WO2024145622A1 - Recombinant retroviruses, compositions, and methods of use - Google Patents
Recombinant retroviruses, compositions, and methods of use Download PDFInfo
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- WO2024145622A1 WO2024145622A1 PCT/US2023/086505 US2023086505W WO2024145622A1 WO 2024145622 A1 WO2024145622 A1 WO 2024145622A1 US 2023086505 W US2023086505 W US 2023086505W WO 2024145622 A1 WO2024145622 A1 WO 2024145622A1
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- recombinant retrovirus
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Abstract
The present disclosure provides recombinant retroviruses, retroviral vectors, packaging cell lines, and in vivo methods of use for expansion of immune effector cell populations for treatment of a disease, disorder, or condition.
Description
RECOMBINANT RETROVIRUSES, COMPOSITIONS, AND METHODS OF USE
CROSS REFERENCE TO REEATED APPLICATIONS
This application claims the benefit under 35 U.S. C. § 119(e) of U.S. Provisional Application No. 63/477,821, filed December 29, 2022, and U.S. Provisional Application No. 63/453,037, filed March 17, 2023, each of which is incorporated by reference herein in its entirety.
STATEMENT REGARDING SEQUENCE LISTING
The Sequence Listing associated with this application is provided in text format in lieu of a paper copy and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is KELO-405-WOl_ST26.xml. The text file is 126 KB, was created on December 12, 2023, and is being submitted electronically via EFS-Web, concurrent with the filing of the specification.
BACKGROUND
Technical Field
The present disclosure relates to recombinant retroviruses, retroviral vectors, packaging cell lines, and in vivo methods of use for expansion of immune effector cell populations for treatment of a disease, disorder, or condition.
Description of the Related Art
Adoptive cellular immunotherapy, although promising, has yet to realize its potential. Expensive manufacturing strategies combined with a dearth of targets contribute to the obstacles preventing widespread adoption of this treatment modality. Adoptive cellular immunotherapies are primarily manufactured ex vivo from autologous sources, which contributes to the expensive price tags associated with such therapies. Allogenic
strategies would theoretically alleviate some of this burden but have failed to yield durable treatments in the clinic and are plagued by graft vs. host disease.
BRIEF SUMMARY
The present disclosure is based, in part, on recombinant retroviruses engineered for in vivo delivery of T cell/NK cell/NKT cell activation receptors. Administration of recombinant retroviruses contemplated herein to a subject and transduction of immune effector cells allows for in vivo expansion of the transduced cells in the presence of a small molecule.
In various embodiments, the disclosure contemplates a recombinant retrovirus comprising a viral envelope comprising (i) one or more mutated viral envelope glycoproteins modified to retain fusogenic activity and decrease, reduce, substantially ablate, ablate, abolish or eliminate cell binding or attachment activity, z.e., the ability to bind its cognate receptor expressed on a cell and (ii) a non-viral membrane-bound tropism polypeptide and a recombinant retroviral vector comprising a polynucleotide encoding a promoter operably linked to one or more polynucleotides encoding one or more components of an inducible T cell/NK cell/NKT cell activation receptor. Inducible T cell/NK cell/NKT cell activation receptors contemplated herein are capable of being activated by a small molecule.
In various embodiments, a recombinant retrovirus or retroviral particle for activating and efficiently transducing T cells, comprises (a) a viral envelope comprising (i) one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity and (ii) a non-viral membrane-bound tropism polypeptide, and (b) a recombinant retroviral vector comprising a polynucleotide encoding a promoter operably linked to one or more polynucleotides encoding one or more components of an inducible T cell/NK cell/NKT cell activation receptor.
In particular embodiments, the presence of a small molecule induces activation of the T cell/NK cell/NKT cell activation receptor.
In particular embodiments, the recombinant retrovirus is a recombinant lentivirus.
In certain embodiments, the recombinant retrovirus is a recombinant lentivirus selected from the group consisting of: human immunodeficiency vims 1 (HIV-1); human immunodeficiency vims 2 (HIV-2), visna-maedi vims (VMV); caprine arthritis-
encephalitis virus (CAEV); equine infectious anemia virus (EIAV); feline immunodeficiency virus (FIV); bovine immune deficiency virus (BIV); and simian immunodeficiency virus (SIV).
In additional embodiments, the one or more mutated viral envelope glycoproteins comprise a vesiculovirus envelope glycoprotein, one or more morbillivirus envelope glycoproteins or one or more henipavirus envelope glycoproteins.
In particular embodiments, the vesiculovirus is selected from the group consisting of: vesicular stomatitis Alagoas virus (VSAV; Alagoas vesiculovirus), Carajas vims (CJSV; Carajas vesiculovirus), Chandipura vims (CHPV; Chandipura vesiculovirus), Cocal vims (COCV; Cocal vesiculovims), vesicular stomatitis Indiana vims (VSIV; Indiana vesiculovims), Isfahan vims (ISFV; Isfahan vesiculovims), Maraba vims (MARAV; Maraba vesiculovims), Morreton vims (MORV; Morreton vesiculovims), vesicular stomatitis New Jersey vims (VSNJV; New Jersey vesiculovims), and Piry vims (PIRYV; Piry vesiculovims).
In further embodiments, the vesiculovims envelope glycoprotein is a vesiculovims G protein.
In particular embodiments, the vesiculovims G protein is a COCV G glycoprotein (COCV-G) or a VSIV G glycoprotein (VSIV-G).
In particular embodiments, the VSIV-G envelope protein comprises one or more of: (a) one or more amino acid substitutions at H8, N9, Q10, K47, K50, A51, S183, S179, N180, 1182, M184, Y209, 1347, T350, T352, E353, and R354; (b) an insertion of TT between N9 and Q10, an insertion of GGS between H8 and N9, an insertion of GGS between N9 and Q10, an insertion of TT between N208 and Y209, an insertion of GGS between P46 and K47, and an insertion of GGS between N208 and Y209; (c) amino acid substitutions at K47 and/or R354; or (d) a deletion of residues 1-8.
In particular embodiments, the VSIV-G envelope protein comprises one or more amino acid substitutions at H8, K47, Y209, and R354.
In certain embodiments, the VSIV-G envelope protein comprises one or more amino acid substitutions selected from the group consisting of: K47A and R354A; K47A and R354G; K47A and R354F; K47A and R354Q; K47G and R354A; K47G and R354G; K47G and R354F; K47G and R354Q;K47F and R354A; K47F and R354G; K47F and R354F; K47F and R354Q; K47Q and R354A; K47Q and R354G; K47Q and R354F; and K47Q and R354Q.
In particular embodiments, the VSIV-G envelope protein comprises the amino acid sequence set forth in SEQ ID NO: 2, wherein Xi= I, X2 = A, X3 = Q, and X4 = A; Xi= I, X2 = A, X3 = Q, and X4 = G; Xi= I, X2 = A, X3 = Q, and X4 = F; Xi= I, X2 = A, X3 = Q, and X4 = Q; Xi= E, X2 = A, X3 = Q, and X4 = A; Xi= E, X2 = A, X3 = Q, and X4 = G; Xi= E, X2 = A, X3 = Q, and X4 = F; Xi= E, X2 = A, X3 = Q, and X4 = Q; Xi= I, X2 = A, X3 = H, and X4 = A; Xi= I, X2 = A, X3 = H, and X4 = G; Xi= I, X2 = A, X3 = H, and X4 = F; Xi= I, X2 = A, X3 = H, and X4 = Q; Xi= E, X2 = A, X3 = H, and X4 = A; Xi= E, X2 = A, X3 = H, and X4 = G; Xi= E, X2 = A, X3 = H, and X4 = F; Xi= E, X2 = A, X3 = H, and X4 = Q; Xi= I, X2 = G, X3 = Q, and X4 = A; Xi= I, X2 = G, X3 = Q, and X4 = G; Xi= I, X2 = G, X3 = Q, and X4 = F; Xi= I, X2 = G, X3 = Q, and X4 = Q; Xi= L, X2 = G, X3 = Q, and X4 = A; Xi= L, X2 = G, X3 = Q, and X4 = G; Xi= L, X2 = G, X3 = Q, and X4 = F; Xi= L, X2 = G, X3 = Q, and X4 = Q; Xi= I, X2 = G, X3 = H, and X4 = A; Xi= I, X2 = G, X3 = H, and X4 = G; Xi= I, X2 = G, X3 = H, and X4 = F; Xi= I, X2 = G, X3 = H, and X4 = Q; Xi= L, X2 = G, X3 = H, and X4 = A; Xi= L, X2 = G, X3 = H, and X4 = G; Xi= L, X2 = G, X3 = H, and X4 = F; Xi= L, X2 = G, X3 = H, and X4 = Q; Xi= I, X2 = F, X3 = Q, and X4 = A; Xi= I, X2 = F, X3 = Q, and X4 = G; Xi= I, X2 = F, X3 = Q, and X4 = F; Xi= I, X2 = F, X3 = Q, and X4 = Q; Xi= L, X2 = F, X3 = Q, andX4 = A; Xi= L, X2 = F, X3 = Q, and X4 = G; Xi= L, X2 = F, X3 = Q, and X4 = F; Xi= L, X2 = F, X3 = Q, and X4 = Q; Xi= I, X2 = F, X3 = H, and X4 = A; Xi= I, X2 = F, X3 = H, and X4 = G; Xi= I, X2 = F, X3 = H, and X4 = F; Xi= I, X2 = F, X3 = H, and X4 = Q; Xi= L, X2 = F, X3 = H, and X4 = A; Xi= L, X2 = F, X3 = H, and X4 = G; Xi= L, X2 = F, X3 = H, and X4 = F; Xi= L, X2 = F, X3 = H, and X4 = Q; Xi= I, X2 = Q, X3 = Q, and X4 = A; Xi= I, X2 = Q, X3 = Q, and X4 = G; Xi= I, X2 = Q, X3 = Q, and X4 = F; Xi= I, X2 = Q, X3 = Q, and X4 = Q; Xi= L, X2 = Q, X3 = Q, and X4 = A; Xi= L, X2 = Q, X3 = Q, and X4 = G; Xi= L, X2 = Q, X3 = Q, and X4 = F; Xi= L, X2 = Q, X3 = Q, and X4 = Q; Xi= I, X2 = Q, X3 = H, and X4 = A; Xi= I, X2 = Q, X3 = H, and X4 = G; Xi= I, X2 = Q, X3 = H, and X4 = F; Xi= I, X2 = Q, X3 = H, and X4 = Q; Xi= L, X2 = Q, X3 = H, and X4 = A; Xi= L, X2 = Q, X3 = H, and X4 = G; Xi= L, X2 = Q, X3 = H, and X4 = F; and Xi= L, X2 = Q, X3 = H, and X4 = Q.
In further embodiments, the vesiculovirus G protein is COCV-G.
In particular embodiments, the COCV-G envelope protein comprises one or more amino acid substitutions at K47 and R354.
In additional embodiments, the COCV-G envelope protein comprises one or more amino acid substitutions selected from the group consisting of: K47A and R354A; K47A
and R354G; K47A and R354F; K47A and R354Q; K47G and R354A; K47G and R354G; K47G and R354F; K47G and R354Q;K47F and R354A; K47F and R354G; K47F and R354F; K47F and R354Q; K47Q and R354A; K47Q and R354G; K47Q and R354F; and K47Q and R354Q.
In particular embodiments, the COCV-G envelope protein comprises the amino acid sequence set forth in SEQ ID NO: 4, wherein Xi= A and X2 = A; Xi= A and X2 = G; Xi= A and X2 = F; Xi= A and X2 = Q; Xi= G and X2 = A; Xi= G and X2 = G; Xi= G and X2 = F; Xi= G and X2 = Q; Xi= F and X2 = A; Xi= F and X2 = G; Xi= F and X2 = F; Xi= F and X2 = Q; Xi= Q and X2 = A; Xi= Q and X2 = G; Xi= Q and X2 = F; orXi= A and X2 = Q.
In particular embodiments, the one or more morbillivirus envelope glycoproteins are measles virus F (MV-F) and measles vims H (MV-H).
In certain embodiments, the MV-H protein comprises one or more amino acid substitutions at Y481, R533, S548, and F549.
In particular embodiments, the MV-H protein comprises one or more amino acid substitutions selected from the group consisting of: Y481A, R533A, S548L, and F549S.
In particular embodiments, the one or more henipavirus envelope glycoproteins are nipah vims F (NiV-F) and nipah vims G (NiV-G).
In additional embodiments, the NiV-G protein comprises one or more amino acid substitutions at E501, W504, Q530, and E533.
In further embodiments, the NiV-G protein comprises one or more amino acid substitutions at E501A, W504A, Q530A, and E533A.
In particular embodiments, the non-viral membrane-bound tropism polypeptide comprises an extracellular antigen targeting domain, a spacer polypeptide, and a transmembrane domain.
In particular embodiments, the extracellular antigen targeting domain binds an antigen expressed on an immune effector cell.
In certain embodiments, the extracellular antigen targeting domain binds an antigen expressed on an immune effector cell selected from the group consisting of: the alpha, beta, gamma, or delta chain of the T cell receptor, CD2, CD35, CD3s CD3y, CD4, CD8a, and CD8p.
In further embodiments, the extracellular antigen targeting domain comprises an antibody or antigen binding fragment thereof that binds an antigen expressed on the immune effector cell.
In additional embodiments, the extracellular antigen targeting domain comprises an anti-CD3 antibody or antigen binding fragment selected from the group consisting of 0KT3, UCHT1, YTH12.5, TR66, and humanized variants thereof, e.g., teplizumab, and antibodies and antigen binding fragments that have at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identity thereto.
In particular embodiments, the viral envelope further comprises one or more transduction enhancers, wherein the transduction enhancer is selected from the group consisting of a T cell activation receptor, a NK cell activation receptor, and a co-stimulatory molecule.
In certain embodiments, the one or more transduction enhancers comprise one or more of CD80, CD86, CD137L, OX40L, and ICOSL.
In particular embodiments, the T cell/NK cell/NKT cell activation receptor comprises a signaling domain selected from the group consisting of (i) a cytokine receptor signaling domain, (ii) a co-stimulatory receptor signaling domain, (iii) a T cell receptor subunit signaling domain, (iv) an NK cell receptor subunit signaling domain, and (v) a growth factor receptor signaling domain.
In additional embodiments, the signaling domain comprises a cytokine receptor signaling domain of IL2Ry.
In further embodiments, the signaling domain comprises a cytokine receptor signaling domain of IL2Rp.
In particular embodiments, the signaling domain comprises an IT AM.
In particular embodiments, the signaling domain comprises a tyrosine capable of binding an SH2-domain when the tyrosine is phosphorylated.
In particular embodiments, the T cell/NK cell/NKT cell activation receptor comprises FK506 binding protein (FKBP) polypeptide or a functional homolog thereof.
In certain embodiments, the T cell/NK cell/NKT cell activation receptor comprises FKBP12-rapamycin binding (FRB) polypeptide or a functional homolog thereof.
In particular embodiments, the retroviral vector further comprises a polynucleotide encoding a checkpoint inhibitor, optionally wherein the inhibitor is an antibody or antigen binding fragment thereof.
In particular embodiments, the checkpoint inhibitor blocks PD-1, PD-L1, PD-L2, TIM3, VISTA, LAG3 or TIGIT.
In further embodiments, the retroviral vector further comprises a polynucleotide encoding a protein that provides resistance to an immunosuppressive drug.
In particular embodiments, the immunosuppressive drug is selected from the group consisting of methotrexate, rapamycin, a rapalog, tacrolimus, and cyclosporine.
In certain embodiments, the retroviral vector further comprises a polynucleotide encoding one or more 2A peptides, dispersed between two or more polypeptides encoded by the polynucleotide.
In further embodiments, the retroviral vector further comprises a polynucleotide encoding a woodchuck post-transcriptional regulatory element (WPRE).
