5 CAR is linked to a costimulatory domain, such as a 4-1BB or CD28 costimulatory domain, and a signaling domain, such as a CD3 ⁇ signaling domain.
  • a costimulatory domain such as a 4-1BB or CD28 costimulatory domain
  • a signaling domain such as a CD3 ⁇ signaling domain.
  • certain embodiments include tLNPs encapsulating a FCRL5 CAR payload encoded by RNA and having a T cell targeting moiety, such as an anti- CD8 antibody.
  • the tLNP comprises nucleic acids encoding one or more CARs that target one or multiple antigens.
  • the tLNP comprises distinct mRNAs that are encapsulated together in a single tLNP, with each mRNA encoding one monospecific CAR.
  • the tLNP can comprise an mRNA encoding an anti-CD19 CAR and an mRNA encoding an anti-CD20 CAR, an mRNA encoding an anti-CD19 CAR and an mRNA encoding an anti-BCMA CAR, an mRNA encoding an anti-GPRC5D CAR and an mRNA encoding an anti-BCMA CAR, or an mRNA encoding an anti-FCRL5 CAR and an mRNA encoding an anti-BCMA CAR.
  • the tLNP comprises a single mRNA encoding a bicistronic mRNA encoding two monospecific CARs.
  • the bicistronic mRNA can encode an anti-CD19 CAR and an anti-CD20 CAR, an anti-CD19 CAR and an anti-BCMA CAR, an anti-GPRC5D CAR and an anti-BCMA CAR, or an anti-FCRL5 CAR and an anti-BCMA CAR.
  • the tLNP comprises a single mRNA encoding an mRNA encoding a multispecific CAR. In some embodiments, the tLNP comprises a single mRNA encoding an mRNA encoding a bispecific CAR.
  • the mRNA can encode an anti-CD19 and anti-CD20 bispecific CAR, an anti-CD19 and anti-BCMA bispecific CAR, an anti-GPRC5D and anti-BCMA bispecific CAR, or an anti-FCRL5 and anti-BCMA bispecific CAR.
  • multiple tLNPs can be co-formulated in a combination with each comprising one mRNA encoding one monospecific CAR.
  • two tLNPs can be co-formulated with one tLNP comprising an mRNA encoding an anti-CD19 CAR and the other tLNP comprising an mRNA encoding an anti-CD20 CAR, one tLNP comprising an mRNA encoding an anti-C19 CAR and the other tLNP comprising an mRNA encoding an anti- BCMA CAR, one tLNP comprising an mRNA encoding an anti-GPRC5D CAR and the other tLNP comprising an mRNA encoding an anti-BCMA CAR, or one tLNP comprising an mRNA encoding an anti-FCRL5 CAR and the other tLNP comprising an mRNA encoding an anti- BCMA CAR.
  • multiple tLNPs can be co-administered in a combination, either simultaneously or sequentially, wherein each comprises one mRNA encoding one monospecific CAR.
  • two tLNPs can be co-administered in a combination, either simultaneously or sequentially, with one tLNP comprising an mRNA encoding an anti-CD19 CAR and the other tLNP comprising an mRNA encoding an anti-CD20 CAR, one tLNP comprising an mRNA encoding an anti-C19 CAR and the other tLNP comprising an mRNA encoding an anti-BCMA CAR, one tLNP comprising an mRNA encoding an anti-GPRC5D CAR and the other tLNP comprising an mRNA encoding an anti-BCMA CAR, or one tLNP comprising an mRNA encoding an anti-FCRL5 CAR and the other tLNP comprising an mRNA encoding an encoding an
  • the targeting can be mediated by any of the CARs described herein which constitute means for targeting cells expressing the indicated antigen.
  • Cellular therapy involving the administration of genetically engineered cells to a patient has generally required depleting or ablative conditioning to facilitate engraftment of the engineered cells (for example, T cells or HSC). In the context of in vivo engineering and reprogramming such conditioning would be counterproductive as the conditioning would eliminate the very cells that are to be engineered.
  • conditioning agents include biological response modifiers (BRMs) that can be delivered directly to a subject or encoded in nucleic acid molecules, including as mRNA, and delivered to a subject using the LNP and tLNP compositions and formulations disclosed herein.
  • BRMs biological response modifiers
  • an encoded conditioning agent comprises a ⁇ -chain receptor agonist, an inflammatory chemokine, a pan-activating cytokine, an antigen presenting cell activity enhancer, an immune checkpoint inhibitor, or an anti-CCR4 antibody.
  • the ⁇ -chain receptor cytokine comprises IL-15, IL-2, IL-7, or IL-21.
  • the immune checkpoint inhibitor comprises an anti- CTLA-4, anti-PD-1, anti-PD-L1, anti-Tim-3, or anti-LAG-3 antibody.
  • the inflammatory chemokine comprises CCL2, CCL3, CCL4, CCL5, CCL11, CXCL1, CXCL2, CXCL-8, CXCL9, CXCL10, or CXCL11.
  • the antigen presenting cell activity enhancer comprises Flt-3 ligand, gm-CSF, or IL-18.
  • a pan- activating cytokine comprises IL-12 of IL 18.
  • a conditioning agent comprises a transcription factor, for example, one selected from the group consisting of nuclear factor of activated T-cells (NFAT), NF- ⁇ B, T-bet, signal transducer and activator of transcription 4 (STAT4), Blimp-1, c-Jun, and Eomesodermin (Eomes) and the tLNP is targeted to a T cell.
  • NFAT nuclear factor of activated T-cells
  • STAT4 signal transducer and activator of transcription 4
  • Blimp-1 Blimp-1
  • c-Jun c-Jun
  • Eomes Eomes
  • a tLNP encapsulating the nucleic acid-encoded conditioning agent is administered systemically, for example, by intravenous or subcutaneous infusion or injection.
  • the tLNP is administered locally, for example, by intralesional or intraperitoneal injection or infusion.
  • nucleic acid molecules encoding the conditioning agent and the engineering agent are encapsulated in the same tLNP while in other embodiments they are encapsulated in separate tLNPs. These two modes of delivery of conditioning agents are described in greater detail in PCT application PCT/US 2023/072426, which is incorporated by reference for all that it teaches about conditioning agents and their delivery of LNPs or tLNPs that is not inconsistent with this disclosure.
  • the nucleic acid comprises mRNA.
  • treating broadly includes any kind of treatment activity, including the mitigation, cure or prevention of disease, or aspect thereof, in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.
  • Treatment activity includes the administration of the medicaments, dosage forms, and pharmaceutical compositions described herein to a patient, especially according to the various methods of treatment disclosed herein, whether by a healthcare professional, the patient his/herself, or any other person.
  • Treatment activities include the orders, instructions, and advice of healthcare professionals such as physicians, physician’s assistants, nurse practitioners, and the like, that are then acted upon by any other person including other healthcare professionals or the patient him/herself.
  • the orders, instructions, and advice aspect of treatment activity can also include encouraging, inducing, or mandating that a particular medicament, or combination thereof, be chosen for treatment of a condition - and the medicament is actually used - by approving insurance coverage for the medicament, denying coverage for an alternative medicament, including the medicament on, or excluding an alternative medicament, from a drug formulary, or offering a financial incentive to use the medicament, as might be done by an insurance company or a pharmacy benefits management company, and the like.
  • treatment activity can also include encouraging, inducing, or mandating that a particular medicament be chosen for treatment of a condition - and the medicament is actually used - by a policy or practice standard as might be established by a hospital, clinic, health maintenance organization, medical practice or physicians group, and the like. All such orders, instructions, and advice are to be seen as conditioning receipt of the benefit of the treatment on compliance with the instruction.
  • a financial benefit is also received by the patient for compliance with such orders, instructions, and advice.
  • a financial benefit is also received by the healthcare professional for compliance with such orders, instructions, and advice.
  • Some embodiments of these methods of treatment comprise administration of an effective amount of a compound or a composition disclosed herein.
  • a therapeutically effective amount is not necessarily a clinically effective amount, that is, while there can be therapeutic benefit as compared to no treatment, a method of treatment may not be equivalent or superior to a standard of care treatment existing at some point in time.
  • Other instances relate to a pharmacologically effective amount, that is an amount or dose that produces an effect that correlates with or is reasonably predictive of therapeutic (or prophylactic) utility.
  • therapeutically effective amount is synonymous with “therapeutically effective dose” and means at least the minimum dose of a compound or composition disclosed herein necessary to achieve the desired therapeutic or prophylactic effect.
  • a pharmacologically effective dose means at least the minimum dose of a compound or composition disclosed herein necessary to achieve the desired pharmacologic effect. Some embodiments refer to an amount sufficient to prevent or disrupt a disease process, or to reduce the extent or duration of pathology. Some embodiments refer to a dose sufficient to reduce a symptom associated with the disease or condition being treated.
  • Example 2 Synthesis of tert-butyl rel-(2S,4R)-2,4- bis(hydroxymethyl)azetidine-1-carboxylate (2) [00641] To a solution of 1 (4.00g, 16.1mmol) in EtOH (200mL) was added Pd(OH) 2 (0.80g, 20% w/w and BOC 2 O (5.27g, 2.15mmol), and the mixture was placed under 30psi of hydrogen. The mixture was shaken under 30psi of hydrogen for 20hours, then the catalyst was removed by filtration through a pad of Celite, the filter cake was rinsed with EtOH (50mL) and the combined filtrates were concentrated in vacuo to give crude 2 as a yellow oil.
  • Crude 2 was purified by chromatography on a column of silica gel (250g, 100-200 mesh), packed and eluted with petroleum ether-EtOAc (4:1). Fractions containing 2 were pooled and concentrated in vacuo to furnish 2 (2.10g, HPLC purity 97.9%, 9.20mmol, 57% yield) as a clear, pale yellow, oil.
  • Example 3 Synthesis of O'1,O1-((Rel-(2S,4R)-1-((2- (Dimethylamino)ethoxy)carbonyl) azetidine-2,4-diyl)bis(methylene)) 5,5'-dioctyl bis(3- (2-(octyloxy)-2-oxoethyl)pentanedioate): CICL-252
  • Example 4 Synthesis of tert-Butyl rel-(2R,4R)-2,4- bis(hydroxymethyl)azetidine-1-carboxylate (8) [00646] To a solution of 7 (7.90g, 38.11mmol, Tetrahedron Asymmetry 2001, 12, 605) in EtOH (240mL) was added 10% Pd/C (1.60g, 20% w/w) and BOC 2 O (12.48g, 57.16mmol), and the mixture was placed under 30psi of hydrogen.
  • Example 5 Synthesis of O'1,O1-(Rel-((2R,4R)-1-((2- (Dimethylamino)ethoxy)carbonyl) azetidine-2,4-diyl)bis(methylene)) 5,5'-dioctyl bis(3- (2-(octyloxy)-2-oxoethyl)pentanedioate): CICL-253
  • Example 6 Synthesis of 1-(((2S,4R)-1-(tert-butoxycarbonyl)-4-((5- (octyloxy)-3-(2-(octyloxy)-2-oxoethyl)-5-oxopentanoyl)oxy)pyrrolidin-2-yl)methyl) 5- octyl 3-(2-(octyloxy)-2-oxoethyl)pentanedioate: 13
  • Example 8 Synthesis of 1-(((2S,4R)-1-(1H-imidazole-1-carbonyl)-4-((5- (octyloxy)-3-(2-(octyloxy)-2-oxoethyl)-5-oxopentanoyl)oxy)pyrrolidin-2-yl)methyl) 5- octyl 3-(2-(octyloxy)-2-oxoethyl) pentanedioate 15 [00657] To a solution of 14 (8.40g, crude, 8.20mmol, 86.3% HPLC purity), in dichloromethane (250mL) under nitrogen, was added carbonyldiimidazole (14.90g, 92.31mmol).
  • Example 9 Synthesis of 1-(((2S,4R)-1-((2- (dimethylamino)ethoxy)carbonyl)-4-((5-(octyloxy)-3-(2-(octyloxy)-2-oxoethyl)-5- oxopentanoyl)oxy)pyrrolidin-2-yl)methyl) 5-octyl 3-(2-(octyloxy)-2- oxoethyl)pentanedioate: CICL-251 [00660] A solution of 15 (8.40g, crude, assumed 8.37mmol) in acetonitrile, was cooled in and ice-water bath under nitrogen and methyl trifluoromethanesulfonate (1.51g, 9.20mmol) was added over a period of 5 minutes.
  • Example 10 Synthesis of 1-(((2S,4S)-1-((2-(dimethylamino)ethoxy)carbonyl)- 4-((5-(octyloxy)-3-(2-(octyloxy)-2-oxoethyl)-5-oxopentanoyl)oxy)pyrrolidin-2-yl)methyl) 5-octyl 3-(2-(octyloxy)-2-oxoethyl)pentanedioate: CICL-254
  • Example 11 1-(((2R,4S)-1-((2-(dimethylamino)ethoxy)carbonyl)-4-((5- (octyloxy)-3-(2-(octyloxy)-2-oxoethyl)-5-oxopentanoyl)oxy)pyrrolidin-2-yl)methyl) 5- octyl 3-(2-(octyloxy)-2-oxoethyl)pentanedioate: CICL-255
  • Example 12 1-(((2R,4R)-1-((2-(dimethylamino)ethoxy)carbonyl)-4-((5- (octyloxy)-3-(2-(octyloxy)-2-oxoethyl)-5-oxopentanoyl)oxy)pyrrolidin-2-yl)methyl) 5- octyl 3-(2-(octyloxy)-2-oxoethyl)pentanedioate: CICL-256
  • Example 13 O'1,O1-(Rel-(3S,4R)-1-((2-(dimethylamino)ethoxy) carbonyl)pyrrolidine-3,4-diyl) 5,5'-dioctyl bis(3-(2-(octyloxy)-2-oxoethyl) pentanedioate): CICL-257 [00668]
  • the coupling of diester 3 with diol 28 (Nature Communications 2019, 10, 21), utilizing EDC-HCl and DMAP in CH 3 CN, results in 29.
  • Deprotection of the BOC-amine 29, with CF 3 CO 2 H in CH 2 Cl 2 provides ammonium trifluoroacetate salt 30.
  • Example 14 O'1,O1-((3S,4S)-1-((2- (dimethylamino)ethoxy)carbonyl)pyrrolidine-3,4-diyl) 5,5'-dioctyl bis(3-(2-(octyloxy)-2- oxoethyl)pentanedioate): CICL-258
  • Example 15 Synthesis of O'1,O1-(Rel-((2R,5S)-1-((2-(dimethylamino) ethoxy)carbonyl) pyrrolidine-2,5-diyl)bis(methylene)) 5,5'-dioctyl bis(3-(2-(octyloxy)-2- oxoethyl)pentanedioate): CICL-259
  • Example 16 Synthesis of O'1,O1-(((2S,5S)-1-((2-(dimethylamino) ethoxy)carbonyl) pyrrolidine-2,5-diyl)bis(methylene)) 5,5'-dioctyl bis(3-(2-(octyloxy)-2- oxoethyl)pentanedioate): CICL-260
  • Example 17 O'1,O1-((3R,5R)-1-((2- (dimethylamino)ethoxy)carbonyl)piperidine-3,5-diyl) 5,5'-dioctyl bis(3-(2-(octyloxy)-2- oxoethyl)pentanedioate): CICL-261
  • Example 18 Synthesis of tert-Butyl Rel-(3R,5S)-3,5-dihydroxypiperidine-1- carboxylate:49 [00678] To a solution of 48 (WO2013149362, 8.00g, 38.6mmol) in EtOH (160mL) was added BOC 2 O (12.64g, 57.9mmol) and Pd/C (1.60g, 20wt%). The resulting solution was placed under hydrogen (15atm) at room temperature for 24 hours. The mixture filtered through a pad of Celite®, the filter cake was rinsed with EtOH (3 x 50mL) and the combined filtrates were concentrated in vacuo to provide crude 49 as a pale yellow oil.
  • Example 19 O'1,O1-(Rel-(3R,5S)-1-((2- (dimethylamino)ethoxy)carbonyl)piperidine-3,5-diyl) 5,5'-dioctyl bis(3-(2-(octyloxy)-2- oxoethyl)pentanedioate): CICL-262
  • Example 20 Synthesis of O'1,O1-((Rel-(2S,6R)-1-((2-(dimethylamino) ethoxy)carbonyl) piperidine-2,6-diyl)bis(methylene)) 5,5'-dioctyl bis(3-(2-(octyloxy)-2- oxoethyl)pentanedioate): CICL-263
  • Example 21 Synthesis of O'1,O1-((Rel-(2S,6S)-1-((2- (dimethylamino)ethoxy)carbonyl)piperidine-2,6-diyl)bis(methylene)) 5,5'-dioctyl bis(3- (2-(octyloxy)-2-oxoethyl)pentanedioate): CICL-264
  • Example 22 Synthesis of O'1,O1-(Rel-(3R,6S)-1-(tert-butoxycarbonyl)- 2,3,6,7-tetrahydro-1H-azepine-3,6-diyl) 5,5'-dioctyl bis(3-(2-(octyloxy)-2- oxoethyl)pentanedioate): CICL-265
  • Example 23 Synthesis of O'1,O1-(Rel-(3S,6S)-1-((2-(dimethylamino) ethoxy)carbonyl)-2,3,6,7-tetrahydro-1H-azepine-3,6-diyl) 5,5'-dioctyl bis(3-(2-(octyloxy)- 2-oxoethyl)pentanedioate): CICL-266
  • Example 24 Synthesis of O'1,O1-((Rel-(2R,7S)-1-((2-(dimethylamino) ethoxy)carbonyl)-2,3,6,7-tetrahydro-1H-azepine-2,7-diyl)bis(methylene)) 5,5'-dioctyl bis(3-(2-(octyloxy)-2-oxoethyl)pentanedioate): CICL-267
  • acyl-imidazole 75 Treatment of 74 with carbonyl-di-imidazole and Et 3 N in CH 2 Cl 2 , results in acyl-imidazole 75. Alkylation of 75 with MeOTf in CH 3 CN, followed by the reaction of the derived acyl-imidazolium salt with 2-dimethylaminoethanol and (CH 3 ) 3 N results in CICL-267.
  • Example 25 Synthesis of O'1,O1-(Rel-((2R,7S)-1-((2-(dimethylamino) ethoxy)carbonyl)-2,3,6,7-tetrahydro-1H-azepine-2,7-diyl)bis(methylene)) 5,5'-dioctyl bis(3-(2-(octyloxy)-2-oxoethyl)pentanedioate): CICL-268
  • Example 27 Synthesis of O'1,O1-(Rel-((2S,7S)-1-((2-(dimethylamino) ethoxy)carbonyl) azepane-2,7-diyl)bis(methylene)) 5,5'-dioctyl bis(3-(2-(octyloxy)-2- oxoethyl)pentanedioate): CICL-270
  • Example 28 Synthesis of Tetraoctyl 2,2',2'',2''-((((((Rel-(2S,4R)-1-((2- (dimethylamino) ethoxy) carbonyl)azetidine-2,4-diyl)bis(methylene))bis(oxy))bis(2- oxoethane-2,1-diyl))bis(azanetriyl))tetraacetate: CICL-271 [00699] 2,2'-((2-(Benzyloxy)-2-oxoethyl)azanediyl)diacetic acid 90 (WO2018006063 p251), when coupled (EDC-HCl, DMAP) with 1-octanol, provides triester 91.
  • Example 30 Synthesis of Dioctyl 2,2'-((2-(((2S,4R)-4-((bis(2-(octyloxy)-2- oxoethyl)glycyl)oxy)-1-((2-(dimethylamino)ethoxy)carbonyl)pyrrolidin-2-yl)methoxy)-2- oxoethyl)azanediyl)diacetate: CICL-273 [00703] The coupling of diester 92 with diol 12, utilizing EDC-HCl and DMAP in CH 3 CN, results in 99.
  • Example 31 Synthesis of Dioctyl 2,2'-((2-(((2S,4S)-4-((bis(2-(octyloxy)-2- oxoethyl)glycyl)oxy)-1-((2-(dimethylamino)ethoxy)carbonyl)pyrrolidin-2-yl)methoxy)-2- oxoethyl)azanediyl)diacetate: CICL-274 [00705] The coupling of diester 92 with diol 16, utilizing EDC-HCl and DMAP in CH 3 CN, results in 102.
  • Example 32 Synthesis of dioctyl 2,2'-((2-(((2R,4S)-4-((bis(2-(octyloxy)-2- oxoethyl)glycyl)oxy)-1-((2-(dimethylamino)ethoxy)carbonyl)pyrrolidin-2-yl)methoxy)-2- oxoethyl)azanediyl)diacetate: CICL-275 [00707] The coupling of diester 92 with diol 20, utilizing EDC-HCl and DMAP in CH 3 CN, results in 105.
  • Example 33 Synthesis of Dioctyl 2,2'-((2-(((2R,4R)-4-((bis(2-(octyloxy)-2- oxoethyl)glycyl)oxy)-1-((2-(dimethylamino)ethoxy)carbonyl)pyrrolidin-2-yl)methoxy)-2- oxoethyl)azanediyl)diacetate: CICL-276 [00709] The coupling of diester 92 with diol 24, utilizing EDC-HCl and DMAP in CH 3 CN, results in 108.
  • Example 34 Synthesis of Tetraoctyl 2,2',2'',2''-((((Rel-(3S,4R)-1-((2- (dimethylamino) ethoxy)carbonyl)pyrrolidine-3,4-diyl)bis(oxy))bis(2-oxoethane-2,1- diyl))bis(azanetriyl))tetraacetate: CICL-277 CICL-277 [00711] The coupling of diester 92 with diol 28, utilizing EDC-HCl and DMAP in CH 3 CN, results in 111.
  • Example 35 Synthesis of Tetraoctyl 2,2',2'',2''-(((((3S,4S)-1-((2- (dimethylamino)ethoxy)carbonyl)pyrrolidine-3,4-diyl)bis(oxy))bis(2-oxoethane-2,1- diyl))bis(azanetriyl))tetraacetate: CICL-278
  • Example 36 Synthesis of Tetraoctyl 2,2',2'',2''-((((((Rel-(2R,5S)-1-((2- (dimethylamino) ethoxy)carbonyl)pyrrolidine-2,5-diyl)bis(methylene))bis(oxy))bis(2- oxoethane-2,1-diyl))bis(azanetriyl))tetraacetate: CICL-279
  • Example 37 Synthesis of Tetraoctyl 2,2',2'',2''-((((((2S,5S)-1-((2- (dimethylamino) ethoxy)carbonyl)pyrrolidine-2,5-diyl)bis(methylene))bis(oxy))bis(2- oxoethane-2,1-diyl))bis(azanetriyl))tetraacetate: CICL-280
  • Example 38 Synthesis of Tetraoctyl 2,2',2'',2''-(((((3R,5R)-1-((2- (dimethylamino) ethoxy)carbonyl)piperidine-3,5-diyl)bis(oxy))bis(2-oxoethane-2,1- diyl))bis(azanetriyl))tetraacetate: CICL-281 [0023] The coupling of diester 92 with diol 44, utilizing EDC-HCl and DMAP in CH 3 CN, results in 123. Deprotection of the BOC-amine 123, with CF 3 CO 2 H in CH 2 Cl 2 , provides ammonium trifluoroacetate salt 124. Treatment of 124 with carbonyl-di-imidazole and Et 3 N in
  • Example 39 Synthesis of Tetraoctyl 2,2',2'',2''-((((Rel-(3R,5S)-1-((2- (dimethylamino) ethoxy)carbonyl)piperidine-3,5-diyl)bis(oxy))bis(2-oxoethane-2,1- diyl))bis(azanetriyl))tetraacetate: CICL-282
  • Example 40 Synthesis of Tetraoctyl 2,2',2'',2''-((((((Rel-(2S,6R)-1-((2- (dimethylamino)ethoxy)carbonyl)piperidine-2,6-diyl)bis(methylene))bis(oxy))bis(2- oxoethane-2,1-diyl))bis(azanetriyl))tetraacetate: CICL-283
  • Example 41 Synthesis of Tetraoctyl 2,2',2'',2''-((((((Rel-(2S,6S)-1-((2- (dimethylamino) ethoxy)carbonyl)piperidine-2,6-diyl)bis(methylene))bis(oxy))bis(2- oxoethane-2,1-diyl))bis(azanetriyl))tetraacetate: CICL-284
  • Example 42 Synthesis of Tetraoctyl 2,2',2'',2''-((((Rel-(3R,6S)-1-((2- (dimethylamino)ethoxy)carbonyl)-2,3,6,7-tetrahydro-1H-azepine-3,6-diyl)bis(oxy))bis(2- oxoethane-2,1-diyl))bis(azanetriyl))tetraacetate: CICL-285
  • Example 43 Tetraoctyl 2,2',2'',2''-((((Rel-(3S,6S)-1-((2-(dimethylamino) ethoxy)carbonyl)-2,3,6,7-tetrahydro-1H-azepine-3,6-diyl)bis(oxy))bis(2-oxoethane-2,1- diyl))bis(azanetriyl))tetraacetate: CICL-286
  • Example 44 Synthesis of Tetraoctyl 2,2',2'',2''-((((((Rel-(2R,7S)-1-((2- (dimethylamino) ethoxy) carbonyl)-2,3,6,7-tetrahydro-1H-azepine-2,7- diyl)bis(methylene))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(azanetriyl))tetraacetate: CICL-287
  • Example 45 Synthesis of Tetraoctyl 2,2',2'',2''-((((((Rel-(2S,7S)-1-((2- (dimethylamino) ethoxy)carbonyl)-2,3,6,7-tetrahydro-1H-azepine-2,7-diyl) bis(methylene))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(azanetriyl))tetraacetate: CICL- 288 [00732] The coupling of diester 92 with diol 76, utilizing EDC-HCl and DMAP in CH 3 CN, results in 144.
  • Example 46 Synthesis of Tetraoctyl 2,2',2'',2''-((((((Rel-(2S,7R)-1-((2- (dimethylamino)ethoxy)carbonyl)azepane-2,7-diyl)bis(methylene))bis(oxy))bis(2- oxoethane-2,1-diyl))bis(azanetriyl))tetraacetate: CICL-289
  • Example 47 Synthesis of Tetraoctyl 2,2',2'',2''-((((((Rel-(2S,7S)-1-((2- (dimethylamino) ethoxy)carbonyl)azepane-2,7-diyl)bis(methylene))bis(oxy))bis(2- oxoethane-2,1-diyl))bis(azanetriyl))tetraacetate: CICL-290 [00736] The coupling of diester 92 with diol 86, utilizing EDC-HCl and DMAP in CH 3 CN, results in 150.
  • Example 48 Synthesis of 1-(((2S,4R)-1-(((1-methylazetidin-3- yl)oxy)carbonyl)-4-((5-(octyloxy)-3-(2-(octyloxy)-2-oxoethyl)-5-oxopentanoyl)oxy) pyrrolidin-2-yl)methyl) 5-octyl 3-(2-(octyloxy)-2-oxoethyl)pentanedioate: CICL-251-153 [00738] Alkylation of acylimidazole 15 with MeOTf in CH 3 CN, followed by the reaction of the derived acyl-imidazolium salt with alcohol 153 (CombiBlocks # JL-5330) and (CH 3 ) 3 N results in CICL-251-153.
  • the numbering paradigm utilized for cyclic-amino-alcohol head groups is based on an ionizable cationic lipid described above that was generated from an acylimidazolide, in this case 15, when it was reacted with 2-dimethylaminoethanol, with the number of the head group- forming alcohol appended, in this case 153.
  • Acylimidazolide 15 was converted to lipid CICL- 251 in Example 6.
  • the utilization of the chemistry described in Example 48 to generate the active imidazolium species enables the synthesis of a selection of lipids containing cyclic head groups by substitution of the alcohol 153 (vide supra) with the alcohols appearing in Table 3.
  • Example 49 Synthesis of 2-(2-(tert-butoxy)-2-oxoethyl)propane-1,3-diyl dinonanoate 170 1 70
  • tert-butyl 4-hydroxy-3-(hydroxymethyl)butanoate Org. Proc. Res. Dev.2011, 15, 515; 44.0g, 0.231mol
  • nonanoic acid 76.86g, 0.486mol
  • DMAP 28.22g, 0.231mol
  • EDC-HCl 97.8g, 0.513mol
  • the mixture was stirred for 1 hour, then was allowed to warm to room temperature and was stirred for 12 hours.
  • the solution was cast into n-heptane (1.40L) and water (0.9L) and the organic phase was separated.
  • the organic phase was washed twice with MeOH:10% aq. citric acid (0.90L), followed by washing twice with a mixture of MeOH:water:triethyl amine (0.90L, 3:1:0.1). The organic phase was then washed with 10% aq.
  • Example 50 Synthesis of 4-(nonanoyloxy)-3-((nonanoyloxy)methyl) butanoic acid 171 [00745] To a solution of 170 (90.0g, 96.3% purity, 0.184mol) in toluene (0.41L), cooled in an ice-water bath under nitrogen, was added TFA (208.46g, 1.83mol, 140mL) over a period of 30 minutes. After the addition was complete the mixture was warmed to 15°C and the mixture was stirred for 18 hours. The chilled solution was cast into n-heptane (1.50L) and the resulting solution was extracted with 5% aq. potassium phosphate (2.0L) and the aqueous phase was collected.
  • TFA 208.46g, 1.83mol, 140mL
  • Example 51 Synthesis of 1-(((2S,4R)-1-((2- (dimethylamino)ethoxy)carbonyl)-4-((3-((nonanoyloxy)methyl)-5-(octyloxy)-5- oxopentanoyl)oxy)pyrrolidin-2-yl)methyl) 5-octyl 3- ((nonanoyloxy)methyl)pentanedioate: CICL-304
  • Example 52 Synthesis of 1-(((2S,4R)-1-(tert-butoxycarbonyl)-4- hydroxypyrrolidin-2-yl)methyl) 5-octyl 3-((nonanoyloxy)methyl)pentanedioate: 179 and 1-((3R,5S)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)pyrrolidin-3-yl) 5-octyl 3- ((nonanoyloxy)methyl)pentanedioate: 180 [00750] The coupling of alcohol 175 (1 equiv.) with diol 12, utilizing EDCl and DMAP in CH 3 CN, results in a mixture of esters 179 and 180, which are separated by chromatographic purification to furnish mono-alcohols 179 and 180.
  • Example 53 Synthesis of 1-(((2S,4R)-1-((2- (dimethylamino)ethoxy)carbonyl)-4-((5-(octyloxy)-3-(2-(octyloxy)-2-oxoethyl)-5- oxopentanoyl)oxy)pyrrolidin-2-yl)methyl) 5-octyl 3- ((nonanoyloxy)methyl)pentanedioate: CICL-305
  • Alcohol 179 is coupled with acid 3 utilizing EDCl and DMAP in CH 3 CN, which results in 181.
  • Deprotection of the BOC-blocked amine with TFA in CH 2 Cl 2 provides ammonium trifluoracetate salt 182.
  • Treatment of 182 with carbonyl-diimidazole and Et 3 N in CH 2 Cl 2 results in acyl-imidazole 183.
  • Alkylation of 183 with MeOTf in CH 3 CN, followed by the reaction of the derived acyl-imidazolium salt with 2-dimethylaminoethanol and (CH 3 ) 3 N results in CICL-305.
  • Example 54 Synthesis of 1-(((2S,4R)-1-((2- (dimethylamino)ethoxy)carbonyl)-4-((3-((nonanoyloxy)methyl)-5-(octyloxy)-5- oxopentanoyl)oxy)pyrrolidin-2-yl)methyl) 5-octyl 3-(2-(octyloxy)-2- oxoethyl)pentanedioate: CICL-306
  • Alcohol 180 is coupled with acid 3 utilizing EDCl and DMAP in CH 3 CN, which results in 184.
  • Deprotection of the BOC-blocked amine with TFA in CH 2 Cl 2 provides ammonium trifluoracetate salt 185.
  • Treatment of 185 with carbonyl-diimidazole and Et 3 N in CH 2 Cl 2 results in acyl-imidazole 186.
  • Alkylation of 186 with MeOTf in CH 3 CN, followed by the reaction of the derived acyl-imidazolium salt with 2-dimethylaminoethanol and (CH 3 ) 3 N results in CICL-306.
  • Example 55 Synthesis of 1-(((2S,4R)-1-((2- (dimethylamino)ethoxy)carbonyl)-4-((4-(nonanoyloxy)-3- ((nonanoyloxy)methyl)butanoyl)oxy)pyrrolidin-2-yl)methyl) 5-octyl 3- ((nonanoyloxy)methyl)pentanedioate: CICL-307
  • Alcohol 179 is coupled with acid 171 utilizing EDCl and DMAP in CH 3 CN, which results in 187.
  • Deprotection of the BOC-blocked amine with TFA in CH 2 Cl 2 provides ammonium trifluoracetate salt 188.
  • Treatment of 188 with carbonyl-diimidazole and Et 3 N in CH 2 Cl 2 results in acyl-imidazole 189.
  • Alkylation of 189 with MeOTf in CH 3 CN, followed by the reaction of the derived acyl-imidazolium salt with 2-dimethylaminoethanol and (CH 3 ) 3 N results in CICL-307.
  • Example 56 Synthesis of 1-((3R,5S)-1-((2-(dimethylamino)ethoxy)carbonyl)- 5-(((4-(nonanoyloxy)-3-((nonanoyloxy)methyl)butanoyl)oxy)methyl)pyrrolidin-3-yl) 5- octyl 3-((nonanoyloxy)methyl)pentanedioate: CICL-308
  • Alcohol 180 is coupled with acid 171 utilizing EDCl and DMAP in CH 3 CN, which results in 190.
  • Deprotection of the BOC-blocked amine with TFA in CH 2 Cl 2 provides ammonium trifluoracetate salt 191.
  • Treatment of 191 with carbonyl-diimidazole and Et 3 N in CH 2 Cl 2 results in acyl-imidazole 192.
  • Alkylation of 192 with MeOTf in CH 3 CN, followed by the reaction of the derived acyl-imidazolium salt with 2-dimethylaminoethanol and (CH 3 ) 3 N results in CICL-308.
  • the alcohols selected for this pairing are 154, 155, 157, 159, 160, and 167 which give rise to CICL-251- 154, CICL-251-155, CICL-251-157, CICL-251-159, CICL-251-160, and CICL-251-167.
  • alcohols 154, 155, 157, 159, 160, and 167 are selected for a combination with the following trans acylimidazolides: 11, 23, 35, 43, 47, 60, 68, 79, 89, 98, 101, 107, 116, 122, 125, 134, 140, 146, 152, 178, 183, 186, 189, and 192.
  • Table 4 Lipids Formed from the Combination of Lipid Precursors 11, 23, 35, 43, 47, 60, 68, 79, 89, 98, 101, 107, 116, 122, 125, 134, 140, 146, 152, 178, 183, 186, 189, and 192 with Alcohols 154, 155, 157, 159, 160, and 167
  • An identical analytical paradigm starting with calculated pKa, can be performed with the head groups (i.e., X as described herein) to select candidates appropriate for measured pKa alteration for the frameworks of listed directly above.
  • the propensity of cis- acylimidazolides to provide lipids that result in measured pKa values in formulation that are above the mid-point of the pKa 6-7 range has been described.
  • the amnio-alcohol from the grouping shown in Table 3 that was selected in anticipation of lowering the measured pKa of the cis-lipids toward the mid-point of the pKa 6-7 range was 164.
  • Example 57 In Vivo Delivery of mRNA by LNP Incorporating CICL-251 as the Ionizable Cationic Lipid [00764] To assess the ability of an ionizable cationic lipids to facilitate in vivo transfection of T cells with mRNA, tLNP incorporating CICL-251, or for comparison, CICL-1, and conjugated to an anti-mouse CD5 antibody were prepared and administered to C57BL/6 mice.
  • the tLNP comprised either CICL-251 or CICL-1, DSPC, cholesterol, DSG-PEG(2000), and DSPE-PEG(2000)-maleimide in the proportions indicated in Table 6 (below) and an N/P ratio of 6.
  • CICL-1 has the structure: [00765] Briefly, to prepare the tLNP, N1-methylpseudouridine (m1 ⁇ )-substituted mCherry mRNA (SEQ ID NO: 2) was encapsulated in LNP using a self-assembly process in which an aqueous solution of mRNA at pH 3.5 was rapidly mixed with a solution of lipids dissolved in ethanol, then followed by stepwise phosphate and Tris buffer dilution and tangential flow filtration (TFF) purification. Then an anti-CD5 mAb was conjugated to the above LNP to generate tLNP.
  • m1 ⁇ N1-methylpseudouridine
  • SEQ ID NO: 2 N1-methylpseudouridine (m1 ⁇ )-substituted mCherry mRNA
  • SEQ ID NO: 2 N1-methylpseudouridine (m1 ⁇ )-substituted
  • rat anti-mouse CD5 antibody clone 53-7.3 (BioLegend) was coupled to LNP via N-succinimidyl S-acetylthioacetate (SATA)–maleimide conjugation chemistry.
  • SATA N-succinimidyl S-acetylthioacetate
  • LNPs with DSPE-PEG(2000)-maleimide incorporated were formulated and stored at 4°C on the day of conjugation.
  • the antibody was modified with SATA (Sigma-Aldrich) to introduce sulfhydryl groups at accessible lysine residues allowing conjugation to maleimide.
  • SATA was deprotected using 0.5 M hydroxylamine followed by removal of the unreacted components by G-25 Sephadex Quick Spin Protein columns (Roche Applied Science, Indianapolis, IN).
  • the reactive sulfhydryl group on the antibody was then conjugated to maleimide moieties on the LNPs using thioether conjugation chemistry.
  • Purification was performed using Sepharose CL-4B gel filtration columns (Sigma-Aldrich).
  • tLNPs LNPs conjugated with a targeting antibody
  • tLNPs were frozen at -80°C.
  • the particle size (hydrodynamic diameter) and polydispersity index of the targeted lipid nanoparticles were determined using dynamic light scattering (DLS) on a Malvern Zetasizer Nano ZS (Malvern Instruments, Worcestershire, UK). Size measurement was carried out in pH 7.4 Tris buffer at 25°C in disposable capillary cells.
  • NIBS non-invasive back scatter system
  • mRNA content was determined using a Quant-iT TM RiboGreen RNA assay kit (Invitrogen TM ).
  • tLNP antibody to mRNA weight ratio was determined with the BCA (bicinchoninic acid) total protein assay and Ribogreen® assay of mRNA content.
  • BCA bisinchoninic acid
  • Ribogreen® assay of mRNA content.
  • Table 6 Physicochemical properties of the tLNP [00767] As seen in Table 6, all of these tLNP compositions had hydrodynamic diameters and polydispersity indices within the acceptable ranges of 50-150 nm and ⁇ 0.2 for PDI. Encapsulation efficiency is acceptable at ⁇ 80% although ⁇ 85% and ⁇ 90% are preferred. Binder density (Ab:mRNA ratio (wt:wt)) is acceptable at ratios of 0.3 to 1.0.
  • the apparent or measured pKa of ionizable lipid in the lipid nanoparticle was determined using 6-(p-toluidino)-2-naphthalenesulfonic acid sodium salt (TNS salt, Toronto Research Chemicals, Toronto, ON, Canada). Lipid nanoparticles were diluted in 1xDulbecco's PBS to a concentration of 1 mM total lipids. TNS salt was prepared as a 1 mg/mL stock solution in DMSO and then further diluted using distilled water to a working solution of 60 ⁇ g/mL (179 mM).
  • Diluted lipid nanoparticle samples were further diluted to 90 ⁇ M total lipids in 165 ⁇ L of buffered solution containing 10 mM HEPES, 10 mM MES, 10 mM ammonium acetate, 130 mM NaCl, and final TNS concentration of 1.33 ⁇ g/mL (4 ⁇ M) with the pH ranging from 3.5 to 12.2.
  • fluorescence intensity was measured at room temperature in a BioTek Synergy H1 plate reader using excitation and emission wavelengths of 321 and 445 nm, respectively.
  • the fluorescence signal was blank subtracted and plotted as a function of the pH, then analyzed using a nonlinear (Boltzmann) regression analysis with the apparent pKa determined as the pH giving rise to half maximal fluorescence intensity as calculated by the Henderson ⁇ Hasselbalch equation.
  • mice All tLNP test articles were thawed at room temperature for 30 minutes and then diluted 1:2 with sterile water for injection to achieve a final dose concentration of 100 ⁇ g mRNA/mL.100 ⁇ L (10 ⁇ g mRNA) of each test article was then injected via the tail vein into 8-week-old female C57Bl/6 mice. All treated mice were then sacrificed at 24 hours post-treatment, their spleen and liver harvested and disaggregated, and expression of mCherry in splenic T cells, hepatocytes, and Kupffer cells assessed by flow cytometry.
  • tLNP comprising either CICL-251 or CICL-1 had similar performance in splenic T cells for both transfection rate and expression level (measured as molecular equivalent of soluble fluorochrome (MESF)).
  • the tLNP incorporating CICL-251 and CICL-1 had similarly low levels in liver Kupffer cells (CD45 + /CD11 + liver cells) ( Figure 1C).
  • Additional aspects of the disclosure are provided by the following enumerated embodiments, which can be combined in any number and in any combination not technically or logically inconsistent.
  • the ionizable cationic lipid of embodiment 1, wherein in each tail group both R 2 groups are O and both R 3 groups are C O.
  • Embodiment 8. The ionizable cationic lipid of any one of embodiment 6, wherein each W is N.
  • Embodiment 12. The ionizable cationic lipid of any one of embodiments 1, 4, or 5, wherein both R 3 at a beta position of a W are O and that W is CH.
  • Embodiment 14 The ionizable cationic lipid of embodiment 13, wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 0 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 1 , and A 5 is (CH 2 ) 1 .
  • Embodiment 15. The ionizable cationic lipid of embodiment 13, wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 0 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 1 , and A 5 is (CH 2 ) 2 .
