WO2021146487A2 - Il2 orthologs and methods of use - Google Patents

Il2 orthologs and methods of use Download PDF

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Publication number
WO2021146487A2
WO2021146487A2 PCT/US2021/013521 US2021013521W WO2021146487A2 WO 2021146487 A2 WO2021146487 A2 WO 2021146487A2 US 2021013521 W US2021013521 W US 2021013521W WO 2021146487 A2 WO2021146487 A2 WO 2021146487A2
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cells
orthogonal
cell
receptor
ligand
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WO2021146487A3 (en
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Paul-Joseph PENAFLOR ASPURIA
Patrick J. Lupardus
Richard B. Murphy
Martin Oft
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Synthekine Inc
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Synthekine Inc
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Priority to IL294388A priority Critical patent/IL294388A/en
Priority to CN202180022163.8A priority patent/CN115315273A/zh
Priority to EP21740881.4A priority patent/EP4090383A4/en
Priority to CA3166420A priority patent/CA3166420A1/en
Priority to JP2022542908A priority patent/JP2023511274A/ja
Priority to MX2022008772A priority patent/MX2022008772A/es
Priority to US17/758,830 priority patent/US20230076768A1/en
Priority to KR1020227027980A priority patent/KR20220141299A/ko
Application filed by Synthekine Inc filed Critical Synthekine Inc
Priority to AU2021207901A priority patent/AU2021207901A1/en
Publication of WO2021146487A2 publication Critical patent/WO2021146487A2/en
Publication of WO2021146487A3 publication Critical patent/WO2021146487A3/en
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Definitions

  • TILs from a wide variety of other tumor types including but not limited to cervical cancer (Stevanovic, et al (2015) J Clin Oncol 33:1543-1550), renal cell cancer (Andersen, et al (2016) Cancer Immunol Res 6:222-235), breast cancer (Lee, et al (2017) Oncotarget 8:113345-113359), non-small cell lung cancer (Ben-Avi ,et al (2016) Cancer Immunol Immunother 67:1221- 1230) gastrointestinal cancers (Turcotte (2013) J Immunol 191:2217-2225 and Turcotte, et al (2014) Clin Cancer Res 20:331-343), cholangiocarcinoma (Tran, et
  • the administration of the orthogonal ligand is administered periodically to the subject to maintain a level of between 100,000 and 1,000,000 activate immune cells per kg of body weight of the subject for a period of time of at least two weeks
  • a cell product substantially enriched for a population of activated orthogonal immune cells the product obtained by a process comprising the steps of:
  • Orthogonal Receptor refers to a variant of a receptor, the orthogonal receptor comprising modifications to the amino acid sequence so that the orthogonal receptor exhibits significantly reduced binding to its cognate ligand but exhibits specific binding for an orthogonal ligand engineered to interact with the orthogonal receptor.
  • the orthogonal receptor may comprise an extracellular domain that is exhibits significantly reduced binding to its cognate native ligand, while an orthogonal ligand exhibits significantly reduced binding to the ECD of its cognate native receptor(s).
  • cysteine residues may be incorporated at various positions within the IL2 molecule to facilitate site-specific PEGylation via the cysteine side chain as described in Greve, et al. PCT International Patent Application Number PCT/US2015/044462 published as WO2016/025385 on February 18, 2016.
  • the present disclosure provides methods and compositions for treating a subject suffering from a neoplastic disease by the administration of a plurality of engineered T cells expressing an orthogonal CD 122 receptor and a chimeric antigen receptor the extracellular domain of which specifically binds a tumor antigen and the contemporaneous administration of orthogonal IL2 ligand the prevention of relapse of said neoplastic disease by the administration to said subject of a maintenance therapy comprising the periodic administration of an orthogonal IL2 ligand of Formula 1, wherein the orthogonal ligand used in the treatment phase is the same or different than the orthogonal ligand used in the maintenance phase.
  • the orthogonal ligand is modified to extend half- life.
  • the supplementary agent is selected from one or more of: CODOX-M (cyclophosphamide, doxorubicin, vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate) optionally in combination with rituximab; dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) optionally in combination with rituximab; hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) optionally in combination with high-dose methotrexate and cytarabine optionally in combination with rituximab; RICE (rituximab, ifosfamide, carboplatin, etoposide) optionally in combination with
  • CD19_28z a construct comprising a GMCSF receptor signal peptide, FMC63 scFv, AAA spacer, CD28 hinge and costimulatory domain and CD3 zeta:
  • supplementary agents useful in the treatment of multiple myeloma include one or more agents selected from the group consisting of thalidomide, lenalidomide, dexamethasone, bortezomib, vincristine, doxorubicin, dexamethasone, melphalan, carfdzomib, cyclophosphamide, cisplatin, etoposide, bortezomib, prednisone, daratumumab, carfdzomib, and ixazomib.
  • Prostate-specific membrane antigen is considered an ideal target for antigen- redirected immunotherapy because it is expressed at the surface of prostate cancer cells at all tumor stages, and in particular shows an Increased expression in the more severe androgen- independent and metastatic stages of the disease.
