Redirected vectors for cd3, components thereof and uses of the vectors and components thereof

Description

Vectors redirected to CD3, their components, and the uses of these vectors and their components. CROSS-REFERENCE TO RELATED REQUESTS

[001] This application claims the priority benefit of U.S. Provisional Patent Application No. 63 / 495,702, filed April 12, 2023; U.S. Provisional Patent Application No. 63 / 502,585, filed May 16, 2023; U.S. Provisional Patent Application No. 63 / 586,976, filed September 29, 2023; U.S. Provisional Patent Application No. 63 / 625,842, filed January 26, 2024; U.S. Provisional Patent Application No. 63 / 626,979, filed January 30, 2024; U.S. Provisional Patent Application No. 63 / 560,911, filed March 4, 2024; and U.S. Provisional Patent Application No. 63 / 633,553, filed April 12, 2024; the descriptions of each are incorporated herein by reference in their entirety. Incorporation by reference of material submitted electronically.

[002] Incorporated by reference in its entirety herein is a machine-readable nucleotide / amino acid sequence listing submitted concurrently with this document and identified as follows: An 832,673-byte Extensible Markup Language (XML) file named 770399.xml created on April 12, 2024. BACKGROUND

[003] There is a continuing need in the art for components that can be used in a virus or enveloped delivery vehicle to target the virus or enveloped delivery vehicle to specific cells. There is also a continuing need in the art for viruses and enveloped delivery vehicles that incorporate such components. Petition 870250093142, dated 10 / 10 / 2025, page 31 / 819 2 / 640 ntes. BRIEF SUMMARY

[004] In aspects, the present invention provides a recombinant fusion protein comprising, consisting essentially of, or consisting of (a) a rhabdoviral G glycoprotein or a functional fragment or derivative thereof and (b) a polypeptide antibody construct, wherein the polypeptide antibody construct has the ability to bind to human CD3.

[005] In aspects, the present invention provides a membranous vesicle comprising, consisting essentially of, or consisting of a recombinant fusion protein, as described herein.

[006] In aspects, the present invention provides an enveloped viral particle comprising, consisting essentially of, or consisting of a recombinant fusion protein, as described herein.

[007] In aspects, the present invention provides a recombinant viral vector comprising, consisting essentially of, or consisting of a nucleotide encapsulated by a membranous vesicle, as described herein, or an enveloped viral particle, as described herein.

[008] In aspects, the present invention provides a composition comprising, consisting essentially of, or consisting of a pharmaceutically acceptable vehicle and a membranous vesicle, as described herein, an enveloped viral particle, as described herein, or a recombinant viral vector, as described herein.

[009] In aspects, the present invention provides a method of delivering a payload to a T cell, the method comprising, essentially consisting of, or consisting of placing the T cell in contact with a membranous vesicle, as described herein, a Petition 870250093142, dated 10 / 10 / 2025, page 32 / 819 3 / 640 enveloped viral particle, as described herein, a recombinant viral vector, as described herein, or a composition, as described herein.

[0010] In aspects, the present invention provides a retroviral vector expression system comprising, consisting essentially of, or consisting of one or more nucleotide sequences encoding a recombinant fusion protein, as described herein.

[0011] In some respects, the present invention provides a method for producing a membranous vesicle, an enveloped viral particle or a recombinant viral vector, the method comprising, consisting essentially of, or consisting of: a) transfect or transduce a packaging host cell with a retroviral vector expression system, as described herein; and b) to recover the membranous vesicle, enveloped viral particle, or recombinant viral vector produced by the transfected or transduced packaging host cell.

[0012] In aspects, the present invention provides a plasmid comprising, consisting essentially of, or consisting of one or more nucleotide sequences encoding a recombinant fusion protein, as described herein.

[0013] In some respects, the present invention provides a composition, as described herein, or a retroviral vector expression system, as described herein, for use in the treatment of a disease in a mammal.

[0014] In aspects, the present invention provides a method for producing a mixed rhabdoviral G glycoprotein trimer, the method comprising, essentially consisting of, or consisting of: a) transfect or transduce a host cell packaging system with a retroviral vector expression system, such as Petition 870250093142, dated 10 / 10 / 2025, page 33 / 819 4 / 640 described here; and b) recovery of the mixed rhabdoviral G glycoprotein trimer.

[0015] In aspects, the present invention provides a method for reducing the inactivation of a rhabdoviral G glycoprotein or a functional or derivative fragment thereof by serum, LDL or vLDL, the method comprising, essentially consisting of, or consisting of producing the rhabdoviral G glycoprotein or functional or derivative fragment thereof as a recombinant fusion protein, and exposing the recombinant fusion protein to serum, LDL or vLDL, wherein the inactivation by serum, LDL or vLDL is reduced.

[0016] In aspects, the present invention provides a method for reducing the inactivation of a rhabdoviral G glycoprotein or a functional or derivative fragment thereof by serum, LDL or vLDL, the method comprising, essentially consisting of, or consisting of producing a rhabdoviral G glycoprotein or a functional or derivative fragment thereof as a recombinant fusion protein, as described herein, and exposing the recombinant fusion protein to serum, LDL or vLDL, wherein the inactivation by serum, LDL or vLDL is reduced.

[0017] In some respects, the present invention provides a method of activating T lymphocytes by means of contact of the T lymphocyte with a composition, as described herein.

[0018] In aspects, the present invention provides a nucleic acid construct comprising, consisting essentially of, or consisting of a nucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 221.

[0019] In aspects, the present invention provides a nucleic acid construct comprising, consisting essentially of, or consisting of a nucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 222. Petition 870250093142, dated 10 / 10 / 2025, page 34 / 819 5 / 640

[0020] Additional aspects are described here.

[0021] Without intending to adhere to any specific theory, there may be discussion here regarding underlying beliefs or understandings of principles related to the materials and methods described herein. It is recognized that, regardless of the ultimate correctness of any mechanistic explanation or hypothesis, an aspect of the invention may still be operational and useful. BRIEF DESCRIPTION OF THE FIGURES

[0022] Figure 1 shows a diagram of the general structure of chimeric antigen receptors (CARs).

[0023] Figure 2A shows an illustration of the current state of ex vivo stem and T cell gene therapies and genome editing, where target cells are removed from the body, modified ex vivo, and reinfused, making the process slow, inconvenient, and expensive compared to an illustration of the potential state of in vivo stem and T cell gene therapies and genome editing enabled by redirection vectors, which allow the delivery of genes or genome editors directly to specified target cells in vivo, making the process comparatively fast, convenient, and inexpensive.

[0024] Figure 2B is an illustration of a receptor-blind trimer of a rhabdoviral G glycoprotein fused with a targeting molecule against human CD3.

[0025] Figure 3 shows a schematic diagram of the envelope plasmids version 1, version 2, and version 3 encoding a blind low-density lipoprotein receptor (LDLR) Indian Vesiculovirus (VSV-G) G glycoprotein with Q substitutions at residues K47 and R354 (VSV-G K47QR354Q) (SEQ ID NO: 25) fused to a CD3-targeting molecule (UCHT1 scFv (SEQ ID NOs: 45 and 46), HuM291 scFv (SEQ ID NOs: 37 and 38), OKT3 Petition 870250093142, dated 10 / 10 / 2025, page 35 / 819 6 / 640 scFv (SEQ ID NOs: 39 and 40), TR66 scFv (SEQ ID NOs: 41 and 42), or TR66-opt scFv (SEQ ID NOs: 43 and 44) ​​are used to produce lentiviral particles. The CD3 scFv of plasmids from versions 1 and 2 are oriented with the N-terminal of the heavy chain (VH) towards the light chain (VL), while plasmids from version 3 are oriented with the N-terminal of the VL towards the VH, except for the UCHT1 constructs, which exhibit the reverse orientation of VH and VL in all three versions. Plasmids from version 1 encode an IgG1 hinge linker (SEQ ID NO: 175), and plasmids from versions 2 and 3 encode a 19-amino acid (AA) flexible linker (SEQ ID NO: 130). The plasmids also encode a signal peptide (SP) of VSIV-G (SEQ ID NO: 60). Throughout the figures, VSIV-G and VSV-G refer to the G glycoprotein of the Indian Vesiculovirus.

[0026] Figure 4 is an illustration summarizing how lentiviruses (LVs) pseudotyped with rhabdoviral G glycoproteins alone or fused with a CD3 targeting molecule were prepared. ScFv-G-QQ indicates a VSIV-G with Q substitutions at residues K47 and R354 (QQ) (SEQ ID NO: 25) fused with an scFv targeting molecule, G-WT indicates a VSIV-G without any mutations (SEQ ID NO: 21), and G-QQ indicates a VSIV-G with Q substitutions at residues K47 and R354 (QQ) (SEQ ID NO: 25).

[0027] Figure 5 is a set of western blots of cell lysate from HEK293T cells 72 hours after transduction of each of the 3 versions of VSIV-G CD3 scFv fusion protein plasmids showing the binding of a VSIV antibody to CD3 scFv bands fused with VSIV-G (scFv-VSV-G) and labeled VSIV-G bands (VSV-G). A recombinant human stem cell factor ligand targeting molecule (hSCF) fusion protein (SEQ ID NO: 52) is N-terminally fused to the VSIV-G fusion protein (SEQ ID NO: 21) via a flexible 19-amino acid (19aaL) ligand (SEQ Petition 870250093142, dated 10 / 10 / 2025, page 36 / 819 7 / 640 ID NO: 130) was included as a positive control. GAPDH was used as a load control.

[0028] Figure 6 is a set of western blots of lentivirus particles pseudotyped with the VSIV-G-QQ antiCD3 scFv (αCD3 scFv-VSV-G-QQ) fusion proteins of versions 1, 2, and 3, showing the binding of an antibody against VSIV with VSIV-G bands fused with CD3 scFv (scFv-VSV-G) and labeled VSIV-G (VSV-G) bands. Concentrated lentivirus particles were used, except where labeled prior to concentration. The p24 protein was used as a loading control.

[0029] Figure 7 is a set of micrographs showing Jurkat cells 5 days after transduction with lentivirus pseudotyped with VSIV-G (VSV-G-WT) (SEQ ID NO: 21), VSIV-G-QQ (G-QQ) (SEQ ID NO: 25) or with an anti-CD3 scFv fused to VSIV-G-QQ (αCD3 scFv-VSV-G-QQ) made using all three envelope plasmid versions.

[0030] Figures 8A-8C show the targeting specificity of lentiviruses pseudotyped with scFv anti-CD3 fused to VSIVG-QQ (SEQ ID NO: 25). Figure 8A is a set of micrographs showing Jurkat cells and Nalm6 cells 3 days after transduction with lentivirus with a GFP expression cassette (SEQ ID NO: 176) pseudotyped with VSIV-G (VSV-G-WT) (SEQ ID NO: 21), VSIV-G-QQ (G-QQ) or with an anti-CD3 scFv fused to VSIV-G-QQ (SEQ ID NO: 25) (scFv αCD3-VSV-G-QQ) made using version 3 envelope plasmids. Figures 8B-8C are a set of cytometer images showing GFP-positive Jurkat cells, Nalm6 cells and K562 cells 3 days after transduction with lentivirus with a GFP expression cassette (SEQ ID NO: 176) pseudotyped with VSIV-G (VSV-GWT) (SEQ ID NO: 21), VSIV-G-QQ (G-QQ) (SEQ ID NO: 25) or with an anti-CD3 scFv fused to VSIV-G-QQ (αCD3 scFv-VSV-G-QQ) made Petition 870250093142, dated 10 / 10 / 2025, page 37 / 819 8 / 640 using envelope plasmids version 3 (FIG. 8B) and bar graphs quantifying the K562 cells (left), Nalm6 cells (middle) and Jurkat cells (right) that are positive for GFP for each group (FIG. 8C).

[0031] Figure 9A is an illustration summarizing how lentiviruses (LVs) pseudotyped with VSIV-G-QQ (G-QQ) (SEQ ID NO: 25) and scFv anti-CD3 fused with VSIV-G-QQ were prepared.