In some embodiments, the recombinant retroviral vector comprises a polynucleotide encodes a dominant negative TGFP receptor or a TGFP signal convertor.
In particular embodiments, the promoter is selected from the group consisting of an MNDU3 promoter, a T cell specific promoter, a CD4 T cell specific promoter, a CD8 T cell specific promoter, an NK cell specific promoter, a T cell and NK cell specific promoter, a CD4 T cell and NK cell specific promoter, and a CD8 T cell and NK cell specific promoter.
In various embodiments, the disclosure contemplates a packaging cell line for generating recombinant retrovirus that is capable of activating and efficiently transducing immune effector cells.
In various embodiments, a packaging cell line for generating a recombinant retrovirus contemplated herein comprises a cell line engineered to express one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity and/or one or more non-viral membrane-bound tropism polypeptides and/or one or more transduction enhancers.
In particular embodiments, the packaging cell line is a HEK-293T cell line.
In some embodiments, the packaging cell line is genetically modified to lack MHC class I expression and/or MHC class II expression and/or expression of one or more checkpoint inhibitors.
In various embodiments, the disclosure contemplates a method for preventing, treating, or ameliorating at least one symptom of a subject suffering from a disorder, disease, or condition, e.g., cancer, comprising administering a recombinant retrovirus contemplated herein to the subject, and administering a small molecule to the subject,
whereby the disorder, disease, or condition is prevented, treated, or ameliorated in the subject.
In various embodiments, the disclosure contemplates a method for expanding immune effector cells in vivo, comprising administering a recombinant retrovirus contemplated herein to the subject, and administering a small molecule to the subject, whereby the transduced immune effector cells are expanded in the subject.
In various embodiments, a method for treating a subject suffering from cancer, comprises a) administering a recombinant retrovirus contemplated herein to the subject, and b) administering a small molecule that induces activation of the T cell/NK cell/NKT cell activation receptor to the subject, whereby the cancer is treated in the subject.
In various embodiments, a method for expanding T cells capable of recognizing and killing tumor cells in a subject in need thereof, comprises a) administering a recombinant retrovirus contemplated herein to the subject, and b) administering a small molecule that induces activation of the T cell/NK cell/NKT cell activation receptor to the subject, whereby T cells transduced by the recombinant retrovirus are expanded.
In particular embodiments, the recombinant retrovirus is administered by intravenous injection, intratumoral injection, intravenous injection, or orally.
In some embodiments, the small molecule is rapamycin or a rapalog.
In certain embodiments, the small molecule causes dimerization of the T cell/NK cell/NKT cell activation receptor resulting in a cell activation signal.
In some embodiments, methods contemplated herein further comprise administering to the subject an immunosuppressive agent, optionally wherein the immunosuppressive agent is tacrolimus or cyclosporine.
In various embodiments, a nucleic acid encodes a retroviral vector contemplated herein.
Additional aspects and embodiments of the disclosure will be apparent from the Detailed Description that follows.
BRIEF DESCRIPTION OF THE SEQUENCE IDENTIFIERS
SEQ ID NOs: 1-10 set forth amino acid sequences of fusogens.
SEQ ID NOs: 11-12 set forth amino acid sequences of anti-CD3 antibodies.
SEQ ID NOs: 13-92 set forth amino acid sequences of fusogens.
SEQ ID NO: 93 sets forth an amino acid sequence of an anti-CD19 antibody.
SEQ ID NOs: 94-95 set forth amino acid sequences of viral self-cleaving polypeptides.
In the foregoing sequences, X, if present, refers to any amino acid, a specified group of amino acids or the absence of an amino acid.
Throughout the disclosure, the amino acid position(s) of a fusogen is with reference to the fusogen lacking a signal sequence (i.e., the amino acid sequence after the signal peptide has been cleaved).
DETAILED DESCRIPTION
A. OVERVIEW
The present disclosure generally relates to, in part, recombinant retroviruses engineered to redirect and expand immune effector cells in vivo for the prevention, treatment, or amelioration of at least one symptom of a disease, disorder, or condition in a subject.
In various embodiments, the disclosure contemplates a recombinant retrovirus comprising a viral envelope comprising (i) one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity (i.e., modified to retain fusogenic activity and decrease, reduce, substantially ablate, ablate, abolish or eliminate cell binding or attachment activity) and (ii) a non-viral membranebound tropism polypeptide and a recombinant retroviral vector comprising a polynucleotide encoding a promoter operably linked to one or more polynucleotides encoding one or more components of an inducible T cell/NK cell/NKT cell activation receptor. Inducible T cell/NK cell/NKT cell activation receptors contemplated herein are capable of being activated by a small molecule.
Techniques for recombinant i.e., engineered) DNA, peptide and oligonucleotide synthesis, immunoassays, tissue culture, transformation (e.g., electroporation, lipofection), enzymatic reactions, purification and related techniques and procedures may be generally performed as described in various general and more specific references in microbiology, molecular biology, biochemistry, molecular genetics, cell biology, virology and immunology as cited and discussed throughout the present specification. See, e.g.,
Sambrook et al., Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (John Wiley and Sons, updated July 2008); Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience (2002); Glover, DNA Cloning: A Practical Approach, vol. I & II (IRL Press, Oxford Univ. Press USA, 1985); Current Protocols in Immunology (Edited by: John E. Coligan, Ada M. Kruisbeek, David H. Margulies, Ethan M. Shevach, Warren Strober 2001 John Wiley & Sons, NY, NY); Real-Time PCR: Current Technology and Applications, Edited by Julie Logan, Kirstin Edwards and Nick Saunders, 2009, Caister Academic Press, Norfolk, UK; Anand, Techniques for the Analysis of Complex Genomes, (Academic Press, New York, 1992); Guthrie and Fink, Guide to Yeast Genetics and Molecular Biology (Academic Press, New York, 1991); Oligonucleotide Synthesis (N. Gait, Ed., 1984); Nucleic Acid the Hybridization (B. Hames & S. Higgins, Eds., 1985);
Transcription and Translation (B. Hames & S. Higgins, Eds., 1984); Animal Cell Culture (R. Freshney, Ed., 1986); Perbal, A Practical Guide to Molecular Cloning (1984); Next- Generation Genome Sequencing (Janitz, 2008 Wiley-VCH); PCR Protocols (Methods in Molecular Biology) (Park, Ed., 3rd Edition, 2010 Humana Press); Immobilized Cells and Enzymes (IRL Press, 1986); the treatise, Methods in Enzymology (Academic Press, Inc., N.Y.); Gene Transfer Vectors for Mammalian Cells (J. H. Miller and M. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Harlow and Lane, Antibodies, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1998); Immunochemical Methods in Cell and Molecular Biology (Mayer and Walker, eds., Academic Press, London, 1987); Handbook of Experimental Immunology, Volumes I- IV (D. M. Weir and CC Blackwell, eds., 1986); Roitt, Essential Immunology, 6th Edition, (Blackwell Scientific Publications, Oxford, 1988); Current Protocols in Immunology (Q. E. Coligan, A. M. Kruisbeek, D. H.
Margulies, E. M. Shevach and W. Strober, eds., 1991); Annual Review of Immunology, as well as monographs in journals such as Advances in Immunology.
B. RECOMBINANT RETROVIRAL PARTICLES
Retroviruses include, without limitation, lentiviruses, gamma-retro viruses, and alpha-retroviruses. Retroviruses contemplated herein are used to deliver polynucleotides to immune effector cells. Lentiviruses are complex retroviruses, which, in addition to the common retroviral genes gag, pol, and env, contain other viral accessory genes. Illustrative
retroviruses suitable for use in particular embodiments contemplated herein, include, but are not limited to: Moloney murine leukemia vims (M-MuLV), Moloney murine sarcoma vims (MoMSV), Harvey murine sarcoma vims (HaMuSV), murine mammary tumor vims (MuMTV), gibbon ape leukemia vims (GaLV), feline leukemia vims (FLV), spumavims, Friend murine leukemia vims, Murine Stem Cell Vims (MSCV) and Rous Sarcoma Vims (RSV) and lend vims.
As used herein, the terms “recombinant retrovirus,” “recombinant retroviral particle” and “retroviral particle” are used synonymously and refer to an enveloped retrovirus comprising an engineered retroviral vector.
As used herein, the term “lentivims” refers to a group (or genus) of complex retroviruses. Illustrative lentivimses include, but are not limited to, HIV (human immunodeficiency vims; including HIV type 1, and HIV type 2); visna-maedi vims (VMV); the caprine arthritis-encephalitis vims (CAEV); equine infectious anemia vims (EIAV); feline immunodeficiency vims (FIV); bovine immune deficiency vims (BIV); and simian immunodeficiency vims (SIV).
Recombinant retroviruses contemplated herein comprise genomes that lack one or more viral accessory genes, e.g., the genes env, vif, vpr, vpu and nef, thereby increasing the safety of the retroviruses. In particular embodiments, a recombinant vims contains two copies of a vector, a genomic RNA comprising backbone sequences derived from a lentivims genome. It is understood that many different sources of retroviral and/or lentiviral sequences can be used, or combined and numerous substitutions and alterations in certain of the lentiviral sequences may be accommodated without impairing the ability of a vector to package polynucleotides into a recombinant retrovims or retroviral particle and to transfer the polynucleotide into a target cell. Illustrative examples of recombinant retroviruses and retroviral vectors include, but are not limited to those described in Naldini et al., (1996a, 1996b, and 1998); Zufferey et al., (1997); Dull et al., 1998, U.S. Pat. Nos. 6,013,516; and U.S. Pat. No. 5,994,136, each of which are incorporated herein by reference in its entirety.
In particular embodiments, a lentivims is manufactured using a third-generation lentiviral vector system comprising an envelope plasmid encoding a viral envelope glycoprotein (e.g., one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity) and optionally, one or more non- viral membrane-bound tropism polypeptide and/or transduction enhancer polypeptides, two
packaging plasmids (e.g., one encoding gag-pol and one encoding rev) and a transfer plasmid. The “transfer plasmid” encodes a viral genomic RNA (e.g., vector backbone) comprising the polynucleotide sequence that is delivered by recombinant lentivirus to a target cell. In particular embodiments, a transfer plasmid comprises one or more transgene sequences of interest flanked by long terminal repeat (LTR) sequences, which facilitate packaging, reverse transcription and integration of the viral vector and associated polynucleotide sequences into the host genome. Viral vectors contemplated herein are replication incompetent, i.e., lack the genetic elements necessary for generation of infective particles in the host cell. For example, the viral vector may be designed with a deletion of the 3' LTR, rendering the virus “self-inactivating” (SIN).
In particular embodiments, the envelope plasmid and/or packaging plasmids further encodes one or more non- viral membrane-bound tropism polypeptide and/or transduction enhancer polypeptides.
Recombinant retroviruses or retroviral particles are manufacturing using a “packaging cell line.” In particular embodiments, recombinant retroviruses or retroviral particles are produced by transfecting a packaging cell line with the transfer plasmid, packaging plasmid(s), and envelope plasmid(s).
As used herein, the terms “retroviral vector” or “lentiviral vector” refer to a nucleic acid that encodes a modified retroviral or lentiviral genome comprising one or more polynucleotide sequences to be delivered to a target cell. In particular embodiments, a recombinant retrovirus or lentivirus comprises a genomic RNA, e.g., a vector, a lipidbilayer envelope, and other accessory proteins including integrase, protease, and matrix protein. The vectors may further comprise one of more accessory elements to increase transduction efficiency (e.g., a FLAP element that includes the central polypurine tract and central termination sequences (cPPT and CTS)), viral packaging (e.g., a Psi ( ) packaging signal, a rev response element (RRE)), and/or other elements that increase therapeutic gene expression (e.g., poly (A) sequences), and may optionally comprise a woodchuck post- transcriptional regulatory element (WPRE) or hepatitis B virus post-transcriptional regulatory element (HPRE).
The efficiency of retroviral or lentiviral vector manufacturing may be assessed in various ways, including measurement of vector copy number (VCN) or vector genomes (vg) such as by quantitative polymerase chain reaction (qPCR), or titer of the virus in
infectious units per milliliter (lU/mL). For example, the titer may be assessed using a functional assay performed on the cultured tumor cell line HT1080 or on HeLa cells.
In particular embodiments, a recombinant retrovirus contemplated herein comprises a vector encoding a promoter operably linked to one or more polynucleotides encoding one or more components of an inducible T cell/NK cell/NKT cell activation receptor. Illustrative promoters suitable for use in particular embodiments contemplated herein include, but are not limited to, an EFla promoter, a cytomegalovirus (CMV) promoter, a CAG promoter, an SV40 promoter, an SV40/CD43 promoter, a murine stem cell virus (MSCV) promoter, a phosphoglycerate kinase (PGK) promoter, and a MNDU3 promoter. Other illustrative promoters include but are not limited to a T cell specific promoter, a CD4 T cell specific promoter, a CD8 T cell specific promoter, an NK cell specific promoter, a T cell and NK cell specific promoter, a CD4 T cell and NK cell specific promoter, and a CD8 T cell and NK cell specific promoter.
In particular embodiments, a recombinant retrovirus comprises a viral envelope comprising or expressing one or more non- viral membrane-bound tropism polypeptides and/or one or more transduction enhancers.
In particular embodiments, a recombinant retrovirus comprises a retroviral vector comprising a polynucleotide comprising, from 5' to 3 : a 5' long terminal repeat (LTR) comprising an R region and U5 region, a polynucleotide encoding a promoter, one or more polynucleotides encoding one or more components of an inducible T cell/NK cell/NKT cell activation receptor, and a 3' LTR comprising a U3 region, an R region, a polyadenylation signal and a poly(A) tail.
In particular embodiments, a recombinant retrovirus is a lentiviral particle comprising: a viral envelope that expresses a mutated viral envelope glycoprotein that retain fusogenic activity and lack cognate receptor binding activity, and a non- viral membrane-bound tropism polypeptide comprising an anti-CD3 scFv, and optionally a transduction enhancer; and a SIN retroviral vector comprising an MNDU3 promoter, an EFla promoter, a cytomegalovirus (CMV) promoter, a CAG promoter, an SV40 promoter, an SV40/CD43 promoter, a murine stem cell virus (MSCV) promoter, a phosphoglycerate kinase (PGK) promoter, a T cell specific promoter, a CD4 T cell specific promoter, a CD8 T cell specific promoter, an NK cell specific promoter, a T cell and NK cell specific promoter, a CD4 T cell and NK cell specific promoter, or a CD8 T cell and NK cell specific promoter, a transgene encoding one or more polynucleotides encoding one or more
components of an inducible T cell/NK cell/NKT cell activation receptor, and/or an FRB polypeptide.
C. VIRAL ENVELOPE
In particular embodiments, a recombinant retrovirus or retroviral particle comprises a viral envelope comprising one or more mutated viral envelope glycoproteins that mediate fusion of the viral particle and the target host cell but that do not bind its cognate receptor expressed on the target host cell and one or more non-viral membrane-bound tropism polypeptides.
In particular embodiments, one or more mutated viral envelope glycoproteins comprise a vesiculovirus envelope glycoprotein or one or more morbillivirus envelope glycoproteins or henipavirus envelope glycoproteins. In particular embodiments, the mutated viral envelope glycoprotein comprises a heterologous signal peptide.
In particular embodiments, one or more mutated viral envelope glycoproteins comprise a vesiculovirus envelope glycoprotein or one or more morbillivirus envelope glycoproteins or henipavirus envelope glycoproteins.