  • a variety of antibodies targeting PSM are described in the literature which may be modified for use in the context of CAR including but not limited to J591, 3D8, D2B, and 3/F 11,
  • the present disclosure provides an orthogonal PSMA CAR T cell, comprising a PSMA CAR is PSMA_28z:
  • An anti-PSMA CAR comprising a CD8a signal peptide, a deimmunized J591 scFv, a AAA spacer, CD28 hinge/transmembrane/co- stimulatory domain and CD3zeta: which can be co-expressed with the ortho CD 122 receptor using a T2a linker with an amino acid sequence of:
  • the present disclosure provides an orthogonal GPC3 CAR T cell
  • the methods and compositions of the present disclosure are useful in the treatment of GPC3 expressing cancers including but not limited to liver cancer.
  • Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths in the world.
  • Glypican-3 a cell-surface glycoprotein, is overexpressed in HCC tissues but not in the healthy adult liver and as such provides a useful targeting domain for the ABD of the CAR.
  • HPV-16 E6 TCR cell for use in the treatment of HPV related tumors.
  • HPV-16 E6 CARs which may be incorporated into the an orthogonal cell of the present disclosure include but are not limited to a CAR having the sequence :
  • the recombinant viral vector is a recombinant adeno-associated virus (rAAV) or recombinant adenovirus (rAd), for example in some embodiments, a replication deficient adenovirus derived from human adenovirus serotypes 3 and/or 5.
  • the replication deficient adenovirus has one or more modifications to the El region which interfere with the ability of the virus to initiate the cell cycle and/or apoptotic pathways.
  • the replication deficient adenoviral vector may optionally comprise deletions in the E3 domain.
  • the adenovirus is a replication competent adenovirus.
  • the adenovirus is a replication competent recombinant virus engineered to selectively replicate in neoplastic cells.
  • substitutions are designated herein by the one letter amino acid code followed by the IL2 amino acid position followed by the one letter amino acid code which is substituted.
  • an IL2 ortholog having the modification “K35A” refers to a substitution of the lysine (K) residue at position 35 of the wild-type IL2 sequence with an alanine (A) residue at this position.
  • a deletion of an amino acid reside is referred to as “des” followed by the amino acid residue and its position in SEQ ID NO:4.
  • the term “des- Alai” or “desAl” refers to the deletion of the alanine at position 1 of the polypeptide of wild-type IL2 sequence.
  • the orthologs of the present disclosure are hIL2 orthologs that are cognate ligands of a receptor comprising the extracellular domain of a hCD122 molecule comprising and amino acid substitutions at position H133. In some embodiments, the orthologs of the present disclosure are hIL2 orthologs that are cognate ligands of a receptor comprising the extracellular domain of a hCD122 molecule comprising amino acid substitutions at position HI 33 the ICD of which comprises one or more STAT3 binding motifs.
  • IL2 Orthologs (FORMULA #1):
  • the present disclosure provides an hIL2 ortholog, the amino acid sequence of which has at least 80%, 90%, 95%, 98%, 99% or 100% identity to polypeptide of the Formula #1: wherein:
  • AA16 is H (wildtype), N or Q or deleted;
  • AA18 is L (wild type) or R, L, G, M, F, E, H, W, K, Q, S, V, I, Y, H, D or T;
  • AA89 is I (wild type) or V;
  • hIL2 orthologs which are hIL2 polypeptides comprising the following sets of amino acid modifications:
  • the IL2 orthologs or the present invention comprise one of the following sets of amino acid modifications:
  • the IL2 ortholog comprises one or more of the amino acid substitutions: Q74N, L80F, R81D, L85V, I86V and I92F. In some embodiments, the IL2 ortholog comprises one or more of the amino acid substitutions: Q74S, R81T, L85V, and I92F. In some embodiments, the IL2 ortholog comprises [L80F-R81D-L85V-I86V-I92F] In some embodiments, the present disclosure provides hIL2 orthologs which comprise one of the following sets of amino acid modifications:
  • the orthologs comprise the substitution L85V that has been identified as increasing affinity of IL2 to CD 122.
  • the present disclosure provides hIL2 orthologs which are hIL2 polypeptides comprising one of the following sets of amino acid modifications:
  • the IL2 ortholog may comprise one or more modifications to its primary structure that provide minimal effects on the activity IL2.
  • the IL2 ortholog is conjugated (either chemically or as a fusion protein) with an XTEN which provides extended duration of akin to PEGylation and may be produced as a recombinant fusion protein in E. coli.
  • XTEN polymers suitable for use in conjunction with the IL2 orthologs of the present disclosure are provided in Podust, et al. (2016) “ Extension of in vivo half-life of biologically active molecules by XTEN protein polymers J Controlled Release 240:52-66 and Haeckel et al.
  • the molecular mass is from about 5kDa to about lOkDa, from about 5kDa to about 15kDa, from about 5kDa to about 20kDa, from about lOkDa to about 15kDa, from about lOkDa to about 20kDa, from about lOkDa to about 25kDa or from about lOkDa to about 30kDa.