[0032] Figures 9B-9C are a set of western blots of cell lysate (FIG. 9B) and virions (FIG. 9C) from HEK293T cells transfected with a constant amount of transfer plasmid, packaging plasmid, and UCHT1 scFv VSIV-GQQ plasmid (SEQ ID NO: 193) and increasing ratios of VSIV-G-QQ plasmid (SEQ ID NO: 97) (1:0, 1:1, 1:2, 1:3, and 1:4) showing the binding of a VSIV-G antibody to bands of fused UCHT1 scFv VSIV-G-QQ (aCD3 UCHT1-G-QQ) and labeled VSIV-G (VSV-G) bands. p24 was used as a loading control.

[0033] Figures 9D-9E are a set of cytometer images showing GFP-positive Jurkat cells and Nalm6 cells 3 days after transduction with a sham treatment or lentivirus with a GFP expression cassette (LV-SFFV-GFP) (SEQ ID NO: 176) pseudotyped with VSIV-G (G-WT) (SEQ ID NO: 21), VSIV-G-QQ (GQQ) (SEQ ID NO: 25) or with UCHT1 scFv (SEQ ID NOs: 45 and 46) fused to VSIV-G-QQ (SEQ ID NO: 25) and VSIV-G-QQ (SEQ ID NO: 25) in a ratio of 1:0, 1:1, 1:2, 1:3 and 1:4 (UCHT1:G-QQ) made using envelope plasmids version 3 (FIG. 9D) and bar graphs quantifying the Nalm6 cells (left) and Jurkat cells (right) that are GFP positive for each group (FIG. 9E).

[0034] Figures 10A-10B are a set of micrographs showing Jurkat cells and Nalm6 cells 24 hours after transduction with lentivirus containing a GFP expression cassette (SEQ ID NO: 176) Petition 870250093142, dated 10 / 10 / 2025, page 38 / 819 9 / 640 pseudotyped with VSIV-G (WT-G) (SEQ ID NO: 21), VSIV-G-QQ (GQQ) (SEQ ID NO: 25), or with a recombinant fusion protein of an anti-EGFR scFv with the N-terminal of the VH fused to the N-terminal of the VL to VSIV-G-QQ (SEQ ID NO: 25) via a RAAASGGS(G4S)2 GP (SEQ ID NO: 208) (G-QQ-αEGFR) linker, a 1:1 ratio of a recombinant fusion protein of the αCD3 UCHT1 scFv with the N-terminal of the VH (SEQ ID NO: 46) fused to the VL (SEQ ID NO: 45) via a (G4S)3 (SEQ ID NO: 36) linker fused to the N-terminal via a 19-amino acid linker (SEQ ID NO: 130) for VSIV-G-QQ (SEQ ID NO: 25) (G-QQ-19aaL-UCHT1) and VSIV-GQQ (G-QQ) (SEQ ID NO: 25), a ratio of 1:0, 1:1, 1:3,1:6 or 1:9 of a recombinant αCD3 scFv TR66-opt fusion protein with the N-terminus fused VL (SEQ ID NO: 43) to VH (SEQ ID NO: 44) via a (G4S)3 linker (SEQ ID NO: 36) fused to the N-terminus via a 19-amino acid linker (SEQ ID NO: 130) to VSIVG-QQ (SEQ ID NO: 25) (G-QQ-19aaL-TR66opt) and VSIV-G-QQ (GQQ) (SEQ ID NO: 25), and a ratio of 1:0, 1:1, 1:3, 1:6 or 1:9 of a recombinant αCD3 scFv TR66-opt fusion protein with the N-terminus fused VH (SEQ ID NO: 44) to the N-terminus fused VL (SEQ ID NO: 43) via a (G4S)3 ligand (SEQ ID NO: 36) via an IgG1 ligand (SEQ ID NO: 175) to VSIV-G-QQ (SEQ ID NO: 25) (G-QQ-IG1-TR66opt) and VSIV-G-QQ (G-QQ) (SEQ ID NO: 25) (FIG. 10A) and bar graphs quantifying Jurkat cells (left) and Nalm6 cells (right) that are GFP positive for each group (FIG. 10B).

[0035] Figure 10C is a set of micrograph images showing Jurkat cells and Nalm6 cells after transduction with lentivirus containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with LDL-R-blind VSIV-G (VSIV-G-QQQ), a 1:3 ratio of a recombinant scFv αCD3 fusion protein. Petition 870250093142, dated 10 / 10 / 2025, page 39 / 819 10 / 640 UCHT1 with the N-terminal fused with VL (SEQ ID NO: 45) to the N-terminal fused with VH (SEQ ID NO: 46) via a (G4S)3 ligand (SEQ ID NO: 36) via an IgG1 ligand (SEQ ID NO: 175) to VSIV-G-QQQ (SEQ ID NO: 26) (VSIV-G-QQQ-IgG1-UCHT1) and VSIV-G-QQ (G-QQQ) (SEQ ID NO: 26), or a 1:3 ratio of a recombinant αCD3 scFv Hum291 fusion protein with the N-terminal fused VH (SEQ ID NO: 38) to VL (SEQ ID NO: 37) via a (G4S)3 ligand (SEQ ID NO: 36) fused via an IgG1 ligand (SEQ ID NO: 175) for VSIV-G-QQQ (SEQ ID NO: 26) (VSIV-GQQQ-IgG1-Hum291) and VSIV-G-QQ (G-QQQ) (SEQ ID NO: 26).

[0036] Figures 11A-11C are a set of micrographs showing Jurkat cells 24 hours after transduction with lentivirus containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with VSIV-G (WT) or VSIV-G-QQ (WT-GQQ) (FIG. 11A), or pseudotyped with a 1:1 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein with the N-terminal fused VH (SEQ ID NO: 46) to the N-terminal fused VL (SEQ ID NO: 45) via a (G4S)3 linker (SEQ ID NO: 36) via a 19-amino acid linker (SEQ ID NO: 130) to VSIV-G-QQ (SEQ ID NO: 25) and VSIV-G-QQ (GQQ) (SEQ ID NO: 25) (UCHT1 (19aa) GQQ) (FIG.11B), or pseudotyped with a 1:1, 1:3, 1:6, or 1:9 ratio of a recombinant αCD3 scFv TR66-opt fusion protein with the N-terminus fused with VH (SEQ ID NO: 44) to VL (SEQ ID NO: 43) via an N-terminus fused with a (G4S)3 linker (SEQ ID NO: 36) to a 19-amino acid linker (SEQ ID NO: 130) or an IgG1A linker (SEQ ID NO: 175) to the N-terminus of VSIV-G-QQ (Tr66opt (19aa) GQQ or Tr66opt (Ig1a) GQQ) and VSIV-G-QQ (G-QQ) (SEQ ID NO: 25) (FIG. 11C) grown in media containing Opti-MEM™ (Medium) or human serum (Serum).

[0037] Figures 11D-11E are a set of micrographs showing Petition 870250093142, dated 10 / 10 / 2025, p. 40 / 819 11 / 640 trando Jurkat cells 24 hours after transduction with lentivirus containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with VSIV-G harvested from HEK-293T cells (LV-WT-G-293 Parental) or HEK-293T cells expressing mouse CD55 (LV-WT-G-293 mouse CD55), or pseudotyped with VSIV-G-QQ (LV-GQQ), or a 1:1 ratio of a recombinant scFv UCHT1 anti-CD3 fusion protein with the N-terminal fused VH (SEQ ID NO: 46) to VL (SEQ ID NO: 45) via a (G4S)3 linker (SEQ ID NO: 36) fused via a 19-amino acid linker (SEQ ID NO: 130) to VSIV-G-QQ (SEQ ID NO: 25) and VSIV-G-QQ (G-QQ) (SEQ ID NO: 25) (UCHT1 (19aa) GQQ)],or a 1:6 ratio of a recombinant scFv TR66-opt αCD3 fusion protein with the N-terminal fused VH (SEQ ID NO: 44) to VL (SEQ ID NO: 43) via an N-terminal fused with a (G4S)3 ligand (SEQ ID NO: 36) to an N-terminal fused with an IgG1A ligand (SEQ ID NO: 175) to VSIV-G-QQ (Tr66opt (Ig1a) GQQ) and VSIV-G-QQ (G-QQ) (SEQ ID NO: 25) cultured in media containing Opti-MEM™ (Optimem), human serum, mouse serum, heat-inactivated (HI) human serum or mouse serum HI (FIG. 11D) and a bar graph quantifying the fold change in GFP-positive Jurkat cells cultured in medium containing Opti-MEM™ over positive Jurkat cells for GFP cultured in medium containing human HI serum, mouse HI serum, human serum, or mouse serum that were transduced with lentivirus pseudotyped with LV-WT-G-293 Parental (left bar),a 1:6 ratio of Tr66opt-IgG1A-G-QQ and G-QQ (LV-TR66-IgG1-opt + GQQ 1:6) (middle bar) or a 1:1 ratio of UCHT1-(19aa)-GQQ and G-QQ (LV-UCHT1-19aa + GQQ 1:1) (right bar) (FIG. 11E).

[0038] Figure 11F is a flow cytometry histogram showing the number of mouse CD55-positive cells. Petition 870250093142, dated 10 / 10 / 2025, page 41 / 819 12 / 640 (mCD55+) in the parental HEK-293T and HEK-293T-mCD55 groups.

[0039] Figures 12A-12D are flow cytometry dot plots showing GFP intensity vs. CD3 in human peripheral blood mononuclear cells (PBMCs) cultured in media containing interleukin-2 (IL-2) or in media containing interleukin-7 (IL7) and interleukin-15 (IL-15) (cytokine-activated) that were infected with lentivirus containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with VSIV-G (WT-G) (SEQ ID NO: 21), VSIVG-QQ (G-QQ) (SEQ ID NO: 25) or a 1:1 ratio of a recombinant anti-CD3 scFv TR66-opt fusion protein (SEQ ID NOs: 43 and 44) ​​fused N-terminally to an IgG1 ligand (SEQ ID NO: 175) fused N-terminally to VSIV-G-QQ (SEQ ID NO: 25) and VSIV-G-QQ (SEQ ID NO: 25) (TR66opt) (FIG.12A) or a 1:1 ratio of a recombinant scFv anti-CD3 TR66 fusion protein (SEQ ID NOs: 41 and 42) or UCHT1 (SEQ ID NOs: 45 and 46) fused N-terminal to VSIV-GQQ (SEQ ID NO: 25) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQ (SEQ ID NO: 25) (TR66 or UCHT1) ligand (FIG. 12C), quantified in a bar graph showing the percentage of GFP-positive cells that are CD3-positive (CD3+, black bar) or CD3-negative (CD3-, gray bar) cultured in media containing IL-2 or IL-7 and IL-15 (activated) for each lentivirus group (FIGs. 12B and 12D).

[0040] Figures 13A-13F are a set of flow cytometry dot plots showing GFP vs. CD3 intensity in lentivirus-transduced human PBMCs containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with wild-type G (G-WT) (SEQ ID NO: 21), K47Q+R354Q G substitution (G-QQ) (SEQ ID NO: 25), K47Q+R354Q+Y209Q G substitution (G-QQQ) (SEQ ID NO: 26), or SpyTag K47Q+R354Q+Y209Q G substitution (ST-G-QQQ) (SEQ ID NO: 66) alone or linked to SpyCatcher (SEQ ID NO: 30) with targeting molecule. Petition 870250093142, dated 10 / 10 / 2025, p. 42 / 819 13 / 640 menthol UCHT1 (SEQ ID NOs: 45 and 46) (G-QQQ-ST-UCHT1), TR66-opt (SEQ ID NOs: 43 and 44) ​​(G-QQQ-ST-TR66-opt), or TR66 (SEQ ID NOs: 41 and 42) (G-QQQ-ST-TR66) grown in medium containing hIL-2 (FIG. 13A) or hIL-7 and hIL-15 (FIG. 13C), a set of flow cytometry histograms showing the intensity of CD25 in the same PBMCS transduced with lentivirus particles and grown in medium containing hIL-2 (FIG. 13B) or hIL-7 and hIL-15 (FIG. 13D), a pair of bar graphs showing the average fluorescence intensity for the same PBMCS transduced with lentivirus particles Lentivirus and cultured in media containing hIL-2 (left graph) or hIL-7 and hIL-15 (right graph) (FIG. 13E), and a pair of bar graphs showing the percentage of CD25 in the same PBMCs transduced with lentivirus particles and cultured in media containing hIL-2 (left graph) or hIL-7 and hIL-15 (right graph) (FIG. 13F).