  • Embodiment 17. The ionizable cationic lipid of embodiment 13, wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 0 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 1 , and A 5 is (CH 2 ) 4 .
  • the ionizable cationic lipid of embodiment 13, wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 0 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 1 , and A 5 is CH 2 -CH CH-CH 2 .
  • Embodiment 19 The ionizable cationic lipid of any one of embodiments 1 to 6, wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 1 .
  • Embodiment 20 The ionizable cationic lipid of any one of embodiments 1 to 6, wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 1 .
  • the ionizable cationic lipid of any one of embodiments 1 to 12, wherein A 1 is (CH 2 ) 1 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 0 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 2 or CH CH.
  • the ionizable cationic lipid of any one of embodiments 1 to 22, wherein A 1 through A 4 are such that there are only two main chain atoms between the ring nitrogen and each nearest ester oxygen in the nearest tail group.
  • Embodiment 24 The ionizable cationic lipid of any one of embodiments 1 to 23 wherein Embodiment 25.
  • the ionizable cationic lipid of any one of embodiments 1 to 23, wherien X is .
  • Embodiment 32. The ionizable cationic lipid of any one of embodiments 1 to 23, wherein X is .
  • Embodiment 33. The ionizable cationic lipid of any one of embodiments 1 to 23, Y -(CH2)2-4 N O wherein X is .
  • Embodiment 34 The ionizable cationic lipid of any one of embodiments 1 to 23, wherein Embodiment 35.
  • the ionizable cationic lipid of embodiment 1 to 23, wherein X is .
  • Embodiment 43 The ionizable cationic lipid of any one of embodiments 1 to 23, wherein Embodiment 44.
  • Embodiment 48 The ionizable cationic lipid of any one of embodiments 1 to 23, wherein Embodiment 49.
  • Embodiment 68 The ionizable cationic lipid of any one of embodiments 1 to 37, wherein Y is NH.
  • Embodiment 68 The ionizable cationic lipid of any one of embodiments 1 to 37, wherein Y is NCH 3 .
  • Embodiment 69 The ionizable cationic lipid of any one of embodiments 1 to 23 and 39 to 64, wherein Z is O.
  • Embodiment 70 The ionizable cationic lipid of any one of embodiments 1 to 23 and 39 to 64, wherein Z is NH.
  • Embodiment 71 The ionizable cationic lipid of any one of embodiments 1 to 23 and 39 to 64, wherein Z is NCH 3 .
  • Embodiment 72 The ionizable cationic lipid of any one of embodiments 1 to 23 and 39 to 64, wherein Z is NCH 3 .
  • each R 1 is independently C7-C 10 alkyl or C 7 -C 9 alkyl.
  • Embodiment 73 The ionizable cationic lipid of any one of embodiments 1 to 71, wherein each R 1 is independently a linear C 7 -C 11 alkyl, e.g., a linear C 7 -C 10 alkyl, or a linear C 7 -C 9 alkyl.
  • Embodiment 74 The ionizable cationic lipid of any one of embodiments 1 to 71, wherein each R 1 is independently (CH 2 ) 6-8 CH 3 .
  • Embodiment 75 The ionizable cationic lipid of any one of embodiments 1 to 71, wherein each R 1 is independently (CH 2 ) 6-8 CH 3 .
  • Embodiment 76. The ionizable cationic lipid of any one of embodiments 1 to 71, wherein each R 1 is independently a linear C 7 -C 11 alkenyl, e.g., a linear C 7 -C 10 alkenyl, or a linear C 7 -C 9 alkenyl.
  • Embodiment 77. The ionizable cationic lipid of any one of embodiments 1 to 71, wherein each R 1 is a linear C 8 alkenyl.
  • each R 1 is independently a branched C 7 -C 11 alkyl, e.g., C 7 -C 10 alkyl, or C 7 -C 9 alkyl.
  • Embodiment 79 The ionizable cationic lipid of any one of embodiments 1 to 70, wherein each R 1 is a branched C 8 alkyl.
  • Embodiment 80 The ionizable cationic lipid of any one of embodiments 1 to 71, wherein each R 1 is independently a branched C 7 -C 11 alkyl, e.g., C 7 -C 10 alkyl, or C 7 -C 9 alkyl.
  • each R 1 is independently a branched C 7 -C 11 alkenyl, e.g., C 7 -C 10 alkenyl, or C 7 - C 9 alkenyl.
  • Embodiment 81 The ionizable cationic lipid of any one of embodiments 1 to 70, wherein each R 1 is a branched C 8 alkenyl.
  • Embodiment 82 The ionizable cationic lipid of any one of embodiments 1 to 71, wherein each R 1 is independently a branched C 7 -C 11 alkenyl, e.g., C 7 -C 10 alkenyl, or C 7 - C 9 alkenyl.
  • Embodiment 83. The ionizable cationic lipid of any one of embodiments 1 to 82, wherein each R 1 is the same.
  • Embodiment 84. The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 86 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 87. The ionizable cationic lipid of embodiment 86 having the structure:
  • Embodiment 88 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 89. The ionizable cationic lipid of embodiment 88 having the structure:
  • Embodiment 90 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 91 The ionizable cationic lipid of embodiment 90 having the structure:
  • Embodiment 92 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 93 The ionizable cationic lipid of embodiment 92 having the structure:
  • Embodiment 94 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 95 The ionizable cationic lipid of embodiment 94 having the structure:
  • Embodiment 96 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 97 The ionizable cationic lipid of embodiment 96 having the structure:
  • Embodiment 98 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 99 The ionizable cationic lipid of embodiment 98 having the structure:
  • Embodiment 100 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 101 The ionizable cationic lipid of embodiment 100 having the structure:
  • Embodiment 102 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 103 The ionizable cationic lipid of embodiment 102 having the structure:
  • Embodiment 104 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 105 The ionizable cationic lipid of embodiment 104 having the structure:
  • Embodiment 106 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 107 The ionizable cationic lipid of embodiment 106 having the structure:
  • Embodiment 108 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 109. The ionizable cationic lipid of embodiment 108 having the structure:
  • Embodiment 110 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 111 The ionizable cationic lipid of embodiment 110 having the structure:
  • Embodiment 112. The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 113. The ionizable cationic lipid of embodiment 112 having the structure:
  • Embodiment 114 The ionizable cationic lipid of embodiment 1 having the structure: herein.
  • Embodiment 115. The ionizable cationic lipid of embodiment 114 having the structure: .
  • Embodiment 117 The ionizable cationic lipid of embodiment 116 having the structure: .
  • the ionizable cationic lipid of embodiment 1 having the structure: herein.
  • Embodiment 119 The ionizable cationic lipid of embodiment 118 having the structure:
  • Embodiment 120 The ionizable cationic lipid of embodiment 1 having the structure: herein.
  • Embodiment 123 The ionizable cationic lipid of embodiment 122 having the structure: Embodiment 124. The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein. Embodiment 125. The ionizable cationic lipid of embodiment 124 having the structure:
  • Embodiment 126 The ionizable cationic lipid of embodiment 1 having the structure: Embodiment 127. The ionizable cationic lipid of embodiment 126 having the structure:
  • Embodiment 128 The ionizable cationic lipid of embodiment 1 having the structure: Embodiment 129. The ionizable cationic lipid of embodiment 128 having the structure:
  • Embodiment 130 The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 132 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 133 The ionizable cationic lipid of embodiment 132 having the structure:
  • Embodiment 134 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 135. The ionizable cationic lipid of embodiment 134 having the structure:
  • Embodiment 136 The ionizable cationic l of embodiment 1 having the structure: wherein X is as disclosed herein.
  • Embodiment 137 The ionizable cationic lipid of embodiment 136 having the structure:
  • Embodiment 138 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 139. The ionizable cationic lipid of embodiment 138 having the structure:
  • Embodiment 140 The ionizable cationic lipid of embodiment 1 having the structure: wherein X is as disclosed Embodiment 141.
  • Embodiment 143 The ionizable cationic lipid of embodiment 142 having the structure: Embodiment 144.
  • the ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 145 The ionizable cationic lipid of embodiment 144 having the structure:
  • Embodiment 146 The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 147 The ionizable cationic lipid of embodiment 146 having the structure:
  • Embodiment 148 The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 149 The ionizable cationic lipid of embodiment 148 having the structure:
  • Embodiment 150 The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 151 The ionizable cationic lipid of embodiment 150 having the structure:
  • Embodiment 152 The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 153 The ionizable cationic lipid of embodiment 152 having the structure:
  • Embodiment 154 The ionizable cationic lipid of embodiment 1 having the structure: wherein X is as disclosed herein.
  • Embodiment 155 The ionizable cationic lipid of embodiment 154 having the structure:
  • Embodiment 156 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 157. The ionizable cationic lipid of embodiment 156 having the structure:
  • Embodiment 158 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 159. The ionizable cationic lipid of embodiment 158 having the structure:
  • Embodiment 160 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 161. The ionizable cationic lipid of embodiment 160 having the structure:
  • Embodiment 162 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 164 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 165 The ionizable cationic lipid of embodiment 164 having the structure:
  • Embodiment 166 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 167 The ionizable cationic lipid of embodiment 166 having the structure:
  • Embodiment 168 The ionizable cationic lipid of embodiment 1 having the structure: disclosed herein.
  • Embodiment 170 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 171. The ionizable cationic lipid of embodiment 170 having the structure:
  • Embodiment 172 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 173. The ionizable cationic lipid of embodiment 172 having the structure:
  • Embodiment 174 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 175. The ionizable cationic lipid of embodiment 174 having the structure:
  • Embodiment 176 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 178 The ionizable cationic lipid of embodiment 1 having the structure: disclosed herein.
  • Embodiment 180 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 181. The ionizable cationic lipid of embodiment 180 having the structure:
  • Embodiment 182 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein. Embodiment 183. The ionizable cationic lipid of embodiment 182 having the structure:
  • Embodiment 184 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 185. The ionizable cationic lipid of embodiment 184 having the structure:
  • Embodiment 186 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 187. The ionizable cationic lipid of embodiment 186 having the structure:
  • Embodiment 188 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 189. The ionizable cationic lipid of embodiment 188 having the structure:
  • Embodiment 190 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 191. The ionizable cationic lipid of embodiment 190 having the structure:
  • Embodiment 192 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 193. The ionizable cationic lipid of embodiment 192 having the structure:
  • Embodiment 194 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 195. The ionizable cationic lipid of embodiment 194 having the structure:
  • Embodiment 196 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 197. The ionizable cationic lipid of embodiment 196 having the structure:
  • Embodiment 198 The ionizable cationic lipid of embodiment 1 having the structure: , wherein X is as disclosed herein.
  • Embodiment 199 The ionizable cationic lipid of embodiment 198 having the structure: .
  • Embodiment 200 The ionizable cationic lipid of embodiment 1 having the structure: wherein X is as disclosed herein.
  • Embodiment 201 The ionizable cationic lipid of embodiment 200 having the structure: .
  • Embodiment 202 The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 203 The ionizable cationic lipid of embodiment 202 having the structure: .
  • Embodiment 204. The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 205 The ionizable cationic lipid of embodiment 204 having the structure: .
  • Embodiment 206. The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 207 The ionizable cationic lipid of embodiment 206 having the structure: .
  • Embodiment 208. The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 209 The ionizable cationic lipid of embodiment 208 having the structure: .
  • Embodiment 210. The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 211 The ionizable cationic lipid of embodiment 210 having the structure: .
  • Embodiment 212. The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 214. The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 215. The ionizable cationic lipid of embodiment 214 having the structure: .
  • Embodiment 217 The ionizable cationic lipid of embodiment 216 having the structure: .
  • Embodiment 218. The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 220. The ionizable cationic lipid of embodiment 1 having the structure:
  • Embodiment 221. The ionizable cationic lipid of embodiment 220 having the structure: .
  • Embodiment 223. The ionizable cationic lipid of embodiment 222 having the structure: .
  • Embodiment 226 The ionizable cationic lipid of embodiment 225, wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 0 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 1 , and A 5 is (CH 2 ) 1 .
  • Embodiment 227 The ionizable cationic lipid of embodiment 224, wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 0 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 1 , and A 5 is
  • the ionizable cationic lipid of embodiment 225 wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 0 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 1 , and A 5 is (CH 2 ) 2 .
  • Embodiment 228. The ionizable cationic lipid of embodiment 225, wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 0 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 1 , and A 5 is (CH 2 ) 3 .
  • the ionizable cationic lipid of embodiment 225 wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 0 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 1 , and A 5 is (CH 2 ) 4 .
  • the ionizable cationic lipid of embodiment 225, wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 0 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 1 , and A 5 is CH 2 -CH CH-CH 2 .
  • the ionizable cationic lipid of embodiment 224 wherein A 1 is (CH 2 ) 0 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 1 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 1 .
  • Embodiment 232. The ionizable cationic lipid of embodiment 224, wherein A 1 is (CH 2 ) 1 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 0 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 0 .
  • the ionizable cationic lipid of embodiment 224 wherein A 1 is (CH 2 ) 1 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 0 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 1.
  • the ionizable cationic lipid of embodiment 224, wherein A 1 is (CH 2 ) 1 , A 2 is (CH 2 ) 1 , A 3 is (CH 2 ) 0 , A 4 is (CH 2 ) 0 , and A 5 is (CH 2 ) 2 or CH CH.
  • Embodiment 235 Embodiment 235.
  • the ionizable cationic lipid of any one of embodiments 224 to 234, wherein W is N and both R 3 groups at a beta position of W are C O.
  • the ionizable cationic lipid of any one of embodiments 224 to 236, wherein A 1 through A 4 are such that there are only two main chain atoms between the ring nitrogen and each nearest ester oxygen in the nearest tail group.
  • Embodiment 238. The ionizable cationic lipid of any one of embodiments 224 to Embodiment 239.
  • the ionizable cationic lipid of any one of embodiments 224 to 237, wherien X is Embodiment 243.
  • the ioinzable cationic lipid of any one of embodiments 224 to 237, wherein X is Embodiment 244.
  • the ionizable cationic lipid of any one of embodiments 224 to 237, wherein X is .
  • the ionizable cationic lipid of any one of embodiments 224 to 237, wherein X is .
  • Embodiment 266 The ionizable cationic lipid of any one of embodiments 224 to 237, Embodiment 267.
  • Embodiment 280. The ionizable cationic lipid of any one of embodiments 224 to 251, wherein Y is S.
  • Embodiment 281. The ionizable cationic lipid of any one of embodiments 224 to 251, wherein Y is NH.
  • Embodiment 282. The ionizable cationic lipid of any one of embodiments 224 to 251, wherein Y is NCH 3 .
  • Embodiment 283. The ionizable cationic lipid of any one of embodiments 224 to 237 and 253 to 278, wherein Z is O.
  • Embodiment 285. The ionizable cationic lipid of any one of embodiments 224 to 237 and 253 to 278, wherein Z is NCH 3 .
  • Embodiment 286. The ionizable cationic lipid of any one of embodiments 224 to 285, wherein each R 1 is independently C7-C 10 alkyl or C 7 -C 9 alkyl.
  • each R 1 is independently a linear C 7 -C 11 alkyl, e.g., a linear C 7 -C 10 alkyl, or a linear C 7 -C 9 alkyl.
  • Embodiment 288 The ionizable cationic lipid of any one of embodiments 224 to 285, wherein each R 1 is independently (CH 2 ) 6-8 CH 3 .
  • Embodiment 289. The ionizable cationic lipid of any one of embodiments 224 to 285, wherein R 1 is (CH 2 ) 7 CH 3 .
  • Embodiment 290 Embodiment 290.
  • each R 1 is independently a linear C 7 -C 11 alkenyl, e.g., a linear C 7 -C 10 alkenyl, or a linear C 7 -C 9 alkenyl.
  • Embodiment 291. The ionizable cationic lipid of any one of embodiments 224 to 285, wherein each R 1 is a linear C 8 alkenyl.
  • each R 1 is independently a branched C 7 -C 11 alkyl, e.g., C 7 -C 10 alkyl, or C 7 -C 9 alkyl.
  • Embodiment 293. The ionizable cationic lipid of any one of embodiments 224 to 285, wherein each R 1 is a branched C 8 alkyl.
  • each R 1 is independently a branched C 7 -C 11 alkenyl, e.g., C 7 -C 10 alkenyl, or C 7 - C 9 alkenyl.
  • Embodiment 295. The ionizable cationic lipid of any one of embodiments 224 to 285, wherein each R 1 is a branched C 8 alkenyl.
  • Embodiment 297. The ionizable cationic lipid of any one of embodiments 224 to 296, wherein each R 1 is the same.
  • Embodiment 298. The ionizable cationic lipid of embodiment 224 having the structure: , wherein X is as disclosed herein. Embodiment 299. The ionizable cationic lipid of embodiment 298 having the structure: .
  • Embodiment 300 The ionizable cationic lipid of embodiment 224 having the structure CICL-252: .
  • Embodiment 301 The ionizable cationic lipid of embodiment 224 having the structure CICL-253: , as a racemate, any other mixture of enantiomers, or either individual enantiomer.
  • Embodiment 302. The ionizable cationic lipid of embodiment 224 having the structure: wherein X is as disclosed herein.
  • Embodiment 303 The ionizable cationic lipid of embodiment 302 having the structure: .
  • Embodiment 304 The ionizable cationic lipid of embodiment 302 having the structure:
  • the ionizable cationic lipid of embodiment 224 having the structure CICL-251: , its enantiomer, or a racemate or other mixture comprising CICL-255. Embodiment 305.
  • the ionizable cationic lipid of embodiment 224 having the structure: wherein X is as disclosed herein.
  • Embodiment 309. The ionizable cationic lipid of embodiment 308 having the structure: .
  • Embodiment 310 The ionizable cationic lipid of embodiment 224 having the structure CICL-257: .
  • Embodiment 311. The ionizable cationic lipid of embodiment 224 having the structure CICL-258: , or a racemate, or other mixture comprising CICL-257.
  • Embodiment 312. The ionizable cationic lipid of embodiment 224 having the structure:
  • Embodiment 313. The ionizable cationic lipid of embodiment 312 having the structure: . Embodiment 314.
  • Embodiment 315. The ionizable cationic lipid of embodiment 224 having the structure CICL-260: , its enantiomer, or a racemate or any other mixture thereof.
  • Embodiment 316. The ionizable cationic lipid of embodiment 224 having the structure: wherein X is as disclosed herein.
  • Embodiment 318. The ionizable cationic lipid of embodiment 224 having the structure CICL-261:
  • Embodiment 319 The ionizable cationic lipid of embodiment 224 having the structure .
  • Embodiment 322. The ionizable cationic lipid of embodiment 224 having the structure CICL-263: .
  • Embodiment 323. The ionizable cationic lipid of embodiment 224 having the structure CICL-264: , a racemate, any other mixture of enantiomers, or either individual enantiomer.
  • Embodiment 324. The ionizable cationic lipid of embodiment 224 having the structure:
  • Embodiment 325 The ionizable cationic lipid of embodiment 324 having the structure: .
  • Embodiment 326 The ionizable cationic lipid of embodiment 224 having the structure CICL-265: .
  • Embodiment 327 The ionizable cationic lipid of embodiment 224 having the structure CICL-266: , as a racemate, any other mixture of enantiomers, or either individual enantiomer.
  • Embodiment 328 The ionizable cationic lipid of embodiment 224 having the structure: wherein X is as disclosed herein.
  • Embodiment 329 The ionizable cationic lipid of embodiment 224 having the structure: wherein X is as disclosed herein.
  • the ionizable cationic lipid of embodiment 328 having the structure: .
  • Embodiment 330 The ionizable cationic lipid of embodiment 224 having the structure CICL-267: .
  • Embodiment 331 The ionizable cationic lipid of embodiment 224 having the structure CICL-268: , a racemate, any other mixture of enantiomers, or either individual enantiomer.
  • Embodiment 332. The ionizable cationic lipid of embodiment 224 having the structure:
  • Embodiment 333 The ionizable cationic lipid of embodiment 332 having the structure: .
  • Embodiment 336 The ionizable cationic lipid of embodiment 224 having the structure: wherein X is as disclosed herein.
  • Embodiment 338 The ionizable cationic lipid of embodiment 224 having the structure CICL-271: .
  • Embodiment 339 The ionizable cationic lipid of embodiment 224 having the structure CICL-272: , a racemate, any other mixture of enantiomers, or either individual enantiomer.
  • Embodiment 340 The ionizable cationic lipid of embodiment 224 having the structure: wherein X is as disclosed herein.
  • Embodiment 341. The ionizable cationic lipid of embodiment 340 having the structure:
  • Embodiment 342 The ionizable cationic lipid of embodiment 224 having the structure CICL-273: , a racemate, any other mixture of enantiomers, or either individual enantiomer.
  • Embodiment 343. The ionizable cationic lipid of embodiment 224 having the structure CICL-274: CICL-274 .
  • Embodiment 344 The ionizable cationic lipid of embodiment 224 having the structure CICL-275: , a racemate, any other mixture of enantiomers, or either individual enantiomer.
  • Embodiment 345 The ionizable cationic lipid of embodiment 224 having the structure CICL-276: Embodiment 346.
  • the ionizable cationic lipid of embodiment 350 having the structure: . Embodiment 352.
  • Embodiment 354 The ionizable cationic lipid of embodiment 224 having the structure: , wherein X is as disclosed herein.
  • Embodiment 357 The ionizable cationic lipid of embodiment 224 having the structure CICL-282: .
  • Embodiment 358 The ionizable cationic lipid of embodiment 224 having the structure: , wherein X is as disclosed herein.
  • Embodiment 359. The ionizable cationic lipid of embodiment 224 having the structure:
  • Embodiment 360 The ionizable cationic lipid of embodiment 224 having the structure CICL-283: .
  • Embodiment 362. The ionizable cationic lipid of embodiment 224 having the structure:
  • Embodiment 363. The ionizable cationic lipid of embodiment 363 having the structure: .
  • Embodiment 366 The ionizable cationic lipid of embodiment 224 having the structure: , wherein X is as disclosed herein.
  • Embodiment 367 The ionizable cationic lipid of embodiment 366 having the structure: .
  • Embodiment 368 The ionizable cationic lipid of embodiment 224 having the structure CICL-287: .
  • Embodiment 369 The ionizable cationic lipid of embodiment 224 having the structure CICL-288: , a racemate, any other mixture of enantiomers, or either individual enantiomer.
  • Embodiment 370 The ionizable cationic lipid of embodiment 224 having the structure:
  • Embodiment 371. The ionizable cationic lipid of embodiment 370 having the structure: .
  • Embodiment 373 The ionizable cationic lipid of embodiment 224 having the structure CICL-290: , a racemate, any other mixture of enantiomers, or either individual enantiomer.
  • Embodiment 374 The ionizable cationic lipid of embodiment 1 having a structure as shown in Table 2.
  • Embodiment 375 The ionizable cationic lipid of embodiment 1 having a structure as shown in Table 3.
  • Embodiment 376 The ionizable cationic lipid of embodiment 1 having a structure as shown in Table 4.
  • Embodiment 377 The ionizable cationic lipid of embodiment 1 having a structure as shown in Table 5.
  • Embodiment 378 The ionizable cationic lipid of embodiment 224 having the structure CICL-290: , a racemate, any other mixture of enantiomers, or either individual enantiomer.
  • Embodiment 374 The ionizable cati
  • the ionizable cationic lipid of any one of embodiments 1 to 377 having a c-pKa ranging from about 8.2 to about 9.0 or from 8.2 to 9.0.
  • the ionizable cationic lipid of any one of embodiments 1 to 381 having a cLogD is about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, or about 18.
  • the ionizable cationic lipid of any one of embodiments 1 to 381 having a cLogD ranging from about 13.6 to about 14.4 or from 13.6 to 14.4.
  • a lipid nanoparticle (LNP) comprising at least one ionizable cationic lipid of any one of embodiments 1-387.
  • a targeted lipid nanoparticle comprising at least one ionizable cationic lipid of any one of embodiments 1-387 and a functionalized PEG-lipid, wherein the functionalized PEG-lipid has been conjugated with a binding moiety.
  • tLNP lipid nanoparticle
  • the LNP or tLNP of embodiment 390 wherein the phospholipid comprises dioleoylphosphatidyl ethanolamine (DOPE), dimyristoylphosphatidyl choline (DMPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidyl glycerol (DMPG), dipalmitoyl phosphatidylcholine (DPPC), or 1,2-diarachidoyl-sn-glycero-3- phosphocholine (DAPC), or a combination thereof.
  • DOPE dioleoylphosphatidyl ethanolamine
  • DMPC dimyristoylphosphatidyl choline
  • DSPC distearoylphosphatidylcholine
  • DMPG dimyristoylphosphatidyl glycerol
  • DPPC dipalmitoyl phosphatidylcholine
  • DAPC 1,2-diarachidoyl-sn-g
  • Embodiment 393 The LNP or tLNP of any one of embodiments 390 to 39392, wherein the co-lipid comprises cholesterol hemisuccinate (CHEMS) or a quaternary ammonium head group containing lipid.
  • CHEMS cholesterol hemisuccinate
  • Embodiment 394 Embodiment 394.
  • the LNP or tLNP of embodiment 393, wherein the quaternary ammonium head group containing lipid comprises 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium (DOTMA), or 3 ⁇ -(N-(N',N'-Dimethylaminoethane)carbamoyl)cholesterol (DC-Chol), or combinations thereof.
  • DOTAP 1,2-dioleoyl-3-trimethylammonium propane
  • DOTMA N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium
  • DC-Chol 3 ⁇ -(N-(N',N'-Dimethylaminoethane)carbamoyl)cholesterol
  • the LNP of any one of embodiments 390-395 or the tLNP of any one of embodiments 389 to 395, wherein the unfunctionalized PEG-lipid and/or the functionalized PEG-lipid comprises fatty acids with a fatty acid chain length of C 14 -C 18 .
  • Embodiment 397 Embodiment 397.
  • Embodiment 398 The LNP or tLNP of any one of embodiments 390 to 397, comprising a phospholipid in an amount in the range from 7 to 30 mol%.
  • Embodiment 399 The LNP or tLNP of any one of embodiments 390 to 398, comprising a sterol in an amount in the range from 20 to 45 mol%.
  • Embodiment 400 The LNP or tLNP of any one of embodiments 390 to 399, comprising at least one co-lipid in an amount in the range from 1 to 30 mol%.
  • Embodiment 401 The LNP or tLNP of any one of embodiments 390 to 399, comprising at least one co-lipid in an amount in the range from 1 to 30 mol%.
  • the LNP or tLNP of any one of embodiments 390 to 400 comprising at least one unfunctionalized PEG-lipid in an amount in the range from 0.1 to 5 mol%.
  • Embodiment 402. The LNP or tLNP of any one of embodiments 390 to 401, comprising at least one functionalized PEG-lipid in an amount in the range from 0.1 to 5 mol%.
  • Embodiment 403. The tLNP of any one of embodiments 390 to 402, wherein the binding moiety comprises an antigen, a ligand-binding domain of a receptor, a receptor ligand, an antibody, or an antigen binding domain of an antibody.
  • Embodiment 405. The LNP or tLNP of embodiment 404, wherein the weight ratio of total lipid to nucleic acid is 10:1 to 50:1.
  • Embodiment 406. The LNP or tLNP of embodiment 404, wherein the N/P ratio is from 3 to 9.
  • Embodiment 409 The tLNP of any one of embodiments 389 to 407, wherein the binding moiety is a F(ab’) or F(ab’) analog.
  • Embodiment 410 The tLNP of any one of embodiment 404 to 409, wherein the tLNP is targeted to a T cell.
  • Embodiment 411 The tLNP of any one of embodiments 404 to 410, wherein the tLNP is targeted to a CD8+ T cell.
  • Embodiment 414. A method of delivering a biologically active payload (e.g., one or more species of nucleic acid molecule) into a cell comprising contacting the cell with the LNP or tLNP of any one of embodiments 404 to 413.
  • a biologically active payload e.g., one or more species of nucleic acid molecule
  • Embodiment 416 The lipid of embodiment 415, wherein R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , A 4 , and A 5 are as otherwise described here.
  • Embodiment 417 The lipid of embodiment 415 or 416, wherein R 4 is H.
  • Embodiment 418 The lipid of embodiment 415 or 416, wherein R 4 is a protecting group (e.g., t-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), or a trimethylsilylethoxycarbonyl moiety.
  • Embodiment 419 Embodiment 419.
  • Embodiment 420 The lipid of embodiment 419, wherein R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , A 4 , and A 5 are as otherwise described here.
  • Embodiment 421. A synthesis method of an ionizable cationic lipid of formula M6, the method comprising: providing a lipid of formula M6-5; reacting the lipid of formula M6-5 with carbonyldiimidazole to provide a lipid of formula M6-6; and coupling the lipid of formula M6-6 with H-X in the presence of a base to provide the ionizable cationic lipid of formula M6; wherein H-X is from the group consisting of: of Embodiment 422.
  • Embodiment 423 The lipid of embodiment 422, wherein R 1 , A 1 , A 2 , A 3 , A 4 , and A 5 are as otherwise described here.
  • Embodiment 424 The lipid of embodiment 422 or 423, wherein R 4 is H.
  • Embodiment 425 The lipid of embodiment 425.
  • lipid of embodiment 422 or 423 wherein R 4 is a protecting group (e.g., t-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), or a trimethylsilylethoxycarbonyl moiety.
  • R 4 is a protecting group (e.g., t-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), or a trimethylsilylethoxycarbonyl moiety.
  • R 426 A lipid having the structure of formula M3-2, a stereoisomer thereof, or a mixture of such stereoisomers,
  • Embodiment 427 The lipid of embodiment 426, wherein R 1 , A 1 , A 2 , A 3 , A 4 , and A 5 are as otherwise described here.
  • Embodiment 428 is lipid of embodiment 426, wherein R 1 , A 1 , A 2 , A 3 , A 4 , and A 5 are as otherwise described here.
  • Embodiment 429 A method of treating a disease or disorder comprising administration of a tLNP of any one of embodiments 404 to 411 to a subject in need thereof.
  • Embodiment 430. The method of embodiment 429, wherein the disease or disorder is an autoimmune disease.
  • Embodiment 431 The method of embodiment 430, wherein the autoimmune disease is a T cell-mediated autoimmunity or a B-cell mediated autoimmunity.
  • Embodiment 432 The method of embodiment 429, wherein the disease or disorder is a rejection of an allogeneic organ or tissue graft.
  • Embodiment 433. The method of embodiment 429, wherein the disease or disorder is cancer.
  • Embodiment 429 wherein the disease or disorder is a fibrotic disease or disorder.
  • Embodiment 435 The method of embodiment 429, wherein the disease or disorder is a graft versus host disease (GVHD).
  • Embodiment 436 A method of treating a disease or disorder comprising administration of a tLNP of any one of embodiments 404-409 or 412-413 to a subject in need thereof.
  • Embodiment 437 The method of embodiments 436, wherein the disease or disorder is a genetic disease or disorder.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Sont divulgués des lipides cationiques ionisables, leurs procédés de synthèse, des intermédiaires utiles dans la synthèse des lipides cationiques ionisables et des procédés de synthèse des intermédiaires. Les lipides cationiques ionisables sont utiles en tant que composant de nanoparticules lipidiques (LNP), qui à son tour peut être utilisé pour administrer des acides nucléiques dans des cellules in vivo ou ex vivo. Sont divulguées également des compositions de LNP, notamment des LNP comprenant un lipide fonctionnalisé pour permettre la conjugaison d'une fraction de liaison, et des LNP ciblées (tLNP), les LNP dans lesquelles une fraction de liaison a été conjuguée au lipide fonctionnalisé et pouvant servir de fraction de ciblage pour diriger les tLNP vers un type de tissu ou de cellule souhaité.
PCT/US2025/024153 2024-04-11 2025-04-10 Lipides cationiques ionisables contraints et nanoparticules lipidiques Pending WO2025217452A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US202463632944P 2024-04-11 2024-04-11
US63/632,944 2024-04-11
US202463654930P 2024-05-31 2024-05-31
US202463654928P 2024-05-31 2024-05-31
US202463654720P 2024-05-31 2024-05-31
US63/654,928 2024-05-31
US63/654,720 2024-05-31
US202463708529P 2024-10-17 2024-10-17
US202463708461P 2024-10-17 2024-10-17
US63/708,529 2024-10-17