Illustrative examples of vesiculoviruses suitable for use in particular embodiments from which G glycoproteins can be isolated from include, but are not limited to vesicular stomatitis Alagoas virus (VSAV; Alagoas vesiculovirus), Carajas virus (CJSV; Carajas vesiculovirus), Chandipura virus (CHPV; Chandipura vesiculovirus), Cocal virus (COCV; Cocal vesiculovirus), vesicular stomatitis Indiana vims (VSIV, f.k.a. VSV; Indiana vesiculovirus), Isfahan vims (ISFV; Isfahan vesiculovirus), Maraba vims (MARAV; Maraba vesiculovirus), Morreton vims (MORV; Morreton vesiculovims), vesicular stomatitis New Jersey vims (VSNJV; New Jersey vesiculovims), and Piry vims (PIRYV; Piry vesiculovims).
In particular embodiments, a vesiculovims G envelope protein comprises one or more amino acid substitutions that that enable the polypeptide to mediate fusion of the viral particle and the target host cell but that ablate the polypeptide’s ability to bind its cognate receptor expressed on the target host cell, e.g., LDL-R. In particular embodiments, a vesiculovims G envelope protein comprises an amino acid sequence set forth in any one of SEQ ID NOs: 15-322 disclosed in U.S. Patent Application No. 20200216502, each said sequence incorporated by reference herein in its entirety, or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto that enables the polypeptide to mediate
fusion of the viral particle and the target host cell but that ablate the polypeptide’s ability to bind its cognate receptor expressed on the target host cell, e.g., LDL-R. In particular embodiments, a vesiculovirus G envelope protein comprises amino acid substitution at positions 47 and/or 354 (or 358 in some strains, e.g., CJSV, VSNJV) with reference to the vesiculovirus G envelope protein lacking a signal peptide.
In particular embodiments, a vesiculovirus is vesicular stomatitis Indiana virus (VSIV). In particular embodiments, a mutated viral envelope glycoprotein is derived from a VSIV envelope glycoprotein (VSIV-G; e.g., SEQ ID NO: 1: KFDVFPHNQKGNWKNVPSNYHYCPSSSDLNWHNDLIGTALQVKMPKSHKAIQA DGWMCHASKWVTTCDFRWYGPKYITHSIRSFTPSVEQCKESIEQTKQGTWLNPG FPPQSCGYATVTDAEAVIVQVTPHHVLVDEYTGEWVDSQFINGKCSNYICPTVHN STTWHSDYKVKGLCDSNLISMDITFFSEDGELSSLGKEGTGFRSNYFAYETGGKA CKMQYCKHWGVRLPSGVWFEMADKDLFAAARFPECPEGSSISAPSQTSVDVSLI QDVERILDYSLCQETWSKIRAGLPISPVDLSYLAPKNPGTGPAFTIINGTLKYFETR YIRVDIAAPILSRMVGMISGTTTERELWDDWAPYEDVEIGPNGVLRTSSGYKFPLY MIGHGMLDSDLHLSSKAQVFEHPHIQDAASQLPDDESLFFGDTGLSKNPIELVEG WFSSWKSSIASFFFnGLnGLFLVLRVGIHLCIKLKHTKKRQIYTDIEMNRLGK) or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto comprising one or more modifications that enable the polypeptide to mediate fusion of the viral particle and a cell but that substantially ablate or ablate the polypeptide’s ability to bind its cognate receptor expressed on a cell, e.g., LDL-R. In particular embodiments, a mutated viral envelope glycoprotein is derived from a VSIV-G polypeptide set forth in SEQ ID NO: 1 comprising L47I and/or H80Q amino acid substitutions, such substitutions being present in naturally occurring variants of VSIV.
In particular embodiments, a mutated VSIV-G envelope protein comprises one or more of: one or more amino acid substitutions at H8, N9, Q10, K47, K50, A51, S183, S179, N180, 1182, M184, Y209, 1347, T350, T352, E353, and R354 (substitution with any amino acid; a conservation substitution; a disruptive substitution; substitution with D, E, A, G, F, or Q; or substitution with A, G, F, or Q); an insertion of TT between N9 and Q10, an insertion of GGS between H8 and N9, an insertion of GGS between N9 and Q10, an insertion of TT between N208 and Y209, an insertion of GGS between P46 and K47, and an insertion of GGS between N208 and Y209; or a deletion of residues 1-8. In particular embodiments, a VSIV-G envelope protein comprises one or more amino acid substitutions
at H8, K47, Y209, and R354. In particular embodiments, a VSIV-G envelope protein comprises one or more amino acid substitutions at H8, K47, Y209, and R354, wherein each substitution can be with A, G, F, or Q. Amino acid positions are with reference to a VSIV- G envelope protein that lacks a signal peptide, e.g., SEQ ID NO: 1. In particular embodiments, a mutated viral envelope glycoprotein is derived from a VSIV-G polypeptide set forth in SEQ ID NO: 1 comprising L47I and/or H80Q amino acid substitutions, such substitutions present in naturally occurring variants of VSIV.
In particular embodiments, a mutated VSIV-G polypeptide comprises one or more amino acid substitutions at K47, 1182, and/or R354 (substitution with any amino acid; a conservation substitution; a disruptive substitution; substitution with D, E, A, G, F, or Q; or substitution with A, G, F, or Q). In particular embodiments, a mutated VSIV-G polypeptide comprises amino acid substitutions at K47, 1182, or R354; K47 and 1182; K47 and R354; 1182 and R354; or at K47, 1182, and R354 of SEQ ID NO: 1.
In particular embodiments, a mutated VSIV-G polypeptide comprises one or more of the following amino acid substitutions: K47A, K47Q, I182E, I182D, R354A, and/or R354Q. In particular embodiments, a mutated VSIV-G polypeptide comprises the following amino acid substitutions: K47A, K47Q, I182E, I182D, R354A, or R354Q; K47A and I182E; K47A and I182D; K47Q and I182E; K47Q and I182D; I182E and R354A; I182E and R354Q; I182D and R354A; I182D and R354Q; K47A and R354A; K47A and R354Q; K47Q and R354A; K47Q and R354Q; K47A, I182E, and R354A; K47A, I182D, and R354A; K47Q, I182E, and R354A; K47Q, I182D, and R354A; K47A, I182E, and R354Q; K47A, I182D, and R354Q; K47Q, I182E, and R354Q; or K47Q, I182D, and R354Q of SEQ ID NO: 1.
In particular embodiments, a VSIV-G envelope protein comprises one or more amino acid substitutions at H8, K47, Y209, and R354. In particular embodiments, a VSIV- G envelope protein comprises one or more amino acid substitutions at H8, K47, Y209, and R354, wherein each substitution can be with A, G, F, or Q. In particular embodiments, a VSIV-G envelope protein comprises one or more amino acid substitutions at K47 and R354 (with reference to a VSIV-G envelope protein that lacks a signal peptide, e.g., SEQ ID NO: 1). In particular embodiments, a VSIV-G envelope protein comprises one or more amino acid substitutions selected from the group consisting of: K47A and R354A; K47A and R354G; K47A and R354F; K47A and R354Q; K47G and R354A; K47G and R354G; K47G and R354F; K47G and R354Q;K47F and R354A; K47F and R354G; K47F and
R354F; K47F and R354Q; K47Q and R354A; K47Q and R354G; K47Q and R354F; and K47Q and R354Q. In preferred embodiments, a VSIV-G envelope comprises the amino acid substitutions K47Q or K47A and R354A or R354Q. Amino acid positions are with reference to a VSIV-G envelope protein that lacks a signal peptide.
In particular embodiments, a VSIV-G envelope protein comprises an amino acid sequence set forth in SEQ ID NO: 2 (wherein Xi= I, X2 = A, X3 = Q, and X4 = A; Xi= I, X2 = A, X3 = Q, and X4 = G; Xi= I, X2 = A, X3 = Q, and X4 = F; Xi= I, X2 = A, X3 = Q, and X4 = Q; Xi= L, X2 = A, X3 = Q, and X4 = A; Xi= L, X2 = A, X3 = Q, and X4 = G; Xi= L, X2 = A, X3 = Q, and X4 = F; Xi= L, X2 = A, X3 = Q, and X4 = Q; Xi= I, X2 = A, X3 = H, and X4 = A; Xi= I, X2 = A, X3 = H, and X4 = G; Xi= I, X2 = A, X3 = H, and X4 = F; Xi= I, X2 = A, X3 = H, and X4 = Q; Xi= L, X2 = A, X3 = H, and X4 = A; Xi= L, X2 = A, X3 = H, and X4 = G; Xi= L, X2 = A, X3 = H, and X4 = F; Xi= L, X2 = A, X3 = H, and X4 = Q; Xi= I, X2 = G, X3 = Q, and X4 = A; Xi= I, X2 = G, X3 = Q, and X4 = G; Xi= I, X2 = G, X3 = Q, and X4 = F; Xi= I, X2 = G, X3 = Q, and X4 = Q; Xi= L, X2 = G, X3 = Q, and X4 = A; Xi= L, X2 = G, X3 = Q, and X4 = G; Xi= L, X2 = G, X3 = Q, and X4 = F; Xi= L, X2 = G, X3 = Q, and X4 = Q; Xi= I, X2 = G, X3 = H, and X4 = A; Xi= I, X2 = G, X3 = H, and X4 = G; Xi= I, X2 = G, X3 = H, and X4 = F; Xi= I, X2 = G, X3 = H, and X4 = Q; Xi= L, X2 = G, X3 = H, and X4 = A; Xi= L, X2 = G, X3 = H, and X4 = G; Xi= L, X2 = G, X3 = H, and X4 = F; Xi= L, X2 = G, X3 = H, and X4 = Q; Xi= I, X2 = F, X3 = Q, and X4 = A; Xi= I, X2 = F, X3 = Q, and X4 = G; Xi= I, X2 = F, X3 = Q, and X4 = F; Xi= I, X2 = F, X3 = Q, and X4 = Q; Xi= L, X2 = F, X3 = Q, andX4 = A; Xi= L, X2 = F, X3 = Q, and X4 = G; Xi= L, X2 = F, X3 = Q, and X4 = F; Xi= L, X2 = F, X3 = Q, and X4 = Q; Xi= I, X2 = F, X3 = H, and X4 = A; Xi= I, X2 = F, X3 = H, and X4 = G; Xi= I, X2 = F, X3 = H, and X4 = F; Xi= I, X2 = F, X3 = H, and X4 = Q; Xi= L, X2 = F, X3 = H, and X4 = A; Xi= L, X2 = F, X3 = H, and X4 = G; Xi= L, X2 = F, X3 = H, and X4 = F; Xi= L, X2 = F, X3 = H, and X4 = Q; Xi= I, X2 = Q, X3 = Q, and X4 = A; Xi= I, X2 = Q, X3 = Q, and X4 = G; Xi= I, X2 = Q, X3 = Q, and X4 = F; Xi= I, X2 = Q, X3 = Q, and X4 = Q; Xi= L, X2 = Q, X3 = Q, and X4 = A; Xi= L, X2 = Q, X3 = Q, and X4 = G; Xi= L, X2 = Q, X3 = Q, and X4 = F; Xi= L, X2 = Q, X3 = Q, and X4 = Q; Xi= I, X2 = Q, X3 = H, and X4 = A; Xi= I, X2 = Q, X3 = H, and X4 = G; Xi= I, X2 = Q, X3 = H, and X4 = F; Xi= I, X2 = Q, X3 = H, and X4 = Q; Xi= L, X2 = Q, X3 = H, and X4 = A; Xi= L, X2 = Q, X3 = H, and X4 = G; Xi= L, X2 = Q, X3 = H, and X4 = F; and Xi= L, X2 = Q, X3 = H, and X4 = Q) or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto
that mediates fusion of the viral particle and the target host cell but that does not bind its cognate receptor expressed on the target host cell, e.g., LDL-R.
In particular embodiments, a mutated VSIV-G envelope protein comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13-76 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto that mediates fusion of the viral particle and a cell but that substantially ablates or ablates the polypeptide’s ability to bind its cognate receptor expressed on a cell, e.g., LDL-R. In particular embodiments, a mutated VSIV-G envelope protein comprises an amino acid sequence set forth in any one of SEQ ID NOs: 61-76 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto that mediates fusion of the viral particle and a cell but that substantially ablates or ablates the polypeptide’s ability to bind its cognate receptor expressed on a cell, e.g., LDL- R. In particular embodiments, a mutated VSIV-G envelope protein comprises an amino acid sequence set forth in any one of SEQ ID NOs: 61, 65, 69, and 73 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto that mediates fusion of the viral particle and a cell but that substantially ablates or ablates the polypeptide’s ability to bind its cognate receptor expressed on a cell, e.g., LDL-R.
Table 2
In particular embodiments, a vesiculovirus is cocal virus (COCV). In particular embodiments, a mutated viral envelope glycoprotein is derived from a COCV envelope glycoprotein (COCV-G; e.g., SEQ ID NO: 3: KFSIVFPQSQKGNWKNVPSSYHYCPSSSDQNWHNDLLGITMKVKMPKTHKAIQA DGWMCHAAKWITTCDFRWYGPKYITHSIHSIQPTSEQCKESIKQTKQGTWMSPGF PPQNCGYATVTDSVAVVVQATPHHVLVDEYTGEWIDSQFPNGKCETEECETVHN STVWYSDYKVTGLCDATLVDTEITFFSEDGKKESIGKPNTGYRSNYFAYEKGDKV CKMNYCKHAGVRLPSGVWFEFVDQDVYAAAKLPECPVGATISAPTQTSVDVSLI LDVERILDYSLCQETWSKIRSKQPVSPVDLSYLAPKNPGTGPAFTIINGTLKYFETR YIRIDIDNPIISKMVGKISGSQTERELWTEWFPYEGVEIGPNGILKTPTGYKFPLFMI GHGMLDSDLHKTSQAEVFEHPHLAEAPKQLPEEETLFFGDTGISKNPVELIEGWFS SWKSTVVTFFFAIGVFILLYVVARIVIAVRYRYQGSNNKRIYNDIEMSRFRK) or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto comprising one or more modifications that enable the polypeptide to mediate fusion of the viral particle
and a cell but that substantially ablate or ablate the polypeptide’s ability to bind its cognate receptor expressed on a cell, e.g., LDL-R. In particular embodiments, a COCV-G envelope protein comprises one or more amino acid substitutions at K47 and/or R354. In particular embodiments, a COCV-G envelope protein comprises one or more amino acid substitutions at K47 and/or R354, wherein each amino acid can be substituted with A, G, F, or Q. In particular embodiments, a COCV-G envelope protein comprises one or more amino acid substitutions at K47 and/or R354 (with reference to a COCV-G envelope protein that lacks a signal peptide, e.g., SEQ ID NO: 3). In particular embodiments, a COCV-G envelope protein comprises one or more amino acid substitutions selected from the group consisting of: K47A and R354A; K47A and R354G; K47A and R354F; K47A and R354Q; K47G and R354A; K47G and R354G; K47G and R354F; K47G and R354Q;K47F and R354A; K47F and R354G; K47F and R354F; K47F and R354Q; K47Q and R354A; K47Q and R354G; K47Q and R354F; and K47Q and R354Q. In particular embodiments, a COCV-G envelope protein comprises an amino acid sequence set forth in SEQ ID NO: 4 (wherein Xi= A and X2 = A; Xi= A and X2 = G; Xi= A and X2 = F; Xi= A and X2 = Q; Xi= G and X2 = A; Xi= G and X2 = G; Xi= G and X2 = F; Xi= G and X2 = Q; Xi= F and X2 = A; Xi= F and X2 = G; Xi= F and X2 = F; Xi= F and X2 = Q; Xi= Q and X2 = A; Xi= Q and X2 = G; Xi= Q and X2 = F; or Xi= A and X2 = Q) or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto that mediates fusion of the viral particle and a cell but that substantially ablates or ablates the polypeptide’s ability to bind its cognate receptor expressed on a cell, e.g., LDL-R.