[0041] Figures 14A and 14B are a set of cytometry images showing the number of GFP-positive human peripheral blood mononuclear cells (PBMCs) cultured in media containing fetal bovine serum (FBS) and IL-2 (FBS), IL-2 and human serum, or IL-7, IL-15 and human serum, and transduced with lentivirus containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with VSIV-G (WT-G) (SEQ ID NO: 21), VSIV-G-QQ (G-QQ) (SEQ ID NO: 25), or a mixture of a recombinant antiCD3 scFv TR66-opt fusion protein (SEQ ID NOs: 43 and 44) ​​fused N-terminal to VSIV-G-QQ (SEQ ID NO: 25) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQ (SEQ ID NO: 25) in a 1:1 ratio (TR66opt 1:1) or a 1:6 ratio (TR66opt 1:6) (FIG. 14A), or a set of flow cytometry dot plots showing the intensity of GFP vs. CD3 of the same (FIG. 14B).

[0042] Figure 15A is a diagram of the plasmid encoding αCD19-CAR (SEQ ID NO: 165), which contains sequences encoding Petition 870250093142, dated 10 / 10 / 2025, page 43 / 819 14 / 640 elongation factor 1 alpha (EF1α), a signaling peptide for CD8 (SP) (SEQ ID NO: 148), the anti-CD19 scFv FMC63 (SEQ ID NOs: 155 and 156), a CD8α hinge domain (CD8α-hinge) (SEQ ID NO: 149), a CD8 transmembrane domain (CD8-TM) (SEQ ID NO: 150), an intracellular signaling domain comprising a human 4-1BB costimulatory domain (SEQ ID NO: 151) and a human CD3 zeta activating domain (SEQ ID NO: 152), a peptide 2A (P2A) and emerald green fluorescent protein (EmGFP) (SEQ ID NO: 153).

[0043] Figure 15B is a flow cytometry dot plot showing GFP intensity vs CD19.

[0044] Figures 15C-15E are a set of flow cytometry dot plots showing GFP intensity vs. CD3 in human PBMCs cultured in media without IL-2 (without IL-2) or containing IL-2 (with rhIL-2) without lentivirus (Simulated), transduced with lentivirus containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with VSIV-G (G-WT) (SEQ ID NO: 21), or transduced with lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) or a recombinant scFv anti-CD3 TR66opt fusion protein (SEQ ID NOs: 43 and 44) ​​fused N-terminal to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) (FIG. 15C), a set of flow cytometry histograms showing the intensity of CD25 in the same PBMCs (FIG.15D) and a set of bar graphs showing the fold change in the number of cells in the same PBMCs 6 days after infection (FIG. 15E).

[0045] Figure 15F is a set of bar graphs showing the levels of the cytokines interferon gamma (IFNy), tumor necrosis factor alpha (TNFα), and IL2 as picograms per mL in human PBMCs. Petition 870250093142, dated 10 / 10 / 2025, p. 44 / 819 15 / 640 in cultured media without IL-2 or with IL-2 without lentivirus (NT), transduced with lentivirus containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with VSIV-G (G-WT) (SEQ ID NO: 21), or transduced with lentivirus containing a plasmid encoding αCD19-CAR CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) or a recombinant scFv anti-CD3 TR66opt fusion protein (SEQ ID NOs: 43 and 44) ​​N-terminal fused to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26).

[0046] Figure 16A is a flowchart showing the experimental design of an experiment demonstrating efficient targeted transduction of CD3+ T cells in fresh human whole blood by a lentivirus pseudotyped with a recombinant fusion protein of an anti-CD3 scFv fused at the N-terminal to a blind LDLR VSIV-G (SEQ ID NO: 26) and containing a plasmid encoding a chimeric αCD19 antigen receptor (CAR) (SEQ ID NO: 165).

[0047] Figure 16B is a diagram of the plasmid encoding αCD19-CAR, which contains the encoding elongation factor 1 alpha (EF1α), a signaling peptide for CD8 (SP) (SEQ ID NO: 148), the anti-CD19 scFv FMC63 (SEQ ID NOs: 155 and 156), a CD8α hinge domain (CD8α-hinge) (SEQ ID NO: 149), a CD8 transmembrane domain (CD8-TM) (SEQ ID NO: 150), an intracellular signaling domain comprising a human 4-1BB costimulatory domain (SEQ ID NO: 151) and a human CD3 zeta activating domain (SEQ ID NO: 152), a peptide 2A (P2A), and emerald green fluorescent protein (EmGFP) (SEQ ID NO: 153).

[0048] Figures 16C-16D are a set of flow cytometry dot plots showing GFP vs. CD3 intensity in human PBMCs from two lentivirus-free (LV-free) transducers. Petition 870250093142, dated 10 / 10 / 2025, page 45 / 819 16 / 640 cells were transduced with lentiviruses containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with VSIV-G (G-WT) (SEQ ID NO: 21), or transduced with lentiviruses containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) fused N-terminal to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-GQQQ (SEQ ID NO: 26) (FIG. 16C) and a set of flow cytometry histograms showing CD25 intensity in the same PBMCs (FIG. 16D).

[0049] Figure 16E is a set of flow cytometry dot plots showing CD8 vs. CD4 intensity (middle plot) in lentivirus-transduced human PBMCs containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) fused N-terminal to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) ligand, or GFP vs. CD25 intensity in a CD8+ (left plot) or CD4+ (right plot) T cell subpopulation of PBMCs.

[0050] Figure 17A shows a summary of the experimental design to test the in vivo generation of CAR-T cells in humanized NSG mice without tumors via intravenous (IV) injection.

[0051] Figures 17B and 17C are flow cytometry dot plots showing the intensity of GFP vs. human CD3 in blood cells from humanized NSG mice administered intravenously (IV) injection (FIG. 17B) with saline solution, lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (SEQ ID NO: 21) (G-WT), or lentivirus. Petition 870250093142, dated 10 / 10 / 2025, page 46 / 819 Figure 17 / 640 contains a plasmid encoding aCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 TR66opt fusion protein (SEQ ID NOs: 43 and 44) ​​fused N-terminal to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) (G-TR66opt) ligand and plots of CAR / GFP+ cell lines as a percentage of hCD45+ cells in blood cells from the same mice that received saline or lentivirus by intravenous injection (FIG. 17C). The -1 or -2 attached to the samples in the bar graph indicates individual mice in the study.

[0052] Figures 17D-17F are flow cytometry dot plots showing the intensity of human CD19 vs. Human CD3 in humanized NSG mouse blood cells administered via IV injection (FIG. 17D) with saline solution, lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (SEQ ID NO: 21) (G-WT), or lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 TR66opt fusion protein (SEQ ID NOs: 43 and 44) ​​fused N-terminal to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) (G-TR66opt) ligand and CAR / GFP+ cell line graphs (FIG. 17E) or CD3+ T cells (FIG. 17F) as a percentage of hCD45+ cells in blood cells from the same mice administered with saline solution or lentivirus by intravenous injection.

[0053] Figures 17G-17H are a set of flow cytometry dot plots showing the intensity of GFP vs. human CD3 (FIG. 17G) or the intensity of human CD19 vs. human CD3 (FIG. 17H) in the bone marrow, spleen, and liver of humanized NSG mice administered intravenously with solution Petition 870250093142, dated 10 / 10 / 2025, page 47 / 819 18 / 640 saline, lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (SEQ ID NO: 21) (G-WT) or lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 TR66opt fusion protein (SEQ ID NOs: 43 and 44) ​​fused N-terminal to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) (GTR66-opt).

[0054] Figure 17I shows a summary of the experimental design to test the in vivo generation of CAR-T cells in humanized NSG mice without tumors via intravenous (IV) injection.

[0055] Figures 17J and 17K are flow cytometry dot plots showing the intensity of GFP vs. human CD3 in blood cells from humanized NSG mice administered via intraperitoneal (IP) injection (FIG.17J) with saline solution, lentivirus containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) fused N-terminal to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) (G-CD3GFP), lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (SEQ ID NO: 21) (G-WTCAR / GFP), or lentivirus containing a plasmid encoding αCD19CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a Recombinant scFv anti-CD3 TR66opt fusion protein (SEQ ID NOs: 43 and 44) ​​fused N-terminal to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) pseudotyped with VSIV-G (G-CD3-CAR / GFP), and graphs of CAR / GFP+ cell lines as a percentage of cells. Petition 870250093142, dated 10 / 10 / 2025, page 48 / 819 19 / 640 hCD45+ in blood cells from the same mice administered with saline solution or intraperitoneal lentivirus injection (FIG. 17K). The -1 or -2 attached to the samples in the bar graph indicates individual mice in the study.

[0056] Figures 17L-17N are flow cytometry dot plots showing the intensity of human CD19 vs. human CD3 in blood cells from humanized NSG mice administered via IP injection (FIG.17L) with saline lentivirus containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with a 1:3 ratio of a recombinant scFv antiCD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) fused N-terminal to VSIV-GQQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) (G-CD3-GFP), lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (SEQ ID NO: 21) (G-WT-CAR / GFP), or lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a protein Recombinant fusion of scFv anti-CD3 TR66opt (SEQ ID NOs: 43 and 44) ​​N-terminally fused to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) pseudotyped with VSIV-G (G-CD3-CAR / GFP), and line graphs of CAR / GFP+ cells (FIG. 17M) or CD3+ T cells (FIG.17N) as a percentage of hCD45+ cells in blood cells from the same mice administered with saline or lentivirus by IP injection. The -1 or -2 attached to the samples in the bar graph indicates individual mice in the study.

[0057] Figure 18A shows a summary of the experimental design to test the efficacy of CAR-T cells generated in vivo via IP administration in humanized mice bearing tumors.

[0058] Figures 18B-18D are a cytometry dot plot. Petition 870250093142, dated 10 / 10 / 2025, page 49 / 819 20 / 640 flow showing the intensity of GFP vs. CD3 in blood cells of humanized mice on day 16 (D16) or day 23 (D23) after tumor implantation that was administered via IP injection with lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (SEQ ID NO: 21) (G-WTCAR / GFP) or a lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) fused N-terminally to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-GQQQ (SEQ ID NO: 26) ligand on day 3 (G-aCD3-CART D3) or day 10 (GaCD3-CART D10) after tumor implantation (FIG. 18B), and graphs showing the number of CAR-positive and GFP-positive T cells per μL of blood (FIG. 18C) or the amount of CAR-T cells as a percentage of human CD45-positive (hCD45+) cells (FIG. 18D) in the same mice.

[0059] Figure 18E is a bar graph showing the number of CAR-T CD8+ (left bar) and CD4+ (right bar) cells per μL of blood in humanized mice that received IP administration of lentivirus containing a plasmid encoding aCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) N-terminally fused to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) ligand on day 10 (G-aCD3-CART D10) after tumor implantation.

[0060] Figure 18F is a bar graph showing the levels of the cytokine human interferon gamma (hIFNy) in picograms per mL on day 16 and day 23 after tumor implantation in the blood of mice that received IP administration of lentivirus containing a plasmid encoding aCD19-CAR (SEQ ID NO: 165) pseudotyped. Petition 870250093142, dated 10 / 10 / 2025, page 50 / 819 21 / 640 with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) fused at the N-terminus to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) on day 3 (G-aCD3-CART D3) or day 10 (G-aCD3-CART D10) after tumor implantation.

[0061] Figure 18G is a set of bioluminescence images of humanized mice implanted with Nalm6 tumors on day 0 and administered via IP injection with saline or lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) N-terminal fused to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) on day 3 (G-aCD3-CART D3) or day 10 (G-aCD3-CART D10) after tumor implantation.