Publications (1)

Publication Number Publication Date
WO2025217452A1 true WO2025217452A1 (fr) 2025-10-16

Family

ID=95605624

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/024153 Pending WO2025217452A1 (fr) 2024-04-11 2025-04-10 Lipides cationiques ionisables contraints et nanoparticules lipidiques

Country Status (1)

Country Link
WO (1) WO2025217452A1 (fr)

Citations (441)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989006968A1 (fr) 1988-02-03 1989-08-10 Xoma Corporation Utilisation therapeutique d'immunotoxiques anti-cellules t contre des maladies autoimmunes
US5283173A (en) 1990-01-24 1994-02-01 The Research Foundation Of State University Of New York System to detect protein-protein interactions
WO2001023573A1 (fr) 1999-09-30 2001-04-05 Kyowa Hakko Kogyo Co., Ltd. Anticorps transplantes a domaine de determination de complementation de type humain, dresse contre le ganglioside gd2, et derive de cet anticorps
WO2002030459A1 (fr) 2000-10-11 2002-04-18 Tegenero Gmbh Utilisation d"anticorps monoclonaux specifiques a la molecule cd28 en vue de stimuler des cellules sanguines qui ne portent aucune molecule cd28
WO2002047721A1 (fr) 2000-12-14 2002-06-20 Fujisawa Pharmaceutical Co., Ltd. Anticorps anti-cd28 silencieux et leur utilisation
WO2004045512A2 (fr) 2002-11-15 2004-06-03 Genmab A/S Anticorps monoclonaux humains contre cd25
WO2004055056A1 (fr) 2002-12-17 2004-07-01 Merck Patent Gmbh Forme humanisee de l'anticorps de souris 14.18 (h14.18) se liant au gd2 et fusion de celle-ci avec il-2
WO2005035584A1 (fr) 2003-10-10 2005-04-21 Bristol-Myers Squibb Company Anticorps entierement humains agissant contre la 4-1bb humaine (cd137)
WO2005037999A2 (fr) 2003-10-14 2005-04-28 Biogen Idec Ma Inc. Traitement anticancereux a base d'anticorps diriges contre lrrc15
US6924360B2 (en) 2001-12-28 2005-08-02 Abgenix, Inc. Antibodies against the MUC18 antigen
WO2006108670A2 (fr) 2005-04-15 2006-10-19 Novartis Ag Utilisation d'anticorps cd25 en immunotherapie
WO2007009065A2 (fr) 2005-07-11 2007-01-18 Macrogenics, Inc. Methodes de traitement d'une maladie auto-immune au moyen d'anticorps anti-cd16a humanises
WO2007084321A2 (fr) 2006-01-12 2007-07-26 Alexion Pharmaceuticals, Inc. Anticorps dirigés contre ox-2/cd200 et utilisations correspondantes
US7378504B2 (en) 2004-06-03 2008-05-27 Medarex, Inc. Human monoclonal antibodies to Fc gamma receptor I (CD64)
WO2008079246A2 (fr) 2006-12-21 2008-07-03 Medarex, Inc. Anticorps anti-cd44
WO2008117049A1 (fr) 2007-03-26 2008-10-02 Affitech As Anticorps anti cd166 humain se liant à des cellules tumorales humaines
WO2008121160A2 (fr) 2006-11-21 2008-10-09 Xencor, Inc. Anticorps optimisés qui ciblent cd5
US7446190B2 (en) 2002-05-28 2008-11-04 Sloan-Kettering Institute For Cancer Research Nucleic acids encoding chimeric T cell receptors
WO2008144890A1 (fr) 2007-05-30 2008-12-04 F. Hoffmann-La Roche Ag Anticorps chimères et humanisés anti-cd44 influençant la cytotoxicité des cellules cancéreuses
US20100040540A1 (en) 2003-11-19 2010-02-18 Institut National De La Sante Et De La Recherche Medicale (Inserm) Anti cd44 antibodies for eradicating leukaemic stem cells and breast cancer stem cells
WO2010022737A1 (fr) 2008-08-29 2010-03-04 Symphogen A/S Anticorps anti-cd5
WO2010032059A2 (fr) 2008-09-19 2010-03-25 Medimmune Llc Agents de liaison ciblés dirigés sur cd105 et leurs utilisations
WO2010039873A2 (fr) 2008-10-01 2010-04-08 Tracon Pharmaceuticals, Inc. Anticorps humanisés anti-endogline
US7722869B2 (en) 2007-04-27 2010-05-25 Novartis Ag Antibody molecules and nucleic acids
WO2010104949A2 (fr) 2009-03-10 2010-09-16 Biogen Idec Ma Inc. Anticorps anti-bcma
US7825222B2 (en) 2001-02-12 2010-11-02 Novartis Ag Therapeutic binding molecules
US7915391B2 (en) 2006-04-24 2011-03-29 Amgen Inc. Humanized c-Kit antibody
WO2011094259A2 (fr) 2010-01-28 2011-08-04 Glaxo Group Limited Protéines de liaison à cd127
WO2011104687A1 (fr) 2010-02-24 2011-09-01 Rinat Neuroscience Corporation Anticorps récepteurs anti-il-7 antagonistes et procédés
WO2011127324A2 (fr) 2010-04-08 2011-10-13 JN Biosciences, LLC Anticorps anti-cd122
US20110280881A1 (en) 2010-04-13 2011-11-17 Riken Novel anti-hsp90 monoclonal antibody
US8124738B2 (en) 2005-09-26 2012-02-28 Medarex, Inc. Human monoclonal antibodies to CD70
WO2012032433A1 (fr) 2010-09-09 2012-03-15 Pfizer Inc. Molécules de liaison 4-1bb
WO2012071216A2 (fr) 2010-11-22 2012-05-31 Duke University Anticorps dirigés contre des gangliosides tumoraux
US8221753B2 (en) 2009-09-30 2012-07-17 Tracon Pharmaceuticals, Inc. Endoglin antibodies
US8236318B2 (en) 2007-11-07 2012-08-07 Celldex Therapeutics Inc. Antibodies that bind human dendritic and epithelial cell 205 (DEC-205)
US8278036B2 (en) 2005-08-23 2012-10-02 The Trustees Of The University Of Pennsylvania RNA containing modified nucleosides and methods of use thereof
WO2012138537A1 (fr) 2011-04-01 2012-10-11 Immunogen, Inc. Compositions et méthodes de traitement du cancer de l'ovaire, du péritoine et de la trompe de fallope
WO2012149412A2 (fr) 2011-04-29 2012-11-01 Immunogen Inc. Anticorps anti-endogline (cd105), immunoconjugués et leurs utilisations
WO2012163805A1 (fr) 2011-05-27 2012-12-06 Glaxo Group Limited Protéines de liaison à bcma (cd269/tnfrsf17)
US8383117B2 (en) 2004-06-10 2013-02-26 Viventia Biotechnologies Inc. CD44E tumor specific antibody
WO2013056984A1 (fr) 2011-10-19 2013-04-25 Effimune Anticorps dirigés contre la chaîne alpha du récepteur d'il7 et leur utilisation pour préparer des candidats de médicament
US20130115274A1 (en) 2011-11-04 2013-05-09 Nitto Denko Corporation Method of producing lipid nanoparticles for drug delivery
US20130122022A1 (en) 2006-01-30 2013-05-16 Beverly Torok-Storb Sequence of stro-1 antibody variable region
US8454959B2 (en) 2008-07-18 2013-06-04 Bristol-Meyers Squibb Company Compositions monovalent for CD28 binding and methods of use
US8507657B2 (en) 2008-06-30 2013-08-13 Morphotek, Inc. Anti-GD2 antibodies
US8552157B2 (en) 2011-05-12 2013-10-08 Imclone Llc c-Kit antibodies and uses thereof
WO2013167259A1 (fr) 2012-05-09 2013-11-14 Ganymed Pharmaceuticals Ag Anticorps anti-claudin 18.2 utiles dans le diagnostic du cancer
WO2014000338A1 (fr) 2012-06-28 2014-01-03 中国科学院生物物理研究所 Application d'un composite d'anticorps anti-cd146 et d'anticorps anti-vegf dans la préparation d'un médicament destiné à supprimer les tumeurs
US8679500B2 (en) 2009-05-14 2014-03-25 Institute National De La Sante Et De La Recherche Medicale (Inserm) Compositions containing antibodies for treating CD5+ HLA-DR+ B or T cell related diseases
US8722858B2 (en) 2007-06-25 2014-05-13 Chugai Seiyaku Kabushiki Kaisha Anti-Prominin-1 antibody having ADCC activity or CDC activity
WO2014083379A1 (fr) 2012-11-30 2014-06-05 Institut Pasteur Utilisation d'anticorps anti-fcyri et/ou anti-fcyriia pour traiter une arthrite, une inflammation, une thrombopénie et un choc anaphylactique
US8785604B2 (en) 2010-02-18 2014-07-22 Effimune Anti-CD28 humanized antibodies
WO2014128185A1 (fr) 2013-02-21 2014-08-28 Universitätsklinikum Freiburg Anticorps bispécifique de recombinaison se liant à l'antigène cd133 sur des cellules tumorales et au récepteur des lymphocytes t cd3
WO2014158821A1 (fr) 2013-03-12 2014-10-02 Imaginab, Inc. Constructions de liaison d'antigène à cd70
US20140308301A1 (en) 2011-10-26 2014-10-16 The Regents Of The University Of California Cd44 monoclonal antibody for the treatment of b-cell chronic lymphocytic leukemia and other hematological malignancies
US8951524B2 (en) 2006-10-10 2015-02-10 Universite De Nantes Use of monoclonal antibodies specific to the O-acetylated form of GD2 ganglioside for treatment of certain cancers
WO2015050959A1 (fr) 2013-10-01 2015-04-09 Yale University Anticorps anti-kits et leurs méthodes d'utilisation
WO2015052538A1 (fr) 2013-10-10 2015-04-16 Ucl Business Plc Récepteur d'antigène chimérique
WO2015076425A1 (fr) 2013-11-25 2015-05-28 リンク・ジェノミクス株式会社 Nouvel anticorps monoclonal
WO2015118031A2 (fr) 2014-02-06 2015-08-13 Oncomatryx Biopharma, S.L. Conjugués anticorps-médicament et immunotoxines
US9115192B2 (en) 2010-09-27 2015-08-25 Zestagen S.A. Compositions and methods for treating neoplasia
WO2015132604A1 (fr) 2014-03-06 2015-09-11 Ucl Business Plc Récepteur antigénique chimérique
WO2015140591A1 (fr) 2014-03-21 2015-09-24 Nordlandssykehuset Hf Anticorps anti-cd14 et leurs utilisations
US20150337039A1 (en) 2014-05-22 2015-11-26 Case Western Reserve University Mac-1 antibodies and uses thereof
WO2015184203A1 (fr) 2014-05-29 2015-12-03 Macrogenics, Inc. Molécules de liaison trispécifiques et leurs procédés d'utilisation
WO2015187528A1 (fr) 2014-06-02 2015-12-10 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Récepteurs d'antigènes chimériques ciblant cd-19
WO2015189302A1 (fr) 2014-06-10 2015-12-17 Effimune Anticorps anti-cd127
US9220772B2 (en) 2010-07-22 2015-12-29 The Regents Of The University Of California Anti-tumor antigen antibodies and methods of use
US9243058B2 (en) 2012-12-07 2016-01-26 Amgen, Inc. BCMA antigen binding proteins
US9249225B2 (en) 2010-05-26 2016-02-02 Regents Of The University Of Minnesota Single chain variable fragment anti-CD133 antibodies and uses thereof
US9273141B2 (en) 2011-05-27 2016-03-01 Glaxo Group Limited B cell maturation antigen (BCMA) binding proteins
US9284375B2 (en) 2005-04-15 2016-03-15 Macrogenics, Inc. Covalent diabodies and uses thereof
US9315585B2 (en) 2010-06-19 2016-04-19 Memorial Sloan Kettering Cancer Center Anti-GD2 antibodies
US9328156B2 (en) 2010-12-09 2016-05-03 The Trustees Of The University Of Pennsylvania Use of chimeric antigen receptor-modified T cells to treat cancer
WO2016090337A1 (fr) 2014-12-05 2016-06-09 Memorial Sloan-Kettering Cancer Center Récepteurs antigéniques chimériques ciblant le récepteur fc-like 5 et leurs utilisations
WO2016090329A2 (fr) 2014-12-05 2016-06-09 Memorial Sloan-Kettering Cancer Center Anticorps ciblant le récepteur couplé aux protéines g et procédés d'utilisation
US9382321B2 (en) 2014-11-26 2016-07-05 Adventis Health System/Sunbelt, Inc. Effector-deficient anti-CD32A antibodies
US9388249B2 (en) 2006-07-10 2016-07-12 Amano Enzyme Inc. Method of classifying antibody, method of identifying antigen, method of obtaining antibody or antibody set, method of constructing antibody panel and antibody or antibody set and use of the same
WO2016130598A1 (fr) 2015-02-09 2016-08-18 University Of Florida Research Foundation, Inc. Récepteur antigénique chimérique bispécifique et ses utilisations
US9447190B2 (en) 2012-09-10 2016-09-20 Prothena Biosciences Limited Anti-MCAM antibodies and associated methods of use
WO2016149578A1 (fr) 2015-03-19 2016-09-22 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Récepteurs doubles spécifiques de l'antigène chimère anti-cd22-anti-cd19
WO2016166630A1 (fr) 2015-04-13 2016-10-20 Pfizer Inc. Récepteurs antigéniques chimériques ciblant l'antigène de maturation des cellules b
US9493740B2 (en) 2010-09-08 2016-11-15 Baylor College Of Medicine Immunotherapy of cancer using genetically engineered GD2-specific T cells
WO2016187216A1 (fr) 2015-05-18 2016-11-24 Bluebird Bio, Inc. Récepteurs antigéniques chimériques anti-ror1
WO2016197974A1 (fr) 2015-06-12 2016-12-15 Yen-Ta Lu Méthodes et anticorps pour moduler une réponse immunitaire
US9540443B2 (en) 2011-01-26 2017-01-10 Kolltan Pharmaceuticals, Inc. Anti-kit antibodies
WO2017009473A1 (fr) 2015-07-16 2017-01-19 Ucb Biopharma Sprl Molécules d'anticorps qui se lient à cd45
WO2017021540A1 (fr) 2015-08-06 2017-02-09 Agency For Science, Technology And Research Anticorps anti-il-2-r beta/chaîne gamma commune
US20170051068A1 (en) 2015-08-17 2017-02-23 Janssen Pharmaceutica Nv Anti-BCMA Antibodies, Bispecific Antigen Binding Molecules that Bind BCMA and CD3, and Uses Thereof
WO2017048770A1 (fr) 2015-09-15 2017-03-23 Regulus Therapeutics, Inc. Systèmes, compositions et procédés de formulation de compositions d'acides nucléiques
WO2017058866A1 (fr) 2015-09-28 2017-04-06 Precision Immune, Inc. Anticorps anti-trem2 et leurs utilisations
WO2017055385A1 (fr) 2015-10-02 2017-04-06 F. Hoffmann-La Roche Ag Molécules bispécifiques de liaison à l'antigène activant les lymphocytes t anti-cd3xgd2
US9617349B2 (en) 2004-01-22 2017-04-11 Merck Patent Gmbh Anti-cancer antibodies with reduced complement fixation
WO2017062271A2 (fr) 2015-10-06 2017-04-13 Merck Sharp & Dohme Corp. Conjugué anticorps-médicament pour applications anti-inflammatoires
WO2017062748A1 (fr) 2015-10-07 2017-04-13 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anticorps spécifiques d'il-7r-alpha pour le traitement la leucémie lymphoblastique aiguë
WO2017064221A1 (fr) 2015-10-13 2017-04-20 Affimed Gmbh Anticorps fv polyvalents
WO2017096120A1 (fr) 2015-12-04 2017-06-08 Memorial Sloan-Kettering Cancer Center Anticorps ciblant la protéine de type récepteur fc 5 et procédés d'utilisation
US20170166638A1 (en) 2014-03-26 2017-06-15 Fraunhofer-Gesellschaft Zur Foerderung Der Angewandten Forschung E.V. USE OF CD-64-BLOCKING AGENTS AS ENHANCER OF AN ANTI-TNF-a ANTIBODY THERAPY
US9688755B2 (en) 2007-05-14 2017-06-27 Novimmune S.A. Fc receptor-binding polypeptides with modified effector functions
US9701756B2 (en) 2014-11-26 2017-07-11 Miltenyi Biotec Gmbh Humanized antibody or fragment thereof specific for CD45R0
US9701752B2 (en) 2005-04-19 2017-07-11 Seattle Genetics, Inc. Humanized anti-CD70 binding agents and uses thereof
WO2017118613A1 (fr) 2016-01-08 2017-07-13 Syddansk Universitet Anticorps bispécifiques ciblant cd73 humain
WO2017123650A2 (fr) 2016-01-11 2017-07-20 Inhibrx Lp Protéines de fusion se liant à gitr multivalentes et multispécifiques
WO2017130223A2 (fr) 2016-01-29 2017-08-03 Virocan Therapeutics Pvt. Ltd. Récepteur antigénique chimérique spécifique d'un antigène de maturation des lymphocytes b, vecteur d'expression recombinant et procédé associé
WO2017134306A1 (fr) 2016-02-05 2017-08-10 Orionis Biosciences Nv Agents de liaison au cd8
WO2017156479A1 (fr) 2016-03-11 2017-09-14 Bluebird Bio, Inc. Récepteurs antigéniques chimériques anti-ror1
US9765148B2 (en) 2011-03-16 2017-09-19 Argen-X N.V. Antibodies to CD70
US9777068B2 (en) 2012-06-18 2017-10-03 Apeiron Biologics Ag Method for treating a GD2 positive cancer
WO2017173256A1 (fr) 2016-04-01 2017-10-05 Kite Pharma, Inc. Récepteurs antigéniques chimériques et récepteurs de lymphocytes t et leurs procédés d'utilisation
US9782500B2 (en) 2013-09-24 2017-10-10 Oncoinvent As Monoclonal antibody and derivatives
US9789203B2 (en) 2013-03-15 2017-10-17 Novartis Ag cKIT antibody drug conjugates
US20170335016A1 (en) 2008-04-25 2017-11-23 Kyowa Hakko Kirin Co., Ltd Stable multivalent antibody
WO2017213979A1 (fr) 2016-06-06 2017-12-14 St. Jude Children's Research Hospital Récepteur d'antigène chimérique anti-cd7 et son procédé d'utilisation
US9856324B2 (en) 2014-06-04 2018-01-02 MabVax Therapeutics, Inc. Human monoclonal antibodies to ganglioside GD2
WO2018006882A1 (fr) 2016-07-08 2018-01-11 科济生物医药（上海）有限公司 Anticorps dirigé contre la claudine 18a2 et son utilisation
WO2018010846A1 (fr) 2016-07-15 2018-01-18 Ogd2 Pharma Anticorps humanisé contre le ganglioside gd2 o-acétylé (oacgd2)
WO2018017786A2 (fr) 2016-07-20 2018-01-25 Janssen Pharmaceutica Nv Anticorps anti-gprc5d, molécules bispécifiques de liaison à l'antigène qui se lient à gprc5d et cd3 et leurs utilisations
WO2018028647A1 (fr) 2015-08-11 2018-02-15 Legend Biotech Usa Inc. Récepteurs d'antigène chimériques ciblant bcma et leurs procédés d'utilisation
WO2018039626A1 (fr) 2016-08-25 2018-03-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anticorps humains à domaine unique ciblant cd16a pour la médiation de l'adcc
WO2018045880A1 (fr) 2016-09-06 2018-03-15 Guangzhou Bainifu Biotech Co., Ltd Récepteur d'antigène chimère, cellules car133-nkt et leur utilisation
US9926375B2 (en) 2014-11-12 2018-03-27 Tracon Pharmaceuticals, Inc. Anti-endoglin antibodies and uses thereof
US9932410B2 (en) 2013-11-05 2018-04-03 Inserm (Institut National De La Sante Et De La Recherche Medicale Human neutralizing anti-kit antibodies and uses thereof
US9938356B2 (en) 2014-11-10 2018-04-10 Medimmune Limited Binding molecules specific for CD73 and uses thereof
WO2018072025A1 (fr) 2016-10-19 2018-04-26 The Governing Council Of The University Of Toronto Agents de liaison à cd133 et leurs utilisations
WO2018098306A1 (fr) 2016-11-22 2018-05-31 National University Of Singapore Blocage de l'expression de cd7 et récepteurs d'antigènes chimériques pour l'immunothérapie de malignités de lymphocytes t
WO2018147245A1 (fr) 2017-02-07 2018-08-16 第一三共株式会社 Anticorps anti-gprc5d et molécule le contenant
WO2018152516A1 (fr) 2017-02-20 2018-08-23 Adimab, Llc Protéines de liaison à cd33, nkg2d et cd16
WO2018158349A1 (fr) 2017-02-28 2018-09-07 Affimed Gmbh Di-anticorps en tandem pour la mise en contact de cellules nk dirigées par cd16a
US10081682B2 (en) 2013-10-11 2018-09-25 Oxford Bio Therapeutics Ltd. Conjugated antibodies against LY75 for the treatment of cancer
US10100129B2 (en) 2014-11-21 2018-10-16 Bristol-Myers Squibb Company Antibodies against CD73 and uses thereof
US10106623B2 (en) 2014-02-12 2018-10-23 Michael Uhlin Bispecific antibodies for use in stem cell transplantation
US10106609B2 (en) 2014-06-04 2018-10-23 PeronGen BioTherapeutics (Suzhou) Co., Ltd. CD7 nanobodies, encoding sequence and use thereof
US10108123B2 (en) 2016-09-29 2018-10-23 Canon Kabushiki Kaisha Image forming apparatus
WO2018191786A1 (fr) 2017-04-21 2018-10-25 Implicit Bioscience Pty Ltd Anticorps antagonistes de cd 14 pour le traitement de maladies neurodégénératives
WO2018197675A1 (fr) 2017-04-28 2018-11-01 Julius-Maximilians-Universität Würzburg Récepteurs antigéniques chimériques (car) spécifiques à ror1 ayant des domaines de ciblage humanisés
WO2018199337A1 (fr) 2017-04-28 2018-11-01 味の素株式会社 Composé renfermant une substance ayant une affinité pour une protéine soluble, fraction clivable, et groupe réactif, ou sel de celui-ci
WO2018213337A1 (fr) 2017-05-15 2018-11-22 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Récepteurs d'antigènes chimériques bicistroniques et leurs utilisations
WO2018220467A1 (fr) 2017-05-30 2018-12-06 Foroogh Nejatollahi Immunotoxine humaine anti-muc18 et ses applications
WO2018235247A1 (fr) 2017-06-22 2018-12-27 学校法人順天堂 Anticorps anti-cd10
WO2019006072A1 (fr) 2017-06-30 2019-01-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Récepteurs antigéniques chimériques vers l'antigène de maturation des lymphocytes b présentant des domaines humains
US10174122B2 (en) 2017-01-06 2019-01-08 Eutilex Co., Ltd. Anti-human 4-1BB antibodies and uses thereof
WO2019033043A2 (fr) 2017-08-11 2019-02-14 Genentech, Inc. Anticorps anti-cd8 et utilisations associées
WO2019032661A1 (fr) 2017-08-09 2019-02-14 Orionis Biosciences Inc. Agents de liaison au cd8
WO2019059771A2 (fr) 2017-09-21 2019-03-28 Umc Utrecht Holding B.V. Anticorps anti-gd2 pour le traitement d'un neuroblastome
US10266604B2 (en) 2011-09-22 2019-04-23 Amgen Inc. CD27L antigen binding proteins
US10273295B2 (en) 2014-08-19 2019-04-30 Miltenyi Biotec Gmbh Chimeric antigen receptor specific for SSEA4 antigen
US10273294B2 (en) 2010-10-11 2019-04-30 University Of Southern California Compositions and methods for treating HIF-1α over-expressing cancers
WO2019084067A1 (fr) 2017-10-24 2019-05-02 Magenta Therapeutics, Inc. Anticorps anti-cd117 et leurs méthodes d'utilisation
WO2019085102A1 (fr) 2017-11-03 2019-05-09 西安宇繁生物科技有限责任公司 Lymphocyte t à récepteur antigénique chimérique spécifique de bcma et utilisation associée
WO2019092451A1 (fr) 2017-11-13 2019-05-16 Crescendo Biologics Limited Anticorps à domaine unique qui se lient à cd137
WO2019108863A1 (fr) 2017-11-29 2019-06-06 Magenta Therapeutics, Inc. Compositions et procédés pour la déplétion des cellules cd5+
US10316101B2 (en) 2014-04-14 2019-06-11 Cellectis BCMA (CD269) specific chimeric antigen receptors for cancer immunotherapy
WO2019126536A1 (fr) 2017-12-20 2019-06-27 Alexion Pharmaceuticals Inc. Anticorps humanisés anti-cd200 et leurs utilisations
WO2019119822A1 (fr) 2017-12-23 2019-06-27 Uwell Biopharma Inc. Composition pharmaceutique de récepteur chimérique et procédé associé
WO2019133639A2 (fr) 2017-12-26 2019-07-04 The Regents Of The University Of California Anticorps humains qui se lient et sont assimilés par des cellules de mésothéliome et autres cellules cancéreuses
WO2019137309A1 (fr) 2018-01-09 2019-07-18 南京任诺药业有限公司 Anticorps monoclonal anti-cd146 humain humanisé ayant une activité de neutralisation élevée
WO2019154890A1 (fr) 2018-02-09 2019-08-15 F. Hoffmann-La Roche Ag Anticorps se liant à gprc5d
US10383929B2 (en) 2014-12-12 2019-08-20 Bluebird Bio, Inc. BCMA chimeric antigen receptors
US10385137B2 (en) 2004-12-16 2019-08-20 Inserm (Institut National De La Sante Et De La Recherche Medicale) Production of antibody formats and immunological applications of said formats
WO2019159193A1 (fr) 2018-02-13 2019-08-22 Indian Institute Of Technology Bombay Nouveau récepteur antigénique chimérique anti-cd19 humanisé, séquence d'acide nucléique associée et préparation correspondante
US10407506B2 (en) 2014-03-12 2019-09-10 Prothena Biosciences Limited Anti-MCAM antibodies and associated methods of use
US10406179B2 (en) 2014-08-26 2019-09-10 The Board Of Trustees Of The Leland Stanford Junior University Engraftment of stem cells with a combination of an agent that targets stem cells and modulation of immunoregulatory signaling
WO2019170131A1 (fr) 2018-03-07 2019-09-12 复旦大学 Anticorps cd73 ciblé et conjugué anticorps-médicament, procédé de préparation associé et utilisations correspondantes
WO2019173692A2 (fr) 2018-03-09 2019-09-12 Agenus Inc. Anticorps anti-cd73 et leurs procédés d'utilisation
US10414820B2 (en) 2013-03-13 2019-09-17 Imaginab, Inc. Antigen binding constructs to CD8
WO2019175223A1 (fr) 2018-03-13 2019-09-19 Tusk Therapeutics Ltd Anticorps anti-cd25 pour la déplétion de cellules spécifiques d'une tumeur
US10426797B2 (en) 2017-03-24 2019-10-01 Lentigen Technology, Inc. Compositions and methods for treating cancer with anti-CD33 immunotherapy
US10428141B2 (en) 2017-11-03 2019-10-01 Lentigen Technology, Inc. Compositions and methods for treating cancer with anti-ROR1 immunotherapy
WO2019190952A1 (fr) 2018-03-29 2019-10-03 Lan Bo Chen Anticorps monoclonaux qui se lient à ssea4 et leurs utilisations
US10442867B2 (en) 2017-07-31 2019-10-15 Lentigen Technology, Inc. Compositions and methods for treating cancer with anti-CD19/CD20 immunotherapy
US20190321404A1 (en) 2016-12-30 2019-10-24 Nanjing Legend Biotech Co., Ltd. Novel chimeric antigen receptor and use thereof
US10457726B2 (en) 2016-06-30 2019-10-29 University Of Connecticut Antibody and antigen-binding fragment compositions targeting cell surface antigens in tumors and methods of use thereof
WO2019219089A1 (fr) 2018-05-18 2019-11-21 Bridge Health Bio-Tech Co., Ltd Anticorps anti-claudine 18.2 et leurs utilisations
US10508148B2 (en) 2017-12-12 2019-12-17 Pionyr Immunotherapeutics, Inc. Anti-TREM2 antibodies and related methods
WO2019241426A1 (fr) 2018-06-13 2019-12-19 Novartis Ag Récepteurs d'antigènes chimériques bcma et leurs utilisations
WO2019240287A1 (fr) 2018-06-14 2019-12-19 味の素株式会社 Composé comprenant une substance ayant une affinité pour un anticorps, site de clivage et groupe réactif, ou sel correspondant
WO2020011706A1 (fr) 2018-07-09 2020-01-16 Oslo Universitetssykehus Hf Deux récepteurs antigéniques chimériques se liant de manière spécifique à cd19 et igkappa
WO2020014366A1 (fr) 2018-07-10 2020-01-16 Intrexon Corporation Récepteurs antigéniques chimériques specifiques de ror-1 et utilisations associées
WO2020011966A1 (fr) 2018-07-12 2020-01-16 F-Star Beta Limited Molécules d'anticorps se liant à cd137 et ox40
WO2020011964A1 (fr) 2018-07-12 2020-01-16 F-Star Beta Limited Molécules d'anticorps qui se lient à pd-l1 et cd137
US10543263B2 (en) 2017-10-16 2020-01-28 Lentigen Technology Inc. Compositions and methods for treating cancer with anti-CD22 immunotherapy
WO2020020194A1 (fr) 2018-07-24 2020-01-30 Beijing Meikang Geno-Immune Biotechnology Co., Ltd. Récepteur antigénique chimérique à base de gd2 et utilisation associée
US10548987B2 (en) 2015-07-31 2020-02-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Antibody-drug conjugates for targeting CD56-positive tumors
WO2020025792A1 (fr) 2018-08-03 2020-02-06 Amgen Research (Munich) Gmbh Constructions d'anticorps pour cldn18.2 et cd3
US20200040101A1 (en) 2018-07-18 2020-02-06 Askgene Pharma Inc. Novel antibodies and methods for making and using the same
WO2020038146A1 (fr) 2018-08-24 2020-02-27 深圳普瑞金生物药业有限公司 Récepteur antigénique chimérique bcma basé sur un anticorps à domaine unique et son utilisation
US10584169B2 (en) 2017-01-24 2020-03-10 I-Mab Biopharma Us Limited Anti-CD73 antibodies and uses thereof
WO2020055975A1 (fr) 2018-09-11 2020-03-19 Washington University Anticorps agonistes anti-trem-2
WO2020060924A1 (fr) 2018-09-17 2020-03-26 Dualogics, Llc Utilisation d'un anticorps bispécifique cd4/cd8 pour le traitement de troubles auto-immuns/inflammatoires
WO2020065330A2 (fr) 2018-09-27 2020-04-02 Autolus Limited Récepteur antigénique chimérique
US10611838B2 (en) 2018-02-09 2020-04-07 Ultrahuman Five Limited C-KIT antibodies
WO2020076105A1 (fr) 2018-10-10 2020-04-16 주식회사 노벨티노빌리티 Nouvel anticorps anti-c-kit
US10633444B2 (en) 2016-04-18 2020-04-28 Celldex Therapeutics, Inc. Agonistic antibodies that bind CD40
WO2020092854A2 (fr) 2018-11-01 2020-05-07 Juno Therapeutics, Inc. Récepteurs antigéniques chimériques spécifiques du gprc5d (élément d du groupe 5 de classe c des récepteurs couplés à la protéine g)
WO2020092654A1 (fr) 2018-10-30 2020-05-07 Magenta Therapeutics, Inc. Anticorps anti-cd45 et leurs conjugués
WO2020098599A1 (fr) 2018-11-12 2020-05-22 江苏恒瑞医药股份有限公司 Anticorps anti-cd73, fragment de liaison à l'antigène de celui-ci et son utilisation
WO2020102591A1 (fr) 2018-11-14 2020-05-22 Rubryc Therapeutics, Inc. Anticorps anti-cd25
US10676525B2 (en) 2017-08-03 2020-06-09 Alector Llc Anti-TREM2 antibodies and methods of use thereof
US20200181260A1 (en) 2017-02-22 2020-06-11 H. Lee Moffitt Cancer Center And Research Institute, Inc. Bispecific antibody for cancer immunotherapy
US10683369B2 (en) 2015-08-03 2020-06-16 Engmab Sàrl Monoclonal antibodies against BCMA
WO2020121195A1 (fr) 2018-12-10 2020-06-18 Mor Research Applications Anticorps trem2 et leurs utilisations
US10689456B2 (en) 2014-12-08 2020-06-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-CD70 chimeric antigen receptors
WO2020132190A1 (fr) 2018-12-21 2020-06-25 Multitude Inc. Anticorps spécifiques à muc18
WO2020127618A1 (fr) 2018-12-21 2020-06-25 F. Hoffmann-La Roche Ag Molécules de liaison à l'antigène cd28 agonistes de ciblage de tumeurs
WO2020135201A1 (fr) 2018-12-28 2020-07-02 四川科伦博泰生物医药股份有限公司 Anticorps et son utilisation
WO2020139956A1 (fr) 2018-12-28 2020-07-02 Sparx Therapeutics Inc. Molécules de liaison spécifiques de la claudine 18.2, compositions et procédés associés, pour le traitement du cancer et d'autres maladies
US10711068B2 (en) 2015-03-26 2020-07-14 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-CD133 monoclonal antibodies and related compositions and methods
WO2020143836A1 (fr) 2019-01-11 2020-07-16 上海开拓者生物医药有限公司 Anticorps cd73, son procédé de préparation et son application
WO2020143710A1 (fr) 2019-01-11 2020-07-16 康诺亚生物医药科技（成都）有限公司 Anticorps monoclonal anti-cd73 et son utilisation
US10716851B2 (en) 2017-07-11 2020-07-21 Compass Therapeutics Llc Agonist antibodies that bind human CD137 and uses thereof
WO2020147321A1 (fr) 2019-01-17 2020-07-23 Beijing Mabworks Biotech Co. Ltd. Anticorps se liant à la claudine 18,2 humaine et leurs utilisations
WO2020148677A1 (fr) 2019-01-18 2020-07-23 Janssen Biotech, Inc. Récepteurs antigéniques chimériques gprc5d et cellules les exprimant
WO2020154293A1 (fr) 2019-01-22 2020-07-30 Bristol-Myers Squibb Company Anticorps contre la sous-unité alpha d'un l'il-7r et leurs utilisations
US10730941B2 (en) 2015-07-31 2020-08-04 Memorial Sloan-Kettering Cancer Center Antigen-binding proteins targeting CD56 and uses thereof
US10730944B2 (en) 2017-07-24 2020-08-04 Regeneron Pharmaceuticals, Inc. Anti-CD8 antibodies and uses thereof
WO2020160242A1 (fr) 2019-02-01 2020-08-06 Regeneron Pharmaceuticals, Inc. Protéines de liaison à l'antigène gamma du récepteur anti-il2