In particular embodiments, a mutated COCV-G envelope protein comprises an amino acid sequence set forth in any one of SEQ ID NOs: 77-92 or an amino acid sequence
at least 95%, 96%, 97%, 98%, or 99% identical thereto that mediates fusion of the viral particle and a cell but that substantially ablates or ablates the polypeptide’s ability to bind its cognate receptor expressed on a cell, e.g., LDL-R. In particular embodiments, a mutated COCV-G envelope protein comprises an amino acid sequence set forth in any one of SEQ ID NOs: 89-92 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto that mediates fusion of the viral particle and a cell but that substantially ablates or ablates the polypeptide’s ability to bind its cognate receptor expressed on a cell, e.g., LDL- R. In particular embodiments, a mutated VSIV-G envelope protein comprises an amino acid sequence set forth in SEQ ID NOs: 89 or 92 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto that mediates fusion of the viral particle and a cell but that substantially ablates or ablates the polypeptide’s ability to bind its cognate receptor expressed on a cell, e.g., LDL-R.
In particular embodiments, one or more mutated morbillivirus envelope glycoproteins are derived from measles virus F (MV-F) and measles virus H (MV-H). In particular embodiments, a recombinant particle comprises one or more measles virus viral envelope glycoproteins modified to lack cell binding activity and retain fusogenic activity. In some embodiments, a recombinant particle comprises a modified MV-F glycoprotein
and an MV-H glycoprotein modified to lack cell binding activity and retain fusogenic activity.
In particular embodiments, one or more mutated morbillivirus envelope glycoproteins are derived from measles virus F (MV-F) polypeptide (e.g., SEQ ID NO: 5: QIHWGNLSKIGVVGIGSASYKVMTRSSHQSLVIKLMPNITLLNNCTRVEIAEYRRL LRTVLEPIRDALNAMTQNIRPVQSVASSRRHKRFAGVVLAGAALGVATAAQITA GIALHQSMLNSQAIDNLRASLETTNQAIEAIRQAGQEMILAVQGVQDYINNELIPS MNQLSCDLIGQKLGLKLLRYYTEILSLFGPSLRDPISAEISIQALSYALGGDINKVLE KLGYSGGDLLGILESRGIKARITHVDTESYFIVLSIAYPTLSEIKGVIVHRLEGVSYN IGSQEWYTTVPKYVATQGYLISNFDESSCTFMPEGTVCSQNALYPMSPLLQECLR GSTKSCARTLVSGSFGNRFILSQGNLIANCASILCKCYTTGTIINQDPDKILTYIAAD HCPVVEVNGVTIQVGSRRYPDAVYLHRIDLGPPISLERLDVGTNLGNAIAKLEDA KELLESSDQILRSMKGLSSTSIVYILIAVCLGGLIGIPALICCCRGR) or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto and a measles virus H (MV-H) polypeptide (e.g., SEQ ID NO: 6: MGSRIVINREHLMIDRPYVLLAVLFVMFLSLIGLLAIAGIRLHRAAIYTAEIHKSLST NLDVTNSIEHQVKDVLTPLFKIIGDEVGLRTPQRFTDLVKFISDKIKFLNPDREYDF RDLTWCINPPERIKLDYDQYCADVAAEELMNALVNSTLLETRTTNQFLAVSKGN CSGPTTIRGQFSNMSLSLLDLYLGRGYNVSSIVTMTSQGMYGGTYLVEKPNLSSK RSELSQLSMYRVFEVGVIRNPGLGAPVFHMTNYLEQPVSNDLSNCMVALGELKL AALCHGEDSmPYQGSGKGVSFQLVKLGVWKSPTDMQSWVPLSTDDPVIDRLYL SSHRGVIADNQAKWAVPTTRTDDKLRMETCFQQACKGKIQALCENPEWAPLKD NRIPSYGVLSVDLSLTVELKIKIASGFGPLITHGSGMDLYKSNHNNVYWLTIPPMK NLALGVINTLEWIPRFKVSPYLFTVPIKEAGGDCHAPTYLPAEVDGDVKLSSNLVI LPGQDLQYVLATYDTSRVEHAVVYYVYSPSRSFSYFYPFRLPIKGVPIELQVECFT WDQKLWCRHFCVLADSESGGHITHSGMVGMGVSCTVTREDGTN) or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto, wherein the MV-H protein lacks cell binding activity and retains fusogenic activity. In particular embodiments, the MV-H polypeptide comprises one or more amino acid substitutions at positions Y463, R515, S530, and F531 of a MV-H polypeptide (e.g., SEQ ID NO 6). In particular embodiments, the MV-H polypeptide comprises one or more of the amino acid substitutions Y463A, R515A, S530L, and F531S in an MV-H polypeptide (e.g., SEQ ID NO: 7:
MGSRIVINREHLMIDRPYVLLAVLFVMFLSLIGLLAIAGIRLHRAAIYTAEIHKSLST NLDVTNSIEHQVKDVLTPLFKIIGDEVGLRTPQRFTDLVKFISDKIKFLNPDREYDF RDLTWCINPPERIKLDYDQYCADVAAEELMNALVNSTLLETRTTNQFLAVSKGN CSGPTTIRGQFSNMSLSLLDLYLGRGYNVSSrVTMTSQGMYGGTYLVEKPNLSSK RSELSQLSMYRVFEVGVIRNPGLGAPVFHMTNYLEQPVSNDLSNCMVALGELKL AALCHGEDSmPYQGSGKGVSFQLVKLGVWKSPTDMQSWVPLSTDDPVIDRLYL SSHRGVIADNQAKWAVPTTRTDDKLRMETCFQQACKGKIQALCENPEWAPLKD NRIPSYGVLSVDLSLTVELKIKIASGFGPLITHGSGMDLYKSNHNNVYWLTIPPMK NLALGVINTLEWIPRFKVSPALFNVPIKEAGGDCHAPTYLPAEVDGDVKLSSNLVI LPGQDLQYVLATYDTSAVEHAVVYYVYSPSRLSSYFYPFRLPIKGVPIELQVECFT WDQKLWCRHFCVLADSESGGHITHSGMVGMGVSCTVTREDGTN) or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto.
In particular embodiments, one or more mutated henipaviruses envelope glycoproteins are derived from nipah virus F (NiV-F) and nipah vims G (NiV-G). In particular embodiments, a recombinant particle comprises one or more nipah vims viral envelope glycoproteins modified to lack cell binding activity and retain fusogenic activity. In some embodiments, a recombinant particle comprises a modified NiV-F glycoprotein and a NiV-G glycoprotein modified to lack cell binding activity and retain fusogenic activity.
In particular embodiments, one or more mutated henipavims envelope glycoproteins are derived from a nipah vims F (NiV-F) polypeptide (e.g., SEQ ID NO: 8: LHYEKLSKIGLVKGVTRKYKIKSNPLTKDIVIKMIPNVSNMSQCTGSVMENYKTR LNGILTPIKGALEIYKNNTHDLVGDVRLAGVIMAGVAIGIATAAQITAGVALYEA MKNADNINKLKSSIESTNEAVVKLQETAEKTVYVLTALQDYINTNLVPTIDKISCK QTELSLDLALSKYLSDLLFVFGPNLQDPVSNSMTIQAISQAFGGNYETLLRTLGYA TEDFDDLLESDSITGQIIYVDLSSYYUVRVYFPILTEIQQAYIQELLPVSFNNDNSEW ISIVPNFILVRNTLISNIEIGFCLITKRSVICNQDYATPMTNNMRECLTGSTEKCPREL VVSSHVPRFALSNGVLFANCISVTCQCQTTGRAISQSGEQTLLMIDNTTCPTAVLG NVIISLGKYLGSVNYNSEGIAIGPPVFTDKVDISSQISSMNQSLQQSKDYIKEAQRL LDTVNPSLISMLSMIILYVLSIASLCIGLITFISFIIVEKKRNT) or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto and a nipah vims G (NiV- G) polypeptide (e.g., SEQ ID NO: 9: MKKINEGLLDSKILSAFNTVIALLGSIVUVMNIMIIQNYTRSTDNQAVIKDALQGIQ
QQIKGLADKIGTEIGPKVSLIDTSSTITIPANIGLLGSKISQSTASINENVNEKCKFTL PPLKIHECNISCPNPLPFREYRPQTEGVSNLVGLPNNICLQKTSNQILKPKLISYTLP VVGQSGTCITDPLLAMDEGYFAYSHLERIGSCSRGVSKQRIIGVGEVLDRGDEVPS LFMTNVWTPPNPNTVYHCSAVYNNEFYYVLCAVSTVGDPILNSTYWSGSLMMT RLAVKPKSNGGGYNQHQLALRSIEKGRYDKVMPYGPSGIKQGDTLYFPAVGFLV RTEFKYNDSNCPITKCQYSKPENCRLSMGIRPNSHYILRSGLLKYNLSDGENPKVV FIEISDQRLSIGSPSKIYDSLGQPVFYQASFSWDTMIKFGDVLTVNPLVVNWRNNT VISRPGQSQCPRFNTCPEICWEGVYNDAFLIDRINWISAGVFLDSNQTAENPVFrV FKDNEILYRAQLASEDTNAQKTITNCFLLKNKIWCISLVEIYDTGDNVIRPKLFAV KIPEQCT) or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto, wherein the NiV-G polypeptide lacks cell binding activity and retains fusogenic activity. In particular embodiments, the NiV-G polypeptide comprises one or more amino acid substitutions at positions E468, W471, Q497, and E500 of an NiV-G polypeptide (e.g., SEQ ID NO: 9). In particular embodiments, the NiV-G polypeptide comprises one or more of the amino acid substitutions E468A, W471A, Q497A, and E500A in an NiV-G polypeptide (e.g., SEQ ID NO: 10:
MKKINEGLLDSKILSAFNTVIALLGSIVUVMNIMIIQNYTRSTDNQAVIKDALQGIQ QQIKGLADKIGTEIGPKVSLIDTSSTITIPANIGLLGSKISQSTASINENVNEKCKFTL PPLKIHECNISCPNPLPFREYRPQTEGVSNLVGLPNNICLQKTSNQILKPKLISYTLP VVGQSGTCITDPLLAMDEGYFAYSHLERIGSCSRGVSKQRIIGVGEVLDRGDEVPS LFMTNVWTPPNPNTVYHCSAVYNNEFYYVLCAVSTVGDPILNSTYWSGSLMMT RLAVKPKSNGGGYNQHQLALRSIEKGRYDKVMPYGPSGIKQGDTLYFPAVGFLV RTEFKYNDSNCPITKCQYSKPENCRLSMGIRPNSHYILRSGLLKYNLSDGENPKVV FIEISDQRLSIGSPSKIYDSLGQPVFYQASFSWDTMIKFGDVLTVNPLVVNWRNNT VISRPGQSQCPRFNTCPAICAEGVYNDAFLIDRINWISAGVFLDSNATAANPVFTV FKDNEILYRAQLASEDTNAQKTITNCFLLKNKIWCISLVEIYDTGDNVIRPKLFAV KIPEQCT) or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical thereto, wherein the NiV-G polypeptide lacks cell binding activity and retains fusogenic activity.
In particular embodiments, a recombinant retrovirus contemplated herein comprises an outer surface, a lipid bilayer, cell membrane, or viral envelope comprising or expressing one or more non- viral membrane bound tropism polypeptides. A “tropism polypeptide” is a polypeptide that binds one or more antigens on a target host cell. A “non- viral membrane
bound tropism polypeptide” is a polypeptide that binds one or more antigens on a target host cell; that is not native to, or derived from, either in whole or in part, a virus; and that is attached to a lipid bilayer, cell membrane, or viral envelope.
In particular embodiments, a non- viral membrane bound tropism polypeptide comprises an extracellular antigen targeting domain, a spacer polypeptide, and a transmembrane domain. In particular embodiments, an extracellular antigen targeting domain binds an antigen expressed on an immune effector cell. In particular embodiments, an extracellular antigen targeting domain comprises an antibody or antigen binding fragment thereof that binds an antigen expressed on the surface of an immune effector cell. In particular embodiments, an extracellular antigen targeting domain binds an antigen expressed on an immune effector cell.
In particular embodiments, the extracellular antigen targeting domain binds CD35, CD3s CD3y, CD4, CD5, CD7, CD8a, or CD8p. In particular embodiments, the extracellular antigen targeting domain comprises an scFv, a murine scFv, a humanized scFv, or a human scFv that binds CD35, CD3s CD3y, CD4, CD5, CD7, CD8a, or CD8p.
In particular embodiments, a tropism polypeptide comprises an anti-CD3s antibody or antigen binding fragment thereof. Illustrative examples of anti-CD3s antibodies or antigen binding fragments thereof suitable for using in particular embodiments include scFvs or other antigen binding fragments isolated from 0KT3, UCHT1, YTH12.5, and TR66, and variants thereof, e.g., teplizumab and variants having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity thereto.
Illustrative anti-CD3 scFvs include the following amino acid sequences.
In particular embodiments, a tropism polypeptide comprises a Gaussia luciferase signal peptide, an anti-CD3 scFv, a hinge domain (e.g., isolated from an IgGl Fc region, an IgGlhinge or a human CD8 stalk, the mouse CD8a stalk, or Glycophorin A) or linker (e.g., a (G4S)i-s), a transmembrane domain (e.g., isolated from CD3, CD4, CD8a, CD28, or Glycophorin A), and a cytoplasmic tail (e.g., isolated from Glycophorin A). Illustrative examples of polypeptides suitable for use in particular embodiments are disclosed in WO202107678 and WO2022164935, each of which is incorporated herein by reference in its entirety.
D. TRANSDUCTION ENHANCERS
In some embodiments, a recombinant retrovirus or retroviral particle contemplated herein comprises a viral envelope comprising or expressing one or more transduction enhancers. A “transduction enhancer” as used herein refers to a non-viral membrane-bound protein that activates T cells. In particular embodiments, a transduction enhancer comprises a mitogenic and/or cytokine-based domain. In particular embodiments, a transduction enhancer comprises T cell activation ligands or receptors, NK cell activation receptors, costimulatory molecules, or portions thereof.
I. MITOGENIC TRANSDUCTION ENHANCERS
In particular embodiments, a recombinant retrovirus or retroviral particle contemplated herein comprises a viral envelope comprising or expressing a mitogenic transduction enhancer. In some embodiments, the mitogenic transduction enhancer is derived from the host cell during recombinant retrovirus production. In some embodiments, a mitogenic transduction enhancer is made by the packaging cell and expressed at the cell surface. When the nascent retroviral vector particle buds from the host cell membrane, the mitogenic transduction enhancer is incorporated in the viral envelope as part of the packaging cell-derived lipid bilayer.
In some embodiments, a transduction enhancer is host cell derived. The term “host cell derived” means that the mitogenic transduction enhancer is derived from the host cell. In some embodiments, a mitogenic transduction enhancer may have the structure: M-S- TM-CT, in which M is a mitogenic domain; S is an optional spacer domain TM is a transmembrane domain, and CT is an optional cytoplasmic tail.
2. TRANSDUCTION ENHANCER MITOGENIC DOMAINS
A mitogenic domain is the part of the mitogenic transduction enhancer which causes T cell activation. It may bind or otherwise interact, directly or indirectly, with a T cell, leading to T cell activation. In particular embodiments, the mitogenic domain binds a T cell surface antigen including but not limited to the alpha or beta chains of a TCR, CD28, CD134 (0X40), CD137 (4-1BB), and CD278 (ICOS).
In particular embodiments, the mitogenic domain comprises an antibody or antigen binding fragment thereof that specifically binds a T cell surface antigen. In particular embodiments, the mitogenic domain comprises an antibody or antigen binding fragment thereof that specifically binds the alpha or beta chains of a TCR, CD28, CD134 (0X40), CD137 (4-1BB), and CD278 (ICOS).
Illustrative examples of anti-CD28 antibodies or antigen binding fragments thereof suitable for use in particular embodiments include those derived from 9.3, 15E8, CD28.2, 10F3and TGN1412 and humanized variants thereof.