[0062] Figures 18H and 18I are a set of graphs showing the percentage change in body weight of humanized mice injected with saline or lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) N-terminally fused to VSIV-GQQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) on day 3 (G-aCD3-CART D3) or day 10 (G-aCD3-CART D10) after tumor implantation (FIG. 18H) and a graph showing the survival rate throughout the experiment in the same mice.

[0063] Figure 19A shows a summary of the experimental design to test the efficacy of CAR-T cells generated in vivo via IP or IV administration in humanized mice implanted with Nalm6 tumors expressing firefly luciferase (Nalm6-Fluc).

[0064] Figures 19B-19C are a graph showing the number Petition 870250093142, dated 10 / 10 / 2025, page 51 / 819 22 / 640 human CD45-positive (hCD45+) cells per μL of blood from humanized mice implanted with Nalm6-Fluc tumors several days post-injection (PI days) and treated without lentivirus (Group 1, No LV), treated via IP injection with lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) N-terminally fused to VSIV-G with a deletion at residue K47 (VSIV-G-ΔK47) (SEQ ID NO: 27) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-ΔK47 (SEQ ID NO: 27) (Group 4, G-CD3 / IP), treated via Intravenous injection with lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (SEQ ID NO: 21) (Group 2, G-WT / IV),lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) fused N-terminally to VSIV-G with a deletion at residue K47 (VSIVG-ΔK47) (SEQ ID NO: 27) via an IgG1 (SEQ ID NO: 175) and VSIV-G-ΔK47 (SEQ ID NO: 27) linker (Group 3, G-CD3 / IV), or lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) fused N-terminal to the Vesiculovirus newjersey G glycoprotein with a deletion at residue K47 (VSNJV-G-ΔK47) (SEQ ID NO: 29) via an IgG1 ligand (SEQ ID NO: 175) and VSNJV-G-ΔK47 (SEQ ID NO: 29) (Group 5 G-CD3-NJ / IV) (FIG. 19B), and graphs showing the number of human CD45-positive (hCD45+) cells per μL of blood from the same mice on day 8 after treatment (graph on the left) and in Group 1 mice on days 9,16, 23, 30 and 37 (graph on the right) (FIG. 19C).

[0065] Figure 19D is a graph of the number of CAR-T cells. Petition 870250093142, dated 10 / 10 / 2025, p. 52 / 819 23 / 640 humans positive for GFP per μL of blood from mice in Groups 1, 2, 3, 4, and 5 over the days following implantation (Days PI) of the Nalm6-Fluc tumor.

[0066] Figure 19E is a pair of bar graphs showing the number of CAR-T CD8-positive (CD8+, left bar) and CD4-positive (CD4+, right bar) cells per μL of blood from mice in Group 3 and Group 4 over the days after lentivirus injection (Days after LV injection).

[0067] Figures 19F-19I are a set of graphs showing the levels of the cytokines interleukin 10 (IL-10) (FIG. 19F), IL-2 (FIG. 19G) or TNFα (FIG. 19H) as picograms per mL, or the cytokine IFNγ (FIG. 19I) as mean fluorescence intensity (MFI) in mice from Groups 1, 2, 3 and 4 over the days after lentivirus injection (Days LV after injection).

[0068] Figure 19J is a set of bioluminescence images of mice from Groups 1, 2, 3, 4, and 5 at various times after Nalm6-Fluc tumor implantation, showing mean radiance measured in the number of photons per second leaving one square centimeter of tissue and radiating at a solid angle of one steradian (p / s / cm2 / sr). Arrows indicate mice with the highest CAR-T levels.

[0069] Figures 19K-19L are graphs showing the total flux in photons per second (p / s) during bioluminescence imaging in mice from Groups 1, 2, 3, 4, and 5 on day 0 of the experiment (FIG. 19K) and over the days following treatment (FIG. 19L).

[0070] Figures 19M-19N are a set of bioluminescence images of mice from Groups 3, 4 and 5 on days 43, 50 and 57 after treatment, showing the mean radiance (p / s / cm2 / sr) (FIG. 19M) and a graph showing the mean radiance in the same mice, measured from the dorsal and ventral views (FIG. 19N). Petition 870250093142, dated 10 / 10 / 2025, page 53 / 819 24 / 640

[0071] Figure 19O is a set of flow cytometry dot plots showing GFP intensity vs human CD3 in the spleen, bone marrow, and liver of mice from Groups 1, 2, 3, 4, and 5 16 days after Nalm6-Fluc tumor implantation.

[0072] Figure 19P shows CAR-T cells as a percentage of hCD45+ cells in the blood of mice from Groups 1, 2, 3, 4 and 5 15 days after implantation of the Nalm6-Fluc tumor.

[0073] Figure 19Q is a set of flow cytometry dot plots showing GFP intensity vs recombinant CD19 in the blood of mice from Groups 1, 2, 3, 4 and 5 36 days after LV injection.

[0074] Figures 19R-19V are a set of flow cytometry dot plots showing the intensity of GFP vs. recombinant CD19 (middle dot plot) and showing the intensity of human CD62L vs. human CD45RA in non-CAR-T cells (left dot plot) and in CAR-T cells (right dot plot) in the blood of mice in Group 2 (FIG. 19R), Group 3 (FIG. 19S), Group 4 (FIG. 19T), Group 5 (FIG. 19U) on day 36 after LV injection and a bar graph quantifying stem-like T cells as a percentage of human T cells in CAR-T+ cells (left bar) and non-CAR-T cells (right bar) for the same mice (FIG. 19V).

[0075] Figures 20A-20D are a set of flow cytometry dot plots showing the intensity of GFP vs. human CD3 (FIG. 20A) and showing the intensity of human CD19 vs. human CD3 (FIG. 20B) in the blood of mice administered via IP injection with saline solution (Group 1) or lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) (Group UCHT-CAR19). Petition 870250093142, dated 10 / 10 / 2025, page 54 / 819 25 / 640 IP), or scFv anti-CD3 TR66opt (SEQ ID NOs: 43 and 44) ​​(TR66optCAR19 IP), N-terminally fused to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) ligand, or a lentivirus containing a plasmid encoding αCD19CAR (SEQ ID NO: 165) pseudotyped with a 1:6:1 ratio of a recombinant fusion protein of scFv anti-CD3 TR66opt (SEQ ID NOs: 43 and 44) ​​N-terminally fused to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) and a recombinant human CD80 fusion protein (HuCD80-G-QQ), or administered by intravenous injection with a lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) fused N-terminus to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) (UCHTCAR19 IV),or the scFv anti-CD3 TR66opt (SEQ ID NOs: 43 and 44) ​​(TR66opt-CAR19 IP) on day 14 after injection (top line) or day 21 after injection (bottom line), and bar graphs showing GFP-positive CAR T cells as a percentage of CD45-positive human cells (FIG. 20B) and CD19-positive B cells as a percentage of CD45-positive human cells (FIG. 20D).

[0076] Figure 21 shows a summary of the experimental design to test the cytotoxicity of lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (GWT LV) or a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) (Group UCHTCAR19 IP) fused N-terminally to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) ligand in fully immunocompetent transgenic mice for the γ, δ and ε subunits of human CD3 (GDE mice) and, Petition 870250093142, dated 10 / 10 / 2025, p. 55 / 819 26 / 640 KaLwRij mice by intravenous administration.

[0077] Figures 22A and 22B are a set of flow cytometry dot plots showing mouse CD3 intensity vs. human CD3 in the blood of GDE mice and KaLwRij mice (FIG. 22A) and a set of flow cytometry dot plots showing mouse CD69 intensity vs. Mouse CD25 in the blood of GDE mice before lentivirus injection and 3, 6, and 24 hours after injection of a lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (G-WT LV) or a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) (Group UCHT-CAR19 IP) fused N-terminally to VSIV-G-QQQ (SEQ ID NO: 26) via IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) (G-CD3 LV) (FIG. 22B).

[0078] Figure 23A shows a summary of the experimental design to test the cytotoxicity of lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) N-terminally fused to VSNJV-G-ΔK47 (SEQ ID NO: 29) via an IgG1 (SEQ ID NO: 175) and VSNJV-G-ΔK47 (SEQ ID NO: 29) ligand in fully immunocompetent mice transgenic for the γ, δ and ε subunits of human CD3 (GDE mice) via IV (Group 1) or IP (Group 2) administration.

[0079] Figures 23B and 23C are a set of flow cytometry dot plots showing CD69 vs CD25 intensity in the blood of lentivirus-injected naive GDE mice and in GDE mice 2 hours and 4 days after lentivirus injection via IV (GR 1(IV)) or IP (Gr 2 (IP)) administration (FIG. 23B) and a graph showing the percentage change in body weight. Petition 870250093142, dated 10 / 10 / 2025, p. 56 / 819 27 / 640 ral each day for the same mice over the 4 days following lentivirus administration (FIG. 23C).

[0080] Figures 24A-24D are superimposed figures showing alternating habdoviral G glycoproteins. Figure 24A represents selected glycoproteins from the genera Vesiculovirus, Sprivivirus, Perhabdovirus, Ledantevirus, and Sigmavirus. Figure 24B represents selected glycoproteins from the genera Ephemerovirus, Tibrovirus, Hapavirus, Curiovirus, Caligrhavirus, Tupavirus, Sripuvirus, and Alphanemrhavirus. Figure 24C represents selected glycoproteins from the genera Lyssavirus, Almendravirus, and Varicosavirus. Figure 24D represents selected glycoproteins from the genera Cytorhabdovirus, Dichorhavirus, Nucleorhabdovirus, and Novirhabdovirus. The arrows indicate nine glycoproteins from nine different genera of rhabdoviruses (arrows pointing to Ledantevirus: KM205001 Fukuoka virus (FIG. 24A); Sigmavirus: GQ375258 Drosophila melanogaster Sigmavirus (FIG. 24A); Ephemerovirus: AF234533 bovine ephemeral fever virus (FIG. 24B); Tibrovirus: JX297815 Bas-Congo virus (FIG.24B); Hapavirus: KM205002 Flanders virus (FIG. 24B); Curiovirus: KM204994 Curionopolis virus (FIG. 24B); Tupavirus: AY840978 Tupaia rhabdovirus (FIG. 24B); Sripuvirus: KC585008 Niakha virus (FIG. 24B); Almendravirus: KF543749 Puerto Almendras virus (FIG. 24C)). DETAILED DESCRIPTION

[0081] In some aspects, the present invention provides a recombinant fusion protein comprising, consisting essentially of, or consisting of (a) a rhabdoviral G glycoprotein or a functional fragment or derivative thereof and (b) a polypeptide antibody construct, wherein the polypeptide antibody construct has the ability to bind to human CD3. In some aspects, the polypeptide antibody construct is N-terminal to the rhabdoviral G glycoprotein or to a functional fragment or derivative thereof. Petition 870250093142, dated 10 / 10 / 2025, p. 57 / 819 28 / 640

[0082] Rhabdoviruses are viruses of the family Rhabdoviridae. The viruses encode proteins called N (nucleoprotein), P (phosphoprotein), M (matrix protein), G (glycoprotein), and L (large protein, which is a polymerase), and appear bullet-shaped when viewed by electron microscopy. The dimensions of rhabdovirus virions can vary from 100 nm to 430 nm in length and from 45 nm to 100 nm in diameter. Exemplary rhabdoviruses, without limitation, contemplated herein are listed in Figures 24A-24D.

[0083] The rhabdoviral G glycoprotein mediates the binding of the rhabdovirus to a receptor on the cell, which in turn mediates the entry of the rhabdovirus into the cell and infection of the cell. A rhabdoviral G glycoprotein or a functional or derived fragment thereof, as described herein, including recombinant fusion proteins comprising the rhabdoviral G glycoprotein or a functional or derived fragment thereof, may be used to pseudotype a virus type other than the native / natural virus of the rhabdoviral G glycoprotein.