US20200246381A1 (en) 2018-02-01 2020-08-06 Nanjing Iaso Biotherapeutics Co., Ltd. Chimeric antigen receptor (car) binding to bcma, and uses thereof
WO2020159754A2 (fr) 2019-01-28 2020-08-06 Multitude Inc. Anticorps spécifiques à cd44
US10738121B2 (en) 2015-02-27 2020-08-11 The General Hospital Corporation Therapeutic use of integrin-binding antibodies
US10745481B2 (en) 2015-05-04 2020-08-18 Cytomx Therapeutics, Inc. Anti-CD166 antibodies, activatable anti-CD166 antibodies, and methods of use thereof
US20200261503A1 (en) 2018-12-01 2020-08-20 Allogene Therapeutics, Inc. Chimeric antigen receptors targeting b-cell maturation antigen and methods of use thereof
US10752684B2 (en) 2014-07-29 2020-08-25 Cellectis ROR1 (NTRKR1) specific chimeric antigen receptors for cancer immunotherapy
US10758625B2 (en) 2015-04-14 2020-09-01 Benhealth Biopharmaceutic (Shenzhen) Co., Ltd. Bispecific antibody capable of being combined with immune cells to enhance tumor killing capability, and preparation method therefor and application thereof
WO2020184944A1 (fr) 2019-03-08 2020-09-17 앱티스 주식회사 Conjugaison d'anticorps spécifique à un site et conjugué anticorps-médicament servant d'exemple spécifique de celui-ci
US20200297634A1 (en) 2019-03-19 2020-09-24 Arcturus Therapeutics, Inc. Method of making lipid-encapsulated rna nanoparticles
WO2020190737A1 (fr) 2019-03-15 2020-09-24 Cartesian Therapeutics, Inc. Récepteurs d'antigènes chimériques anti-bcma
WO2020198531A2 (fr) 2019-03-26 2020-10-01 The Regents Of The University Of California Lymphocytes t modifiés par un récepteur antigénique chimérique (car-t) pour le traitement de cancers hématologiques et tumoraux solides
WO2020212710A1 (fr) 2019-04-18 2020-10-22 Kymab Limited Anticorps anti-cd7 antagonistes
US20200339699A1 (en) 2018-02-01 2020-10-29 Innovent Biologics (Suzhou) Co., Ltd. Fully humanized anti-b cell maturation antigen (bcma) single-chain antibody and use thereof
WO2020216697A1 (fr) 2019-04-23 2020-10-29 Innate Pharma Anticorps bloquant cd73
WO2020219770A1 (fr) 2019-04-24 2020-10-29 Magenta Therapeutics, Inc. Anticorps anti-cd117 et leurs utilisations
WO2020219876A1 (fr) * 2019-04-25 2020-10-29 Intellia Therapeutics, Inc. Lipides aminés ionisables et nanoparticules lipidiques
US10822426B2 (en) 2015-12-09 2020-11-03 Corvus Pharmaceuticals, Inc. Humanized anti-CD73 antibodies
US10844128B2 (en) 2018-09-20 2020-11-24 Lentigen Technology, Inc. Compositions and methods for treating cancer with anti-CD123 immunotherapy
WO2020253568A1 (fr) 2019-06-19 2020-12-24 海正生物制药有限公司 Anticorps anti-cd73 et son utilisation
WO2020254827A1 (fr) 2019-06-21 2020-12-24 Vhsquared Limited Polypeptides
US20210002384A1 (en) 2018-02-15 2021-01-07 St. Jude Children's Research Hospital Process for producing hu14.18k322a monoclonal antibody
WO2021008463A1 (fr) 2019-07-12 2021-01-21 明济生物制药（北京）有限公司 Anticorps cldn18.2 et son utilisation
WO2021018859A2 (fr) 2019-07-31 2021-02-04 F. Hoffmann-La Roche Ag Anticorps se liant à gprc5d
WO2021017892A1 (fr) 2019-07-26 2021-02-04 上海复宏汉霖生物技术股份有限公司 Procédé et composition pour anticorps anti-cd73 et variants
WO2021018925A1 (fr) 2019-07-31 2021-02-04 F. Hoffmann-La Roche Ag Anticorps se liant à gprc5d
WO2021022304A2 (fr) 2019-07-30 2021-02-04 Qlsf Biotherapeutics, Inc. COMPOSÉS DE LIAISON MULTISPÉCIFIQUES QUI SE LIENT À LRRC15 ET CD3ε
US10920246B2 (en) 2015-05-26 2021-02-16 Ramot At Tel-Aviv University Ltd. Targeted lipid particles for systemic delivery of nucleic acid molecules to leukocytes
US10919967B2 (en) 2016-06-21 2021-02-16 Albert-Ludwigs-Universitätfreiburg Antibodies against Mac-1
WO2021027850A1 (fr) 2019-08-12 2021-02-18 I-Mab Biopharma Co., Ltd. Anticorps bispécifiques anti-claudine 18.2 et anti-4-1bb et leurs utilisations
WO2021032173A1 (fr) 2019-08-21 2021-02-25 Harbour Biomed (Shanghai) Co., Ltd. Anticorps anti-cd73 et son application
WO2021032157A1 (fr) 2019-08-20 2021-02-25 Mabspace Biosciences (Suzhou) Co., Limited Nouveaux anticorps anti-cldn18.2
WO2021044008A1 (fr) 2019-09-04 2021-03-11 Universität Zürich Agent de liaison bispécifique qui se lie à cd117/c-kit et cd3
WO2021046159A1 (fr) 2019-09-04 2021-03-11 Genentech, Inc. Agents de liaison à cd8 et leurs utilisations
WO2021044039A1 (fr) 2019-09-06 2021-03-11 Scancell Limited Éléments de liaison à ssea-4
US20210087295A1 (en) 2019-09-23 2021-03-25 The Trustees Of The University Of Pennsylvania Disrupting tumor tissues by targeting fibroblast activation protein (fap)
WO2021055437A1 (fr) 2019-09-16 2021-03-25 The General Hospital Corporation Cellules t de récepteurs antigéniques chimériques (car) ciblées cd70 et leurs utilisations
WO2021072312A1 (fr) 2019-10-11 2021-04-15 The Trustees Of The University Of Pennsylvania Compositions et procédés de ciblage de cd13 et de tim-3 avec des cellules car-t dans le traitement de la leucémie myéloïde aiguë (lma)
WO2021076564A1 (fr) 2019-10-15 2021-04-22 Dragonfly Therapeutics, Inc. Protéines se liant à nkg2d, cd16 et flt3
US10988546B2 (en) 2017-08-01 2021-04-27 Medimmune, Llc BCMA monoclonal antibody-drug conjugate
US20210130483A1 (en) 2018-03-26 2021-05-06 Sutro Biopharma, Inc. Anti-bcma receptor antibodies, compositions comprising anti bcma receptor antibodies and methods of making and using anti-bcma antibodies
WO2021091945A1 (fr) 2019-11-05 2021-05-14 Janssen Biotech, Inc. Thérapie du myélome multiple basée sur des cellules car-t ciblées par bcma
WO2021097223A2 (fr) 2019-11-15 2021-05-20 Genzyme Corporation Anticorps cd73 biparatopique
WO2021101823A1 (fr) 2019-11-22 2021-05-27 Eli Lilly And Company Anticorps trem2 et leurs utilisations
WO2021099418A1 (fr) 2019-11-19 2021-05-27 International - Drug - Development - Biotech Anticorps anti-cd117 et leurs procédés d'utilisation
WO2021102332A1 (fr) 2019-11-22 2021-05-27 Silverback Therapeutics, Inc. Conjugués inhibiteur de tgfbetar2-anticorps anti-lrrc15 et leurs utilisations
WO2021107566A1 (fr) 2019-11-25 2021-06-03 주식회사 노벨티노빌리티 Anticorps dirigé contre c-kit et utilisation correspondante
US11026975B2 (en) 2018-02-01 2021-06-08 Nanjing Iaso Biotherapeutics Co., Ltd. Chimeric antigen receptor (CAR) binding to BCMA, and uses thereof
WO2021111003A1 (fr) 2019-12-06 2021-06-10 SOTIO a.s. Anticorps humanisés anti-cldn18.2
US11034771B2 (en) 2018-07-25 2021-06-15 I-Mab Biopharma Us Limited Anti-CD73 anti-PD-L1 bispecific antibodies
WO2021118955A1 (fr) 2019-12-13 2021-06-17 Aggamin Llc Méthodes et systèmes de traitement ou de prévention de troubles de l'hypertension liés à la grossesse
WO2021127088A1 (fr) 2019-12-18 2021-06-24 Janssen Biotech, Inc. Matériaux et méthodes de ciblage biologique in vivo
US11046775B2 (en) 2017-02-14 2021-06-29 Kite Pharma, Inc. CD70 binding molecules and methods of use thereof
WO2021129765A1 (fr) 2019-12-27 2021-07-01 Nanjing Legend Biotech Co., Ltd. Fractions de liaison à claudin18.2 et leurs utilisations
WO2021138264A1 (fr) 2019-12-30 2021-07-08 Seagen Inc. Méthodes de traitement du cancer à l'aide d'anticorps anti-cd70 non fucosylés
WO2021138378A1 (fr) 2019-12-30 2021-07-08 Obi Pharma, Inc. Anticorps, compositions pharmaceutiques et leurs utilisations
WO2021138467A1 (fr) 2020-01-03 2021-07-08 Incyte Corporation Anticorps anti-cd73 et leurs utilisations
US11078291B2 (en) 2016-02-17 2021-08-03 Seagen Inc. BCMA antibodies and use of same to treat cancer and immunological disorders
WO2021155071A1 (fr) 2020-01-29 2021-08-05 Inhibrx, Inc. Anticorps cd28 à domaine unique et constructions multivalentes et multispécifiques de ceux-ci
WO2021160269A1 (fr) 2020-02-13 2021-08-19 UCB Biopharma SRL Anticorps bispécifiques anti-cd44-ctla4
WO2021160267A1 (fr) 2020-02-13 2021-08-19 UCB Biopharma SRL Anticorps bispécifiques dirigés contre cd9 et cd7
WO2021174198A1 (fr) 2020-02-28 2021-09-02 The Brigham And Women's Hospital, Inc. Modulation sélective de signalisation de la superfamille du facteur de croissance transformant bêta par le biais d'anticorps multi-spécifiques
WO2021178896A1 (fr) 2020-03-06 2021-09-10 Go Therapeutics, Inc. Anticorps anti-glyco-cd44 et leurs utilisations
US11124567B2 (en) 2020-01-13 2021-09-21 Denali Therapeutics Inc. Anti-TREM2 antibodies and methods of use thereof
WO2021188590A2 (fr) 2020-03-16 2021-09-23 Magenta Therapeutics, Inc. Protéines bispécifiques de liaison à des lymphocytes t
WO2021186056A1 (fr) 2020-03-20 2021-09-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Récepteur antigénique chimérique spécifique de cd45rc humain et ses utilisations
US11136403B2 (en) 2017-10-13 2021-10-05 Harpoon Therapeutics, Inc. Trispecific proteins and methods of use
WO2021202642A2 (fr) 2020-04-01 2021-10-07 The Regents Of The University Of California Agent immunothéranostique ciblant des cellules cancéreuses dérivées de cellules souches mésenchymateuses et une maladie associée à des cellules souches mésenchymateuses
WO2021205383A1 (fr) 2020-04-09 2021-10-14 Aprilbio Co., Ltd. Anticorps monoclonaux et leurs fragments de liaison à l'antigène pour supprimer le point de contrôle immunitaire cd73 et leurs utilisations
WO2021213466A1 (fr) 2020-04-22 2021-10-28 中山康方生物医药有限公司 Anticorps anti-cd73 et son utilisation
WO2021222227A1 (fr) 2020-04-27 2021-11-04 Memorial Sloan-Kettering Cancer Center Récepteur antigénique chimérique ciblant cd127 et utilisation associée
WO2021218874A1 (fr) 2020-04-27 2021-11-04 启愈生物技术(上海)有限公司 Anticorps bispécifique ciblant la claudine humaine et les protéines pdl1 humaines, et application de celui-ci
US11174319B2 (en) 2019-06-06 2021-11-16 Jacobio Pharmaceuticals Co., Ltd. Binding molecule specific for CD73 and use of binding molecule
WO2021227307A1 (fr) 2020-05-12 2021-11-18 普米斯生物技术(珠海)有限公司 Anticorps anti-cd73 et son utilisation
US11180554B2 (en) 2016-12-13 2021-11-23 Astellas Pharma Inc. Anti-human CD73 antibody
US20210363245A1 (en) 2018-09-17 2021-11-25 The United States Of America,As Represented By The Secretary,Department Of Health And Human Services Bicistronic chimeric antigen receptors targeting cd19 and cd20 and their uses
US11186636B2 (en) 2017-04-21 2021-11-30 Amgen Inc. Anti-human TREM2 antibodies and uses thereof
WO2021241729A1 (fr) 2020-05-29 2021-12-02 ブライトパス・バイオ株式会社 Anticorps anti-cd73 et son utilisation
WO2021245603A1 (fr) 2020-06-04 2021-12-09 Crispr Therapeutics Ag Anticorps anti-cd70 et leurs utilisations
US11203643B2 (en) 2019-05-10 2021-12-21 Lyvgen Biopharma Holdings Limited Humanized anti-CD137 antibodies and uses thereof
WO2021254481A1 (fr) 2020-06-19 2021-12-23 信达生物制药(苏州)有限公司 Anticorps anti-claudine 18.2 et son utilisation
US11208482B2 (en) 2018-11-26 2021-12-28 Forty Seven, Inc. Humanized antibodies against c-Kit
WO2021259199A1 (fr) 2020-06-22 2021-12-30 信达生物制药(苏州)有限公司 Anticorps anti-cd73 et son utilisation
WO2022002019A1 (fr) 2020-06-30 2022-01-06 江苏恒瑞医药股份有限公司 Anticorps anti-cd70 et son application
US11220544B2 (en) 2017-07-14 2022-01-11 Cytomx Therapeutics, Inc. Anti-CD166 antibodies and uses thereof
WO2022007808A1 (fr) 2020-07-06 2022-01-13 康诺亚生物医药科技（成都）有限公司 Anticorps se liant à la claudine-18.2 et son utilisation
WO2022022749A1 (fr) 2020-12-16 2022-02-03 南通大学 Utilisation d'anticorps cd44 dans la préparation de médicaments destinés à traiter la maladie de parkinson
WO2022022718A1 (fr) 2020-07-31 2022-02-03 北京市神经外科研究所 Anticorps à chaîne unique anti-cd133 et son utilisation dans la préparation d'un médicament pour le traitement d'une tumeur
WO2022022720A1 (fr) 2020-07-31 2022-02-03 北京市神经外科研究所 Anticorps monocaténaire anti-cd44 et son utilisation dans la préparation d'un médicament pour le traitement d'une tumeur
US11242395B2 (en) 2017-08-21 2022-02-08 Adagene Inc. Anti-CD137 molecules and use thereof
US11242385B2 (en) 2017-04-13 2022-02-08 Agenus Inc. Anti-CD137 antibodies and methods of use thereof
WO2022032293A2 (fr) 2020-08-05 2022-02-10 Vigil Neuroscience, Inc. Traitement de maladies associées au dysfonctionnement du récepteur de facteur 1 de stimulation des colonies au moyen d'agonistes de trem2
US11248058B2 (en) 2015-02-19 2022-02-15 University Of Florida Research Foundation, Inc. Chimeric antigen receptors and uses thereof
WO2022037531A1 (fr) 2020-08-17 2022-02-24 中山康方生物医药有限公司 Anticorps anti-cd73 et son utilisation
WO2022040088A2 (fr) 2020-08-21 2022-02-24 Synthekine, Inc. Molécules de liaison à cd45 et méthodes d'utilisation
WO2022040608A1 (fr) 2020-08-21 2022-02-24 City Of Hope Compositions d'anticorps anti-cd5 et leurs utilisations
WO2022040577A1 (fr) 2020-08-20 2022-02-24 City Of Hope Compositions et utilisations de lymphocytes t modifiés par un récepteur d'antigène chimérique ciblant pour cd45
WO2022056199A1 (fr) 2020-09-11 2022-03-17 Janssen Biotech, Inc. Molécules de ciblage immunitaires multispécifiques et leurs utilisations
WO2022064191A1 (fr) 2020-09-25 2022-03-31 Ucl Business Ltd Anticorps anti-cd45 et agents thérapeutiques associés
WO2022063853A1 (fr) 2020-09-25 2022-03-31 Adc Therapeutics Sa Conjugués pyrrolobenzodiazépine-anticorps et leurs utilisations
US11292846B2 (en) 2017-11-02 2022-04-05 Bayer Aktiengesellschaft Bispecific antibodies binding ALK-1 and BMPR-2
WO2022067394A1 (fr) 2020-09-30 2022-04-07 Newsouth Innovations Pty Limited Fragments de liaison à l'antigène et leurs utilisations
WO2022068854A1 (fr) 2020-09-30 2022-04-07 Nanjing GenScript Biotech Co., Ltd. Anticorps ciblant la claudine 18.2 humaine et leurs utilisations
US11299550B2 (en) 2018-03-09 2022-04-12 Phanes Therapeutics, Inc. Anti-CD73 antibodies and uses thereof
US11306145B2 (en) 2016-04-29 2022-04-19 Viela Bio, Inc. Binding molecules specific for FcγRIIA and uses thereof
WO2022081516A1 (fr) 2020-10-13 2022-04-21 Janssen Biotech, Inc. Immunité à médiation par des lymphocytes t biologiquement modifiés, matériaux et autres procédés pour la modulation d'un ensemble de différenciation iv &/ou viii
WO2022082073A2 (fr) 2020-10-16 2022-04-21 Board Of Regents, The University Of Texas System Compositions et méthodes de ciblage de muc18
WO2022078344A1 (fr) 2020-10-12 2022-04-21 南京驯鹿医疗技术有限公司 Anticorps et récepteur antigénique chimérique (car) se liant à cd70, et application associée
US11312785B2 (en) 2018-05-19 2022-04-26 Boehringer Ingelheim International Gmbh Antagonizing CD73 antibody
US11312783B2 (en) 2017-06-22 2022-04-26 Novartis Ag Antibody molecules to CD73 and uses thereof
WO2022083723A1 (fr) 2020-10-23 2022-04-28 中山康方生物医药有限公司 Anticorps anti-cd73 et son utilisation
WO2022083049A1 (fr) 2020-10-19 2022-04-28 中山康方生物医药有限公司 Anticorps anti-cd73 et son utilisation
US11326182B2 (en) 2016-04-29 2022-05-10 Voyager Therapeutics, Inc. Compositions for the treatment of disease
WO2022095803A1 (fr) 2020-11-03 2022-05-12 南京北恒生物科技有限公司 Anticorps humanisé ciblant cd7 et son utilisation
WO2022096020A1 (fr) 2020-11-09 2022-05-12 江苏中新医药有限公司 Séquence d'anticorps anti-ecto-5'-nucléotidase
WO2022095802A1 (fr) 2020-11-03 2022-05-12 南京北恒生物科技有限公司 Récepteur antigénique chimérique ciblant cd7 et son utilisation
WO2022104009A1 (fr) 2020-11-13 2022-05-19 Rubryc Therapeutics, Inc. Anticorps anti-cd25
WO2022105881A1 (fr) 2020-11-20 2022-05-27 Bliss Biopharmaceutical (Hangzhou) Co., Ltd. Anticorps anti-cd73, conjugué anticorps-médicament, et utilisation correspondante
WO2022105914A1 (fr) 2020-11-23 2022-05-27 江苏先声药业有限公司 Anticorps se liant à cd70 et son utilisation
WO2022111616A1 (fr) 2020-11-30 2022-06-02 石药集团巨石生物制药有限公司 Anticorps anti-cldn18.2, conjugué médicamenteux, procédé de préparation s'y rapportant et utilisation associée
WO2022125837A1 (fr) 2020-12-09 2022-06-16 City Of Hope Compositions et utilisations de cellules immunitaires modifiées par un récepteur antigénique chimérique ciblant cd19
US11365258B2 (en) 2017-03-10 2022-06-21 Berlin-Chemie Ag Pharmaceutical combinations comprising an anti-LY75 antibody
WO2022127844A1 (fr) 2020-12-17 2022-06-23 江苏先声药业有限公司 Anticorps cd5 et son utilisation
WO2022136888A1 (fr) 2020-12-23 2022-06-30 Bivictrix Limited Anticorps bispécifiques se liant à cd7 et cd33
US11377500B2 (en) 2018-02-01 2022-07-05 Pfizer Inc. Antibodies specific for CD70 and their uses
WO2022143951A1 (fr) 2020-12-31 2022-07-07 康诺亚生物医药科技（成都）有限公司 Développement et utilisation d'un agent de blocage d'anticorps à fonction améliorée
WO2022147338A1 (fr) 2020-12-30 2022-07-07 Ascendo Biotechnology, Inc. Anticorps monoclonal contre le mac-1 humain et ses utilisations
US11384153B2 (en) 2018-07-19 2022-07-12 Regeneran Pharmaceuticals, Inc. Bispecific anti-BCMA x anti-CD3 antibodies and uses thereof
CN114763383A (zh) 2021-01-13 2022-07-19 博生吉医药科技(苏州)有限公司 靶向人bcma的单克隆抗体及其应用
WO2022155608A2 (fr) 2021-01-15 2022-07-21 The General Hospital Corporation Récepteur chimérique de cd64 et ses utilisations
WO2022151851A1 (fr) 2021-01-12 2022-07-21 上海雅科生物科技有限公司 Cellule immunitaire génétiquement modifiée ciblant cd7, récepteur antigénique chimérique, molécule de blocage de cd7 et utilisation associée
WO2022157094A2 (fr) 2021-01-22 2022-07-28 Bayer Aktiengesellschaft Anticorps lrrc15 et leurs conjugués
US20220233591A1 (en) 2021-01-25 2022-07-28 Beijing Daxi Biotechnology Co., Ltd Preparation method of nk cells and use thereof in the treatment of cancer
WO2022159737A1 (fr) 2021-01-22 2022-07-28 Celldex Therapeutics, Inc. Anticorps anti-kit et leurs utilisations
WO2022161314A1 (fr) 2021-01-27 2022-08-04 信达生物制药(苏州)有限公司 Anticorps à un seul domaine contre cd16a et son utilisation
WO2022166802A1 (fr) 2021-02-04 2022-08-11 上海交通大学 Anticorps monoclonal anti-cd271 humain
US11419933B2 (en) 2016-01-25 2022-08-23 Amgen Inc. Pharmaceutical composition comprising bispecific antibody constructs
WO2022174813A1 (fr) 2021-02-19 2022-08-25 信达生物制药(苏州)有限公司 Anticorps trispécifique anti-gprc5d × bcma × cd3 et son utilisation
WO2022175255A2 (fr) 2021-02-16 2022-08-25 Janssen Pharmaceutica Nv Anticorps trispécifique ciblant bcma, gprc5d et cd3
US11427648B2 (en) 2017-10-06 2022-08-30 Universite D'aix-Marseille Anti-CD146 antibodies and uses thereof
WO2022179039A1 (fr) 2021-02-24 2022-09-01 苏州近岸蛋白质科技股份有限公司 Anticorps anti-cd73 humain et son utilisation
WO2022187050A1 (fr) 2021-03-01 2022-09-09 BioLegend, Inc. Agents anti-cd117 et compositions et procédés de fabrication et d'utilisation de ceux-ci
US11440966B2 (en) 2016-07-14 2022-09-13 Genmab A/S Multispecific antibodies against CD40 and CD137
US11447558B2 (en) 2017-01-03 2022-09-20 Hoffmann-La Roche Inc. Bispecific antigen binding molecules comprising anti-4-1BB clone 20H4.9
US11447548B2 (en) 2017-10-31 2022-09-20 Xenikos B.V. Immunotoxins, formulations thereof and their use in medicine
US11453721B2 (en) 2018-12-19 2022-09-27 Regeneran Pharmaceuticals, Inc. Bispecific anti-MUC16 x anti-CD28 antibodies and uses thereof
WO2022212848A1 (fr) 2021-04-02 2022-10-06 Teneobio, Inc. Anticorps agonistes anti-il-2r et procédés d'utilisation
WO2022214677A1 (fr) 2021-04-09 2022-10-13 Cancer Research Technology Limited Anticorps anti-cd73
WO2022221409A1 (fr) 2021-04-14 2022-10-20 Villaris Therapeutics, Inc. Anticorps anti-cd122 et leurs utilisations
WO2022222910A1 (fr) 2021-04-22 2022-10-27 南京北恒生物科技有限公司 Anticorps ciblant gprc5d et son utilisation
WO2022226317A1 (fr) 2021-04-23 2022-10-27 Profoundbio Us Co. Anticorps anti-cd70, leurs conjugués et leurs procédés d'utilisation
US11492402B2 (en) 2018-10-15 2022-11-08 Novartis Ag TREM2 stabilizing antibodies
US11492409B2 (en) 2018-06-01 2022-11-08 Novartis Ag Binding molecules against BCMA and uses thereof
WO2022241082A1 (fr) 2021-05-14 2022-11-17 Genentech, Inc. Agonistes de trem2
US11505606B2 (en) 2016-09-14 2022-11-22 Teneobio, Inc. CD3 binding antibodies
WO2022243838A1 (fr) 2021-05-18 2022-11-24 Janssen Biotech, Inc. Compositions comprenant un agent thérapeutique de redirection des lymphocytes t et un agent thérapeutique anti-cd44
WO2022242758A1 (fr) 2021-05-21 2022-11-24 百奥泰生物制药股份有限公司 Anticorps anti-cd73 et son utilisation
WO2022247756A1 (fr) 2021-05-23 2022-12-01 上海邦耀生物科技有限公司 Récepteur antigénique chimérique ciblant gprc5d et son utilisation
WO2022247804A1 (fr) 2021-05-23 2022-12-01 上海祥耀生物科技有限责任公司 Anticorps anti-gprc5d, son procédé de préparation et son utilisation
US11525006B2 (en) 2017-01-23 2022-12-13 Crage Medical Co., Limited BCMA-targeting antibody and use thereof
WO2022257835A1 (fr) 2021-06-08 2022-12-15 Beijing Meikang Geno-Immune Biotechnology Co., Ltd. Récepteur antigénique chimérique humanisé à base de cd7 et son utilisation
US11530273B2 (en) 2017-05-23 2022-12-20 Helmholtz Zentrum München—Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Anti-CD73 monoclonal antibody, encoding nucleic acids and method for producing
US11530268B2 (en) 2018-10-09 2022-12-20 Sanofi Trispecific anti-CD38, anti-CD28, and anti-CD3 binding proteins and methods of use for treating viral infection
WO2022263855A1 (fr) 2021-06-18 2022-12-22 Autolus Limited Anticorps à domaine unique anti-cd307e, leurs utilisations dans une cellule car-t et pour le traitement de maladies
WO2022262101A1 (fr) 2021-06-17 2022-12-22 南京蓝盾生物科技有限公司 Anticorps anti-cd70 présentant un effet adcc amélioré et application associée
US11535678B2 (en) 2016-11-21 2022-12-27 Alligator Bioscience Ab Anti-CD137 antibodies and uses thereof
US11535672B2 (en) 2017-02-28 2022-12-27 Affimed Gmbh Combination of an anti-CD16A antibody with a cytokine
US11535869B2 (en) 2021-04-08 2022-12-27 Sana Biotechnology, Inc. CD8-specific antibody constructs and compositions thereof
US20230002489A1 (en) 2019-11-26 2023-01-05 Shanghai Epimab Biotherapeutics Co., Ltd. Antibodies to cd3 and bcma, and bispecific binding proteins made therefrom
WO2023278520A1 (fr) 2021-06-30 2023-01-05 Board Of Regents, The University Of Texas System Polypeptides ciblant des cancers positifs à cd70
WO2023274183A1 (fr) 2021-06-29 2023-01-05 江苏先声药业有限公司 Anticorps anti-cd16 et son utilisation
US11548947B2 (en) 2018-06-21 2023-01-10 Regeneron Pharmaceuticals, Inc. Bispecific anti-PSMA X anti-CD28 antibodies and uses thereof
WO2023280880A1 (fr) 2021-07-05 2023-01-12 Trion Research Gmbh Anticorps multispécifiques se liant à des antigènes associés à une tumeur provoquant une névralgie nulle ou réduite dans le traitement du cancer
US11555077B2 (en) 2017-11-09 2023-01-17 Shanghai Hyamab Biotech Co., Ltd. 4-1BB antibody and preparation method and use thereof
WO2023004304A1 (fr) 2021-07-20 2023-01-26 Inhibrx, Inc. Polypeptides se liant à cd8 et leurs utilisations
WO2023012802A1 (fr) 2021-08-05 2023-02-09 Yeda Research And Development Co. Ltd. Anticorps pour le traitement du cancer
US11591401B2 (en) 2020-08-19 2023-02-28 Xencor, Inc. Anti-CD28 compositions
US20230067770A1 (en) 2020-02-28 2023-03-02 Shanghai Henlius Biotech, Inc. Anti-cd137 constructs, multispecific antibody and uses thereof
WO2023026791A1 (fr) 2021-08-27 2023-03-02 株式会社免疫生物研究所 Fragment d'anticorps spécifique aux tumeurs positives à c-kit
US20230075244A1 (en) 2020-02-20 2023-03-09 The Feinstein Institutes For Medical Research Agonist antibodies against endoglin and uses thereof
WO2023031403A1 (fr) 2021-09-02 2023-03-09 F. Hoffmann-La Roche Ag Anticorps pour traiter la lam
WO2023039450A2 (fr) 2021-09-07 2023-03-16 Duke University Compositions et procédés pour le traitement de la dégénérescence rétinienne
WO2023039612A1 (fr) 2021-09-13 2023-03-16 The Board Of Regents Of The University Of Texas System Protéines de liaison à l'antigène trem2 et leurs utilisations
WO2023037015A1 (fr) 2021-09-13 2023-03-16 Universiteit Gent Anticorps monoclonaux spécifiques de l'aminopeptidase n et leurs utilisations
US11613584B1 (en) 2021-10-13 2023-03-28 Immuneonco Biopharmaceuticals (Shanghai) Inc. Antibodies binding CD70, preparation and use thereof
WO2023047100A1 (fr) 2021-09-21 2023-03-30 Quell Therapeutics Ltd Récepteur antigénique chimérique anti-trem2
US11623961B2 (en) 2017-11-01 2023-04-11 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for B-cell maturation antigen
US11634500B2 (en) 2019-09-06 2023-04-25 Les Laboratoires Servier Anti-CD73 antibodies and compositions
WO2023072307A1 (fr) 2021-10-25 2023-05-04 重庆精准生物技术有限公司 Fragment de liaison à l'antigène ciblant cd70, anticorps à chaîne unique, récepteur antigénique chimérique et utilisation associée
US11643456B2 (en) 2016-07-29 2023-05-09 Obi Pharma, Inc. Human antibodies, pharmaceutical compositions and methods
US20230144142A1 (en) 2020-02-27 2023-05-11 McSAF Inside Oncology Anti-cd56 antibody-drug conjugates and their use in therapy
WO2023078382A1 (fr) 2021-11-05 2023-05-11 正大天晴药业集团股份有限公司 Anticorps se liant à gprc5d et son utilisation
WO2023078113A1 (fr) 2021-11-02 2023-05-11 Epimab Biotherapeutics (Hk) Limited Anticorps anti-cd122, anticorps anti-cd132 et protéines de liaison bispécifiques associées
WO2023091148A1 (fr) 2021-11-22 2023-05-25 National Health Research Institutes ANTICORPS ANTI-HSP90α ET SES UTILISATIONS
US20230193292A1 (en) 2020-08-20 2023-06-22 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Bcma-binding single variable structural domain and antigen-binding molecule
WO2023125728A1 (fr) 2021-12-31 2023-07-06 康源博创生物科技(北京)有限公司 Anticorps anti-gprc5d et son utilisation
WO2023143537A1 (fr) 2022-01-29 2023-08-03 恺兴生命科技(上海)有限公司 Anticorps gprc5d et son utilisation
US11723925B2 (en) 2017-07-05 2023-08-15 Ucl Business Ltd ROR1 CAR T-cells
US20230272089A1 (en) 2020-08-05 2023-08-31 Synthekine, Inc Il2rg binding molecules and methods of use
US20230272090A1 (en) 2020-08-05 2023-08-31 Sandro Vivona Il2rb binding molecules and methods of use
WO2023183927A2 (fr) 2022-03-24 2023-09-28 Actinium Pharmaceuticals, Inc. Anticorps anti-cd45 humanisés
WO2023196444A1 (fr) * 2022-04-05 2023-10-12 Capstan Therapeutics, Inc. Lipides cationiques ionisables et nanoparticules lipidiques
WO2023196445A1 (fr) 2022-04-05 2023-10-12 Capstan Therapeutics, Inc. Lipides peg et nanoparticules lipidiques
US20230331872A1 (en) 2020-08-25 2023-10-19 Cytoimmune Therapeutics, Inc. Bispecific antibody car cell immunotherapy
WO2023201316A2 (fr) 2022-04-13 2023-10-19 Board Of Regents, The University Of Texas System Thérapie par anticorps anti-récepteur de l'interleukine-7 soluble pour traiter des maladies auto-immunes
US11814435B2 (en) 2015-04-13 2023-11-14 Pfizer Inc. Therapeutic antibodies and their uses
WO2023235772A2 (fr) 2022-05-31 2023-12-07 Fred Hutchinson Cancer Center Anticorps anti-cd45 humanisés et leurs utilisations
WO2023236889A1 (fr) 2022-06-06 2023-12-14 山东先声生物制药有限公司 Anticorps multi-spécifique ciblant bcma, gprc5d et lymphocytes t et son application
US20240034816A1 (en) 2022-05-27 2024-02-01 Sanofi NATURAL KILLER (NK) CELL ENGAGERS BINDING TO NKp46 AND BCMA VARIANTS WITH FC-ENGINEERING
WO2024031091A2 (fr) 2022-08-05 2024-02-08 Juno Therapeutics, Inc. Récepteurs antigéniques chimériques spécifiques de gprc5d et bcma
WO2024040195A1 (fr) 2022-08-17 2024-02-22 Capstan Therapeutics, Inc. Conditionnement pour l'ingénierie de cellules immunitaires in vivo
US11919965B2 (en) 2019-12-06 2024-03-05 Regeneron Pharmaceuticals, Inc. Methods of treating multiple myeloma with bispecific anti-BCMA x anti-CD3 antibodies
WO2024047558A2 (fr) 2022-08-31 2024-03-07 Immuneel Therapeutics Private Limited Protéines de liaison à l'antigène et récepteurs antigéniques chimériques spécifiques pour le domaine 9 de cd307e humain
WO2024046239A1 (fr) 2022-08-30 2024-03-07 苏州缔码生物科技有限公司 Anticorps monoclonal humanisé recombinant ciblant gprc5d humain et son utilisation
WO2024064771A1 (fr) 2022-09-20 2024-03-28 Vor Biopharma Inc. Conjugués anticorps-médicament anti-cd45-ign et utilisations associées
WO2024073723A2 (fr) 2022-09-30 2024-04-04 Forte Subsidiary, Inc. Anticorps anti-cd122 et leurs utilisations
WO2024079015A1 (fr) 2022-10-10 2024-04-18 F. Hoffmann-La Roche Ag Polythérapie combinant un anticorps bispécifique (tcb) gprc5d et des imid
WO2024081729A2 (fr) 2022-10-12 2024-04-18 Mythic Therapeutics, Inc. Constructions de protéines de liaison lrrc-15 et leurs utilisations
WO2024086190A1 (fr) 2022-10-18 2024-04-25 Kite Pharma, Inc. Nouveaux liants cd19, constructions car-t les comprenant et leurs procédés d'utilisation
WO2024102770A1 (fr) 2022-11-07 2024-05-16 Tessera Therapeutics, Inc. Conjugués médicamenteux à nanoparticules lipidiques
WO2024131962A1 (fr) 2022-12-23 2024-06-27 成都恩沐生物科技有限公司 Nouvel anticorps anti-gprc5d
US20240228610A9 (en) 2022-10-10 2024-07-11 Medimmune, Llc Compositions and methods of treating cancer with chimeric antigen receptors targeting claudin 18.2
WO2024158047A1 (fr) 2023-01-27 2024-08-02 第一三共株式会社 Anticorps anti-lrrc15
WO2024249954A1 (fr) 2023-05-31 2024-12-05 Capstan Therapeutics, Inc. Formulations et compositions de nanoparticules lipidiques
WO2025076127A1 (fr) * 2023-10-05 2025-04-10 Capstan Therapeutics, Inc. Lipides cationiques ionisables contraints et nanoparticules lipidiques