In particular embodiments, a mitogenic domain comprises all or part of a costimulatory molecule including but not limited to CD80, CD86, OX40L, 4-1 BBL, and ICOSL.
3. TRANSDUCTION ENHANCER SPACER DOMAINS
In particular embodiments, a mitogenic transduction enhancer and/or cytokinebased transduction enhancer comprises a spacer domain that connects the mitogenic domain with the transmembrane domain. A flexible spacer allows the antigen binding domain to orient in different directions to facilitate binding. In particular embodiments, the spacer domain comprises an IgGl Fc region, an IgGl hinge, a human CD8a stalk or the mouse CD8a stalk, a CD2 ectodomain, or a CD34 ectodomain. In particular embodiments, the spacer domain comprises an alternative linker sequence which has similar length and/or domain spacing properties as an IgGl Fc region, an IgGl hinge or a CD8a stalk. In particular embodiments, a human IgGl spacer may be altered to remove Fc binding motifs. In some embodiments, the spacer domain may be derived from a human protein.
4. TRANSDUCTION ENHANCER TRANSMEMBRANE DOMAINS
In particular embodiments, the transduction enhancer comprises a transmembrane domain that tethers the transduction enhancer and/or cytokine-based transduction enhancer
to the membrane. In particular embodiments, the transmembrane domain comprises a hydrophobic alpha helix. In particular embodiments, the transmembrane domain may be derived from CD3, CD4, CD8a, or CD28. In some embodiments, the transmembrane domain is derived from a human protein.
In some embodiments, a transduction enhancer does not comprise a transmembrane domain but instead comprises a membrane-targeting domain such as a GPI anchor. GPI anchoring is a post-translational modification which occurs in the endoplasmic reticulum. Preassembled GPI anchor precursors are transferred to proteins bearing a C-terminal GPI signal sequence. During processing, the GPI anchor replaces the GPI signal sequence and is linked to the target protein via an amide bond. The GPI anchor targets the mature protein to the membrane. In some embodiments, the present tagging protein comprises a GPI signal sequence.
5. CYTOKINE-BASED TRANSDUCTION ENHANCERS
In particular embodiments, a recombinant retrovirus or retroviral particle contemplated herein comprises a viral envelope comprising or expressing a cytokine-based transduction enhancer. In some embodiments, the cytokine-based transduction enhancer is derived from the host cell during viral vector production. In some embodiments, the cytokine-based transduction enhancer is made by the host cell and expressed at the cell surface. When the nascent retroviral vector particle buds from the host cell membrane, the cytokine-based transduction enhancer may be incorporated in the viral envelope as part of the packaging cell-derived lipid bilayer.
In particular embodiments, the cytokine-based transduction enhancer comprises a cytokine domain and a transmembrane domain. It may have the structure C-S-TM, where C is the cytokine domain, S is an optional spacer domain and TM is the transmembrane domain. The spacer domain and transmembrane domains are as defined above.
6. TRANSDUCTION ENHANCER CYTOKINE DOMAINS
In particular embodiments, a cytokine domain comprises part, or all, of a T cell activating cytokine. Illustrative examples of cytokine domains suitable for use in particular embodiments contemplated herein include but are not limited to those isolated or obtained from IL2, IL7, and IL15. In particular embodiments, a cytokine domain comprises a fragment of a cytokine that binds to its cognate receptor and activates T cells.
7. VIRAL VECTORS COMPRISING TRANSDUCTION ENHANCERS
In particular embodiments, a recombinant retrovirus or lentivirus comprises a viral envelope comprising or expression one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity, a non-viral membranebound tropism polypeptide, a mitogenic transduction enhancer which comprises a mitogenic domain and a transmembrane domain; and/or a cytokine-based transduction enhancer which comprises a cytokine domain and a transmembrane domain.
In particular embodiments, a recombinant retrovirus or lentivirus comprises a viral envelope comprising or expression one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity; a non-viral membranebound tropism polypeptide; a mitogenic transduction enhancer having the structure: M-S- TM, in which M is a mitogenic domain; S is an optional spacer domain and TM is a transmembrane domain; and/or a cytokine-based transduction enhancer comprising a cytokine domain and a transmembrane domain.
In particular embodiments, the mitogenic transduction enhancer binds an activating T cell surface antigen, e.g., the alpha or beta chains of a TCR, CD28, CD 134, CD 137, CD278. In particular embodiments, the mitogenic transduction enhancer comprises an agonist for such an activating T cell surface antigen.
In particular embodiments, the mitogenic transduction enhancer comprises the binding domain from an antibody such as 9.3, 15E8, TGN1412; or a costimulatory molecule such as OX40L, 4-1BBL, or ICOSL.
In particular embodiments, a recombinant retrovirus or lentivirus comprises a viral envelope comprising or expressing one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity, a non-viral membranebound tropism polypeptide, and two or more mitogenic transduction enhancers. In one embodiment, a recombinant retrovirus or lentivirus comprises a viral envelope comprising or expressing one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity, a non-viral membrane-bound tropism polypeptide that binds CD3 (e.g., CD3s) and a mitogenic transduction enhancer that binds CD28.
In particular embodiments, a recombinant retrovirus or lentivirus comprises a viral envelope comprising or expressing one or more mutated viral envelope glycoproteins that
retain fusogenic activity and lack cognate receptor binding activity, a non-viral membranebound tropism polypeptide that binds CD3; and a mitogenic transduction enhancer that binds CD28.
In particular embodiments, a recombinant retrovirus or lentivirus comprises a viral envelope comprising or expressing one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity, a non-viral membranebound tropism polypeptide that binds CD3; a mitogenic transduction enhancer that binds CD28; and a cytokine-based transduction enhancer comprising IL2.
In particular embodiments, a recombinant retrovirus or lentivirus comprises a viral envelope comprising or expressing one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity, a non-viral membranebound tropism polypeptide that binds CD3; a mitogenic transduction enhancer that binds CD28; and a cytokine-based transduction enhancer comprising IL7; and/or a cytokinebased transduction enhancer comprising IL15.
E. T CELL/NK CELL/NKT CELL ACTIVATION RECEPTORS
The disclosure contemplates, in part, a recombinant retrovirus or retroviral particle that comprises a viral envelope engineered for in vivo transduction and retroviral vectors and/or polynucleotides encoding one or more components of a T cell/NK cell/NKT cell activation receptors. Without wishing to be bound by any particular theory, it is contemplated that it may be advantageous in particular embodiments to control expansion of transduced immune effector cells in the body. In particular embodiments, the regulation of in vivo expansion of transduced immune effector cells could serve as a failsafe to guard again excessive cell expansion. In particular embodiments, transduced immune effector cells may be expanded in vivo for therapeutic purposes.
As used herein, the term “T cell/NK cell/NKT cell activation receptors” refers to one or more polypeptide components comprising a multimerization binding domain, a transmembrane domain and an intracellular signaling domain that are engineered to be expressed on the cell surface of transduced immune effector cells, such that the T cell/NK cell/NKT cell/NKT cell activation receptor provides a mitogenic signal to the transduced immune effector cell. The present methods can be adapted for use with other cell types by use of an activation receptor that retains activity in another cell type. T cell/NK cell/NKT cell activation receptors useful here may include a signaling domain that is a cytokine
receptor signaling domain, a co- stimulatory receptor signaling domain, a T cell receptor subunit signaling domain, an NK cell receptor subunit signaling domain, a growth factor receptor signaling domain, or the like.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor comprises one or more polypeptide components that each comprise a multimerization domain, the multimerization domains specifically associate with one another through binding to a small molecule. A “multimerization domain,” as used herein, refers to a domain that preferentially interacts or associates with another different domain directly or via a small molecule, wherein the interaction of different multimerization domains substantially contributes to or efficiently promotes multimerization (i.e., the formation of a dimer, trimer, or multipartite complex, which may be a homodimer, heterodimer, homotrimer, heterotrimer, homomultimer, heteromultimer). A multimerization domain may be derived either from a natural, synthetic, semi-synthetic, or recombinant source.
Illustrative examples of multimerization domains suitable for use in particular embodiments contemplated herein include an FKBP polypeptide (e.g., FKBP F36V, FKBP 12), an FRB polypeptide (e.g., FRB T2098L), a calcineurin polypeptide, a cyclophilin polypeptide, a bacterial DHFR polypeptide, a PYL1 polypeptide, an ABI1 polypeptide, a GIB 1 polypeptide, a GAI polypeptide, or homologs or variants thereof.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor comprises a transmembrane domain that anchors one or more polypeptide components of the T cell/NK cell/NKT cell activation receptor to the plasma membrane of a cell. The transmembrane domain may be derived either from a natural, synthetic, semi-synthetic, or recombinant source. Illustrative examples of transmembrane domains suitable for use in one or more components of the T ccll/N K cell/NKT cell activation receptor contemplated herein may be independently selected and include but are not limited to those isolated or obtained from IL-2 Ry, IL-2RP, IL-7Ra, IL-12Rpi, IL-12RP2, IL-21R, IFNRal, IFNRa2, CD4 or CD8a.
Association of the two or more polypeptide components of a T cell/NK cell/NKT cell activation receptor is mediated by a small molecule. The small molecule associates with and is disposed between two or more multimerization domains of the polypeptide components of a T cell/NK cell/NKT cell activation receptor. In particular embodiments, multimerization domains substantially contribute to or efficiently promote formation of a polypeptide complex only in the presence of a small molecule. In particular embodiments,
multimerization domains do not contribute to or do not efficiently promote formation of a polypeptide complex in the absence of a small molecule.
Illustrative examples of small molecules suitable for use in particular embodiments contemplated herein include, but are not limited to rapamycin (sirolimus) or a rapalog thereof, coumermycin or a derivative thereof, gibberellin or a derivative thereof, abscisic acid (ABA) or a derivative thereof, methotrexate or a derivative thereof, cyclosporin A or a derivative thereof, FKCsA or a derivative thereof, trimethoprim (Tmp)-synthetic ligand for FKBP (SLF) or a derivative thereof, HaXS, TMP-HTag, and ABT-737 or functional derivatives thereof or any combination thereof.
In particular embodiments, a small molecule is rapamycin or a rapamycin analog (rapalog).
Rapamycin analogs (rapalogs) include but are not limited to those disclosed in U.S. Pat. No. 6,649,595, which rapalog structures are incorporated herein by reference in their entirety. In certain embodiments, a bridging factor is a rapalog with substantially reduced immunosuppressive effect as compared to rapamycin. In a particular embodiment, the rapalog is AP21967 derivatives (also known as C-16-(S)-7-methylindolerapamycin, IC50=10 nM, a chemically modified non-immunosuppressive rapamycin analogue).
Other illustrative examples of rapalogs include, but are not limited to FK1012, FK506, deforolimus, everolimus, novolimus, pimecrolimus, ridaforolimus, tacrolimus, temsirolimus, umirolimus, and zotarolimus.
In one embodiment, one polypeptide component of a T cell/NK cell/NKT cell activation receptor comprises an FRB T2098L multimerization domain, another polypeptide component of a T ccll/N K ccll/N KT cell activation receptor comprises an FKBP12 multimerization domain, and the small molecule that mediates heterodimerization of the components, formation of the complex and activation of the receptor is rapalog AP21967.
In another embodiment, one polypeptide component of a T cell/NK cell/NKT cell activation receptor comprises an FRB multimerization domain, another polypeptide component of a T cell/NK cell/NKT cell activation receptor comprises an FKBP12 multimerization domain, and the small molecule that mediates heterodimerization of the components, formation of the complex and activation of the receptor is rapamycin, temsirolimus or everolimus.
In another embodiment, both polypeptide components of a T ccll/N K ccll/N KT cell activation receptor comprise an FKBP multimerization domain, and the small molecule that mediates homodimerization of the components, formation of the complex and activation of the receptor is FK1012.
In another embodiment, both polypeptide components of a T cell/NK ccll/N KT cell activation receptor comprise an FKBP F36V multimerization domain, and the small molecule that mediates homodimerization of the components, formation of the complex and activation of the receptor is API 903.
Other illustrative examples of multimerization domain pairs suitable for use in a T cell/NK ccll/N KT cell activation receptor contemplated in particular embodiments include but are not limited to include from FKBP and FRB, FKBP and calcineurin, FKBP and cyclophilin, FKBP and bacterial DHFR, calcineurin and cyclophilin, PYL1 and ABI1, or GIB 1 and GAI, or variants thereof.
In particular embodiments, each component of a T ccll/N K cell/NKT cell activation receptor comprises one or more intracellular signaling domains. In particular embodiments, an intracellular signaling domain comprises a common cytokine receptor gamma chain or a common cytokine receptor beta chain.
In particular embodiments, an intracellular signaling domain comprises an ITAM or a tyrosine capable of binding an SH2-domain when the tyrosine is phosphorylated.
In particular embodiments, an intracellular signaling domain comprises one or more intracellular signaling domains isolated or obtained from CD28, OX-40, 4- IBB, CD2, CD7, CD27, CD30, CD40, Programmed Death- 1 (PD-1), inducible T cell co-stimulator (ICOS), lymphocyte function-associated antigen-1 (LFA-1), CD3y, CD35, CD3s, CD3^, CD247, CD276 (B7-H3), FIGHT, TNFSF14, NKG2C, CD79a, DAP- 10, Fc gamma receptor, a Toll like receptor, TGFpRI, TGFpRII, myd88, CD40, IL-2Ry, IL-2RP, IL-7Ra, IL-12R 1, IL-12R02, IL-21R, IFNRal, IFNRa2, and the like.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing an IL2/IL15 signal comprises a first polypeptide component comprising an IL- 2Ry endodomain and a second polypeptide component comprising an IL-2RP endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing an IL7 signal comprises a first polypeptide component comprising an IL-2RY endodomain and a second polypeptide component comprising an IL-7Ra endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing an IL 12 signal comprises a first polypeptide component comprising an IL- 12Rpi endodomain and a second polypeptide component comprising an IL-12RP2 endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing an IL21 signal comprises a first polypeptide component comprising an IL-2Ry endodomain, and a second polypeptide component comprising an IL-21R endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing a Type 1 Interferon (IFN) signal comprises a first polypeptide component comprising an IFNRal endodomain, and a second polypeptide component comprising an IFNRa2 endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing an IL2/IL15 signal comprises a first polypeptide component comprising a functional FRB domain, a transmembrane domain, and an IL-2Ry endodomain and a second polypeptide component comprising a functional FKPB domain, a transmembrane domain and an IL-2RP endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing an IL7 signal comprises a first polypeptide component comprising a functional FRB domain, a transmembrane domain, and an IL-2Ry endodomain and a second polypeptide component comprising a functional FKPB domain, a transmembrane domain and an IL-7Ra endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing an IL 12 signal comprises a first polypeptide component comprising a functional FRB domain, a transmembrane domain, and an IL-12RP1 endodomain and a second polypeptide component comprising a functional FKPB domain, a transmembrane domain and an IL-12RP2 endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing an IL21 signal comprises a first polypeptide component comprising a functional FRB domain, a transmembrane domain, and an IL-2Ry endodomain, and a second polypeptide component comprising a functional FKPB domain, a transmembrane domain and an IL-21R endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing a Type 1 Interferon (IFN) signal comprises a first polypeptide component
comprising a functional FRB domain, a transmembrane domain, and an IFNRal endodomain, and a second polypeptide component comprising a functional FKPB domain, a transmembrane domain and an IFNRa2 endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing an IL2/IL15 signal comprises a first polypeptide component comprising a functional FKPB domain, a transmembrane domain, and an IL-2Ry endodomain and a second polypeptide component comprising a functional FRB domain, a transmembrane domain and an IL-2RP endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing an IL7 signal comprises a first polypeptide component comprising a functional FKPB domain, a transmembrane domain, and an IL-2Ry endodomain and a second polypeptide component comprising a functional FRB domain, a transmembrane domain and an IL-7Ra endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing an IL 12 signal comprises a first polypeptide component comprising a functional FKPB domain, a transmembrane domain, and an IL-12RP1 endodomain and a second polypeptide component comprising a functional FRB domain, a transmembrane domain and an IL-12RP2 endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing an IL21 signal comprises a first polypeptide component comprising a functional FKPB domain, a transmembrane domain, and an IL-2RY endodomain, and a second polypeptide component comprising a functional FRB domain, a transmembrane domain and an IL-21R endodomain.