[0084] As used herein, a pseudotype of a virus, membranous vesicle, enveloped delivery vehicle, enveloped viral particle, or recombinant viral vector, etc. means a virus, membranous vesicle, enveloped delivery vehicle, enveloped viral particle, or recombinant viral vector, etc., comprising a molecule, for example, a rhabdoviral G glycoprotein or a functional fragment or derivative thereof (including a recombinant fusion protein comprising the rhabdoviral G glycoprotein or a functional fragment or derivative thereof), which is not typically found in the virus, membranous vesicle, enveloped delivery vehicle, enveloped viral particle, or recombinant viral vector, etc. Such a molecule may have a mutation (e.g., a substitution or deletion) that impacts the tropism of the virus, membranous vesicle, enveloped delivery vehicle, enveloped viral particle, or recombinant viral vector, etc. Petition 870250093142, dated 10 / 10 / 2025, page 58 / 819 29 / 640 The impact on tropism can be, for example, contributing to, directing, redirecting, or completely changing, or any combination thereof, the tropism of the virus, membranous vesicle, enveloped delivery vehicle, enveloped viral particle, or recombinant viral vector, etc., when compared to the virus, membranous vesicle, enveloped delivery vehicle, enveloped viral particle, or recombinant viral vector, etc., without the molecule and / or compared to the wild-type virus, membranous vesicle, enveloped delivery vehicle, enveloped viral particle, or recombinant viral vector, etc. The impact on tropism can be, for example, targeting a cell that is different from the normally target cell of the virus, membranous vesicle, enveloped delivery vehicle, enveloped viral particle, or recombinant viral vector, etc. and / or not reaching a cell that is normally targeted by the virus, membranous vesicle, enveloped delivery vehicle, enveloped viral particle or recombinant viral vector, etc.

[0085] As used herein, a functional fragment of a rhabdoviral G glycoprotein means a rhabdoviral G glycoprotein that is not a full-length rhabdoviral G glycoprotein, but rather a portion of a parental rhabdoviral G glycoprotein (e.g., a truncated form of a full-length rhabdoviral G glycoprotein), where the portion retains the fusion function of the parental full-length rhabdoviral G glycoprotein. As used herein, a functional derivative or functional variant of a rhabdoviral G glycoprotein means a rhabdoviral G glycoprotein that has been modified, for example, by conservative amino acid substitution, where the rhabdoviral G glycoprotein retains the fusion function of the parental full-length rhabdoviral G glycoprotein. As used herein, functional fragment or derivative and functional fragment or variant encompass the meanings of functional fragment and functional derivative / functional variant.The fusion function of a rhabdoviral G glycoprotein means that a... Petition 870250093142, dated 10 / 10 / 2025, page 59 / 819 30 / 640 Rhabdoviral G glycoprotein, when part of a virus, can initiate the fusion of the virus with a target cell, for example, so that the virus can infect the target cell. Such fusion may be due to the interaction of the rhabdoviral G glycoprotein with its natural receptor or to the interaction of the rhabdoviral G glycoprotein with a different receptor (for example, the rhabdoviral G glycoprotein is blinded to its natural receptor, so that the rhabdoviral G glycoprotein is engineered to reduce or abolish its binding specificity to the natural receptor, and the rhabdoviral G glycoprotein is redirected to a new receptor). A functional fragment and / or functional derivative / functional variant of a rhabdoviral G glycoprotein may be within a recombinant fusion protein comprising a rhabdoviral G glycoprotein.

[0086] In some respects, the recombinant fusion protein comprises a signal peptide. As used herein, a signal peptide refers to a peptide involved in targeting a glycoprotein to the secretory pathway. In some respects, different signal peptides may be selected to enhance glycoprotein targeting to the secretory pathway. In some respects, the signal peptide may be the natural signal peptide for the rhabdoviral G glycoprotein. In some respects, the signal peptide comprises the amino acid sequence of a signal peptide, as described herein. In some respects, the recombinant fusion protein comprises an N-terminal signal peptide to the target molecule. In some respects, the signal peptide comprises the amino acid sequence of SEQ ID NO: 60, 121, 122, 123, 253, 256, 257, or 265. In some respects, the signal peptide comprises the amino acid sequence of a signal peptide, as described herein.In some respects, the recombinant fusion protein comprises an N-terminal signal peptide attached to the polypeptide antibody construct. In some respects, the signal peptide comprises the amino acid sequence SEQ ID NO: 60. In some respects, the protein... Petition 870250093142, dated 10 / 10 / 2025, page 60 / 819 31 / 640 Recombinant fusion comprises a mature form of a rhabdoviral G glycoprotein or a functional fragment or derivative thereof, wherein the signal peptide is not present in the recombinant fusion protein. In some respects, the recombinant fusion protein comprising a rhabdoviral G glycoprotein or a functional fragment or derivative thereof does not comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more N-terminal amino acids of the mature form of the wild-type rhabdoviral G glycoprotein. In some respects, the recombinant fusion protein comprising a rhabdoviral G glycoprotein or a functional fragment or derivative thereof does not comprise a signal peptide and also does not comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more N-terminal amino acids of the mature form of the wild-type rhabdoviral G glycoprotein.

[0087] In some respects, the recombinant fusion protein comprises a tag for Western blot detection or purification. In some respects, the tag is a Western blot detection tag. In some respects, the tag is a purification tag. In some respects, the tag is a FLAG, GFP, or other tag.

[0088] One advantage of the technology of the present invention is that it provides fine-tuning of the stoichiometry of the ligand-bound rhabdoviral glycoprotein G relative to the free rhabdoviral glycoprotein G. In some respects, the present invention provides methods for evaluating the stoichiometry of the ligand-bound rhabdoviral glycoprotein G relative to the free rhabdoviral glycoprotein G. For example, in some respects, a single antibody in a western blot can indicate the ratio between the ligand-bound protein and the free protein.

[0089] T cell activation typically requires a T cell to experience at least two signals, here referred to as signal 1 and signal 2. Binding of the CD3-TCR complex provides the first signal that Petition 870250093142, dated 10 / 10 / 2025, page 61 / 819 32 / 640 leads to T cell activation and involves signal transduction via cytoplasmic tails of the CD3 subunit containing ITAMs (10 ITAMs per TCR). T cell activation is determined by the involvement of a specific, yet unknown, number of ITAMs (but not all 10 ITAMs) found distributed across all CD3 subunits. The involvement of different ITAMs makes CD3 signaling tunable. Proper T cell activation, resulting in cytolytic activity, generally requires signal 2 from costimulatory molecules and, under some conditions, signal 3 provided by cytokines.

[0090] Unexpectedly, it was discovered that the recombinant fusion protein, as described herein, which possesses a polypeptide antibody construct with the ability to bind to human CD3, providing signal 1, can activate T cells without the need for signal 2 or 3. This activation was confirmed by the upregulation of CD25 on the surface of T cells and by the production and proliferation of IL2 and IFNγ by T cells without any additional stimulus or the presence of activating cytokines such as IL-7 and IL-15. Without wanting to limit oneself to theory, this type of activation can be attributed to the particular way in which the polypeptide antibody construct described herein, when placed on the surface of an enveloped viral particle, binds to the CD3-TCR complex and activates the specific set of ITAMs.

[0091] Another advantage of a recombinant fusion protein, as described herein, which has a polypeptide antibody construct capable of binding to human CD3, is that it can be used in, for example, a virus, a membranous vesicle, an enveloped delivery vehicle, an enveloped viral particle, a recombinant viral vector, etc., to infect T cells in vivo. Since CD3 is a pan-T marker, infection can be targeted directly to T cells and the cells that produce them. Furthermore, the virus, the membranous vesicle, the enveloped delivery vehicle, the enveloped viral particle Petition 870250093142, dated 10 / 10 / 2025, page 62 / 819 33 / 640 lopada, recombinant viral vector, etc., can activate T cells in vivo and cause them to proliferate in vivo. The payload of the virus, membranous vesicle, enveloped delivery vehicle, enveloped viral particle, recombinant viral vector, etc., can be, for example, a nucleotide sequence encoding a chimeric antigen receptor (CAR), for example, as described herein, where the infected T cell expresses the CAR and is targeted to a specific desired antigen. Activated CAR-expressing T cells can proliferate in vivo. The ability to produce specifically targeted activated T cells in vivo that proliferate provides significant time, health, and economic advantages over conventional methods that require extracting T cells from a body, transducing the T cells to express, for example, a CAR, activating the cells, expanding the cells through proliferation, and reintroducing the cells into the body.

[0092] Without intending to limit ourselves to theory, the observed effectiveness in T cell transduction can be partly attributed to the direct binding of the G protein to the target ligand. Rhabdoviral G glycoproteins are known to be efficiently transported to the cell surface, an efficiency that can be used to achieve high-density packing. Thus, with direct binding, the ligand is also efficiently transported to the surface and densely packed. Buchholz et al., J. Virol., 70(6): 3716-3723 (1996), which is incorporated here by reference in its entirety, reveals that the distance between a viral membrane and an endosome can be important for optimizing ligand binding and fusion. The distance between the viral membrane and the target ligand, located at the distal end of the G protein, can provide a favorable distance.

[0093] Another advantage of a recombinant fusion protein, as described in this document, is that it has an antibody construct. Petition 870250093142, dated 10 / 10 / 2025, page 63 / 819 The advantage of a 34 / 640 polypeptide with the ability to bind to human CD3 is that it can be used to activate a T cell at any time during the T cell's lifespan, since T cells always express CD3. T cells only express the natural receptor for the VSV-G glycoprotein when they are already activated. The use of a recombinant fusion protein, as described here, which has a polypeptide antibody construct capable of binding to human CD3 on a virus, a membranous vesicle, an enveloped delivery vehicle, an enveloped viral particle, a recombinant viral vector, etc., would not be limited by the activation state of T cells in the organism.

[0094] In some respects, the recombinant fusion protein comprises a linker between the polypeptide antibody construct and the rhabdoviral G glycoprotein or a functional fragment or derivative thereof. Any suitable linker is considered, for example, as described in Chen et al., Adv. Drug. Deliv. Rev., 65(10: 1357-1369 (2013), which is incorporated herein by reference in its entirety. In some respects, the linker is flexible. Exemplary flexible linkers include, among others, for example, AAASGGSGGGGSGGGGSGP (SEQ ID NO: 130), AAASGGSGGGGSGGGGS (SEQ ID NO: 131), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 132), GGGGSGGGGSGGGGS (SEQ ID NO: 36), GGGGSGGGGS (SEQ ID NO: 133), GGGGS (SEQ ID NO: 134), GGGGGGGG (SEQ ID NO: 135), GGGGGG (SEQ ID NO: 136), GSAGSAAGSGEF (SEQ ID NO: 137) and VPGVGVGVG (SEQ ID NO: 138).

[0095] In some respects, the ligand is rigid. Rigid ligands Petition 870250093142, dated 10 / 10 / 2025, p. 64 / 819 35 / 640 copies include, but are not limited to, for example, PAPAP (SEQ ID NO: 139), EAAAKAAAKAAAK (SEQ ID NO: 140), EAAAKAAAK (SEQ ID NO: 141), EAAAK (SEQ ID NO: 142), AEAAAKEAAAAKEAAAKAAAKALEEAAAAKEAAAKAAAKAAAKA (SEQ ID NO: 143), AEAAAKEAAAKA (SEQ ID NO: 144), ESKYGPPCPPCP (SEQ ID NO: 145), CPPCPAPELLGGPSVF (SEQ ID NO: 146) and repeated alanine-proline (AP) for a total of 10 to 34 amino acids (SEQ ID NO: 147).