Patent Citations (455)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989006968A1 (fr) 1988-02-03 1989-08-10 Xoma Corporation Utilisation therapeutique d'immunotoxiques anti-cellules t contre des maladies autoimmunes
US5283173A (en) 1990-01-24 1994-02-01 The Research Foundation Of State University Of New York System to detect protein-protein interactions
US5468614A (en) 1990-01-24 1995-11-21 The Research Foundation Of State University Of New York System to detect protein-protein interactions
WO2001023573A1 (fr) 1999-09-30 2001-04-05 Kyowa Hakko Kogyo Co., Ltd. Anticorps transplantes a domaine de determination de complementation de type humain, dresse contre le ganglioside gd2, et derive de cet anticorps
WO2002030459A1 (fr) 2000-10-11 2002-04-18 Tegenero Gmbh Utilisation d"anticorps monoclonaux specifiques a la molecule cd28 en vue de stimuler des cellules sanguines qui ne portent aucune molecule cd28
WO2002047721A1 (fr) 2000-12-14 2002-06-20 Fujisawa Pharmaceutical Co., Ltd. Anticorps anti-cd28 silencieux et leur utilisation
US7825222B2 (en) 2001-02-12 2010-11-02 Novartis Ag Therapeutic binding molecules
US6924360B2 (en) 2001-12-28 2005-08-02 Abgenix, Inc. Antibodies against the MUC18 antigen
US7446190B2 (en) 2002-05-28 2008-11-04 Sloan-Kettering Institute For Cancer Research Nucleic acids encoding chimeric T cell receptors
WO2004045512A2 (fr) 2002-11-15 2004-06-03 Genmab A/S Anticorps monoclonaux humains contre cd25
WO2004055056A1 (fr) 2002-12-17 2004-07-01 Merck Patent Gmbh Forme humanisee de l'anticorps de souris 14.18 (h14.18) se liant au gd2 et fusion de celle-ci avec il-2
WO2005035584A1 (fr) 2003-10-10 2005-04-21 Bristol-Myers Squibb Company Anticorps entierement humains agissant contre la 4-1bb humaine (cd137)
WO2005037999A2 (fr) 2003-10-14 2005-04-28 Biogen Idec Ma Inc. Traitement anticancereux a base d'anticorps diriges contre lrrc15
US20100040540A1 (en) 2003-11-19 2010-02-18 Institut National De La Sante Et De La Recherche Medicale (Inserm) Anti cd44 antibodies for eradicating leukaemic stem cells and breast cancer stem cells
US9617349B2 (en) 2004-01-22 2017-04-11 Merck Patent Gmbh Anti-cancer antibodies with reduced complement fixation
US7378504B2 (en) 2004-06-03 2008-05-27 Medarex, Inc. Human monoclonal antibodies to Fc gamma receptor I (CD64)
US8383117B2 (en) 2004-06-10 2013-02-26 Viventia Biotechnologies Inc. CD44E tumor specific antibody
US10385137B2 (en) 2004-12-16 2019-08-20 Inserm (Institut National De La Sante Et De La Recherche Medicale) Production of antibody formats and immunological applications of said formats
US9284375B2 (en) 2005-04-15 2016-03-15 Macrogenics, Inc. Covalent diabodies and uses thereof
WO2006108670A2 (fr) 2005-04-15 2006-10-19 Novartis Ag Utilisation d'anticorps cd25 en immunotherapie
US9701752B2 (en) 2005-04-19 2017-07-11 Seattle Genetics, Inc. Humanized anti-CD70 binding agents and uses thereof
WO2007009065A2 (fr) 2005-07-11 2007-01-18 Macrogenics, Inc. Methodes de traitement d'une maladie auto-immune au moyen d'anticorps anti-cd16a humanises
US8278036B2 (en) 2005-08-23 2012-10-02 The Trustees Of The University Of Pennsylvania RNA containing modified nucleosides and methods of use thereof
US8124738B2 (en) 2005-09-26 2012-02-28 Medarex, Inc. Human monoclonal antibodies to CD70
WO2007084321A2 (fr) 2006-01-12 2007-07-26 Alexion Pharmaceuticals, Inc. Anticorps dirigés contre ox-2/cd200 et utilisations correspondantes
US20130122022A1 (en) 2006-01-30 2013-05-16 Beverly Torok-Storb Sequence of stro-1 antibody variable region
US7915391B2 (en) 2006-04-24 2011-03-29 Amgen Inc. Humanized c-Kit antibody
US9388249B2 (en) 2006-07-10 2016-07-12 Amano Enzyme Inc. Method of classifying antibody, method of identifying antigen, method of obtaining antibody or antibody set, method of constructing antibody panel and antibody or antibody set and use of the same
US8951524B2 (en) 2006-10-10 2015-02-10 Universite De Nantes Use of monoclonal antibodies specific to the O-acetylated form of GD2 ganglioside for treatment of certain cancers
WO2008121160A2 (fr) 2006-11-21 2008-10-09 Xencor, Inc. Anticorps optimisés qui ciblent cd5
WO2008079246A2 (fr) 2006-12-21 2008-07-03 Medarex, Inc. Anticorps anti-cd44
WO2008117049A1 (fr) 2007-03-26 2008-10-02 Affitech As Anticorps anti cd166 humain se liant à des cellules tumorales humaines
US7722869B2 (en) 2007-04-27 2010-05-25 Novartis Ag Antibody molecules and nucleic acids
US9688755B2 (en) 2007-05-14 2017-06-27 Novimmune S.A. Fc receptor-binding polypeptides with modified effector functions
WO2008144890A1 (fr) 2007-05-30 2008-12-04 F. Hoffmann-La Roche Ag Anticorps chimères et humanisés anti-cd44 influençant la cytotoxicité des cellules cancéreuses
US8722858B2 (en) 2007-06-25 2014-05-13 Chugai Seiyaku Kabushiki Kaisha Anti-Prominin-1 antibody having ADCC activity or CDC activity
US8236318B2 (en) 2007-11-07 2012-08-07 Celldex Therapeutics Inc. Antibodies that bind human dendritic and epithelial cell 205 (DEC-205)
US20170335016A1 (en) 2008-04-25 2017-11-23 Kyowa Hakko Kirin Co., Ltd Stable multivalent antibody
US8507657B2 (en) 2008-06-30 2013-08-13 Morphotek, Inc. Anti-GD2 antibodies
US8454959B2 (en) 2008-07-18 2013-06-04 Bristol-Meyers Squibb Company Compositions monovalent for CD28 binding and methods of use
WO2010022737A1 (fr) 2008-08-29 2010-03-04 Symphogen A/S Anticorps anti-cd5
WO2010032059A2 (fr) 2008-09-19 2010-03-25 Medimmune Llc Agents de liaison ciblés dirigés sur cd105 et leurs utilisations
WO2010039873A2 (fr) 2008-10-01 2010-04-08 Tracon Pharmaceuticals, Inc. Anticorps humanisés anti-endogline
WO2010104949A2 (fr) 2009-03-10 2010-09-16 Biogen Idec Ma Inc. Anticorps anti-bcma
US8679500B2 (en) 2009-05-14 2014-03-25 Institute National De La Sante Et De La Recherche Medicale (Inserm) Compositions containing antibodies for treating CD5+ HLA-DR+ B or T cell related diseases
US8221753B2 (en) 2009-09-30 2012-07-17 Tracon Pharmaceuticals, Inc. Endoglin antibodies
WO2011094259A2 (fr) 2010-01-28 2011-08-04 Glaxo Group Limited Protéines de liaison à cd127
US8785604B2 (en) 2010-02-18 2014-07-22 Effimune Anti-CD28 humanized antibodies
WO2011104687A1 (fr) 2010-02-24 2011-09-01 Rinat Neuroscience Corporation Anticorps récepteurs anti-il-7 antagonistes et procédés
WO2011127324A2 (fr) 2010-04-08 2011-10-13 JN Biosciences, LLC Anticorps anti-cd122
US20110280881A1 (en) 2010-04-13 2011-11-17 Riken Novel anti-hsp90 monoclonal antibody
US9249225B2 (en) 2010-05-26 2016-02-02 Regents Of The University Of Minnesota Single chain variable fragment anti-CD133 antibodies and uses thereof
US9315585B2 (en) 2010-06-19 2016-04-19 Memorial Sloan Kettering Cancer Center Anti-GD2 antibodies
US9220772B2 (en) 2010-07-22 2015-12-29 The Regents Of The University Of California Anti-tumor antigen antibodies and methods of use
US9493740B2 (en) 2010-09-08 2016-11-15 Baylor College Of Medicine Immunotherapy of cancer using genetically engineered GD2-specific T cells
WO2012032433A1 (fr) 2010-09-09 2012-03-15 Pfizer Inc. Molécules de liaison 4-1bb
US9115192B2 (en) 2010-09-27 2015-08-25 Zestagen S.A. Compositions and methods for treating neoplasia
US10273294B2 (en) 2010-10-11 2019-04-30 University Of Southern California Compositions and methods for treating HIF-1α over-expressing cancers
WO2012071216A2 (fr) 2010-11-22 2012-05-31 Duke University Anticorps dirigés contre des gangliosides tumoraux
US9328156B2 (en) 2010-12-09 2016-05-03 The Trustees Of The University Of Pennsylvania Use of chimeric antigen receptor-modified T cells to treat cancer
US9540443B2 (en) 2011-01-26 2017-01-10 Kolltan Pharmaceuticals, Inc. Anti-kit antibodies
US9765148B2 (en) 2011-03-16 2017-09-19 Argen-X N.V. Antibodies to CD70
WO2012138537A1 (fr) 2011-04-01 2012-10-11 Immunogen, Inc. Compositions et méthodes de traitement du cancer de l'ovaire, du péritoine et de la trompe de fallope
WO2012149412A2 (fr) 2011-04-29 2012-11-01 Immunogen Inc. Anticorps anti-endogline (cd105), immunoconjugués et leurs utilisations
US8552157B2 (en) 2011-05-12 2013-10-08 Imclone Llc c-Kit antibodies and uses thereof
US9273141B2 (en) 2011-05-27 2016-03-01 Glaxo Group Limited B cell maturation antigen (BCMA) binding proteins
WO2012163805A1 (fr) 2011-05-27 2012-12-06 Glaxo Group Limited Protéines de liaison à bcma (cd269/tnfrsf17)
US10266604B2 (en) 2011-09-22 2019-04-23 Amgen Inc. CD27L antigen binding proteins
WO2013056984A1 (fr) 2011-10-19 2013-04-25 Effimune Anticorps dirigés contre la chaîne alpha du récepteur d'il7 et leur utilisation pour préparer des candidats de médicament
US20140308301A1 (en) 2011-10-26 2014-10-16 The Regents Of The University Of California Cd44 monoclonal antibody for the treatment of b-cell chronic lymphocytic leukemia and other hematological malignancies
US20130115274A1 (en) 2011-11-04 2013-05-09 Nitto Denko Corporation Method of producing lipid nanoparticles for drug delivery
WO2013167259A1 (fr) 2012-05-09 2013-11-14 Ganymed Pharmaceuticals Ag Anticorps anti-claudin 18.2 utiles dans le diagnostic du cancer
US9777068B2 (en) 2012-06-18 2017-10-03 Apeiron Biologics Ag Method for treating a GD2 positive cancer
WO2014000338A1 (fr) 2012-06-28 2014-01-03 中国科学院生物物理研究所 Application d'un composite d'anticorps anti-cd146 et d'anticorps anti-vegf dans la préparation d'un médicament destiné à supprimer les tumeurs
US9447190B2 (en) 2012-09-10 2016-09-20 Prothena Biosciences Limited Anti-MCAM antibodies and associated methods of use
US10414825B2 (en) 2012-09-10 2019-09-17 Prothena Biosciences Limited Anti-MCAM antibodies and associated methods of use
WO2014083379A1 (fr) 2012-11-30 2014-06-05 Institut Pasteur Utilisation d'anticorps anti-fcyri et/ou anti-fcyriia pour traiter une arthrite, une inflammation, une thrombopénie et un choc anaphylactique
US9243058B2 (en) 2012-12-07 2016-01-26 Amgen, Inc. BCMA antigen binding proteins
WO2014128185A1 (fr) 2013-02-21 2014-08-28 Universitätsklinikum Freiburg Anticorps bispécifique de recombinaison se liant à l'antigène cd133 sur des cellules tumorales et au récepteur des lymphocytes t cd3
WO2014158821A1 (fr) 2013-03-12 2014-10-02 Imaginab, Inc. Constructions de liaison d'antigène à cd70
US10414820B2 (en) 2013-03-13 2019-09-17 Imaginab, Inc. Antigen binding constructs to CD8
US9789203B2 (en) 2013-03-15 2017-10-17 Novartis Ag cKIT antibody drug conjugates
US9782500B2 (en) 2013-09-24 2017-10-10 Oncoinvent As Monoclonal antibody and derivatives
WO2015050959A1 (fr) 2013-10-01 2015-04-09 Yale University Anticorps anti-kits et leurs méthodes d'utilisation
WO2015052538A1 (fr) 2013-10-10 2015-04-16 Ucl Business Plc Récepteur d'antigène chimérique
US10081682B2 (en) 2013-10-11 2018-09-25 Oxford Bio Therapeutics Ltd. Conjugated antibodies against LY75 for the treatment of cancer
US9932410B2 (en) 2013-11-05 2018-04-03 Inserm (Institut National De La Sante Et De La Recherche Medicale Human neutralizing anti-kit antibodies and uses thereof
WO2015076425A1 (fr) 2013-11-25 2015-05-28 リンク・ジェノミクス株式会社 Nouvel anticorps monoclonal
WO2015118031A2 (fr) 2014-02-06 2015-08-13 Oncomatryx Biopharma, S.L. Conjugués anticorps-médicament et immunotoxines
US10106623B2 (en) 2014-02-12 2018-10-23 Michael Uhlin Bispecific antibodies for use in stem cell transplantation
WO2015132604A1 (fr) 2014-03-06 2015-09-11 Ucl Business Plc Récepteur antigénique chimérique
US10407506B2 (en) 2014-03-12 2019-09-10 Prothena Biosciences Limited Anti-MCAM antibodies and associated methods of use
WO2015140591A1 (fr) 2014-03-21 2015-09-24 Nordlandssykehuset Hf Anticorps anti-cd14 et leurs utilisations
US20170166638A1 (en) 2014-03-26 2017-06-15 Fraunhofer-Gesellschaft Zur Foerderung Der Angewandten Forschung E.V. USE OF CD-64-BLOCKING AGENTS AS ENHANCER OF AN ANTI-TNF-a ANTIBODY THERAPY
US10316101B2 (en) 2014-04-14 2019-06-11 Cellectis BCMA (CD269) specific chimeric antigen receptors for cancer immunotherapy
US20150337039A1 (en) 2014-05-22 2015-11-26 Case Western Reserve University Mac-1 antibodies and uses thereof
WO2015184203A1 (fr) 2014-05-29 2015-12-03 Macrogenics, Inc. Molécules de liaison trispécifiques et leurs procédés d'utilisation
WO2015187528A1 (fr) 2014-06-02 2015-12-10 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Récepteurs d'antigènes chimériques ciblant cd-19
US10287350B2 (en) 2014-06-02 2019-05-14 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Chimeric antigen receptors targeting CD-19
US9856324B2 (en) 2014-06-04 2018-01-02 MabVax Therapeutics, Inc. Human monoclonal antibodies to ganglioside GD2
US10106609B2 (en) 2014-06-04 2018-10-23 PeronGen BioTherapeutics (Suzhou) Co., Ltd. CD7 nanobodies, encoding sequence and use thereof
WO2015189302A1 (fr) 2014-06-10 2015-12-17 Effimune Anticorps anti-cd127
US10752684B2 (en) 2014-07-29 2020-08-25 Cellectis ROR1 (NTRKR1) specific chimeric antigen receptors for cancer immunotherapy
US10273295B2 (en) 2014-08-19 2019-04-30 Miltenyi Biotec Gmbh Chimeric antigen receptor specific for SSEA4 antigen
US10406179B2 (en) 2014-08-26 2019-09-10 The Board Of Trustees Of The Leland Stanford Junior University Engraftment of stem cells with a combination of an agent that targets stem cells and modulation of immunoregulatory signaling
US9938356B2 (en) 2014-11-10 2018-04-10 Medimmune Limited Binding molecules specific for CD73 and uses thereof
US9926375B2 (en) 2014-11-12 2018-03-27 Tracon Pharmaceuticals, Inc. Anti-endoglin antibodies and uses thereof
US10100129B2 (en) 2014-11-21 2018-10-16 Bristol-Myers Squibb Company Antibodies against CD73 and uses thereof
US9701756B2 (en) 2014-11-26 2017-07-11 Miltenyi Biotec Gmbh Humanized antibody or fragment thereof specific for CD45R0
US9382321B2 (en) 2014-11-26 2016-07-05 Adventis Health System/Sunbelt, Inc. Effector-deficient anti-CD32A antibodies
WO2016090329A2 (fr) 2014-12-05 2016-06-09 Memorial Sloan-Kettering Cancer Center Anticorps ciblant le récepteur couplé aux protéines g et procédés d'utilisation
WO2016090337A1 (fr) 2014-12-05 2016-06-09 Memorial Sloan-Kettering Cancer Center Récepteurs antigéniques chimériques ciblant le récepteur fc-like 5 et leurs utilisations
US10689456B2 (en) 2014-12-08 2020-06-23 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-CD70 chimeric antigen receptors
US10383929B2 (en) 2014-12-12 2019-08-20 Bluebird Bio, Inc. BCMA chimeric antigen receptors
WO2016130598A1 (fr) 2015-02-09 2016-08-18 University Of Florida Research Foundation, Inc. Récepteur antigénique chimérique bispécifique et ses utilisations
US11248058B2 (en) 2015-02-19 2022-02-15 University Of Florida Research Foundation, Inc. Chimeric antigen receptors and uses thereof
US10738121B2 (en) 2015-02-27 2020-08-11 The General Hospital Corporation Therapeutic use of integrin-binding antibodies
WO2016149578A1 (fr) 2015-03-19 2016-09-22 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Récepteurs doubles spécifiques de l'antigène chimère anti-cd22-anti-cd19
US10711068B2 (en) 2015-03-26 2020-07-14 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-CD133 monoclonal antibodies and related compositions and methods
WO2016166630A1 (fr) 2015-04-13 2016-10-20 Pfizer Inc. Récepteurs antigéniques chimériques ciblant l'antigène de maturation des cellules b
US11814435B2 (en) 2015-04-13 2023-11-14 Pfizer Inc. Therapeutic antibodies and their uses
US10758625B2 (en) 2015-04-14 2020-09-01 Benhealth Biopharmaceutic (Shenzhen) Co., Ltd. Bispecific antibody capable of being combined with immune cells to enhance tumor killing capability, and preparation method therefor and application thereof
US10745481B2 (en) 2015-05-04 2020-08-18 Cytomx Therapeutics, Inc. Anti-CD166 antibodies, activatable anti-CD166 antibodies, and methods of use thereof
WO2016187216A1 (fr) 2015-05-18 2016-11-24 Bluebird Bio, Inc. Récepteurs antigéniques chimériques anti-ror1
US10920246B2 (en) 2015-05-26 2021-02-16 Ramot At Tel-Aviv University Ltd. Targeted lipid particles for systemic delivery of nucleic acid molecules to leukocytes
WO2016197974A1 (fr) 2015-06-12 2016-12-15 Yen-Ta Lu Méthodes et anticorps pour moduler une réponse immunitaire
WO2017009473A1 (fr) 2015-07-16 2017-01-19 Ucb Biopharma Sprl Molécules d'anticorps qui se lient à cd45
US10548987B2 (en) 2015-07-31 2020-02-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Antibody-drug conjugates for targeting CD56-positive tumors
US10730941B2 (en) 2015-07-31 2020-08-04 Memorial Sloan-Kettering Cancer Center Antigen-binding proteins targeting CD56 and uses thereof
US10683369B2 (en) 2015-08-03 2020-06-16 Engmab Sàrl Monoclonal antibodies against BCMA
WO2017021540A1 (fr) 2015-08-06 2017-02-09 Agency For Science, Technology And Research Anticorps anti-il-2-r beta/chaîne gamma commune
WO2018028647A1 (fr) 2015-08-11 2018-02-15 Legend Biotech Usa Inc. Récepteurs d'antigène chimériques ciblant bcma et leurs procédés d'utilisation
US10934363B2 (en) 2015-08-11 2021-03-02 Legend Biotech Usa Inc. Chimeric antigen receptors based on single domain antibodies and methods of use thereof
US10072088B2 (en) 2015-08-17 2018-09-11 Janssen Pharmaceutica, Nv Anti-BCMA antibodies and uses thereof
US20170051068A1 (en) 2015-08-17 2017-02-23 Janssen Pharmaceutica Nv Anti-BCMA Antibodies, Bispecific Antigen Binding Molecules that Bind BCMA and CD3, and Uses Thereof
WO2017048770A1 (fr) 2015-09-15 2017-03-23 Regulus Therapeutics, Inc. Systèmes, compositions et procédés de formulation de compositions d'acides nucléiques
WO2017058866A1 (fr) 2015-09-28 2017-04-06 Precision Immune, Inc. Anticorps anti-trem2 et leurs utilisations
WO2017055385A1 (fr) 2015-10-02 2017-04-06 F. Hoffmann-La Roche Ag Molécules bispécifiques de liaison à l'antigène activant les lymphocytes t anti-cd3xgd2
WO2017062271A2 (fr) 2015-10-06 2017-04-13 Merck Sharp & Dohme Corp. Conjugué anticorps-médicament pour applications anti-inflammatoires
WO2017062748A1 (fr) 2015-10-07 2017-04-13 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anticorps spécifiques d'il-7r-alpha pour le traitement la leucémie lymphoblastique aiguë
WO2017064221A1 (fr) 2015-10-13 2017-04-20 Affimed Gmbh Anticorps fv polyvalents
WO2017096120A1 (fr) 2015-12-04 2017-06-08 Memorial Sloan-Kettering Cancer Center Anticorps ciblant la protéine de type récepteur fc 5 et procédés d'utilisation
US10822426B2 (en) 2015-12-09 2020-11-03 Corvus Pharmaceuticals, Inc. Humanized anti-CD73 antibodies
WO2017118613A1 (fr) 2016-01-08 2017-07-13 Syddansk Universitet Anticorps bispécifiques ciblant cd73 humain
WO2017123650A2 (fr) 2016-01-11 2017-07-20 Inhibrx Lp Protéines de fusion se liant à gitr multivalentes et multispécifiques
US11419933B2 (en) 2016-01-25 2022-08-23 Amgen Inc. Pharmaceutical composition comprising bispecific antibody constructs
WO2017130223A2 (fr) 2016-01-29 2017-08-03 Virocan Therapeutics Pvt. Ltd. Récepteur antigénique chimérique spécifique d'un antigène de maturation des lymphocytes b, vecteur d'expression recombinant et procédé associé
WO2017134306A1 (fr) 2016-02-05 2017-08-10 Orionis Biosciences Nv Agents de liaison au cd8
US11078291B2 (en) 2016-02-17 2021-08-03 Seagen Inc. BCMA antibodies and use of same to treat cancer and immunological disorders
WO2017156479A1 (fr) 2016-03-11 2017-09-14 Bluebird Bio, Inc. Récepteurs antigéniques chimériques anti-ror1
WO2017173256A1 (fr) 2016-04-01 2017-10-05 Kite Pharma, Inc. Récepteurs antigéniques chimériques et récepteurs de lymphocytes t et leurs procédés d'utilisation
US10633444B2 (en) 2016-04-18 2020-04-28 Celldex Therapeutics, Inc. Agonistic antibodies that bind CD40
US11326182B2 (en) 2016-04-29 2022-05-10 Voyager Therapeutics, Inc. Compositions for the treatment of disease
US11306145B2 (en) 2016-04-29 2022-04-19 Viela Bio, Inc. Binding molecules specific for FcγRIIA and uses thereof
WO2017213979A1 (fr) 2016-06-06 2017-12-14 St. Jude Children's Research Hospital Récepteur d'antigène chimérique anti-cd7 et son procédé d'utilisation
US10919967B2 (en) 2016-06-21 2021-02-16 Albert-Ludwigs-Universitätfreiburg Antibodies against Mac-1
US10457726B2 (en) 2016-06-30 2019-10-29 University Of Connecticut Antibody and antigen-binding fragment compositions targeting cell surface antigens in tumors and methods of use thereof
WO2018006882A1 (fr) 2016-07-08 2018-01-11 科济生物医药（上海）有限公司 Anticorps dirigé contre la claudine 18a2 et son utilisation
US11440966B2 (en) 2016-07-14 2022-09-13 Genmab A/S Multispecific antibodies against CD40 and CD137
WO2018010846A1 (fr) 2016-07-15 2018-01-18 Ogd2 Pharma Anticorps humanisé contre le ganglioside gd2 o-acétylé (oacgd2)
WO2018017786A2 (fr) 2016-07-20 2018-01-25 Janssen Pharmaceutica Nv Anticorps anti-gprc5d, molécules bispécifiques de liaison à l'antigène qui se lient à gprc5d et cd3 et leurs utilisations
US11643456B2 (en) 2016-07-29 2023-05-09 Obi Pharma, Inc. Human antibodies, pharmaceutical compositions and methods
WO2018039626A1 (fr) 2016-08-25 2018-03-01 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anticorps humains à domaine unique ciblant cd16a pour la médiation de l'adcc
WO2018045880A1 (fr) 2016-09-06 2018-03-15 Guangzhou Bainifu Biotech Co., Ltd Récepteur d'antigène chimère, cellules car133-nkt et leur utilisation
US11505606B2 (en) 2016-09-14 2022-11-22 Teneobio, Inc. CD3 binding antibodies
US10108123B2 (en) 2016-09-29 2018-10-23 Canon Kabushiki Kaisha Image forming apparatus
WO2018072025A1 (fr) 2016-10-19 2018-04-26 The Governing Council Of The University Of Toronto Agents de liaison à cd133 et leurs utilisations
US11535678B2 (en) 2016-11-21 2022-12-27 Alligator Bioscience Ab Anti-CD137 antibodies and uses thereof
WO2018098306A1 (fr) 2016-11-22 2018-05-31 National University Of Singapore Blocage de l'expression de cd7 et récepteurs d'antigènes chimériques pour l'immunothérapie de malignités de lymphocytes t
US11180554B2 (en) 2016-12-13 2021-11-23 Astellas Pharma Inc. Anti-human CD73 antibody
US20190321404A1 (en) 2016-12-30 2019-10-24 Nanjing Legend Biotech Co., Ltd. Novel chimeric antigen receptor and use thereof
US11447558B2 (en) 2017-01-03 2022-09-20 Hoffmann-La Roche Inc. Bispecific antigen binding molecules comprising anti-4-1BB clone 20H4.9
US10174122B2 (en) 2017-01-06 2019-01-08 Eutilex Co., Ltd. Anti-human 4-1BB antibodies and uses thereof
US11525006B2 (en) 2017-01-23 2022-12-13 Crage Medical Co., Limited BCMA-targeting antibody and use thereof
US10584169B2 (en) 2017-01-24 2020-03-10 I-Mab Biopharma Us Limited Anti-CD73 antibodies and uses thereof
WO2018147245A1 (fr) 2017-02-07 2018-08-16 第一三共株式会社 Anticorps anti-gprc5d et molécule le contenant
US11046775B2 (en) 2017-02-14 2021-06-29 Kite Pharma, Inc. CD70 binding molecules and methods of use thereof
WO2018152516A1 (fr) 2017-02-20 2018-08-23 Adimab, Llc Protéines de liaison à cd33, nkg2d et cd16
US20200181260A1 (en) 2017-02-22 2020-06-11 H. Lee Moffitt Cancer Center And Research Institute, Inc. Bispecific antibody for cancer immunotherapy
WO2018158349A1 (fr) 2017-02-28 2018-09-07 Affimed Gmbh Di-anticorps en tandem pour la mise en contact de cellules nk dirigées par cd16a
US11535672B2 (en) 2017-02-28 2022-12-27 Affimed Gmbh Combination of an anti-CD16A antibody with a cytokine
US11365258B2 (en) 2017-03-10 2022-06-21 Berlin-Chemie Ag Pharmaceutical combinations comprising an anti-LY75 antibody
US10426797B2 (en) 2017-03-24 2019-10-01 Lentigen Technology, Inc. Compositions and methods for treating cancer with anti-CD33 immunotherapy
US11242385B2 (en) 2017-04-13 2022-02-08 Agenus Inc. Anti-CD137 antibodies and methods of use thereof
US11186636B2 (en) 2017-04-21 2021-11-30 Amgen Inc. Anti-human TREM2 antibodies and uses thereof
WO2018191786A1 (fr) 2017-04-21 2018-10-25 Implicit Bioscience Pty Ltd Anticorps antagonistes de cd 14 pour le traitement de maladies neurodégénératives
WO2018199337A1 (fr) 2017-04-28 2018-11-01 味の素株式会社 Composé renfermant une substance ayant une affinité pour une protéine soluble, fraction clivable, et groupe réactif, ou sel de celui-ci
WO2018197675A1 (fr) 2017-04-28 2018-11-01 Julius-Maximilians-Universität Würzburg Récepteurs antigéniques chimériques (car) spécifiques à ror1 ayant des domaines de ciblage humanisés
US20200190165A1 (en) 2017-04-28 2020-06-18 Ajinomoto Co., Inc. Compound having affinity substance to soluble protein, cleavable portion and reactive group, or salt thereof
WO2018213337A1 (fr) 2017-05-15 2018-11-22 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Récepteurs d'antigènes chimériques bicistroniques et leurs utilisations
US11530273B2 (en) 2017-05-23 2022-12-20 Helmholtz Zentrum München—Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Anti-CD73 monoclonal antibody, encoding nucleic acids and method for producing
WO2018220467A1 (fr) 2017-05-30 2018-12-06 Foroogh Nejatollahi Immunotoxine humaine anti-muc18 et ses applications
US11312783B2 (en) 2017-06-22 2022-04-26 Novartis Ag Antibody molecules to CD73 and uses thereof
WO2018235247A1 (fr) 2017-06-22 2018-12-27 学校法人順天堂 Anticorps anti-cd10
WO2019006072A1 (fr) 2017-06-30 2019-01-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Récepteurs antigéniques chimériques vers l'antigène de maturation des lymphocytes b présentant des domaines humains
US11723925B2 (en) 2017-07-05 2023-08-15 Ucl Business Ltd ROR1 CAR T-cells
US10716851B2 (en) 2017-07-11 2020-07-21 Compass Therapeutics Llc Agonist antibodies that bind human CD137 and uses thereof
US11220544B2 (en) 2017-07-14 2022-01-11 Cytomx Therapeutics, Inc. Anti-CD166 antibodies and uses thereof
US10730944B2 (en) 2017-07-24 2020-08-04 Regeneron Pharmaceuticals, Inc. Anti-CD8 antibodies and uses thereof
US10442867B2 (en) 2017-07-31 2019-10-15 Lentigen Technology, Inc. Compositions and methods for treating cancer with anti-CD19/CD20 immunotherapy
US10988546B2 (en) 2017-08-01 2021-04-27 Medimmune, Llc BCMA monoclonal antibody-drug conjugate
US10676525B2 (en) 2017-08-03 2020-06-09 Alector Llc Anti-TREM2 antibodies and methods of use thereof
WO2019032661A1 (fr) 2017-08-09 2019-02-14 Orionis Biosciences Inc. Agents de liaison au cd8
WO2019033043A2 (fr) 2017-08-11 2019-02-14 Genentech, Inc. Anticorps anti-cd8 et utilisations associées
US11242395B2 (en) 2017-08-21 2022-02-08 Adagene Inc. Anti-CD137 molecules and use thereof
WO2019059771A2 (fr) 2017-09-21 2019-03-28 Umc Utrecht Holding B.V. Anticorps anti-gd2 pour le traitement d'un neuroblastome
US11427648B2 (en) 2017-10-06 2022-08-30 Universite D'aix-Marseille Anti-CD146 antibodies and uses thereof
US11136403B2 (en) 2017-10-13 2021-10-05 Harpoon Therapeutics, Inc. Trispecific proteins and methods of use
US10543263B2 (en) 2017-10-16 2020-01-28 Lentigen Technology Inc. Compositions and methods for treating cancer with anti-CD22 immunotherapy
WO2019084067A1 (fr) 2017-10-24 2019-05-02 Magenta Therapeutics, Inc. Anticorps anti-cd117 et leurs méthodes d'utilisation
US11447548B2 (en) 2017-10-31 2022-09-20 Xenikos B.V. Immunotoxins, formulations thereof and their use in medicine
US11623961B2 (en) 2017-11-01 2023-04-11 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for B-cell maturation antigen
US11292846B2 (en) 2017-11-02 2022-04-05 Bayer Aktiengesellschaft Bispecific antibodies binding ALK-1 and BMPR-2
WO2019085102A1 (fr) 2017-11-03 2019-05-09 西安宇繁生物科技有限责任公司 Lymphocyte t à récepteur antigénique chimérique spécifique de bcma et utilisation associée
US10428141B2 (en) 2017-11-03 2019-10-01 Lentigen Technology, Inc. Compositions and methods for treating cancer with anti-ROR1 immunotherapy
US11555077B2 (en) 2017-11-09 2023-01-17 Shanghai Hyamab Biotech Co., Ltd. 4-1BB antibody and preparation method and use thereof
WO2019092451A1 (fr) 2017-11-13 2019-05-16 Crescendo Biologics Limited Anticorps à domaine unique qui se lient à cd137
WO2019108863A1 (fr) 2017-11-29 2019-06-06 Magenta Therapeutics, Inc. Compositions et procédés pour la déplétion des cellules cd5+
US10508148B2 (en) 2017-12-12 2019-12-17 Pionyr Immunotherapeutics, Inc. Anti-TREM2 antibodies and related methods
WO2019126536A1 (fr) 2017-12-20 2019-06-27 Alexion Pharmaceuticals Inc. Anticorps humanisés anti-cd200 et leurs utilisations
WO2019119822A1 (fr) 2017-12-23 2019-06-27 Uwell Biopharma Inc. Composition pharmaceutique de récepteur chimérique et procédé associé
WO2019133639A2 (fr) 2017-12-26 2019-07-04 The Regents Of The University Of California Anticorps humains qui se lient et sont assimilés par des cellules de mésothéliome et autres cellules cancéreuses
WO2019137309A1 (fr) 2018-01-09 2019-07-18 南京任诺药业有限公司 Anticorps monoclonal anti-cd146 humain humanisé ayant une activité de neutralisation élevée
US20200246381A1 (en) 2018-02-01 2020-08-06 Nanjing Iaso Biotherapeutics Co., Ltd. Chimeric antigen receptor (car) binding to bcma, and uses thereof
US11026975B2 (en) 2018-02-01 2021-06-08 Nanjing Iaso Biotherapeutics Co., Ltd. Chimeric antigen receptor (CAR) binding to BCMA, and uses thereof
US11377500B2 (en) 2018-02-01 2022-07-05 Pfizer Inc. Antibodies specific for CD70 and their uses
US20200339699A1 (en) 2018-02-01 2020-10-29 Innovent Biologics (Suzhou) Co., Ltd. Fully humanized anti-b cell maturation antigen (bcma) single-chain antibody and use thereof
WO2019154890A1 (fr) 2018-02-09 2019-08-15 F. Hoffmann-La Roche Ag Anticorps se liant à gprc5d
US10611838B2 (en) 2018-02-09 2020-04-07 Ultrahuman Five Limited C-KIT antibodies
WO2019159193A1 (fr) 2018-02-13 2019-08-22 Indian Institute Of Technology Bombay Nouveau récepteur antigénique chimérique anti-cd19 humanisé, séquence d'acide nucléique associée et préparation correspondante
