WO2023288267A1 - Engineered t cell receptors fused to binding domains from antibodies - Google Patents

Engineered t cell receptors fused to binding domains from antibodies Download PDF

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Publication number
WO2023288267A1
WO2023288267A1 PCT/US2022/073725 US2022073725W WO2023288267A1 WO 2023288267 A1 WO2023288267 A1 WO 2023288267A1 US 2022073725 W US2022073725 W US 2022073725W WO 2023288267 A1 WO2023288267 A1 WO 2023288267A1
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antigen
polypeptide
cell
tcr
seq
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English (en)
French (fr)
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Jordan JARJOUR
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2Seventy Bio Inc
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2Seventy Bio Inc
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Priority to US18/578,367 priority Critical patent/US20240342215A1/en
Priority to CN202280059133.9A priority patent/CN117980326A/zh
Priority to IL309957A priority patent/IL309957A/en
Priority to KR1020247004955A priority patent/KR20240034234A/ko
Priority to EP22768562.5A priority patent/EP4370541A1/en
Priority to AU2022310862A priority patent/AU2022310862A1/en
Priority to CA3225252A priority patent/CA3225252A1/en
Priority to JP2024501757A priority patent/JP2024525727A/ja
Publication of WO2023288267A1 publication Critical patent/WO2023288267A1/en
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Definitions