[0096] In aspects, the recombinant fusion protein comprises a rhabdoviral G glycoprotein or a functional fragment or derivative thereof that is a Flanders virus glycoprotein (FLAV-G) (SEQ ID NO: 13), a Chandipura virus glycoprotein (CHPV-G) (SEQ ID NO: 14), a Perinet virus glycoprotein (PERV-G) (SEQ ID NO: 15), a Piry virus glycoprotein (PIRYV-G) (SEQ ID NO: 16), a Fukuoka virus glycoprotein (FUKV-G) (SEQ ID NO: 17), a Joinjakaka virus glycoprotein (JOIV-G) (SEQ ID NO: 18), a Kumasi virus glycoprotein (KRV-G) (SEQ ID NO: 19), a Keuraliba virus glycoprotein (KEUV-G) (SEQ ID NO: 20), a glycoprotein Isfahan (ISFV-G), a glycoprotein Jurona (JURV-G), a glycoprotein Mediterranean Bat (MBV-G), a glycoprotein Malpais Spring (MSPV-G), a glycoprotein Radi (RADV-G), a glycoprotein Rhinolophus affinis-G, a glycoprotein Yug Bugdanavoc (YBVG), a glycoprotein Yinshui Bat (YSBV-G), a glycoprotein Kimberley (KIMV-G),a Kanyawara glycoprotein (KYAV-G), a La Joya glycoprotein (LJV-G), a Mosquiero glycoprotein (MQOV-G), a Parry Creek glycoprotein (PCV-G), a Bas Congo glycoprotein, Petition 870250093142, dated 10 / 10 / 2025, page 65 / 819 36 / 640 (BASV-G), a bovine ephemeral fever glycoprotein (BEFV-G), a Curionopolis glycoprotein (CURV-G), a Drosophila melanogaster Sigmavirus glycoprotein (DMelSV-G), a Niakha glycoprotein (NIAV-G), a Puerto Almandras glycoprotein (PTAMV-G), or a Tupaia rhabdovirus (TUPTV-G). In some respects, the rhabdoviral G glycoprotein or a functional fragment or derivative thereof is from the vesiculovirus glycoprotein or a functional fragment or derivative thereof.In some respects, the rhabdoviral G glycoprotein or functional fragment or derivative thereof is from Indiana Vesiculovirus (e.g., SEQ ID NO: 21, 209, 210 or 258), New Jersey Vesiculovirus (e.g., SEQ ID NO: 129 or 213), Carajás Vesiculovirus (e.g., SEQ ID NO: 23 or 214), Alagoas Vesiculovirus (e.g., SEQ ID NO: 24 or 215), Cocal Vesiculovirus (e.g., SEQ ID NO: 128 or 216), Marraba Vesiculovirus (e.g., SEQ ID NO: 211 or 212), Morreton Vesiculovirus (e.g., SEQ ID NO: 217 or 218), or any other rhabdoviral G glycoprotein or functional fragment or derivative thereof, as provided herein. In some respects, the rhabdoviral G glycoprotein or a functional fragment or derivative thereof is from Vesiculovirus Indiana (e.g., SEQ ID NO: 21 or 210). In other respects, the rhabdoviral G glycoprotein or a functional fragment or derivative thereof is from Vesiculovirus New Jersey (e.g., SEQ ID NO: 129 or 213).In other respects, the rhabdoviral G glycoprotein or a functional fragment or derivative thereof is from Vesiculovirus New Jersey (SEQ ID NO: 22 or 26). In other respects, the rhabdoviral G glycoprotein or a functional fragment or derivative thereof is from Vesiculovirus Alagoas (e.g., SEQ ID NO: 124, 125, 285, or 288). In some respects, the rhabdoviral G glycoprotein or a functional fragment or derivative thereof is from Vesiculovirus Carajás (e.g., SEQ ID NO: 126, 127, 278, or 281). Figures 24A-24D show additional exemplary rhabdoviral G glycoproteins, without limit. Petition 870250093142, dated 10 / 10 / 2025, page 66 / 819 37 / 640 tação, contemplated here.

[0097] In some respects, the recombinant fusion protein comprises a rhabdoviral G glycoprotein or a functional fragment or derivative thereof that has 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, 70%, 65%, or 60% sequence identity compared with a rhabdoviral G glycoprotein or a functional fragment or derivative thereof described herein. In some respects, the rhabdoviral G glycoprotein or a functional fragment or derivative thereof contains one or more conservative amino acid substitutions that do not interfere with the fusion function of the rhabdoviral G glycoprotein or the functional fragment or derivative thereof.

[0098] In some respects, the recombinant fusion protein comprises a substantially intact rhabdoviral G glycoprotein. As used herein, a substantially intact rhabdoviral G glycoprotein means a rhabdoviral G glycoprotein that is a functional fragment of rhabdoviral G glycoprotein, wherein the rhabdoviral G glycoprotein possesses each of the domains of a rhabdoviral G glycoprotein, the domains as defined in Roche et al., Cell. Mol. Life Sci., 65: 1716-1728 (2008), which is incorporated herein by reference in its entirety.

[0099] In some respects, the recombinant fusion protein comprises a rhabdoviral G glycoprotein that is a functional fragment or derivative thereof. In some respects, the cytoplasmic tail of the glycoprotein is truncated, deleted, or replaced by another sequence. Previous work has demonstrated that such truncation or deletion can increase the fusion activity in the rhabdoviral G glycoprotein. In some respects, the C-terminal truncations can be, for example, 1 amino acid, 2 amino acids, 3 amino acids, 4 amino acids, 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9 Petition 870250093142, dated 10 / 10 / 2025, page 67 / 819 38 / 640 amino acids, 10 amino acids, 20 amino acids, 30 amino acids, 40 amino acids, 50 amino acids, 60 amino acids, up to 10 amino acids, up to 20 amino acids, up to 30 amino acids, up to 40 amino acids, up to 50 amino acids, up to 60 amino acids, or more than 60 amino acids. In some aspects, the cytoplasmic tail is replaced by another sequence.

[00100] In some respects, the recombinant fusion protein comprises a rhabdoviral G glycoprotein or a functional fragment or derivative thereof, which is designed to reduce or abolish its natural receptor-binding specificity. The reduction in binding specificity can be of any magnitude, for example, reduced by 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 2%, 1%, or any range between these percentages. Vesicular stomatitis virus (VSV) is a rhabdovirus that possesses a natural receptor of the low-density lipoprotein receptor (LDL-R) or very low-density lipoprotein receptor (VLDL-R), which are expressed on the cell membrane of many cell types.In some respects, the rhabdoviral G glycoprotein, or a functional fragment or derivative thereof, is engineered to exhibit a mutation that reduces or abolishes its natural specificity for binding to the LDL-R or VLDL-R receptor, or other receptors that exhibit cross-reactivity with these receptors. In some respects, the rhabdoviral G glycoprotein, or a functional fragment or derivative thereof, comprises a mutation at one or more positions corresponding to H8, K47, Y209, and K354 in the Indian Vesiculovirus glycoprotein (SEQ ID NO: 21). In some respects, the mutation is a wild-type amino acid substitution for another amino acid. In some respects, the substitution occurs with a Q. In some respects, the mutation is a substitution at three or more positions corresponding to H8, K47, Y209, and K354 in the Indian Vesiculovirus glycoprotein (SEQ ID NO: 21). In some... Petition 870250093142, dated 10 / 10 / 2025, page 68 / 819 In some aspects, the mutation comprises, consists of, or essentially consists of the amino acid sequence of SEQ ID NO: 26, 71, 72, 73, 267, 269, 275, 279, 282, or 286. U.S. Patent Publication No. 2020 / 0216502 is incorporated herein by reference in its entirety. In some aspects, the mutation is a wild-type amino acid deletion. In some aspects, the mutation is the deletion of one or more positions corresponding to H8, K47, Y209, and K354 in the Indian Vesiculovirus glycoprotein (SEQ ID NO: 21), wherein each deleted amino acid is not present in the glycoprotein amino acid sequence. In some aspects, the mutation is a single deletion at K47, wherein the amino acid K47 is not present in the glycoprotein amino acid sequence. In some respects, the mutation comprises, consists of, or essentially consists of the amino acid sequence of SEQ ID NO: 27, 29, 268, 270, 276, 277, 280, 283, 284, or 287.

[00101] In aspects, the preferred full-length rhabdoviral G glycoproteins, ectodomains, signal peptides, and engineered mutations of the ectodomains to reduce or abolish their natural receptor-binding affinity are shown in Table 1. VSIV indicates Indiana Vesiculovirus G glycoprotein, VSNJV indicates New Jersey Vesiculovirus G glycoprotein, VSCV indicates Carajas Vesiculovirus G glycoprotein, VSAV indicates Alagoas Vesiculovirus G glycoprotein, VSCOV indicates Cocal Vesiculovirus G glycoprotein, WT indicates wild type, 41J indicates that residue 41 can be an I or L, K1R indicates an R substitution at residue 1 corresponding to SEQ ID NO: 21, G115A indicates an A substitution at residue 115 corresponding to SEQ ID NO: 21, Delta K47 indicates a deletion at residue 47 corresponding to SEQ ID NO: 21 K47Q+Y209Q+R354Q indicates Q substitutions in residues 47, 209, and 354 corresponding to SEQ ID NO: 21. Petition 870250093142, dated 10 / 10 / 2025, page 69 / 819 40 / 640 Table 1 VSIV VSIV (41J) VSNJ V (WT) VSNJ V (Variant) VSCV (WT) VSCV (K1R) VSCV G115 A VSAV (WT) VSAV (K1R) VSAV G115 A VSC OV Total length G 288 216 Ectodomain G 209 21 129 22 23 126 127 24 124 125 128 Signal peptide 60 60 265 121 123 123 123 122 122 122 Delta K 268 29 276 277 280 283 284 287 270 K47Q+Y209 Q+R354Q 289 26 267 73 275 71 279 282 72 286 269

[00102] It has been discovered that a rhabdoviral G glycoprotein from Indian Vesiculovirus with a K47 deletion reduces or eliminates the natural receptor-binding specificity of the rhabdoviral G glycoprotein, while the rhabdoviral G glycoprotein unexpectedly retains the full function of the G protein in other respects. In particular, this characteristic is observed when incorporated into a lentiviral vector. However, when used in a VSV vector, there is a mutation at the second site (F405I) generated in the VSV G protein during virus amplification. This mutation leads to the loss of the misalignment effect caused by the deletion at residue K47. Without wanting to limit ourselves to theory, this phenomenon may be due to VSV being a replicating virus, while lentivirus is a non-replicating virus.

[00103] The Indian Vesiculovirus glycoprotein with H8 and / or K47 deletions, when incorporated into a lentiviral system, can aid in the production of functional pseudotyped lentiviruses and successful cell transduction. The H8 and / or K47 deletions, but not the Y209 or R354 deletions or combinations of Y209 / R354 deletions, have demonstrated the generation and rescue of pseudotyped lentiviruses with low or no background binding to LDL-R.

[00104] In some respects, recombinant fusion protein Petition 870250093142, dated 10 / 10 / 2025, pp. 70 / 819 41 / 640 comprises a rhabdoviral G glycoprotein or a functional fragment or derivative thereof comprising one or more mutations that increase viral titer. In some respects, the one or more mutations that increase viral titer are one or both of the M184T and F250L mutations in SEQ ID NO: 21 (or the positions corresponding to M184T and F250L). Other exemplary mutations, without limitation, for increasing viral titer include those described in U.S. Patent Publication No. 2022 / 0162266, which is incorporated herein by reference in its entirety. The mutations include H22N and S422I in the ectodomain of the Indian Vesiculovirus G glycoprotein (SEQ ID NO: 21) (or substitutions at positions corresponding to them in other rhabdoviral G glycoproteins).

[00105] Amino acid positions of other rhabdoviral G glycoproteins or functional fragments or derivatives thereof that are positions corresponding to the amino acids described above can be determined using a global sequence alignment algorithm (see, for example, Madeira et al., Nuc. Acids Res., 50(W1): W276-W279 (2022), which is incorporated herein by reference in its entirety) comparing the base rhabdoviral G glycoprotein to another rhabdoviral G glycoprotein.

[00106] In some respects, the rhabdoviral G glycoprotein or a functional fragment or derivative thereof is mutated to reduce or abolish protease cleavage.