In particular embodiments, a T cell/NK cell/NKT cell activation receptor capable of transducing a Type 1 Interferon (IFN) signal comprises a first polypeptide component comprising a functional FKPB domain, a transmembrane domain, and an IFNRal endodomain, and a second polypeptide component comprising a functional FRB domain, a transmembrane domain and an IFNRa2 endodomain.
F. CHIMERIC ANTIGEN RECEPTORS
In particular embodiments, a recombinant vims contemplated herein comprises a retroviral vector encoding a CAR. A “chimeric antigen receptor” or “CAR” refers to a synthetically designed receptor comprising an antigen binding domain of an antibody or
other protein sequence that binds to a molecule expressed or displayed on a target cell (e.g., a cancer cell), a transmembrane domain, one or more intracellular signaling domains, e.g., one or more co- stimulatory domains and/or a primary signaling domain. The antigen binding domain is linked via a hinge domain to a transmembrane domain which is in turn linked, optionally by a spacer or linker domain, to one or more T cell intracellular signaling domains. CARs are engineered antigen receptors that can enable an immune receptor cell specifically recognize a target cell. In particular embodiments, the hinge or spaccr/linkcr domain(s) are selected (e.g., for a particular length of amino acids) to achieve desired binding and/or functional characteristics of the CAR. a. Antigen Binding Domain
In particular embodiments, the antigen binding fragment comprises a Camel Ig, a Llama Ig, an Alpaca Ig, Ig NAR, a Fab' fragment, a F(ab')2 fragment, a bispecific Fab dimer (Fab2), a trispecific Fab trimer (Fab3), an Fv, an single chain Fv protein (“scFv”), a bis-scFv, (scFv)2, a minibody, a diabody, a triabody, a tetrabody, a disulfide stabilized Fv protein (“dsFv”), a single-domain antibody (sdAb, a camelid VHH, Nanobody) or centyrin.
In particular embodiments, the antigen binding domain comprises an scFv or one or more VHHs.
In particular embodiments, the antigen binding domain binds an antigen selected from the group consisting of: FRa, avP6 integrin, BCMA, CD276, B7-H6, CAIX, CD 16, CD19, CD20, CD22, CD30, CD33, CD37, CD38, CD44, CD44v6, CD44v7/8, CD70, CD79a, CD79b, CD123, CD133, CD138, CD171, CEA, CLL-1, CS-1, CSPG4, CTAGE1, EGER, EGFRvin, EGP2, EGP40, EPCAM, EPHA2, FAP, FCRL5, AchR, GD2, GD3, GPC3, GPCR5D, HER2, IL-lORa, IL-13Ra2, LAGE-1A, Lambda, LeY, Ll-CAM, MAGE-A1, MAGE- A3, MAGE-A4, MAGE-A6, MAGE A10, MelanA or MARTI, MSLN, MUC1, MUC16, MICA, MICB, NCAM, NY-ESO-1, PLAC1, PRAME, PSCA, PSMA, R0R1, SSX2, Survivin, TAG72, TEM1/CD248, TEM7R, TPBG, ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, ULBP6, VEGFR2, and WT-1.
In particular embodiments, the antigen is expressed on a cancer cell of a multiple myeloma, a smoldering multiple myeloma, a monoclonal gammopathy of undetermined significance (MGUS), an acute lymphoblastic leukemia (ALL), a diffuse large B-cell lymphoma (DLBCL), a Burkitt's lymphoma (BL), a follicular lymphoma (FL), a mantle-
cell lymphoma (MCL), Waldenstrom's macroglobulinema, a plasma cell leukemia, a light chain amyloidosis (AL), a precursor B-cell lymphoblastic leukemia, a precursor B-cell lymphoblastic leukemia, an acute myeloid leukemia (AML), a myelodysplastic syndrome (MDS), a chronic lymphocytic leukemia (CLL), a B cell malignancy, a chronic myeloid leukemia (CML), a hairy cell leukemia (HCL), a blastic plasmacytoid dendritic cell neoplasm, Hodgkin’s lymphoma, nonHodgkin’s lymphoma, a marginal zone B-cell lymphoma (MZL), a mucosa-associated lymphatic tissue lymphoma (MALT), plasma cell leukemia, anaplastic large-cell lymphoma (ALCL), leukemia or lymphoma.
In particular embodiments, the antigen is expressed on a cancer cell of a prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, melanoma, esophageal cancer, gastric cancer, stomach cancer, renal carcinoma, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma, glioblastoma, colorectal cancer, thyroid cancer, epithelial cancers, or adenocarcinomas . b. Linkers
In particular embodiments, a CAR comprises a linker positioned between the extracellular domain and the transmembrane domain, optionally wherein the linker is about 2 to 100 amino acids in length. The linker can include or be composed of flexible residues such as glycine and serine so that the adjacent protein domains are free to move relative to one another. Longer linkers may be used, e.g., when it is desirable to ensure that two adjacent domains do not sterically interfere with one another. Linkers may be cleavable or non-cleavable. Examples of cleavable linkers include 2A linkers (for example T2A), 2A- like linkers or functional equivalents thereof and combinations thereof.
In particular embodiments, the linker is P2A self-cleaving peptide, a T2A selfcleaving peptide, an E2A self-cleaving peptide, or an IgG4 hinge region polypeptide. c. Transmembrane Domain
The transmembrane region can be any transmembrane region that can be incorporated into a functional CAR. Illustrative examples of transmembrane (TM) domains for use in CARs contemplated herein may be isolated, obtained, or derived from
polypeptides including, but not limited to the alpha, beta, gamma, or delta chain of the T- cell receptor, CD2, CD3, CD4, CD8a, and CD28 d. Intracellular Signaling Domain
In particular embodiments, a CAR comprises one or more intracellular signaling domains. In particular embodiments, a CAR comprises a costimulatory signaling domain and a primary signaling domain.
Illustrative examples of primary signaling domains suitable for use in CARs contemplated herein may be isolated, obtained, or derived from polypeptides including, but not limited to FcRy, FcRp, CD3^, CD79a, CD79b, and CD66d.
Illustrative examples of costimulatory domains suitable for use in CARs contemplated herein may be isolated, obtained, or derived from polypeptides including, but not limited to CD2, CD7, CD1 la, CD27, CD28, CD30, CD40, CD134 (0X40), CD137 (4- 1BB), CD278 (ICOS), and TNF receptor superfamily member 14 (TNFRS14).
In particular embodiments, the viral vector encodes a CAR comprising an antigen binding domain that binds CD19, CD20, CD22, CD38, CD79A, CD79B, GPCR5D, or BCMA, an IgG4 linker, a CD28 derived transmembrane domain, a 4- IBB costimulatory domain, and a CD3^ primary signaling domain.
2. DARICS
In particular embodiments, a recombinant vims contemplated herein comprises a retroviral vector encoding a dimerization activated receptor initiation complex (DARIC). A DARIC provides a binding component and a signaling component that are each expressed as separate fusion proteins comprising an extracellular multimerization domain. The multimerization domains of the components associate by binding to a bridging factor (see U.S. Pat. Appl. No. 2016/0311901, which is incorporated herein by reference in its
entirety). Although the bridging factor leads to formation of the DARIC system components, formation of the DARIC complex does not produce significant signaling on its own. The described DARIC complexes contemplated herein only initiate physiologically relevant signals when the DARIC binding component binds to a target antigen e.g., CD19, CD20, CD22, CD38, CD79A, CD79B, GPCR5D, or BCMA) expressed or displayed on a target cell. In particular embodiments, a DARIC binding component comprises an antigen binding domain that binds to CD19, CD20, CD22, CD38, CD79A, CD79B, GPCR5D, or BCMA.
G. EXPRESSION CONTROL SEQUENCES
The present disclosure further contemplates, in part, retroviral vectors comprising or encoding one or more expression control sequences, e.g., promoters, enhancers, PTE and/or polyA signals, specific to T cells, NK cells, and/or NKT cells. One or more expression control sequences can be operatively linked to a polynucleotide encoding a T cell/NK cell/NKT cell activation receptor, CAR, and/or a DARIC, generally by inserting the expression control sequence 5' and/or 3' to the polynucleotide encoding the T cell/NK cell/NKT cell activation receptor.
Illustrative examples of promoters suitable for use in particular embodiments contemplated herein include but are not limited to a T cell specific promoter, a CD4 T cell specific promoter, a CD8 T cell specific promoter, an NK cell specific promoter, a T cell and NK cell specific promoter, a CD4 T cell and NK cell specific promoter, and a CD8 T cell and NK cell specific promoter.
Further illustrative examples of promoters suitable for use in particular embodiments contemplated herein include but are not limited to an EFla promoter, a cytomegalovirus (CMV) promoter, a CAG promoter, an SV40 promoter, an SV40/CD43 promoter, a murine stem cell virus (MSCV) promoter, a phosphoglycerate kinase (PGK) promoter, and an MNDU3 promoter.
In particular embodiments, the promoter may be a synthetic promoter or an inducible promoter.
In particular embodiments, the expression control sequence is a post-transcriptional element. In particular embodiments, the post-transcriptional element is placed 3 ' of the polynucleotide encoding a polypeptide to be expressed in a target cell, e.g., an immune effector cell. In particular embodiments, the post-transcriptional element is a woodchuck
post-transcriptional regulatory element (WPRE) or hepatitis B virus post-transcriptional regulatory element (HPRE).
In particular embodiments, a retroviral vector comprises one or more polynucleotides encoding one or more polypeptides, wherein a polynucleotide sequence encoding a 2A peptide is disposed between polynucleotides each encoding a polypeptide.
Illustrative examples of 2A peptide amino acid sequences include but are not limited to RAEGRGSLLTCGDVEENPGP (SEQ ID NO: 94) and QCTNYALLKLAGDVESNPGP (SEQ ID NO: 95).
H. RESISTANCE TO IMMUNOSUPPRESSIVE DRUGS
In particular embodiments, a recombinant vims contemplated herein comprises a retroviral vector comprising a polynucleotide that encodes a polypeptide that provides resistance to an immunosuppressive drug. A polypeptide that provides resistance to an immunosuppressive drug will, in some cases, facilitate selective expansion of target cells when the immunosuppressive drug is administered to a patient during any of the methods for treating a subject or any of the methods for expanding T cells capable of recognizing and killing tumor cells in a subject in need thereof provided by the present disclosure.
In particular embodiments, the immunosuppressive drug is methotrexate, rapamycin, a rapalog, tacrolimus, cyclosporine, or any combination thereof. The immunosuppressive drug may be the same as, or different from, the small molecule that induces the activity of the T cell/NK cell/NKT cell activation receptors. In particular embodiments, it may be advantageous to design the retroviral vector to permit control of transduced cell expansion independent of immunosuppression.
In particular embodiments, a retroviral vector encoding a polypeptide that provides resistance to an immunosuppressive drug facilitates selective expansion of target cells by conferring resistance to an immunosuppressive drug to transduced cells and facilitates selective expansion of target cells.
Illustrative examples of immunosuppressive drugs suitable for use in particular embodiments contemplated herein include, but are not limited to, rapamycin or a derivative thereof, a rapalog or a derivative thereof, tacrolimus or a derivative thereof, cyclosporine or a derivative thereof, methotrexate or derivatives thereof, and mycophenolate mofetil (MMF) or derivatives thereof. FRB mediates resistance to rapamycin; calcineurin mutant CNa22 or calcineurin mutant CNb30 mediates resistance to tacrolimus; calcineurin mutant
CNal2 or calcineurin mutant CNb30 mediates resistance to cyclosporine; dihydrofolate reductase (DHFR) mediates resistance to methotrexate; and various inosine monophosphate dehydrogenase (IMPDH) mutants mediate resistance to MMF.
In particular embodiments, an immunosuppressive drug is administered in the methods of prevention, treatment, or amelioration contemplated herein and may improve treatment outcomes and/or diminish side effects of treatment, including, but not limited to, acute graft-versus-host disease, chronic graft-versus-host disease, and post-transplant lymphoproliferative disease.
I. PACKAGING CELL LINES
The present disclosure also provides a host cell for the production of recombinant retrovirus or retroviral particles. In particular embodiments, a host cell expresses a mitogenic transduction enhancer and/or a cytokine-based transduction enhancer at the cell surface. In particular embodiments, a host cell produces a recombinant retrovirus or retroviral particle according to the foregoing embodiments. In particular embodiments, a host cell is engineered to express one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity and/or one or more non-viral membrane-bound tropism polypeptides and/or one or more transduction enhancers and/or a cytokine-based transduction enhancers. In particular embodiments, the host cell is modified to lack MHC class I expression and/or MHC class II expression and/or expression of one or more checkpoint inhibitors.
In particular embodiments, a host cell is a packaging cell and comprises one or more genes encoding: gag, pol, an envelope polypeptide (e.g., one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity), one or more non-viral membrane bound tropism polypeptides, and rev. In particular embodiments, a packaging cell for producing recombinant retrovirus or retroviral particles comprises genes encoding gag, pol, one or more non-viral membrane bound tropism polypeptides, and an envelope polypeptide (e.g., one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity). In particular embodiments, a packaging cell for producing recombinant lentivirus or lentiviral particles comprises genes encoding gag, pol, an envelope polypeptide (e.g., one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack
cognate receptor binding activity), one or more non-viral membrane bound tropism polypeptides, and rev.
In particular embodiments, a host cell is a producer cell and comprises genes encoding gag, pol, an envelope polypeptide (e.g., one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity), one or more non-viral membrane bound tropism polypeptides, and optionally rev and further comprises a retroviral vector or lentiviral vector encoding a T cell/NK cell/NKT cell activation receptor, CAR, DARIC, or other polypeptide to be expressed in the transduced immune effector cell. In particular embodiments, the viral vector is replication-defective, the vector is capable of integrating its genome into a target cell genome but is unable to propagate itself due to a lack of structural proteins.
Packaging cells are used to propagate and isolate quantities of viral vectors, i.e., to prepare suitable titers of the retroviral vector for transduction of a target cell.
In particular embodiments, propagation and isolation comprise isolation of genes encoding a retroviral gag-pol, an envelope polypeptide (e.g., one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity), one or more non-viral membrane bound tropism polypeptides, (and in the case of lentivirus, rev) and introduction of these genes into a host cell to produce a packaging cell line. The packaging cell line produces accessory proteins required for packaging retroviral RNA and when a recombinant vector carrying a psi region is introduced into the packaging cell line, the accessory proteins can package the psi-positive recombinant vector to produce the recombinant viral particles.
A summary of the available packaging lines is presented in “Retroviruses” (1997 Cold Spring Harbor Laboratory Press Eds: JM Coffin, SM Hughes, HE Varmus pp 449).
Packaging cells have also been developed in which separate expression plasmids encoding gag, pol and an envelope polypeptide (e.g., one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity), one or more non-viral membrane bound tropism polypeptides, (and, in the case of lentiviral vectors, rev) are independently transfected into a packaging cell line.