US20210002384A1 (en) 2018-02-15 2021-01-07 St. Jude Children's Research Hospital Process for producing hu14.18k322a monoclonal antibody
WO2019170131A1 (fr) 2018-03-07 2019-09-12 复旦大学 Anticorps cd73 ciblé et conjugué anticorps-médicament, procédé de préparation associé et utilisations correspondantes
US11299550B2 (en) 2018-03-09 2022-04-12 Phanes Therapeutics, Inc. Anti-CD73 antibodies and uses thereof
WO2019173692A2 (fr) 2018-03-09 2019-09-12 Agenus Inc. Anticorps anti-cd73 et leurs procédés d'utilisation
WO2019175226A1 (fr) 2018-03-13 2019-09-19 Tusk Therapeutics Ltd Agents anticorps anti-cd25
WO2019175223A1 (fr) 2018-03-13 2019-09-19 Tusk Therapeutics Ltd Anticorps anti-cd25 pour la déplétion de cellules spécifiques d'une tumeur
WO2019175215A1 (fr) 2018-03-13 2019-09-19 Tusk Therapeutics Ltd Anticorps anti-cd25 pour la déplétion de cellules spécifiques d'une tumeur
US20210130483A1 (en) 2018-03-26 2021-05-06 Sutro Biopharma, Inc. Anti-bcma receptor antibodies, compositions comprising anti bcma receptor antibodies and methods of making and using anti-bcma antibodies
US11446379B2 (en) 2018-03-29 2022-09-20 Cho Pharma Usa, Inc. Monoclonal antibodies that bind to SSEA4 and uses thereof
WO2019190952A1 (fr) 2018-03-29 2019-10-03 Lan Bo Chen Anticorps monoclonaux qui se lient à ssea4 et leurs utilisations
WO2019219089A1 (fr) 2018-05-18 2019-11-21 Bridge Health Bio-Tech Co., Ltd Anticorps anti-claudine 18.2 et leurs utilisations
US11312785B2 (en) 2018-05-19 2022-04-26 Boehringer Ingelheim International Gmbh Antagonizing CD73 antibody
US11492409B2 (en) 2018-06-01 2022-11-08 Novartis Ag Binding molecules against BCMA and uses thereof
WO2019241426A1 (fr) 2018-06-13 2019-12-19 Novartis Ag Récepteurs d'antigènes chimériques bcma et leurs utilisations
US20210139549A1 (en) 2018-06-14 2021-05-13 Ajinomoto Co., Inc. Compound having affinity substance to antibody, cleavable portion, and reactive group, or salt thereof
WO2019240287A1 (fr) 2018-06-14 2019-12-19 味の素株式会社 Composé comprenant une substance ayant une affinité pour un anticorps, site de clivage et groupe réactif, ou sel correspondant
US11548947B2 (en) 2018-06-21 2023-01-10 Regeneron Pharmaceuticals, Inc. Bispecific anti-PSMA X anti-CD28 antibodies and uses thereof
WO2020011706A1 (fr) 2018-07-09 2020-01-16 Oslo Universitetssykehus Hf Deux récepteurs antigéniques chimériques se liant de manière spécifique à cd19 et igkappa
WO2020014366A1 (fr) 2018-07-10 2020-01-16 Intrexon Corporation Récepteurs antigéniques chimériques specifiques de ror-1 et utilisations associées
WO2020011964A1 (fr) 2018-07-12 2020-01-16 F-Star Beta Limited Molécules d'anticorps qui se lient à pd-l1 et cd137
WO2020011966A1 (fr) 2018-07-12 2020-01-16 F-Star Beta Limited Molécules d'anticorps se liant à cd137 et ox40
US20200040101A1 (en) 2018-07-18 2020-02-06 Askgene Pharma Inc. Novel antibodies and methods for making and using the same
US11384153B2 (en) 2018-07-19 2022-07-12 Regeneran Pharmaceuticals, Inc. Bispecific anti-BCMA x anti-CD3 antibodies and uses thereof
WO2020020194A1 (fr) 2018-07-24 2020-01-30 Beijing Meikang Geno-Immune Biotechnology Co., Ltd. Récepteur antigénique chimérique à base de gd2 et utilisation associée
US11034771B2 (en) 2018-07-25 2021-06-15 I-Mab Biopharma Us Limited Anti-CD73 anti-PD-L1 bispecific antibodies
WO2020025792A1 (fr) 2018-08-03 2020-02-06 Amgen Research (Munich) Gmbh Constructions d'anticorps pour cldn18.2 et cd3
WO2020038146A1 (fr) 2018-08-24 2020-02-27 深圳普瑞金生物药业有限公司 Récepteur antigénique chimérique bcma basé sur un anticorps à domaine unique et son utilisation
US20220218746A1 (en) 2018-08-24 2022-07-14 Shenzhen Pregene Biopharma Co. Ltd. Bcma chimeric antigen receptor based on single domain antibody and use thereof
WO2020055975A1 (fr) 2018-09-11 2020-03-19 Washington University Anticorps agonistes anti-trem-2
WO2020060924A1 (fr) 2018-09-17 2020-03-26 Dualogics, Llc Utilisation d'un anticorps bispécifique cd4/cd8 pour le traitement de troubles auto-immuns/inflammatoires
US20210363245A1 (en) 2018-09-17 2021-11-25 The United States Of America,As Represented By The Secretary,Department Of Health And Human Services Bicistronic chimeric antigen receptors targeting cd19 and cd20 and their uses
US10844128B2 (en) 2018-09-20 2020-11-24 Lentigen Technology, Inc. Compositions and methods for treating cancer with anti-CD123 immunotherapy
WO2020065330A2 (fr) 2018-09-27 2020-04-02 Autolus Limited Récepteur antigénique chimérique
US11530268B2 (en) 2018-10-09 2022-12-20 Sanofi Trispecific anti-CD38, anti-CD28, and anti-CD3 binding proteins and methods of use for treating viral infection
WO2020076105A1 (fr) 2018-10-10 2020-04-16 주식회사 노벨티노빌리티 Nouvel anticorps anti-c-kit
US11492402B2 (en) 2018-10-15 2022-11-08 Novartis Ag TREM2 stabilizing antibodies
WO2020092654A1 (fr) 2018-10-30 2020-05-07 Magenta Therapeutics, Inc. Anticorps anti-cd45 et leurs conjugués
WO2020092854A2 (fr) 2018-11-01 2020-05-07 Juno Therapeutics, Inc. Récepteurs antigéniques chimériques spécifiques du gprc5d (élément d du groupe 5 de classe c des récepteurs couplés à la protéine g)
WO2020098599A1 (fr) 2018-11-12 2020-05-22 江苏恒瑞医药股份有限公司 Anticorps anti-cd73, fragment de liaison à l'antigène de celui-ci et son utilisation
WO2020102591A1 (fr) 2018-11-14 2020-05-22 Rubryc Therapeutics, Inc. Anticorps anti-cd25
US11208482B2 (en) 2018-11-26 2021-12-28 Forty Seven, Inc. Humanized antibodies against c-Kit
US20200261503A1 (en) 2018-12-01 2020-08-20 Allogene Therapeutics, Inc. Chimeric antigen receptors targeting b-cell maturation antigen and methods of use thereof
WO2020121195A1 (fr) 2018-12-10 2020-06-18 Mor Research Applications Anticorps trem2 et leurs utilisations
US11453721B2 (en) 2018-12-19 2022-09-27 Regeneran Pharmaceuticals, Inc. Bispecific anti-MUC16 x anti-CD28 antibodies and uses thereof
WO2020127618A1 (fr) 2018-12-21 2020-06-25 F. Hoffmann-La Roche Ag Molécules de liaison à l'antigène cd28 agonistes de ciblage de tumeurs
US11608376B2 (en) 2018-12-21 2023-03-21 Hoffmann-La Roche Inc. Tumor-targeted agonistic CD28 antigen binding molecules
WO2020132190A1 (fr) 2018-12-21 2020-06-25 Multitude Inc. Anticorps spécifiques à muc18
WO2020135201A1 (fr) 2018-12-28 2020-07-02 四川科伦博泰生物医药股份有限公司 Anticorps et son utilisation
WO2020139956A1 (fr) 2018-12-28 2020-07-02 Sparx Therapeutics Inc. Molécules de liaison spécifiques de la claudine 18.2, compositions et procédés associés, pour le traitement du cancer et d'autres maladies
WO2020143836A1 (fr) 2019-01-11 2020-07-16 上海开拓者生物医药有限公司 Anticorps cd73, son procédé de préparation et son application
WO2020143710A1 (fr) 2019-01-11 2020-07-16 康诺亚生物医药科技（成都）有限公司 Anticorps monoclonal anti-cd73 et son utilisation
WO2020147321A1 (fr) 2019-01-17 2020-07-23 Beijing Mabworks Biotech Co. Ltd. Anticorps se liant à la claudine 18,2 humaine et leurs utilisations
WO2020148677A1 (fr) 2019-01-18 2020-07-23 Janssen Biotech, Inc. Récepteurs antigéniques chimériques gprc5d et cellules les exprimant
WO2020154293A1 (fr) 2019-01-22 2020-07-30 Bristol-Myers Squibb Company Anticorps contre la sous-unité alpha d'un l'il-7r et leurs utilisations
WO2020159754A2 (fr) 2019-01-28 2020-08-06 Multitude Inc. Anticorps spécifiques à cd44
WO2020160242A1 (fr) 2019-02-01 2020-08-06 Regeneron Pharmaceuticals, Inc. Protéines de liaison à l'antigène gamma du récepteur anti-il2
US20230248842A1 (en) 2019-03-08 2023-08-10 AbTis Co., Ltd. Site-specific antibody conjugation and antibody-drug conjugate as specific embodiment thereof
WO2020184944A1 (fr) 2019-03-08 2020-09-17 앱티스 주식회사 Conjugaison d'anticorps spécifique à un site et conjugué anticorps-médicament servant d'exemple spécifique de celui-ci
US10934337B2 (en) 2019-03-15 2021-03-02 Cartesian Therapeutics, Inc. Anti-BCMA chimeric antigen receptors
WO2020190737A1 (fr) 2019-03-15 2020-09-24 Cartesian Therapeutics, Inc. Récepteurs d'antigènes chimériques anti-bcma
US20200297634A1 (en) 2019-03-19 2020-09-24 Arcturus Therapeutics, Inc. Method of making lipid-encapsulated rna nanoparticles
WO2020198531A2 (fr) 2019-03-26 2020-10-01 The Regents Of The University Of California Lymphocytes t modifiés par un récepteur antigénique chimérique (car-t) pour le traitement de cancers hématologiques et tumoraux solides
WO2020212710A1 (fr) 2019-04-18 2020-10-22 Kymab Limited Anticorps anti-cd7 antagonistes
WO2020216697A1 (fr) 2019-04-23 2020-10-29 Innate Pharma Anticorps bloquant cd73
WO2020219770A1 (fr) 2019-04-24 2020-10-29 Magenta Therapeutics, Inc. Anticorps anti-cd117 et leurs utilisations
WO2020219876A1 (fr) * 2019-04-25 2020-10-29 Intellia Therapeutics, Inc. Lipides aminés ionisables et nanoparticules lipidiques
US11203643B2 (en) 2019-05-10 2021-12-21 Lyvgen Biopharma Holdings Limited Humanized anti-CD137 antibodies and uses thereof
US11174319B2 (en) 2019-06-06 2021-11-16 Jacobio Pharmaceuticals Co., Ltd. Binding molecule specific for CD73 and use of binding molecule
WO2020253568A1 (fr) 2019-06-19 2020-12-24 海正生物制药有限公司 Anticorps anti-cd73 et son utilisation
WO2020254827A1 (fr) 2019-06-21 2020-12-24 Vhsquared Limited Polypeptides
WO2021008463A1 (fr) 2019-07-12 2021-01-21 明济生物制药（北京）有限公司 Anticorps cldn18.2 et son utilisation
WO2021017892A1 (fr) 2019-07-26 2021-02-04 上海复宏汉霖生物技术股份有限公司 Procédé et composition pour anticorps anti-cd73 et variants
WO2021022304A2 (fr) 2019-07-30 2021-02-04 Qlsf Biotherapeutics, Inc. COMPOSÉS DE LIAISON MULTISPÉCIFIQUES QUI SE LIENT À LRRC15 ET CD3ε
WO2021018925A1 (fr) 2019-07-31 2021-02-04 F. Hoffmann-La Roche Ag Anticorps se liant à gprc5d
WO2021018859A2 (fr) 2019-07-31 2021-02-04 F. Hoffmann-La Roche Ag Anticorps se liant à gprc5d
WO2021027850A1 (fr) 2019-08-12 2021-02-18 I-Mab Biopharma Co., Ltd. Anticorps bispécifiques anti-claudine 18.2 et anti-4-1bb et leurs utilisations
WO2021032157A1 (fr) 2019-08-20 2021-02-25 Mabspace Biosciences (Suzhou) Co., Limited Nouveaux anticorps anti-cldn18.2
WO2021032173A1 (fr) 2019-08-21 2021-02-25 Harbour Biomed (Shanghai) Co., Ltd. Anticorps anti-cd73 et son application
WO2021046159A1 (fr) 2019-09-04 2021-03-11 Genentech, Inc. Agents de liaison à cd8 et leurs utilisations
WO2021044008A1 (fr) 2019-09-04 2021-03-11 Universität Zürich Agent de liaison bispécifique qui se lie à cd117/c-kit et cd3
US11634500B2 (en) 2019-09-06 2023-04-25 Les Laboratoires Servier Anti-CD73 antibodies and compositions
WO2021044039A1 (fr) 2019-09-06 2021-03-11 Scancell Limited Éléments de liaison à ssea-4
WO2021055437A1 (fr) 2019-09-16 2021-03-25 The General Hospital Corporation Cellules t de récepteurs antigéniques chimériques (car) ciblées cd70 et leurs utilisations
US20210087295A1 (en) 2019-09-23 2021-03-25 The Trustees Of The University Of Pennsylvania Disrupting tumor tissues by targeting fibroblast activation protein (fap)
WO2021072312A1 (fr) 2019-10-11 2021-04-15 The Trustees Of The University Of Pennsylvania Compositions et procédés de ciblage de cd13 et de tim-3 avec des cellules car-t dans le traitement de la leucémie myéloïde aiguë (lma)
WO2021076564A1 (fr) 2019-10-15 2021-04-22 Dragonfly Therapeutics, Inc. Protéines se liant à nkg2d, cd16 et flt3
WO2021091945A1 (fr) 2019-11-05 2021-05-14 Janssen Biotech, Inc. Thérapie du myélome multiple basée sur des cellules car-t ciblées par bcma
WO2021097223A2 (fr) 2019-11-15 2021-05-20 Genzyme Corporation Anticorps cd73 biparatopique
WO2021099418A1 (fr) 2019-11-19 2021-05-27 International - Drug - Development - Biotech Anticorps anti-cd117 et leurs procédés d'utilisation
WO2021102332A1 (fr) 2019-11-22 2021-05-27 Silverback Therapeutics, Inc. Conjugués inhibiteur de tgfbetar2-anticorps anti-lrrc15 et leurs utilisations
WO2021101823A1 (fr) 2019-11-22 2021-05-27 Eli Lilly And Company Anticorps trem2 et leurs utilisations
WO2021107566A1 (fr) 2019-11-25 2021-06-03 주식회사 노벨티노빌리티 Anticorps dirigé contre c-kit et utilisation correspondante
US20230002489A1 (en) 2019-11-26 2023-01-05 Shanghai Epimab Biotherapeutics Co., Ltd. Antibodies to cd3 and bcma, and bispecific binding proteins made therefrom
US11919965B2 (en) 2019-12-06 2024-03-05 Regeneron Pharmaceuticals, Inc. Methods of treating multiple myeloma with bispecific anti-BCMA x anti-CD3 antibodies
WO2021111003A1 (fr) 2019-12-06 2021-06-10 SOTIO a.s. Anticorps humanisés anti-cldn18.2
WO2021118955A1 (fr) 2019-12-13 2021-06-17 Aggamin Llc Méthodes et systèmes de traitement ou de prévention de troubles de l'hypertension liés à la grossesse
WO2021127088A1 (fr) 2019-12-18 2021-06-24 Janssen Biotech, Inc. Matériaux et méthodes de ciblage biologique in vivo
WO2021129765A1 (fr) 2019-12-27 2021-07-01 Nanjing Legend Biotech Co., Ltd. Fractions de liaison à claudin18.2 et leurs utilisations
WO2021138264A1 (fr) 2019-12-30 2021-07-08 Seagen Inc. Méthodes de traitement du cancer à l'aide d'anticorps anti-cd70 non fucosylés
WO2021138378A1 (fr) 2019-12-30 2021-07-08 Obi Pharma, Inc. Anticorps, compositions pharmaceutiques et leurs utilisations
WO2021138467A1 (fr) 2020-01-03 2021-07-08 Incyte Corporation Anticorps anti-cd73 et leurs utilisations
US11124567B2 (en) 2020-01-13 2021-09-21 Denali Therapeutics Inc. Anti-TREM2 antibodies and methods of use thereof
WO2021155071A1 (fr) 2020-01-29 2021-08-05 Inhibrx, Inc. Anticorps cd28 à domaine unique et constructions multivalentes et multispécifiques de ceux-ci
WO2021160267A1 (fr) 2020-02-13 2021-08-19 UCB Biopharma SRL Anticorps bispécifiques dirigés contre cd9 et cd7
WO2021160269A1 (fr) 2020-02-13 2021-08-19 UCB Biopharma SRL Anticorps bispécifiques anti-cd44-ctla4
US20230075244A1 (en) 2020-02-20 2023-03-09 The Feinstein Institutes For Medical Research Agonist antibodies against endoglin and uses thereof
US20230144142A1 (en) 2020-02-27 2023-05-11 McSAF Inside Oncology Anti-cd56 antibody-drug conjugates and their use in therapy
US20230067770A1 (en) 2020-02-28 2023-03-02 Shanghai Henlius Biotech, Inc. Anti-cd137 constructs, multispecific antibody and uses thereof
WO2021174198A1 (fr) 2020-02-28 2021-09-02 The Brigham And Women's Hospital, Inc. Modulation sélective de signalisation de la superfamille du facteur de croissance transformant bêta par le biais d'anticorps multi-spécifiques
WO2021178896A1 (fr) 2020-03-06 2021-09-10 Go Therapeutics, Inc. Anticorps anti-glyco-cd44 et leurs utilisations
WO2021188590A2 (fr) 2020-03-16 2021-09-23 Magenta Therapeutics, Inc. Protéines bispécifiques de liaison à des lymphocytes t
WO2021186056A1 (fr) 2020-03-20 2021-09-23 INSERM (Institut National de la Santé et de la Recherche Médicale) Récepteur antigénique chimérique spécifique de cd45rc humain et ses utilisations
WO2021202642A2 (fr) 2020-04-01 2021-10-07 The Regents Of The University Of California Agent immunothéranostique ciblant des cellules cancéreuses dérivées de cellules souches mésenchymateuses et une maladie associée à des cellules souches mésenchymateuses
WO2021205383A1 (fr) 2020-04-09 2021-10-14 Aprilbio Co., Ltd. Anticorps monoclonaux et leurs fragments de liaison à l'antigène pour supprimer le point de contrôle immunitaire cd73 et leurs utilisations
WO2021213466A1 (fr) 2020-04-22 2021-10-28 中山康方生物医药有限公司 Anticorps anti-cd73 et son utilisation
WO2021222227A1 (fr) 2020-04-27 2021-11-04 Memorial Sloan-Kettering Cancer Center Récepteur antigénique chimérique ciblant cd127 et utilisation associée
WO2021218874A1 (fr) 2020-04-27 2021-11-04 启愈生物技术(上海)有限公司 Anticorps bispécifique ciblant la claudine humaine et les protéines pdl1 humaines, et application de celui-ci
WO2021227307A1 (fr) 2020-05-12 2021-11-18 普米斯生物技术(珠海)有限公司 Anticorps anti-cd73 et son utilisation
WO2021241729A1 (fr) 2020-05-29 2021-12-02 ブライトパス・バイオ株式会社 Anticorps anti-cd73 et son utilisation
WO2021245603A1 (fr) 2020-06-04 2021-12-09 Crispr Therapeutics Ag Anticorps anti-cd70 et leurs utilisations
WO2021254481A1 (fr) 2020-06-19 2021-12-23 信达生物制药(苏州)有限公司 Anticorps anti-claudine 18.2 et son utilisation
WO2021259199A1 (fr) 2020-06-22 2021-12-30 信达生物制药(苏州)有限公司 Anticorps anti-cd73 et son utilisation
WO2022002019A1 (fr) 2020-06-30 2022-01-06 江苏恒瑞医药股份有限公司 Anticorps anti-cd70 et son application
WO2022007808A1 (fr) 2020-07-06 2022-01-13 康诺亚生物医药科技（成都）有限公司 Anticorps se liant à la claudine-18.2 et son utilisation
WO2022022718A1 (fr) 2020-07-31 2022-02-03 北京市神经外科研究所 Anticorps à chaîne unique anti-cd133 et son utilisation dans la préparation d'un médicament pour le traitement d'une tumeur
WO2022022720A1 (fr) 2020-07-31 2022-02-03 北京市神经外科研究所 Anticorps monocaténaire anti-cd44 et son utilisation dans la préparation d'un médicament pour le traitement d'une tumeur
US20230272089A1 (en) 2020-08-05 2023-08-31 Synthekine, Inc Il2rg binding molecules and methods of use
US20230272090A1 (en) 2020-08-05 2023-08-31 Sandro Vivona Il2rb binding molecules and methods of use
WO2022032293A2 (fr) 2020-08-05 2022-02-10 Vigil Neuroscience, Inc. Traitement de maladies associées au dysfonctionnement du récepteur de facteur 1 de stimulation des colonies au moyen d'agonistes de trem2
WO2022037531A1 (fr) 2020-08-17 2022-02-24 中山康方生物医药有限公司 Anticorps anti-cd73 et son utilisation
US11591401B2 (en) 2020-08-19 2023-02-28 Xencor, Inc. Anti-CD28 compositions
WO2022040577A1 (fr) 2020-08-20 2022-02-24 City Of Hope Compositions et utilisations de lymphocytes t modifiés par un récepteur d'antigène chimérique ciblant pour cd45
US20230193292A1 (en) 2020-08-20 2023-06-22 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Bcma-binding single variable structural domain and antigen-binding molecule
WO2022040608A1 (fr) 2020-08-21 2022-02-24 City Of Hope Compositions d'anticorps anti-cd5 et leurs utilisations
WO2022040088A2 (fr) 2020-08-21 2022-02-24 Synthekine, Inc. Molécules de liaison à cd45 et méthodes d'utilisation
US20230331872A1 (en) 2020-08-25 2023-10-19 Cytoimmune Therapeutics, Inc. Bispecific antibody car cell immunotherapy
WO2022056199A1 (fr) 2020-09-11 2022-03-17 Janssen Biotech, Inc. Molécules de ciblage immunitaires multispécifiques et leurs utilisations
WO2022064191A1 (fr) 2020-09-25 2022-03-31 Ucl Business Ltd Anticorps anti-cd45 et agents thérapeutiques associés
WO2022063853A1 (fr) 2020-09-25 2022-03-31 Adc Therapeutics Sa Conjugués pyrrolobenzodiazépine-anticorps et leurs utilisations
WO2022067394A1 (fr) 2020-09-30 2022-04-07 Newsouth Innovations Pty Limited Fragments de liaison à l'antigène et leurs utilisations
WO2022068854A1 (fr) 2020-09-30 2022-04-07 Nanjing GenScript Biotech Co., Ltd. Anticorps ciblant la claudine 18.2 humaine et leurs utilisations
WO2022078344A1 (fr) 2020-10-12 2022-04-21 南京驯鹿医疗技术有限公司 Anticorps et récepteur antigénique chimérique (car) se liant à cd70, et application associée
WO2022081516A1 (fr) 2020-10-13 2022-04-21 Janssen Biotech, Inc. Immunité à médiation par des lymphocytes t biologiquement modifiés, matériaux et autres procédés pour la modulation d'un ensemble de différenciation iv &/ou viii
WO2022082073A2 (fr) 2020-10-16 2022-04-21 Board Of Regents, The University Of Texas System Compositions et méthodes de ciblage de muc18
WO2022083049A1 (fr) 2020-10-19 2022-04-28 中山康方生物医药有限公司 Anticorps anti-cd73 et son utilisation
WO2022083723A1 (fr) 2020-10-23 2022-04-28 中山康方生物医药有限公司 Anticorps anti-cd73 et son utilisation
WO2022095802A1 (fr) 2020-11-03 2022-05-12 南京北恒生物科技有限公司 Récepteur antigénique chimérique ciblant cd7 et son utilisation
WO2022095803A1 (fr) 2020-11-03 2022-05-12 南京北恒生物科技有限公司 Anticorps humanisé ciblant cd7 et son utilisation
WO2022096020A1 (fr) 2020-11-09 2022-05-12 江苏中新医药有限公司 Séquence d'anticorps anti-ecto-5'-nucléotidase
WO2022104009A1 (fr) 2020-11-13 2022-05-19 Rubryc Therapeutics, Inc. Anticorps anti-cd25
WO2022105881A1 (fr) 2020-11-20 2022-05-27 Bliss Biopharmaceutical (Hangzhou) Co., Ltd. Anticorps anti-cd73, conjugué anticorps-médicament, et utilisation correspondante
WO2022105914A1 (fr) 2020-11-23 2022-05-27 江苏先声药业有限公司 Anticorps se liant à cd70 et son utilisation
WO2022111616A1 (fr) 2020-11-30 2022-06-02 石药集团巨石生物制药有限公司 Anticorps anti-cldn18.2, conjugué médicamenteux, procédé de préparation s'y rapportant et utilisation associée
WO2022125837A1 (fr) 2020-12-09 2022-06-16 City Of Hope Compositions et utilisations de cellules immunitaires modifiées par un récepteur antigénique chimérique ciblant cd19
WO2022022749A1 (fr) 2020-12-16 2022-02-03 南通大学 Utilisation d'anticorps cd44 dans la préparation de médicaments destinés à traiter la maladie de parkinson
WO2022127844A1 (fr) 2020-12-17 2022-06-23 江苏先声药业有限公司 Anticorps cd5 et son utilisation
WO2022136888A1 (fr) 2020-12-23 2022-06-30 Bivictrix Limited Anticorps bispécifiques se liant à cd7 et cd33
WO2022147338A1 (fr) 2020-12-30 2022-07-07 Ascendo Biotechnology, Inc. Anticorps monoclonal contre le mac-1 humain et ses utilisations
WO2022143951A1 (fr) 2020-12-31 2022-07-07 康诺亚生物医药科技（成都）有限公司 Développement et utilisation d'un agent de blocage d'anticorps à fonction améliorée
WO2022151851A1 (fr) 2021-01-12 2022-07-21 上海雅科生物科技有限公司 Cellule immunitaire génétiquement modifiée ciblant cd7, récepteur antigénique chimérique, molécule de blocage de cd7 et utilisation associée
CN114763383A (zh) 2021-01-13 2022-07-19 博生吉医药科技(苏州)有限公司 靶向人bcma的单克隆抗体及其应用
WO2022155608A2 (fr) 2021-01-15 2022-07-21 The General Hospital Corporation Récepteur chimérique de cd64 et ses utilisations
WO2022157094A2 (fr) 2021-01-22 2022-07-28 Bayer Aktiengesellschaft Anticorps lrrc15 et leurs conjugués
WO2022159737A1 (fr) 2021-01-22 2022-07-28 Celldex Therapeutics, Inc. Anticorps anti-kit et leurs utilisations
US20220233591A1 (en) 2021-01-25 2022-07-28 Beijing Daxi Biotechnology Co., Ltd Preparation method of nk cells and use thereof in the treatment of cancer
WO2022161314A1 (fr) 2021-01-27 2022-08-04 信达生物制药(苏州)有限公司 Anticorps à un seul domaine contre cd16a et son utilisation
WO2022166802A1 (fr) 2021-02-04 2022-08-11 上海交通大学 Anticorps monoclonal anti-cd271 humain
WO2022175255A2 (fr) 2021-02-16 2022-08-25 Janssen Pharmaceutica Nv Anticorps trispécifique ciblant bcma, gprc5d et cd3
WO2022174813A1 (fr) 2021-02-19 2022-08-25 信达生物制药(苏州)有限公司 Anticorps trispécifique anti-gprc5d × bcma × cd3 et son utilisation
WO2022179039A1 (fr) 2021-02-24 2022-09-01 苏州近岸蛋白质科技股份有限公司 Anticorps anti-cd73 humain et son utilisation
WO2022187050A1 (fr) 2021-03-01 2022-09-09 BioLegend, Inc. Agents anti-cd117 et compositions et procédés de fabrication et d'utilisation de ceux-ci
WO2022212848A1 (fr) 2021-04-02 2022-10-06 Teneobio, Inc. Anticorps agonistes anti-il-2r et procédés d'utilisation
US11535869B2 (en) 2021-04-08 2022-12-27 Sana Biotechnology, Inc. CD8-specific antibody constructs and compositions thereof
WO2022214677A1 (fr) 2021-04-09 2022-10-13 Cancer Research Technology Limited Anticorps anti-cd73
WO2022221409A1 (fr) 2021-04-14 2022-10-20 Villaris Therapeutics, Inc. Anticorps anti-cd122 et leurs utilisations
WO2022222910A1 (fr) 2021-04-22 2022-10-27 南京北恒生物科技有限公司 Anticorps ciblant gprc5d et son utilisation
WO2022226317A1 (fr) 2021-04-23 2022-10-27 Profoundbio Us Co. Anticorps anti-cd70, leurs conjugués et leurs procédés d'utilisation
WO2022241082A1 (fr) 2021-05-14 2022-11-17 Genentech, Inc. Agonistes de trem2
WO2022243838A1 (fr) 2021-05-18 2022-11-24 Janssen Biotech, Inc. Compositions comprenant un agent thérapeutique de redirection des lymphocytes t et un agent thérapeutique anti-cd44
WO2022242758A1 (fr) 2021-05-21 2022-11-24 百奥泰生物制药股份有限公司 Anticorps anti-cd73 et son utilisation
WO2022247756A1 (fr) 2021-05-23 2022-12-01 上海邦耀生物科技有限公司 Récepteur antigénique chimérique ciblant gprc5d et son utilisation
WO2022247804A1 (fr) 2021-05-23 2022-12-01 上海祥耀生物科技有限责任公司 Anticorps anti-gprc5d, son procédé de préparation et son utilisation
WO2022257835A1 (fr) 2021-06-08 2022-12-15 Beijing Meikang Geno-Immune Biotechnology Co., Ltd. Récepteur antigénique chimérique humanisé à base de cd7 et son utilisation
WO2022262101A1 (fr) 2021-06-17 2022-12-22 南京蓝盾生物科技有限公司 Anticorps anti-cd70 présentant un effet adcc amélioré et application associée
WO2022263855A1 (fr) 2021-06-18 2022-12-22 Autolus Limited Anticorps à domaine unique anti-cd307e, leurs utilisations dans une cellule car-t et pour le traitement de maladies
WO2023274183A1 (fr) 2021-06-29 2023-01-05 江苏先声药业有限公司 Anticorps anti-cd16 et son utilisation
WO2023278520A1 (fr) 2021-06-30 2023-01-05 Board Of Regents, The University Of Texas System Polypeptides ciblant des cancers positifs à cd70
WO2023280880A1 (fr) 2021-07-05 2023-01-12 Trion Research Gmbh Anticorps multispécifiques se liant à des antigènes associés à une tumeur provoquant une névralgie nulle ou réduite dans le traitement du cancer
WO2023004304A1 (fr) 2021-07-20 2023-01-26 Inhibrx, Inc. Polypeptides se liant à cd8 et leurs utilisations
WO2023012802A1 (fr) 2021-08-05 2023-02-09 Yeda Research And Development Co. Ltd. Anticorps pour le traitement du cancer
WO2023026791A1 (fr) 2021-08-27 2023-03-02 株式会社免疫生物研究所 Fragment d'anticorps spécifique aux tumeurs positives à c-kit
WO2023031403A1 (fr) 2021-09-02 2023-03-09 F. Hoffmann-La Roche Ag Anticorps pour traiter la lam
WO2023039450A2 (fr) 2021-09-07 2023-03-16 Duke University Compositions et procédés pour le traitement de la dégénérescence rétinienne
WO2023037015A1 (fr) 2021-09-13 2023-03-16 Universiteit Gent Anticorps monoclonaux spécifiques de l'aminopeptidase n et leurs utilisations
WO2023039612A1 (fr) 2021-09-13 2023-03-16 The Board Of Regents Of The University Of Texas System Protéines de liaison à l'antigène trem2 et leurs utilisations
WO2023047100A1 (fr) 2021-09-21 2023-03-30 Quell Therapeutics Ltd Récepteur antigénique chimérique anti-trem2
US11613584B1 (en) 2021-10-13 2023-03-28 Immuneonco Biopharmaceuticals (Shanghai) Inc. Antibodies binding CD70, preparation and use thereof
WO2023072307A1 (fr) 2021-10-25 2023-05-04 重庆精准生物技术有限公司 Fragment de liaison à l'antigène ciblant cd70, anticorps à chaîne unique, récepteur antigénique chimérique et utilisation associée
WO2023078113A1 (fr) 2021-11-02 2023-05-11 Epimab Biotherapeutics (Hk) Limited Anticorps anti-cd122, anticorps anti-cd132 et protéines de liaison bispécifiques associées
WO2023078382A1 (fr) 2021-11-05 2023-05-11 正大天晴药业集团股份有限公司 Anticorps se liant à gprc5d et son utilisation
WO2023091148A1 (fr) 2021-11-22 2023-05-25 National Health Research Institutes ANTICORPS ANTI-HSP90α ET SES UTILISATIONS
WO2023125728A1 (fr) 2021-12-31 2023-07-06 康源博创生物科技(北京)有限公司 Anticorps anti-gprc5d et son utilisation
WO2023143537A1 (fr) 2022-01-29 2023-08-03 恺兴生命科技(上海)有限公司 Anticorps gprc5d et son utilisation
WO2023183927A2 (fr) 2022-03-24 2023-09-28 Actinium Pharmaceuticals, Inc. Anticorps anti-cd45 humanisés
WO2023196445A1 (fr) 2022-04-05 2023-10-12 Capstan Therapeutics, Inc. Lipides peg et nanoparticules lipidiques
WO2023196444A1 (fr) * 2022-04-05 2023-10-12 Capstan Therapeutics, Inc. Lipides cationiques ionisables et nanoparticules lipidiques
WO2023201316A2 (fr) 2022-04-13 2023-10-19 Board Of Regents, The University Of Texas System Thérapie par anticorps anti-récepteur de l'interleukine-7 soluble pour traiter des maladies auto-immunes
US20240034816A1 (en) 2022-05-27 2024-02-01 Sanofi NATURAL KILLER (NK) CELL ENGAGERS BINDING TO NKp46 AND BCMA VARIANTS WITH FC-ENGINEERING
WO2023235772A2 (fr) 2022-05-31 2023-12-07 Fred Hutchinson Cancer Center Anticorps anti-cd45 humanisés et leurs utilisations
WO2023236889A1 (fr) 2022-06-06 2023-12-14 山东先声生物制药有限公司 Anticorps multi-spécifique ciblant bcma, gprc5d et lymphocytes t et son application
WO2024031091A2 (fr) 2022-08-05 2024-02-08 Juno Therapeutics, Inc. Récepteurs antigéniques chimériques spécifiques de gprc5d et bcma
WO2024040195A1 (fr) 2022-08-17 2024-02-22 Capstan Therapeutics, Inc. Conditionnement pour l'ingénierie de cellules immunitaires in vivo
WO2024046239A1 (fr) 2022-08-30 2024-03-07 苏州缔码生物科技有限公司 Anticorps monoclonal humanisé recombinant ciblant gprc5d humain et son utilisation
WO2024047558A2 (fr) 2022-08-31 2024-03-07 Immuneel Therapeutics Private Limited Protéines de liaison à l'antigène et récepteurs antigéniques chimériques spécifiques pour le domaine 9 de cd307e humain
WO2024064771A1 (fr) 2022-09-20 2024-03-28 Vor Biopharma Inc. Conjugués anticorps-médicament anti-cd45-ign et utilisations associées
WO2024073723A2 (fr) 2022-09-30 2024-04-04 Forte Subsidiary, Inc. Anticorps anti-cd122 et leurs utilisations
WO2024079015A1 (fr) 2022-10-10 2024-04-18 F. Hoffmann-La Roche Ag Polythérapie combinant un anticorps bispécifique (tcb) gprc5d et des imid
US20240228610A9 (en) 2022-10-10 2024-07-11 Medimmune, Llc Compositions and methods of treating cancer with chimeric antigen receptors targeting claudin 18.2
WO2024081729A2 (fr) 2022-10-12 2024-04-18 Mythic Therapeutics, Inc. Constructions de protéines de liaison lrrc-15 et leurs utilisations
WO2024086190A1 (fr) 2022-10-18 2024-04-25 Kite Pharma, Inc. Nouveaux liants cd19, constructions car-t les comprenant et leurs procédés d'utilisation
WO2024102770A1 (fr) 2022-11-07 2024-05-16 Tessera Therapeutics, Inc. Conjugués médicamenteux à nanoparticules lipidiques
WO2024131962A1 (fr) 2022-12-23 2024-06-27 成都恩沐生物科技有限公司 Nouvel anticorps anti-gprc5d
WO2024158047A1 (fr) 2023-01-27 2024-08-02 第一三共株式会社 Anticorps anti-lrrc15
WO2024249954A1 (fr) 2023-05-31 2024-12-05 Capstan Therapeutics, Inc. Formulations et compositions de nanoparticules lipidiques
WO2025076127A1 (fr) * 2023-10-05 2025-04-10 Capstan Therapeutics, Inc. Lipides cationiques ionisables contraints et nanoparticules lipidiques