[00107] In some respects, the polypeptide antibody construct is a CD3 agonist. In some respects, the polypeptide antibody construct comprises a variable single-chain fragment (scFv). In some respects, the scFv has the N-terminus of the VL to VH. In some respects, the scFv has the N-terminus of the VH to VL. In some respects, the scFv is UCHT1, HuM291, OKT3, or TR66. In some respects, the scFv is a humanized UCHT1. In some respects, the Petition 870250093142, dated 10 / 10 / 2025, pp. 71 / 819 42 / 640 scFv comprises a variable heavy chain (VH) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 46 and a variable light chain (VL) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 45. In some respects, the VH and VL are separated by a flexible linker. In some respects, the flexible linker is SEQ ID NO: 36. In some respects, the scFv is TR66 and wherein the TR66 is codon-optimized for human expression and wherein the scFv comprises a variable heavy chain (VH) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 44 and a variable light chain (VL) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 43.In some aspects, scFv is TR66opt, wherein scFv comprises a variable heavy chain (VH) comprising, essentially consisting of, or consisting of the amino acid sequences of a complementarity-determining region 1 (CDR1) of SEQ ID NO: 247, a complementarity-determining region 2 (CDR2) of SEQ ID NO: 248, and a complementarity-determining region 3 (CDR3) of SEQ ID NO: 249, and a variable light chain (VL) comprising, essentially consisting of, or consisting of the amino acid sequences of a CDR1 of SEQ ID NO: 250, a CDR2 of SEQ ID NO: 251, and a CDR3 of SEQ ID NO: 252. In some aspects, scFv is UCHT1, wherein scFv comprises a variable heavy chain (VH) comprising, essentially consisting of, or consisting of the amino acid sequence of SEQ ID NO: 46 and a variable light chain. (VL) comprising, essentially consisting of, or consisting of the amino acid sequence of SEQ ID NO: 45.In some respects, scFv is UCHT1 and in that scFv comprises a variable heavy chain (VH) which essentially comprises, consists of, or consists of the amino acid sequences. Petition 870250093142, dated 10 / 10 / 2025, page 72 / 819 43 / 640 of a CDR1 of SEQ ID NO: 223, a CDR2 of SEQ ID NO: 224 and a CDR3 of SEQ ID NO: 225, and a variable light chain (VL) comprising, essentially consists of, or consists of the amino acid sequences of a CDR1 of SEQ ID NO: 226, a CDR2 of SEQ ID NO: 227 and a CDR3 of SEQ ID NO: 228. In some respects, scFv is HuM291, where scFv comprises a variable heavy chain (VH) comprising, essentially consists of, or consists of the amino acid sequence of SEQ ID NO: 38 and a variable light chain (VL) comprising, essentially consists of, or consists of the amino acid sequence of SEQ ID NO: 37.In some respects, scFv is Hum291, wherein scFv comprises a variable heavy chain (VH) comprising, essentially consisting of, or consisting of the amino acid sequences of a CDR1 from SEQ ID NO: 235, a CDR2 from SEQ ID NO: 236, and a CDR3 from SEQ ID NO: 237, and a variable light chain (VL) comprising, essentially consisting of, or consisting of the amino acid sequences of a CDR1 from SEQ ID NO: 235, a CDR2 from SEQ ID NO: 236, and a CDR3 from SEQ ID NO: 237, a CDR2 from SEQ ID NO: 239, and a CDR3 from SEQ ID NO: 240. In some respects, scFv is OKT3, wherein scFv comprises a variable heavy chain (VH) comprising, essentially consisting of, or consisting of the amino acid sequence of SEQ ID NO: 40 and a variable light chain (VL) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 39.In some respects, scFv is OKT3 and wherein scFv comprises a variable heavy chain (VH) comprising, consisting essentially of, or consisting of the amino acid sequences of a CDR1 of SEQ ID NO: 241, a CDR2 of SEQ ID NO: 242 and a CDR3 of SEQ ID NO: 243, and a variable light chain (VL) comprising, consisting essentially of, or consisting of the sequences of. Petition 870250093142, dated 10 / 10 / 2025, page 73 / 819 44 / 640 amino acids from a CDR1 of SEQ ID NO: 244, a CDR2 of SEQ ID NO: 245, and a CDR3 of SEQ ID NO: 246. In some respects, scFv is TR66, wherein scFv comprises a variable heavy chain (VH) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 42 and a variable light chain (VL) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 41. In some respects, scFv is TR66 e wherein scFv comprises a variable heavy chain (VH) comprising, consisting essentially of, or consisting of the amino acid sequences of a CDR1 of SEQ ID NO: 229, a CDR2 of SEQ ID NO: 230, and a CDR3 of SEQ ID NO: 231, and a variable light chain (VL) comprising, consisting essentially of in, or consisting of the amino acid sequences of a CDR1 from SEQ ID NO: 232, a CDR2 from SEQ ID NO: 233, and a CDR3 from SEQ ID NO: 234.

[00108] In some respects, the polypeptide antibody construct is derived from a mammal. The mammal may be any suitable mammal; exemplary mammals include the mammals to be treated, identified herein.

[00109] In aspects, the present invention provides a polynucleotide encoding any of the proteins and polypeptides described herein, including any rhabdoviral G glycoprotein or functional fragment or derivatives thereof, and their recombinant fusion proteins described herein.

[00110] In aspects, the present invention provides a membranous vesicle comprising, consisting essentially of, or consisting of a recombinant fusion protein, as described herein.

[00111] As used herein, a membranous vesicle is a vesicle bounded (delimited) by a lipid bilayer. In some aspects Petition 870250093142, dated 10 / 10 / 2025, page 74 / 819 45 / 640 tos, the membranous vesicle is either naturally derived or artificially modified. In other respects, the vesicle is either a gesicle or an exosome. A gesicle may be as described in Mangeot et al., Mol. Ther., 19: 1656-1666 (2011), which is incorporated here by reference in its entirety, where overexpression of the glycoprotein VSV-G in human cells induced the release of fusogenic vesicles. A membranous vesicle may be cell-derived and therefore be a cell-derived enveloped particle (CDEP).

[00112] In aspects, the present invention provides an enveloped viral particle comprising, consisting essentially of, or consisting of a recombinant fusion protein, as described herein.

[00113] As used herein, an enveloped viral particle is a vesicle bound (enclosed) by a lipid bilayer and possessing the ability to infect a cell and produce additional enveloped viral particles. An enveloped viral particle may include one or more components of a virus, in addition to a rhabdoviral G glycoprotein or functional fragment or derivative thereof, or recombinant fusion protein thereof. Exemplary components of a virus include, without limitation, the gag, pol, or env gene or lentivirus gene product. A virus-like particle, as used herein, means an enveloped viral particle that cannot produce additional virus-like particles (e.g., is incompetent for replication).

[00114] In some respects, membranous vesicles, cell-derived enveloped particles, enveloped viral particles, and virus-like particles can encapsulate proteins, lipids, nucleic acids, etc. for delivery, so that membranous vesicles, cell-derived enveloped particles, enveloped viral particles, and virus-like particles can be considered Petition 870250093142, dated 10 / 10 / 2025, page 75 / 819 46 / 640 delivery vehicles wrapped.

[00115] In certain respects, an enveloped delivery vehicle, a membranous vesicle, or an enveloped viral particle comprises a mixed trimer, wherein the mixed trimer comprises (a) at least one recombinant fusion protein comprising a polypeptide antibody construct, wherein the polypeptide antibody construct has the ability to bind to human CD3, and (b) at least one rhabdoviral G glycoprotein or functional fragment or derivative thereof that does not comprise a polypeptide antibody construct. Without being limited to theory, reducing the number of units in a recombinant rhabdoviral G glycoprotein trimer that has a polypeptide antibody construct allows for better transformation of the trimer from a pre-fusion conformation to a fusion conformation. In certain respects, an enveloped delivery vehicle described herein comprises a mixed trimer.

[00116] In some aspects, the enveloped delivery vehicle, membranous vesicle, or enveloped viral particle comprises an unmixed trimer, wherein the unmixed trimer comprises only the rhabdoviral glycoprotein G or a functional fragment or derivative thereof that is not contained in a recombinant fusion protein. In some aspects, an enveloped delivery vehicle described herein comprises an unmixed trimer.

[00117] In certain respects, an enveloped delivery vehicle, a membranous vesicle, or an enveloped viral particle comprises the maximum number of recombinant fusion proteins that can be accommodated within the membrane of the enveloped delivery vehicle, membranous vesicle, or enveloped viral particle, wherein each recombinant fusion protein comprises a polypeptide antibody construct, wherein the polypeptide antibody construct has the ability to bind to human CD3. In certain aspects Petition 870250093142, dated 10 / 10 / 2025, p. 76 / 819 47 / 640 tos, an enveloped delivery vehicle, a membranous vesicle or an enveloped viral particle comprises less than the maximum number of recombinant fusion proteins that can be accommodated within the membrane of the enveloped delivery vehicle, membranous vesicle or enveloped viral particle, wherein each recombinant fusion protein comprises a polypeptide antibody construct, wherein the polypeptide antibody construct has the ability to bind to human CD3. Less than the maximum amount may be any amount less than 100%, for example, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 2% or 1%, or any interval between these percentages.In some respects, any enveloped delivery vehicle, as described herein, comprises the maximum number of recombinant fusion proteins that can be accommodated within the membrane, wherein each recombinant fusion protein comprises a polypeptide antibody construct, wherein the polypeptide antibody construct has the ability to bind to human CD3.

[00118] In aspects, the present invention provides a recombinant viral vector comprising, consisting essentially of, or consisting of a nucleotide encapsulated by an enveloped delivery vehicle, as described herein, a membranous vesicle, as described herein, or an enveloped viral particle, as described herein.

[00119] In some respects, the present invention provides a composition comprising, essentially consisting of, or consisting of a pharmaceutically acceptable carrier and an enveloped delivery vehicle, as described herein, a membranous vesicle, as described herein, an enveloped viral particle, as described herein, or a recombinant viral vector, as described herein. Pharmaceutically acceptable carriers are well known in the art.

[00120] In some respects, the present invention provides a me Petition 870250093142, dated 10 / 10 / 2025, page 77 / 819 48 / 640 all to deliver a payload to a target cell, the method comprising, essentially consisting of, or consisting of contacting the target cell with a membranous vesicle, as described herein, an enveloped viral particle, as described herein, an enveloped delivery vehicle, as described herein, a recombinant viral vector, as described herein, or a composition, as described herein. In some respects, the target cell is in vitro or ex vivo. In some respects, the target cell is in vivo. In some respects, the payload is a nucleotide sequence encoding a chimeric antigen receptor (CAR) comprising, essentially consisting of, or consisting of an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some respects, the CAR has antigenic specificity for CD19 (e.g., SEQ ID NO: 165) or BCMA (e.g., SEQ ID NOs: 166-170).In some respects, the CAR comprises a hinge domain, wherein the hinge domain is the hinge domain of CD28α or CD8α (SEQ ID NO: 149). In some respects, the transmembrane domain is the transmembrane domain of CD28 or CD8 (SEQ ID NO: 150). In some respects, the intracellular signaling domain comprises a co-stimulatory domain and an activator domain. In some respects, the co-stimulatory domain is 4-1BB (SEQ ID NO: 151). In some respects, the activator domain is CD3zeta (SEQ ID NO: 152). In some respects, the payload is a gene-editing system or a nucleotide encoding a transgene. In some respects, the gene-editing system comprises one or more nucleases, such as CRISPR-Cas9, CasMINI, TALENs, or zinc finger nucleases, as well as guide RNAs or other molecules that direct the nucleases to specific genomic loci.