Transient transfection avoids the longer time required to generate stable vectorproducing cell lines. In one embodiment, transient transfection is because the vector or retroviral packaging components are toxic to the packaging cells. Components typically used to generate retroviral/lentiviral particles include a plasmid encoding gag/pol
polypeptides, a plasmid encoding an envelope polypeptide (e.g., one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity), a plasmid encoding one or more non- viral membrane bound tropism polypeptides, and in the case of lentiviral vectors, a plasmid encoding the rev polypeptide, and a plasmid encoding the rctroviral/lcnti viral vector genomic RNA encoding a T cell/NK cell/NKT cell activation receptor, CAR, DARIC, or other polypeptide to be expressed in a transduced immune effector cell. In a particular embodiment, virus production involves transient transfection of one or more of these components into host cells comprising the other components required producing virus. In particular embodiments, packaging cells are selected from any mammalian cell type capable of producing retroviral/lentiviral vector particles. In particular embodiments, the packaging cells are 293T cells, or variants of 293T cells which have been adapted to grow in suspension without serum.
In particular embodiments, packaging cells are made by transient transfection with a transfer vector (a polynucleotide encoding a viral vector) and one or more expression vectors encoding gag-pol, one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity, one or more tropism polypeptides, and optionally rev and/or one or more transduction enhancers.
In particular embodiments, a host cell or packaging cell expresses one or more tropism polypeptides and/or transduction enhancers at the cell surface.
In particular embodiments, a host cell or packaging cell comprises or expresses at the cell surface: a mitogenic transduction enhancer comprising a mitogenic domain and a transmembrane domain; and/or a cytokine-based transduction enhancer which comprises a cytokine domain and a transmembrane domain; and/or a tropism polypeptide.
In particular embodiments, a host cell refers to packaging cell or a producer cell.
J. PHARMACEUTICAL COMPOSITIONS AND FORMULATIONS
Formulations and compositions contemplated herein comprise a recombinant retrovirus or a combination of any number of retroviral particles, polypeptides, polynucleotides, small molecules and formulated in pharmaceutically acceptable or physiologically-acceptable compositions for administration to a cell, tissue, organ, or an animal, either alone, or in combination with one or more other modalities of therapy. In particular embodiments, the one or more additional pharmaceutical agents further increases transduction efficiency of viral particles.
In particular embodiments a composition comprises a therapeutically effective amount of a retroviral particle formulated with one or more pharmaceutically acceptable carriers, diluents, excipients or stabilizers, in the form of lyophilized formulations or aqueous solutions. In some embodiments, one or more pharmaceutically acceptable surface-active agents (surfactant), buffers, isotonicity agents, salts, amino acids, sugars, stabilizers and/or antioxidant are used in the formulation.
In some embodiments, the composition further comprises other agents, such as, e.g., cytokines, growth factors, hormones, small molecules or various pharmaceutically active agents.
Suitable pharmaceutically acceptable surfactants comprise but are not limited to polyethylene-sorbitan-fatty acid esters, polyethylene-polypropylene glycols, polyoxyethylene- stearates and sodium dodecyl sulphates. Suitable buffers comprise but are not limited to histidine-buffers, citrate-buffers, succinate-buffers, acetate-buffers and phosphate-buffers.
Isotonicity agents are used to provide an isotonic formulation. Suitable isotonicity agents comprise but are not limited to salts, including but not limited to sodium chloride (NaCl) or potassium chloride, sugars including but not limited to glucose, sucrose, trehalose or and any component from the group of amino acids, sugars, salts and combinations thereof. In some embodiments, isotonicity agents are generally used in a total amount of about 5 mM to about 350 mM.
“Pharmaceutically acceptable” refers to molecular entities and compositions that do not produce an allergic or similar untoward reaction when administered to a human.
The term “carrier” includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like.
A “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible, including pharmaceutically acceptable cell culture media. In some embodiments, a composition comprising a carrier is suitable for parenteral administration, e.g., intravascular (intravenous or intraarterial), intraperitoneal or intramuscular administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
The compositions may further comprise one or more polypeptides, polynucleotides, or compounds that increase the transduction efficiency, formulated in pharmaceutically acceptable or physiologically-acceptable solutions for administration to a cell or an animal, either alone, or in combination with one or more other modalities of therapy.
The pharmaceutical compositions that contain a recombinant retrovirus or retroviral particle comprising an expression cassette or vector may be in any form that is suitable for the selected mode of administration, for example, for intraventricular, intramyocardial, intracoronary, intravenous, intra-arterial, intra-renal, intraurethral, epidural, intrathecal, intraperitoneal, or intramuscular administration. The recombinant vims can be administered, as sole active agent, or in combination with other active agents, in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings. In some embodiments, the pharmaceutical composition comprises cells transduced ex vivo with any of the particles contemplated herein.
In particular embodiments, a recombinant retrovirus or retroviral particle (e.g., lentiviral particle), or a pharmaceutical composition comprising a retroviral particle, is effective when administered systemically (e.g., intravenously). In certain embodiments, the retroviral vectors induce expression of CAR in transduced immune cells when a recombinant retrovirus is administered systemically.
In various embodiments, the pharmaceutical compositions contain vehicles (e.g., carriers, diluents and excipients) that are pharmaceutically acceptable for a formulation capable of being injected. Exemplary excipients include a poloxamer. Formulation buffers for viral particles generally contain salts to prevent aggregation and other excipients (e.g., poloxamer) to reduce stickiness of the viral particle. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze- dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. In particular embodiments, the formulation is stable for storage and use when frozen (e.g., at less than 0°C, about -60°C, or about -72°C). In some embodiments, the formulation is a cryopreserved solution.
In particular embodiments, compositions are formulated for in vivo administration.
The pharmaceutical compositions of the present disclosure, formulation of pharmaceutically acceptable excipients and carrier solutions is well-known to those of skill
in the art, as is the development of suitable dosing and treatment regimens for using the particular compositions described herein in a variety of treatment regimens, including e.g., oral, parenteral, intravenous, intranasal, intraperitoneal, and intramuscular administration and formulation. In certain embodiments, compositions contemplated herein are administered parenterally, intravenously, intramuscularly, or intraperitoneally.
A recombinant retrovirus may be used to transduce cells in vivo at an any effective dosage. In particular embodiments, a recombinant retrovirus is administered to a subject in vivo, by direct injection to the cell, tissue, organ or subject in need of therapy.
A recombinant retrovirus may also be delivered according to viral titer (TU/mL). The amount of retrovirus directly injected is determined by total TU and can vary based on both the volume that could be feasibly injected to the site and the type of tissue to be injected. In particular embodiments, the viral titer delivered is about 1 x 109 to about 1 x 1012 TU. Systemic delivery may accommodate a much larger TU, a load of about 1 x IO10 to about 1 x 1015.
In particular embodiments, a recombinant retrovirus is administered at a dose of between about 1 x 1012 and 5xl015 vector genomes (vg) of the vector per kilogram (vg) of total body mass of the subject (vg/kg). In particular embodiments, a recombinant retrovirus is administered at a dose of between about 1 x 1012 and 5xl015 vector particles (vp) of the vector per kilogram (vp) of total body mass of the subject (vp/kg).
Rapamune® (sirolimus, rapamycin) is available as an oral solution or tablet and is FDA approved. Per the US Prescribing Information (USPI), rapamycin is available in 1 mg/mL oral solution or 0.5, 1, or 2 mg tablets and is to be administered once daily. Rapamycin or rapalogs may also be delivered in other dosage forms and/or by other administration routes. In particular embodiments, rapamycin is administered at a dose of between about 0.1 mg/m2 and 100 mg/m2 of surface area of the subject. In particular embodiments, rapamycin is administered at a dose of between about 0.001 mg/m2 and 100 mg/m2 of surface area of the subject.
In particular embodiments, a dose of rapamycin is administered every day. In certain embodiments, a dose of rapamycin is administered about every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In some embodiments, a dose of rapamycin is administered about every 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks. In other embodiments, a dose of rapamycin is administered about every 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 months.
In particular embodiments, an amount of recombinant retrovirus is administered and a first dose of rapamycin is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, weeks, or months post administration of the recombinant retrovirus.
In particular embodiments, administration of rapamycin or rapalog increases the number immune effector cells transduced by a recombinant retrovirus. In certain embodiments, administration of rapamycin increases the number immune effector cells transduced by retroviral particles by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 1-fold, at least 2- fold, at least 3-fold, at least 5-fold, at least 7-fold, or at least 10-fold, in the subject. In particular embodiments, the increase is evaluated by the number of transduced immune effector cells 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks or months after the first dose of the rapamycin (once the viral particle is administered), wherein the reference number is the number of transduced immune cells on the day of the first dose of rapamycin.
In particular embodiments, a recombinant retrovirus is administered via a route selected from the group consisting of parenteral, intravenous, intramuscular, subcutanous, intratumoral, intraperitoneal, and intralymphatic. In particular embodiments, a recombinant retrovirus is administered multiple times.
In particular embodiments, a recombinant retrovirus is administered by intraperitoneal, subcutaneous, or intranodal injection.
In particular embodiments, a recombinant retrovirus is administered as a single injection. In some embodiments, the retroviral particle is administered as at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 injections.
K. METHODS OF USE
In various embodiments, a recombinant retrovirus and/or composition contemplated herein is used to treat, prevent, or ameliorate at least one symptom of a disease, disorder, or condition. In particular embodiments, the disease, disorder, or condition is cancer. In particular embodiments, the cancer is a hematological malignancy or a solid tumor. In particular embodiments, the subject has relapsed or is refractory to treatment with a prior anti-cancer therapeutic.
In some embodiments, the cancer is a hematological malignancy.
In particular embodiments, a recombinant retrovirus and/or composition contemplated herein treats, prevents, or ameliorates at least one symptom of a multiple myeloma, a smoldering multiple myeloma, a monoclonal gammopathy of undetermined significance (MGUS), an acute lymphoblastic leukemia (ALL), a diffuse large B-cell lymphoma (DLBCL), a Burkitt's lymphoma (BL), a follicular lymphoma (FL), a mantlecell lymphoma (MCL), Waldenstrom's macroglobulinema, a plasma cell leukemia, a light chain amyloidosis (AL), a precursor B-cell lymphoblastic leukemia, a precursor B-cell lymphoblastic leukemia, an acute myeloid leukemia (AML), a myelodysplastic syndrome (MDS), a chronic lymphocytic leukemia (CLL), a B cell malignancy, a chronic myeloid leukemia (CML), a hairy cell leukemia (HCL), a blastic plasmacytoid dendritic cell neoplasm, Hodgkin’s lymphoma, nonHodgkin’s lymphoma, a marginal zone B-cell lymphoma (MZL), a mucosa-associated lymphatic tissue lymphoma (MALT), plasma cell leukemia, anaplastic large-cell lymphoma (ALCL), leukemia or lymphoma.
In particular embodiments, a recombinant retrovirus and/or composition contemplated herein treats, prevents, or ameliorates at least one symptom of a B cell malignancy that expresses CD19, CD20, CD22, CD38, CD79A, CD79B, GPCR5D, and/or BCMA.
In particular embodiments, a recombinant retrovirus and/or composition contemplated herein treats, prevents, or ameliorates at least one symptom of a CD19- expressing B cell malignancy.
In particular embodiments, a recombinant retrovirus and/or composition contemplated herein treats, prevents, or ameliorates at least one symptom of a CD20- expressing B cell malignancy.
In particular embodiments, a recombinant retrovirus and/or composition contemplated herein treats, prevents, or ameliorates at least one symptom of a solid tumor.
In particular embodiments, a recombinant retrovirus and/or compositions contemplated herein treats, prevents, or ameliorates at least one symptom of prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, melanoma, esophageal cancer, gastric cancer, stomach cancer, renal carcinoma, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma, glioblastoma, colorectal cancer, thyroid cancer, epithelial cancers, or adenocarcinomas .
In particular embodiments, a recombinant retrovirus and/or composition contemplated herein is administered in combination with one or more anti-cancer therapies including, but not limited to, an autologous stem cell transplant (ASCT), radiation, surgery, a chemotherapeutic agent, an immunomodulatory agent and a targeted cancer therapy.
In particular embodiments, the one or more anti-cancer therapies is selected from the group consisting of 6-mercaptopurine, abiraterone, alemtuzumab, all-trans retinoic acid, anastrozole, aprepitant, arsenic trioxide, atezolizumab, azacytidine, bafetinib, bevacizumab, bleomycin, bortezomib, bosutinib, cabazitaxel, capecitabine, carboplatin, carfilzomib, cetuximab, cisplatin, cladribine, corticosteroid, crizotinib, cyclophosphamide, cytarabine, dasatinib, daunorubicin, danusertib, decitabine, denosumab, dexamethasone, docetaxel, doxorubicin, elotozumab, eribulin, erlotinib, etoposide, everolimus, exemestane, filgrastim, fludarabine, fluorouracil, fulvestrant, gemcitabine, hydroxyurea, idarubicin, imatinib, imiquimod, ipilimumab, ixabepilone, ixazomib, lapatinib, lenalidomide, letrozole, leuprolide, melphalan, methotrexate, mitoxantrone, nilotinib, nivolumab, oxaliplatin, paclitaxel, palonosetron, pembrolizumab, pemetrexed, pomalidomide, ponatinib, prednisone, radium-223, rituximab, saracatinib, sipuleucel-T, sorafenib, sunitinib, tamoxifen, temozolomide, temsirolimus, thalidomide, tinorelbine, topotecan, tozasertib, trastuzumab, vincristine, and zoledronic acid.
L. DEFINITIONS
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. For the purposes of the present invention, the following terms are defined below.
The singular articles “a,” “an,” and “the” refer to one or more (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one or more elements.
The use of the alternative (e.g., “or”) means either one, both, or any combination thereof of the alternatives.
The term “and/or” means either one, or both, of the alternatives.
As used herein, the term “about” or “approximately” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% to a reference
quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. In one embodiment, the term “about” or “approximately” refers a range of quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1% about a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.
Throughout this specification, unless the context requires otherwise, the words “comprise,” “comprises,” and “comprising” will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements. In particular embodiments, the terms “include,” “has,” “contains,” and “comprise” are used synonymously. By “consisting essentially of’ is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. By “consisting of is meant including, and limited to, whatever follows the phrase “consisting of.” Thus, the phrase “consisting of indicates that the listed elements are required or mandatory, and that no other elements may be present.
All publications and patents mentioned herein are hereby incorporated herein by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment, or any form of suggestion, that they constitute valid prior art or form part of the common general knowledge in any country in the world.
While illustrative embodiments have been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.
In general, in the following claims, the terms used should not be constmed to limit the claims to the specific embodiments disclosed in the specification and the claims but should be constmed to include all possible embodiments along with the full scope of
equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.
Claims
1. A recombinant retrovirus or retroviral particle for activating and efficiently transducing T cells, comprising:
(a) a viral envelope comprising (i) one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity and (ii) a non- viral membrane-bound tropism polypeptide, and
(b) a recombinant retroviral vector comprising a polynucleotide encoding a promoter operably linked to one or more polynucleotides encoding one or more components of an inducible T cell/NK cell/NKT cell activation receptor.
2. The recombinant retrovirus of claim 1, wherein the presence of a small molecule induces activation of the T cell/NK cell/NKT cell activation receptor.
3. The recombinant retrovirus of claim 1, wherein the recombinant retrovirus is a recombinant lentivirus.
4. The recombinant retrovirus of any one of claims 1 to 3, wherein the recombinant retrovirus is a recombinant lentivirus selected from the group consisting of: human immunodeficiency virus 1 (HIV-1); human immunodeficiency virus 2 (HIV-2), visna- maedi virus (VMV); caprine arthritis-encephalitis virus (CAEV); equine infectious anemia virus (EIAV); feline immunodeficiency virus (FIV); bovine immune deficiency virus (BIV); and simian immunodeficiency virus (SIV).
5. The recombinant retrovirus of any one of claims 1 to 4, wherein the one or more mutated viral envelope glycoproteins comprise a vesiculovirus envelope glycoprotein, one or more morbillivirus envelope glycoproteins or one or more henipavirus envelope glycoproteins.