Non-Patent Citations (45)

* Cited by examiner, † Cited by third party
Title
"Introduction to Modern Liquid Chromatography", 1979, JOHN WILEY AND SONS
"The Peptides", vol. 3, 1981, ACADEMIC PRESS
"Thin Layer Chromatography", 1969, SPRINGER-VERLAG
ANZALONE ET AL., NATURE BIOTECHNOLOGY, vol. 38, 2020, pages 824 - 844
BINDER ET AL., FRONT IMMUNOL., vol. 9, no. 11, 2020, pages 1090
CARPENTER ET AL., CLIN. CANCER RES., vol. 19, no. 8, 2013, pages 2048 - 2060
ELKINS, CANCER THER., vol. 11, no. 10, 2012, pages 2222 - 2232
ENDSLEYHO, J. ACQUIR. IMMUNE DEFIC. SYNDR., vol. 61, 2012, pages 417
EVANS, AUSTRALIAN J. CHEM., vol. 60, no. 6, 2007, pages 384
FRANCO ET AL., J. IMMUNOL., vol. 190, no. 11, 2013, pages 5739 - 5746
FRIEDMAN ET AL., HUM. GENE THER., vol. 29, no. 5, 2018, pages 585 - 601
FUJII ET AL., BIOCONJUGATE CHEM., vol. 34, 2023, pages 728
FURNISSHANNAFORDSMITHTATCHELLL: "Vogel's A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis", 1989, LONGMAN
GILLERON ET AL., NAT. BIOTECHNOL., vol. 31, 2013, pages 638 - 646
ISE ET AL., CLIN. CANCER RES., vol. 11, no. 1, 2005, pages 87 - 96
ISE ET AL., CLIN. CHEM. LAB. MED., vol. 44, no. 5, 2006, pages 594 - 602
J. F. W. MCOMIE: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
JOCHEN LEHMANN: "Chemie der Kohlenhydrate: Monosaccharide and Derivate", vol. 15, 1974, GEORG THIEME VERLAG
KOLB ET AL., ANGEWANDTE CHEMIE, vol. 40, no. 11, 2004
LAM ET AL., NAT. COMMUN., vol. 11, no. 1, 2020, pages 283
LI ET AL., J MOL BIOL., vol. 263, 1996, pages 209 - 26
LIANG ET AL., J. CLIN. ONCOL., vol. 39, no. 15, 2021
MAILANKODY ET AL., N ENGL J MED., vol. 387, no. 13, 2022, pages 1196 - 1206
MATSUDA ET AL., MOL. PHARMACEUTICS, vol. 18, 2021, pages 4058
MOLINER-MORRO ET AL., BIOMOLECULES, vol. 10, no. 12, 2020, pages 1661
MUNSON ET AL., COMMUN. BIOL., vol. 4, 2021, pages 211 - 224
NICHOLSON ET AL., MOL. IMMUN., vol. 34, no. 16-17, 1997, pages 1157 - 1165
PARHIZ ET AL., J. CONTROLLED RELEASE, vol. 291, 2018, pages 106 - 115
PILLARISETTI ET AL., BLOOD, vol. 135, 2020, pages 1232 - 43
POLSON ET AL., INT. IMMUNOL., vol. 18, no. 9, 2006, pages 1363 - 1373
RAMISHETTI ET AL., ACS NANO, vol. 9, 2015, pages 6706
RODRIGUEZ-OTERO ET AL., BLOOD CANCER J., vol. 14, no. 1, 2024, pages 24
SAKUMA, GENE AND GENOME EDITING, vol. 3-4, 2022, pages 100017
SCATCHARD ET AL., ANN. N.Y. ACAD. SCI., vol. 51, 1949, pages 660
SHADMAN ET AL., BLOOD, vol. 134, 2019, pages 3235
STILLKAHNMITRA, J. ORG. CHEM., vol. 43, 1978, pages 2923 - 292
T P. G. M. WUTS: "Greene's Protective Groups in Organic Synthesis", 2014, WILEY
TOMBACZ ET AL., MOLECULAR THERAPY, vol. 29, no. 11, 2021, pages 3293 - 3304
VEIGA ET AL., NAT. COMMS., vol. 9, 2018, pages 4493
WILKINSONHALE, MABS, vol. 14, no. 1, 2022, pages 2123299
WU ET AL., PROTEIN ENGINEERING, vol. 14, no. 12, 2001, pages 1025 - 1033
YUAN MUJIE ET AL: "mRNA nanodelivery systems: targeting strategies and administration routes", BIOMATERIALS RESEARCH, vol. 27, no. 1, 22 September 2023 (2023-09-22), London, UK, XP093119998, ISSN: 2055-7124, Retrieved from the Internet <URL:https://biomaterialsres.biomedcentral.com/counter/pdf/10.1186/s40824-023-00425-3.pdf> DOI: 10.1186/s40824-023-00425-3 *
ZHANG ET AL., ISCIENCE, vol. 27, 2024, pages 109804
ZHAO ET AL., J. HEMATOL. ONCOL., vol. 11, no. 1, 2018, pages 141
ZHOU ET AL., MEDCOMM, vol. 3, no. 3, 2022, pages e155