  • Affinity chromatography makes use of the highly specific binding sites usually present in biological macromolecules, separating molecules on their ability to bind a particular ligand. Covalent bonds attach the ligand to an insoluble, porous support medium in a manner that overtly presents the ligand to the protein sample, thereby using natural specific binding of one molecular species to separate and purify a second species from a mixture.
  • Antibodies are commonly used in affinity chromatography.
  • Size selection steps may also be used, e.g. gel filtration chromatography (also known as size-exclusion chromatography or molecular sieve chromatography) is used to separate proteins according to their size.
  • the orthogonal receptor is a fusion protein comprising the ECD of hoCD122 (e.g. SEQ ID NO. 6) and the transmembrane and intracellular domains of a second receptor in the IL2 common gamma chain family of receptors (e.g. IL4 receptor Type II receptor subunit a (hIL4Ra UniProt P24394), IL-7 receptor subunit a (hIL7Ra UniProt 16871), IL9 receptor (hIL9R UniProt Q01113), and the IL21 receptor (hIL21R UniProt Q9HBE5).
  • IL4 receptor Type II receptor subunit a hIL4Ra UniProt P24394
  • IL-7 receptor subunit a hIL7Ra UniProt 16871
  • IL9 receptor hIL9R UniProt Q01113
  • IL21R UniProt Q9HBE5 the IL21 receptor
  • the CAR may also further comprise a signal peptide sequence which is conventionally removed during post-translational processing and presentation of the CAR on the cell surface of a cell transformed with an expression vector comprising a nucleic acid sequence encoding the CAR.
  • CARs may be prepared in accordance with principles well known in the art. See e.g., Eshhar, et al. (United States Patent No. 7,741,465 B1 issued June 22, 2010); Sadelain, et al. (2013) Cancer Discovery 3(4):388-398; Campana and Imai (United States Patent No 8,399,645 issued March 19, 2013) Jensen and Riddell (2015) Current Opinions in Immunology 33:9-15; Gross, et al.
  • Linkers may be composed of flexible residues like glycine and serine so that the adjacent protein domains are free to move relative to one another. Certain embodiments comprise the use of linkers of longer length when it is desirable to ensure that two adjacent domains do not sterically interfere with each another.
  • Examples of CAR architectures useful in the practice of the present invention include but are not limited to the following examples which illustrate the ECD targeting domain(s) and the architecture of the ICD of the CAR include but are not limited to: [anti-CD 19 & anti-CD22] - 41BB - ICOS - O ⁇ 3z [anti-CD 19 & anti-CD22] - 41BB - 0X40 - CD3 , and [anti-CD 19 & anti-CD22] - 41BB - CD28 - CD3 .
  • inhibitory chimeric antigen receptors or “iCARs” are used interchangeably herein to refer to a CAR where binding iCARs use the dual antigen targeting to shut down the activation of an active CAR through the engagement of a second suppressive receptor equipped with inhibitory signaling domains of a secondary CAR binding domain results in inhibition of primary CAR activation.
  • tandem CAR or “TanCAR” refers to CARs which mediate bispecific activation of T cells through the engagement of two chimeric receptors designed to deliver stimulatory or costimulatory signals in response to an independent engagement of two different tumor associated antigens.
  • a promoter is operably linked to a coding sequence if it controls the transcription of the polypeptide; a ribosome binding site is operably linked to a coding sequence if it is positioned to permit translation, a nucleic acid encoding signal peptide is operably linked to a nucleic acid sequence encoding such polypeptide if it is expressed as a fusion protein and participates in directing the fusion protein to the cell membrane or in secretion of the polypeptide.
  • nucleotide sequences that are operably linked are contiguous.
  • the promoter can be constitutively active, activated in response to external stimuli (inducible), active in particular cell type or cell state (tissue specific or tumor specific) promoters, and/or regulatable promoters.
  • inducible promoter refers to promoters that facilitate transcription of the Bioactive polypeptide preferably (or solely) under certain conditions and/or in response to external chemical or other stimuli. Examples of inducible promoters are known in the scientific literature (see, e.g., Yoshida et ak, Biochem. Biophys. Res. Comm., 230:426-430 (1997); Iida et al., J.
  • Tissue specific promoters and tumor specific promoters are well known in the art, e.g., pancreas specific promoters (Palmiter et al., Cell, 50:435 (1987)), liver specific promoters (Rovet et ak, J. Biol. Chem., 267:20765 (1992); Lemaigne et ak, J. Biol. Chem., 268:19896 (1993); Nitsch et ak, Mol. Cell. Biol., 13:4494 (1993)), stomach specific promoters (Kovarik et ak, J. Biol.
  • the expression vector encoding the CAR and/or orthogonal receptor may optionally further encode one or more polypeptide supplementary agents as described herein.
  • expression vector encoding the targeting antigen may optionally further encode one or more polypeptide supplementary agents as described herein the immunological modulators.
  • immunological modulators useful in the practice of the present invention include but are not limited to cytokines.

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US17/758,830 US20230076768A1 (en) 2020-01-14 2021-01-14 IL2 Orthologs and Methods of Use
EP21740881.4A EP4090383A4 (en) 2020-01-14 2021-01-14 Il2 orthologs and methods of use
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