6. The recombinant retrovirus of claim 5, wherein the vesiculovirus is selected from the group consisting of: vesicular stomatitis Alagoas virus (VSAV; Alagoas vesiculovirus), Carajas virus (CJSV; Carajas vesiculovirus), Chandipura virus (CHPV; Chandipura vesiculovirus), Cocal virus (COCV; Cocal vesiculovirus), vesicular stomatitis
Indiana virus (VSIV; Indiana vesiculovirus), Isfahan virus (ISFV; Isfahan vesiculovirus), Maraba virus (MARAV; Maraba vesiculovirus), Morreton virus (MORV; Morreton vesiculovirus), vesicular stomatitis New Jersey virus (VSNJV; New Jersey vesiculovirus), and Piry virus (PIRYV; Piry vesiculovirus).
7. The recombinant retrovirus of claim 5 or claim 6, wherein the vesiculovirus envelope glycoprotein is a vesiculovirus G protein.
8. The recombinant retrovirus of any one of claims 5 to 7, wherein the vesiculovirus G protein is a COCV G glycoprotein (COCV-G) or a VSIV G glycoprotein (VSIV-G).
9. The recombinant retrovirus of claim 8, wherein the VSIV-G envelope protein comprises one or more of:
(a) one or more amino acid substitutions at H8, N9, Q10, K47, K50, A51, S183, S179, N180, 1182, M184, Y209, 1347, T350, T352, E353, and R354;
(b) an insertion of TT between N9 and Q10, an insertion of GGS between H8 and N9, an insertion of GGS between N9 and Q10, an insertion of TT between N208 and Y209, an insertion of GGS between P46 and K47, and an insertion of GGS between N208 and Y209;
(c) amino acid substitutions at K47 and/or R354; or
(d) a deletion of residues 1-8.
10. The recombinant retrovirus of claim 8 or claim 9, wherein the VSIV-G envelope protein comprises one or more amino acid substitutions at H8, K47, Y209, and R354.
11. The recombinant retrovirus of any one of claims 9 to 10, wherein the VSIV-G envelope protein comprises one or more amino acid substitutions selected from the group consisting of: K47A and R354A; K47A and R354G; K47A and R354F; K47A and R354Q; K47G and R354A; K47G and R354G; K47G and R354F; K47G and R354Q;K47F and R354A; K47F and R354G; K47F and R354F; K47F and R354Q; K47Q and R354A; K47Q and R354G; K47Q and R354F; and K47Q and R354Q.
12. The recombinant retrovirus of any one of claims 8 to 11, wherein the VSIV-G envelope protein comprises the amino acid sequence set forth in SEQ ID NO: 2, wherein Xi=
I, X2 = A, X3 = Q, and X4 = A; Xi= I, X2 = A, X3 = Q, and X4 = G; Xi= I, X2 = A, X3 = Q, and X4 = F; Xi= I, X2 = A, X3 = Q, and X4 = Q; Xi= L, X2 = A, X3 = Q, and X4 = A; Xi= L, X2 = A, X3 = Q, and X4 = G; Xi= L, X2 = A, X3 = Q, and X4 = F; Xi= L, X2 = A, X3 = Q, and X4 = Q; Xi= I, X2 = A, X3 = H, and X4 = A; Xi= I, X2 = A, X3 = H, and X4 = G; Xi= I, X2 = A, X3 = H, and X4 = F; Xi= I, X2 = A, X3 = H, and X4 = Q; Xi= L, X2 = A, X3 = H, and X4 = A; Xi= L, X2 = A, X3 = H, and X4 = G; Xi= L, X2 = A, X3 = H, and X4 = F; Xi= L, X2 = A, X3 = H, and X4 = Q; Xi= I, X2 = G, X3 = Q, and X4 = A; Xi= I, X2 = G, X3 = Q, and X4 = G; Xi= I, X2 = G, X3 = Q, and X4 = F; Xi= I, X2 = G, X3 = Q, and X4 = Q; Xi= L, X2 = G, X3 = Q, and X4 = A; Xi= L, X2 = G, X3 = Q, and X4 = G; Xi= L, X2 = G, X3 = Q, and X4 = F; Xi= L, X2 = G, X3 = Q, and X4 = Q; Xi= I, X2 = G, X3 = H, and X4 = A; Xi= I, X2 = G, X3 = H, and X4 = G; Xi= I, X2 = G, X3 = H, and X4 = F; Xi= I, X2 = G, X3 = H, and X4 = Q; Xi= L, X2 = G, X3 = H, and X4 = A; Xi= L, X2 = G, X3 = H, and X4 = G; Xi= L, X2 = G, X3 = H, and X4 = F; Xi= L, X2 = G, X3 = H, and X4 = Q; Xi= I, X2 = F, X3 = Q, and X4 = A; Xi= I, X2 = F, X3 = Q, and X4 = G; Xi= I, X2 = F, X3 = Q, and X4 = F; Xi= I, X2 = F, X3 = Q, and X4 = Q; Xi= L, X2 = F, X3 = Q, and X4 = A; Xi= L, X2 = F, X3 = Q, and X4 = G; Xi= L, X2 = F, X3 = Q, and X4 = F; Xi= L, X2 = F, X3 = Q, and X4 = Q; Xi= I, X2 = F, X3 = H, and X4 = A; Xi= I, X2 = F, X3 = H, and X4 = G; Xi= I, X2 = F, X3 = H, and X4 = F; Xi= I, X2 = F, X3 = H, and X4 = Q; Xi= L, X2 = F, X3 = H, and X4 = A; Xi= L, X2 = F, X3 = H, and X4 = G; Xi= L, X2 = F, X3 = H, and X4 = F; Xi= L, X2 = F, X3 = H, and X4 = Q; Xi= I, X2 = Q, X3 = Q, and X4 = A; Xi= I, X2 = Q, X3 = Q, and X4 = G; Xi= I, X2 = Q, X3 = Q, and X4 = F; Xi= I, X2 = Q, X3 = Q, and X4 = Q; Xi= L, X2 = Q, X3 = Q, and X4 = A; Xi= L, X2 = Q, X3 = Q, and X4 = G; Xi= L, X2 = Q, X3 = Q, and X4 = F; Xi= L, X2 = Q, X3 = Q, and X4 = Q; Xi= I, X2 = Q, X3 = H, and X4 = A; Xi= I, X2 = Q, X3 = H, and X4 = G; Xi= I, X2 = Q, X3 = H, and X4 = F; Xi= I, X2 = Q, X3 = H, and X4 = Q; Xi= L, X2 = Q, X3 = H, and X4 = A; Xi= L, X2 = Q, X3 = H, and X4 = G; Xi= L, X2 = Q, X3 = H, and X4 = F; and Xi= L, X2 = Q, X3 = H, and X4 = Q.
13. The recombinant retrovirus of any one of claims 5 to 8, wherein the vesiculovirus G protein is COCV-G.
14. The recombinant retrovirus of claim 13, wherein the COCV-G envelope protein comprises one or more amino acid substitutions at K47 and R354.
15. The recombinant retrovirus of claim 13 or claim 14, wherein the COCV-G envelope protein comprises one or more amino acid substitutions selected from the group consisting of: K47A and R354A; K47A and R354G; K47A and R354F; K47A and R354Q; K47G and R354A; K47G and R354G; K47G and R354F; K47G and R354Q;K47F and R354A; K47F and R354G; K47F and R354F; K47F and R354Q; K47Q and R354A; K47Q and R354G; K47Q and R354F; and K47Q and R354Q.
16. The recombinant retrovirus of any one of claims 13 to 15, wherein the COCV- G envelope protein comprises the amino acid sequence set forth in SEQ ID NO: 4, wherein Xi = A and X2 = A; Xi = A and X2 = G; Xi = A and X2 = F; Xi = A and X2 = Q; Xi = G and X2 = A; Xi = G and X2 = G; Xi = G and X2 = F; Xi = G and X2 = Q; Xi = F and X2 = A; Xi = F and X2 = G; Xi = F and X2 = F; Xi = F and X2 = Q; Xi = Q and X2 = A; Xi = Q and X2 = G; Xi = Q and X2 = F; or Xi = Q and X2 = Q.
17. The recombinant retrovirus of claim 5, wherein the one or more morbillivirus envelope glycoproteins are measles virus F (MV-F) and measles virus H (MV-H).
18. The recombinant retrovirus of claim 17, wherein the MV-H protein comprises one or more amino acid substitutions at Y481, R533, S548, and F549.
19. The recombinant retrovirus of claim 17 or claim 18, wherein the MV-H protein comprises one or more amino acid substitutions selected from the group consisting of: Y481A, R533A, S548L, and F549S.
20. The recombinant retrovirus of claim 5, wherein the one or more henipavirus envelope glycoproteins are nipah virus F (NiV-F) and nipah virus G (NiV-G).
21. The recombinant retrovirus of claim 20, wherein the NiV-G protein comprises one or more amino acid substitutions at E501, W504, Q530, and E533.
22. The recombinant retrovirus of claim 20 or claim 21, wherein the NiV-G protein comprises one or more amino acid substitutions at E501A, W504A, Q530A, and E533A.
23. The recombinant retrovirus of any one of claims 1 to 22, wherein the non- viral membrane-bound tropism polypeptide comprises an extracellular antigen targeting domain, a spacer polypeptide, and a transmembrane domain.
24. The recombinant retrovirus of claim 23, wherein the extracellular antigen targeting domain binds an antigen expressed on an immune effector cell.
25. The recombinant retrovirus of claim 23 or claim 24, wherein the extracellular antigen targeting domain binds an antigen expressed on an immune effector cell selected from the group consisting of: the alpha, beta, gamma, or delta chain of the T cell receptor, CD2, CD35, CD3s CD3y, CD4, CD8a, and CD8p.
26. The recombinant retrovirus of any one of claims 23 to 25, wherein the extracellular antigen targeting domain comprises an antibody or antigen binding fragment thereof that binds an antigen expressed on the immune effector cell.
27. The recombinant retrovirus of any one of claims 23 to 26, wherein the extracellular antigen targeting domain comprises an anti-CD3 antibody or antigen binding fragment selected from the group consisting of 0KT3, UCHT1, YTH12.5, TR66, and humanized variants thereof, e.g., teplizumab, and antibodies and antigen binding fragments that have at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identity thereto.
28. The recombinant retrovirus of any one of claims 1 to 27, wherein the viral envelope further comprises one or more transduction enhancers, wherein the transduction enhancer is selected from the group consisting of a T cell activation receptor, a NK cell activation receptor, and a co-stimulatory molecule.
29. The recombinant retrovirus of claim 28, wherein the one or more transduction enhancers comprise one or more of CD80, CD86, CD137L, OX40L, and ICOSL.
30. The recombinant retrovirus of any one of claims 1 to 29, wherein the T cell/NK cell/NKT cell activation receptor comprises a signaling domain selected from the group consisting of (i) a cytokine receptor signaling domain, (ii) a co-stimulatory receptor
signaling domain, (iii) a T cell receptor subunit signaling domain, (iv) an NK cell receptor subunit signaling domain, and (v) a growth factor receptor signaling domain.
31. The recombinant retrovirus of claim 30, wherein the signaling domain comprises a cytokine receptor signaling domain of IL2Ry.
32. The recombinant retrovirus of claim 30 or claim 31, wherein the signaling domain comprises a cytokine receptor signaling domain of IL2Rp.
33. The recombinant retrovirus of any one of claims 30 to 32, wherein the signaling domain comprises an IT AM.
34. The recombinant retrovirus of any one of claims 30 to 33, wherein the signaling domain comprises a tyrosine capable of binding an SH2-domain when the tyrosine is phosphorylated.
35. The recombinant retrovirus of any one of claims 1 to 34, wherein the T cell/NK cell/NKT cell activation receptor comprises FK506 binding protein (FKBP) polypeptide or a functional homolog thereof.
36. The recombinant retrovirus of any one of claims 1 to 35, wherein the T cell/NK cell/NKT cell activation receptor comprises FKBP12-rapamycin binding (FRB) polypeptide or a functional homolog thereof.
37. The recombinant retrovirus of any one of claims 1 to 36, wherein the retroviral vector further comprises a polynucleotide encoding a checkpoint inhibitor, optionally wherein the inhibitor is an antibody or antigen binding fragment thereof.
38. The recombinant retrovirus of claim 37, wherein the checkpoint inhibitor blocks PD-1, PD-L1, PD-L2, TIM3, VISTA, LAG3 or TIGIT.
39. The recombinant retrovirus of any one of claims 1 to 38, wherein the retroviral vector further comprises a polynucleotide encoding a protein that provides resistance to an immunosuppressive drug.
40. The recombinant retrovirus of claim 39, wherein the immunosuppressive drug is selected from the group consisting of methotrexate, rapamycin, a rapalog, tacrolimus, and cyclosporine.
41. The recombinant retrovirus of any one of claims 1 to 40, wherein the retroviral vector further comprises a polynucleotide encoding one or more 2A peptides, dispersed between two or more polypeptides encoded by the polynucleotide.
42. The recombinant retrovirus of any one of claims 1 to 41, wherein the retroviral vector further comprises a polynucleotide encoding a woodchuck post-transcriptional regulatory element (WPRE).
43. The recombinant retrovirus of any one of claims 1 to 42, wherein the recombinant retroviral vector comprises a polynucleotide encodes a dominant negative TGFP receptor or a TGFP signal convertor.
44. The recombinant retrovirus of any one of claims 1 to 43, wherein the promoter is selected from the group consisting of an MNDU3 promoter, a T cell specific promoter, a CD4 T cell specific promoter, a CD8 T cell specific promoter, an NK cell specific promoter, a T cell and NK cell specific promoter, a CD4 T cell and NK cell specific promoter, and a CD 8 T cell and NK cell specific promoter.
45. A method for treating a subject suffering from cancer, comprising: a) administering a recombinant retrovirus of any one of claims 1 to 44 to the subject, and b) administering a small molecule that induces activation of the T cell/NK cell/NKT cell activation receptor to the subject, whereby the cancer is treated in the subject.
46. A method for expanding T cells capable of recognizing and killing tumor cells in a subject in need thereof, comprising a) administering a recombinant retrovirus of any one of claims 1 to 44 to the subject, and b) administering a small molecule that induces activation of the T cell/NK cell/NKT cell activation receptor to the subject, whereby T cells transduced by the recombinant retrovirus are expanded.
47. The method of claim 45 or claim 46, wherein the recombinant retrovirus is administered by intravenous injection, intratumoral injection, intravenous injection, or orally.
48. The method of any one of claims 45 to 47, wherein the small molecule is rapamycin or a rapalog.
49. The method of any one of claims 45 to 48, wherein the small molecule causes dimerization of the T cell/NK cell/NKT cell activation receptor resulting in a cell activation signal.
50. The method of any one of claims 45 to 49, further comprising administering to the subject an immunosuppressive agent, optionally wherein the immunosuppressive agent is tacrolimus or cyclosporine.
51. A nucleic acid encoding the retroviral vector of any one of claims 1 to 44.
52. A packaging cell line for generating recombinant retrovirus of any one of claims 1 to 44, wherein the cell line is engineered to express one or more mutated viral envelope glycoproteins that retain fusogenic activity and lack cognate receptor binding activity and/or one or more non- viral membrane-bound tropism polypeptides and/or one or more transduction enhancers.
53. The packaging cell line of claim 52, wherein the packaging cell line is a HEK- 293T cell line.
54. The packaging cell line of claim 52 or claim 53, wherein the packaging cell line is genetically modified to lack MHC class I expression and/or MHC class II expression and/or expression of one or more checkpoint inhibitors.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US63/477,821 | 2022-12-29 | ||
US63/453,037 | 2023-03-17 |
Publications (1)
Publication Number | Publication Date |
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WO2024145622A1 true WO2024145622A1 (en) | 2024-07-04 |
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