Similar Documents

Publication Publication Date Title
WO2024040194A1 (fr) Conditionnement pour l&#39;ingénierie de cellules immunitaires in vivo
US20220218614A1 (en) Ionizable cationic lipids and lipid nanoparticles, and methods of synthesis and use thereof
CN116034114A (zh) 环状rna组合物和方法
JP7458975B2 (ja) Ｃｄ５＋細胞の枯渇のための組成物および方法
Zheng et al. Optimization of CAR-T cell-based therapies using small-molecule-based safety switches
US12311033B2 (en) Lipid nanoparticle formulations and compositions
JP2025511899A (ja) イオン化可能なカチオン性脂質および脂質ナノ粒子
US20240002331A1 (en) Ionizable cationic lipids and lipid nanoparticles, and methods of synthesis and use thereof
WO2025076113A1 (fr) Lipides cationiques ionisables à espacement conservé et nanoparticules lipidiques
CN111479828B (zh) 抗糖-muc1抗体及其用途
JP2022528721A (ja) キラー細胞レクチン様受容体サブファミリーｇメンバー１（ｋｌｒｇ１）除去抗体
JP2023525778A (ja) 抗ｂｃｍａ抗体およびキメラ抗原受容体
US20250127728A1 (en) Constrained Ionizable Cationic Lipids and Lipid Nanoparticles
WO2022151960A1 (fr) Lymphocyte t modifié par un récepteur antigénique chimérique b7-h3 et son utilisation
US20250332281A2 (en) Humanized anti-cd8 antibodies and uses thereof
US20190016812A1 (en) Novel anti-tnfsf9 antibodies and methods of use
US20250161481A1 (en) Targeted lnp delivery
WO2025217452A1 (fr) Lipides cationiques ionisables contraints et nanoparticules lipidiques
WO2025217454A2 (fr) Lipides cationiques ionisables et nanoparticules lipidiques
US20250302763A1 (en) Immune engineering amplification
US20210101990A1 (en) Compositions and methods for the depletion of cd134+ cells
US20250144234A1 (en) RNA for In vivo Transfection with Increased Expression
AU2024279278A1 (en) Lipid nanoparticle formulations and compositions
CN119215188B (zh) 抗Trop2抗体和抗5T4抗体-自然杀伤细胞偶联物及其用途
WO2025027472A2 (fr) Conjugués anticorps anti-cd123-médicament et leurs méthodes d&#39;utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25723078

Country of ref document: EP

Kind code of ref document: A1