  • the one or more antigen-binding domains comprises a second antigen-binding domain linked to the first antigen-binding domain. In various embodiments, the one or more antigen-binding domains comprises a second antigen-binding domain linked to the first antigen-binding domain linked to the TCR ⁇ or TCR ⁇ variable domain. In some embodiments, the one or more antigen-binding domains comprises a second antigen-binding domain linked to the first antigen-binding domain linked to the TCR ⁇ or TCR ⁇ variable domain.
  • a method of treating a solid cancer comprising administering to the subject an effective amount of a cell, composition, or a pharmaceutical composition contemplated herein.
  • the solid cancer is selected from the group consisting of: lung cancer, squamous cell carcinoma, colorectal cancer, pancreatic cancer, breast cancer, thyroid cancer, bladder cancer, cervical cancer, esophageal cancer, ovarian cancer, gastric cancer endometrial cancer, brain cancer, or sarcoma.
  • Figure 3B shows engineered TCR/receptor cytokine response against A549.A2.MAGEA4 cells.
  • Figure 12B shows an illustrative engineered TCR having two VHHs linked to the TCR.
  • Figure 21A shows BCMA-based receptor expression on immune effector cells.
  • an antigen binding domain e.g., a VHH or scFv
  • a TCR component e.g., a TCR ⁇ , TCR ⁇ , TCR ⁇ , and/or TCR ⁇ variable domain / chain
  • the engineered TCRs comprise a linker between the antigen-binding domain and the TCR component, such that the function of each targeting molecule (i.e., the TCR component and secondary antigen-binding domain) is preserved. Accordingly, the invention enables simultaneous targeting of intracellular and extracellular antigens.
  • a “Single-chain Fv” or “scFv” antibody fragments comprise the VH and VL domains of antibody, wherein these domains are present in a single polypeptide chain and in either orientation (e.g., VL-VH or VH-VL).
  • the scFv variable light chain is positioned c-terminal to that of the variable heavy chain.
  • the scFv variable heavy chain is positioned c-terminal to that of the variable light chain.
  • the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding.
  • isolated antibody or antigen binding fragment thereof refers to an antibody or antigen binding fragment thereof which has been identified and separated and/or recovered from a component of its natural environment.
  • references to “VH” or “VH” refer to the variable region of an immunoglobulin heavy chain, including that of an antibody, Fv, scFv, dsFv, Fab, or other antibody fragment as disclosed herein.
  • References to “VL” or “VL” refer to the variable region of an immunoglobulin light chain, including that of an antibody, Fv, scFv, dsFv, Fab, or other antibody fragment as disclosed herein.
  • an antigen-binding domain component and TCR component irrespective of the antigen specificity or any specific sequence, e.g., of its variable domain or CDR sequences, may be linked to produce an engineered TCR or fusion protein meeting the characteristics of the engineered TCRs disclosed herein.
  • the one or more antigen-binding domains bind CD33, CLL1, CD19, CD20, CD22, CD79A, CD79B, or BCMA. In some embodiments, the one or more antigen-binding domains bind CD19, CD20, CD22, CD33, CD79A, CD79B, B7H3, Mucl6, Her2, EGER, FN-EDB, CLDN18.2, DLL3, FLT3, CLL1, CD123, or BCMA.
  • the one or more antigen-binding domains comprise an antibody or antigen binding fragment thereof selected from the group consisting of: 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”), and a single-domain antibody (sdAb, a camelid VHH, Nanobody).
  • a Camel Ig a Llama Ig, an Alpaca Ig, Ig NAR
  • Fab' fragment fragment
  • F(ab')2 fragment fragment
  • Fab2 bispecific Fab dimer
  • the one or more antigen-binding domains comprise a ligand.
  • the one or more polypeptide linkers comprise a linker from about 2 to about 25 amino acids long. In some embodiments, the one or more polypeptide linkers comprise a linker from about 3 to about 20 amino acids long. In some embodiments, the one or more polypeptide linkers comprise a linker from about 4 to about 15 amino acids long. In some embodiments, the one or more polypeptide linkers comprise a linker from about 4 to about 10 amino acids long. In some embodiments, the one or more polypeptide linkers comprise a linker of about 4 amino acids long. In some embodiments, the one or more polypeptide linkers comprise a linker of about 5 amino acids long.
  • an “isolated polypeptide” and the like, as used herein, refer to in vitro synthesis, isolation, and/or purification of a peptide or polypeptide molecule from a cellular environment, and from association with other components of the cell, i.e., it is not significantly associated with in vivo substances.
  • an isolated polypeptide is a synthetic polypeptide, a recombinant polypeptide, or a semi- synthetic polypeptide, or a polypeptide obtained or derived from a recombinant source.
  • polypeptides include polypeptides having at least about 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid identity to any of the polypeptide sequences contemplated herein, typically where the variant maintains at least one biological activity of the reference sequence.
  • an engineered TCR (e.g., an engineered TCR complex)contemplated herein is expressed as a fusion polypeptide comprising: (a) a TCR ⁇ polypeptide comprising a TCR ⁇ variable domain; (b) a polypeptide cleavage signal; and (c) a TCR ⁇ polypeptide comprising one or more antigen-binding domains, a polypeptide linker, and a TCR ⁇ variable domain.
  • an engineered TCR (e.g., an engineered TCR complex)contemplated herein is expressed as a fusion polypeptide comprising (a) a TCR ⁇ polypeptide comprising one or more antigen-binding domains, a polypeptide linker, and a TCR ⁇ variable domain; (b) a polypeptide cleavage signal; and (c) a TCR ⁇ polypeptide comprising a TCR ⁇ variable domain.
  • TEV tobacco etch virus protease cleavage sites
  • EXXYXQ(G/S) e.g., EXXYXQ(G/S)
  • ENLYFQG SEQ ID NO: 114
  • ENLYFQS SEQ ID NO:
  • a “comparison window” refers to a conceptual segment of at least 6 contiguous positions, usually about 50 to about 100, more usually about 100 to about 150 in which a sequence is compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.
  • the comparison window may comprise additions or deletions ⁇ i.e., gaps) of about 20% or less as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences.
  • control elements or “regulatory sequences” present in an expression vector are those non-translated regions of the vector — origin of replication, selection cassettes, promoters, enhancers, translation initiation signals (Shine Dalgarno sequence or Kozak sequence) introns, a polyadenylation sequence, 5' and 3' untranslated regions — which interact with host cellular proteins to carry out transcription and translation.
  • Such elements may vary in their strength and specificity.
  • any number of suitable transcription and translation elements including ubiquitous promoters and inducible promoters may be used.
  • lentiviral vectors contemplated herein may be integrative or non-integrating or integration defective lentivirus.
  • integration defective lentivirus or “IDLV” refers to a lentivirus having an integrase that lacks the capacity to integrate the viral genome into the genome of the host cells. Integration-incompetent viral vectors have been described in patent application WO 2006/010834, which is herein incorporated by reference in its entirety.
  • a mixture of, e.g., one, two, three, four, five or more, different expression vectors can be used in genetically modifying a donor population of immune effector cells wherein each vector encodes a different chimeric antigen receptor protein as contemplated herein.
  • the resulting modified immune effector cells forms a mixed population of modified cells.
  • the treatment may also include administration of mitogens (e.g., PHA) or lymphokines, cytokines, and/or chemokines (e.g., IFN- g, IL-2, IL-12, TNF-alpha, IL-18, and TNF-beta, GM-CSF, IL-4, IL-13, FU3-L, RANTES, MIPla, etc.) as contemplated herein to enhance induction of the immune response.
  • mitogens e.g., PHA
  • lymphokines e.g., lymphokines, cytokines, and/or chemokines (e.g., IFN- g, IL-2, IL-12, TNF-alpha, IL-18, and TNF-beta, GM-CSF, IL-4, IL-13, FU3-L, RANTES, MIPla, etc.)
  • mitogens e.g., PHA
  • lymphokines e.g.,
  • compositions comprising an immune effector cell population modified to express an engineered TCR may comprise buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine; antioxidants; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and preservatives.
  • compositions comprising immune effector cells contemplated herein are formulated in a solution comprising 50:50 PlasmaLyte A to CryoStor CS 10.

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