[00121] In certain respects, a virus, a membranous vesicle, an enveloped delivery vehicle, an enveloped viral particle or Petition 870250093142, dated 10 / 10 / 2025, pp. 78 / 819 49 / 640 A recombinant viral vector, etc., as described herein, comprises a T-cell co-stimulatory molecule or a nucleotide encoding a T-cell co-stimulatory molecule. A nucleotide encoding a T-cell co-stimulatory molecule may be encoded within the membranous vesicle, enveloped delivery vehicle, enveloped viral particle, or recombinant viral vector, etc., as described herein, for example, encoded by a nucleotide encoding a chimeric antigen receptor (CAR) comprising the T-cell co-stimulatory molecule. The co-stimulatory molecule may be present on the surface of the membranous vesicle, enveloped delivery vehicle, enveloped viral particle, or recombinant viral vector, etc., as described herein.Surface presentation can occur, for example, by anchoring a T cell costimulatory molecule to the envelope membrane, by expressing a T cell costimulatory molecule that is a transmembrane protein, by expressing a T cell costimulatory molecule as part of a fusion protein that is a transmembrane protein, etc. The costimulatory molecule can be a complete molecule or a portion of a larger molecule, for example, a costimulatory domain. Non-limiting examples include, for example, CD80, CD83, CD86, 41BB / CD137, CD28, and others known in the art. Without limiting ourselves to theory, it is believed that the costimulatory molecule provides signal 2 for T cell activation.

[00122] In certain respects, a virus, a membranous vesicle, an enveloped delivery vehicle, an enveloped viral particle or a recombinant viral vector, etc., as described herein, does not comprise one or more T cell costimulatory molecules or nucleotides encoding one or more T cell costimulatory molecules. In certain respects, a virus, a membranous vesicle, an enveloped delivery vehicle, an enveloped viral particle or a vector Petition 870250093142, dated 10 / 10 / 2025, pp. 79 / 819 50 / 640 recombinant viral vector, etc., as described herein, does not comprise any T-cell co-stimulatory molecule or any nucleotide encoding a T-cell co-stimulatory molecule. In certain respects, a virus, a membranous vesicle, an enveloped delivery vehicle, an enveloped viral particle, or a recombinant viral vector, etc., as described herein, comprises one or more T-cell co-stimulatory molecules or nucleotides encoding one or more T-cell co-stimulatory molecules, but does not comprise one or more other T-cell co-stimulatory molecules or nucleotides encoding one or more other T-cell co-stimulatory molecules. For example, the membranous vesicle, the enveloped delivery vehicle, the enveloped viral particle, or the recombinant viral vector, etc., as described herein, does not comprise one or more nucleotides encoding one or more T cell costimulatory molecules within the membranous vesicle, enveloped delivery vehicle, enveloped viral particle or recombinant viral vector, etc., as described herein, for example, not encoded by a nucleotide encoding a CAR; wherein the membranous vesicle, enveloped delivery vehicle, enveloped viral particle or recombinant viral vector, etc., as described herein, comprises one or more nucleotides encoding one or more other T cell costimulatory molecules within the membranous vesicle, enveloped delivery vehicle, enveloped viral particle or recombinant viral vector, etc., as described herein, for example, encoded by one or more nucleotides encoding one or more CARs. In certain aspects, a virus, a membranous vesicle, an enveloped delivery vehicle, an enveloped viral particle, or a recombinant viral vector, etc.As described herein, it does not comprise CD80, but it does comprise one or more other T-cell co-stimulatory molecules, for example, CD83, CD86, 4-1BB / CD137, CD28, or others known in the art. Petition 870250093142, dated 10 / 10 / 2025, pages 80 / 819 51 / 640 In certain respects, a virus, a membranous vesicle, an enveloped delivery vehicle, an enveloped viral particle, or a recombinant viral vector, etc., as described herein, does not comprise CD83, but comprises one or more other T-cell co-stimulatory molecules, for example, CD80, CD86, 4-1BB / CD137, CD28, or others known in the art. In certain respects, a virus, a membranous vesicle, an enveloped delivery vehicle, an enveloped viral particle, or a recombinant viral vector, etc., as described herein, does not comprise CD86, but comprises one or more other T-cell co-stimulatory molecules, for example, CD80, CD83, 4-1BB / CD137, CD28, or others known in the art. In certain respects, a virus, a membranous vesicle, an enveloped delivery vehicle, an enveloped viral particle, or a recombinant viral vector, etc.As described herein, it does not comprise 4-1BB / CD137, but it does comprise one or more other T-cell co-stimulatory molecules, for example, CD80, CD83, CD86, CD28, or others known in the art. In some respects, a virus, a membranous vesicle, an enveloped delivery vehicle, an enveloped viral particle, or a recombinant viral vector, etc., as described herein, does not comprise CD28, but it does comprise one or more other T-cell co-stimulatory molecules, for example, CD80, CD83, CD86, 4-1BB / CD137, or others known in the art.

[00123] Without wanting to limit ourselves to theory, CD19 acts as a co-receptor for B cell receptor (BCR) signaling and plays a role in the activation, development, and differentiation of B cells. CD19 is expressed on B cells from the earliest recognizable B lineage cells during development to B cell precursors. It is present in many malignant B-cell neoplasms, including, for example, acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Petition 870250093142, dated 10 / 10 / 2025, pp. 81 / 819 52 / 640

[00124] Without wanting to limit ourselves to theory, BCMA is involved in the regulation of plasma cell survival and proliferation. It is expressed in mature B cells and plasma cells. BCMA is present, for example, in multiple myeloma, as it is a disease characterized by the proliferation of malignant plasma cells.

[00125] In some aspects, the present invention provides a retroviral vector expression system comprising, essentially consisting of, or consisting of one or more nucleotide sequences encoding a recombinant fusion protein, as described herein. In some aspects, the retroviral vector expression system comprises a vector construct and auxiliary constructs, each on separate plasmids. In some aspects, the retroviral vector expression system is a lentirival vector expression system, a foamy vector expression system, or a respiratory syncytial virus (RSV). A rhabdoviral G glycoprotein or a functional fragment or derivative thereof, as described herein, may be expressed within a retroviral vector expression system to pseudotype the vector and alter its tropism.

[00126] As used herein, a vector construct comprises a nucleic acid of interest, for example, encoding a rhabdoviral G glycoprotein or a functional fragment or derivative thereof, or a recombinant fusion protein thereof, as described herein, and auxiliary constructs comprise proteins useful for the formation of, for example, virions. Such auxiliary constructs may encode, for example, structural proteins, and may be packaging vectors which are, for example, plasmids.

[00127] In some respects, the retroviral vector expression system comprises, consists essentially of, or consists of a nucleotide sequence encoding a chimeric antigen receptor (CAR) comprising, consists essentially of, or consists of Petition 870250093142, dated 10 / 10 / 2025, pages 82 / 819 The 53 / 640 system comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some respects, the CAR has antigenic specificity for CD19 or BCMA. In some respects, the CAR comprises a hinge domain, wherein the hinge domain is the hinge domain of CD28α or CD8α. In some respects, the transmembrane domain is the transmembrane domain of CD28 or CD8. In some respects, the intracellular signaling domain comprises a co-stimulatory domain and an activator domain. In some respects, the co-stimulatory domain is 41BB. In some respects, the activator domain is CD3zeta. In some respects, the retroviral vector expression system comprises, consists essentially of, or consists of a gene editing system or one or more nucleotide sequences encoding a transgene.In some respects, the gene-editing system comprises one or more nucleases, such as CRISPR-Cas9, CasMINI, TALENs, or zinc finger nucleases, as well as guide RNAs or other molecules that direct the nucleases to specific genomic loci.

[00128] In aspects, the present invention provides a method for producing a membranous vesicle, an enveloped viral particle, an enveloped delivery vehicle or a recombinant viral vector, the method comprising, essentially consisting of, or consisting of: a) transfecting or transducing a packaging host cell with a retroviral vector expression system, as described herein; and b) recovering the membranous vesicle, the enveloped viral particle or the recombinant viral vector produced by the transfected or transduced packaging host cell.

[00129] Transfection and transfection, as used herein, mean nonviral means of introducing nucleic acid into a cell. Transduction and transduction, as used herein, mean the use of Petition 870250093142, dated 10 / 10 / 2025, pp. 83 / 819 54 / 640 viral means of introducing nucleic acid into a cell.

[00130] In certain aspects, any method of producing an enveloped delivery vehicle, lentivirus, retroviral vector expression system, recombinant viral vector, etc., as described herein, may comprise transduction in a medium comprising a poloxamer-based chemical adjuvant. In certain aspects, the poloxamer-based chemical adjuvant is selected from vectofusin-1, poloxamer F108, and Lentiboost™. In certain aspects, the production method comprises a spinoculation step at the beginning of transduction.

[00131] In aspects, the packaging host cell is HEK 293T or a 293-cell suspension line.

[00132] In aspects, the present invention provides a plasmid comprising, consisting essentially of, or consisting of one or more nucleotide sequences encoding a recombinant fusion protein, as described herein.

[00133] In some respects, the present invention provides a composition, as described herein, or a retroviral vector expression system, as described herein, for use in the treatment of a disease in a mammal.

[00134] The mammal can be any suitable mammal. Mammals include, among others, the order Rodentia, such as mice, and the order Lagomorpha, such as rabbits. The mammal can be of the order Carnivora, including Felines (cats) and Canines (dogs). The mammal can be of the order Artiodactyla, including Bovines (cows) and Swine (pigs), or of the order Perissodactyla, including Equines (horses). The mammal can be of the order Primates, Cebidae or Simioides (monkeys), or of the order Anthropoides (humans and apes). In some respects, the mammal is a human.

[00135] In some respects, the disease is a genetic disease. In Petition 870250093142, dated 10 / 10 / 2025, pp. 84 / 819 55 / 640 In other aspects, the disease is cancer. For example, in some aspects, the disease is glioblastoma, ovarian cancer, mesothelioma, breast cancer, pancreatic cancer, prostate cancer, sarcoma, melanoma, or colorectal cancer. In some aspects, the disease is a lymphoma, such as B-cell lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma (MCL), marginal zone lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system (CNS) lymphoma, primary effusion lymphoma, or hairy cell leukemia.In some aspects, the disease is beta-thalassemia, anemia, sickle cell anemia, Gaucher disease, Parkinson's disease, immunodeficiency syndromes, mucopolysaccharidosis III, severe combined immunodeficiency disease, hepatitis C, chronic hepatitis C, pancytopenia, X-linked combined immunodeficiency diseases, epidermolysis bullosa, solid tumors, melanoma, Fanconi anemia, adenosine deaminase deficiency, granulomatous disease, chronic cystic fibrosis, HIV infections, HIV seropositivity, Hodgkin's lymphoma, Bruton's agammaglobulinemia, hemophilia A, arthritis, or choroidal neovascularization. In other aspects, the disease is any disease or condition that can be treated by administering a gene-editing system.In some respects, the gene-editing system comprises one or more nucleases, such as CRISPR-Cas9, CasMINI, TALENs, or zinc finger nucleases, as well as guide RNAs or other molecules that direct the nucleases to specific genomic loci.

[00136] In some respects, a retroviral vector expression composition or system, as described herein, can be configured to target a disease based on a known cellular marker and / or disease-associated molecular marker. Non-limiting examples Petition 870250093142, dated 10 / 10 / 2025, pages 85 / 819 56 / 640 cell markers and / or molecular markers that may be targets of retroviral vector compositions or expression systems, as described herein, include: CD19, CD20, and / or CD23 to target CLL and / or LCL; CD20, BCL6, and / or MYC to target DLBCL; CD10, CD20, or BCL2 for follicular lymphoma; CD20, CD5, and / or Cyclin D1 for target MCL; CD20 and / or CD21 for target marginal zone lymphoma; CD10, CD20, and / or MYC translocation for target Burkitt lymphoma; CD20 and / or IgM for target lymphoplasmacytic lymphoma; CD20 and / or BCL6 for target primary CNS lymphoma; HHV-8 and / or CD45 for targeting primary effusion lymphoma; and CD20, CD22 and / or CD103 for targeting hairy cell leukemia.

[00137] In some respects, a retroviral vector composition or expression system, as described herein, can be configured to target a solid tumor based on a known cellular marker and / or molecular marker associated with the solid tumor. Non-limiting examples of cellular markers and / or molecular markers that may be targeted by retroviral vector compositions or expression systems, as described herein, include: EGFRvIII to target glioblastoma; MUC16 to target ovarian cancer; mesothelin to target mesothelioma; HER2 to target breast cancer; mesothelin and / or prostate stem cell antigen (PSCA) to target pancreatic cancer; prostate-specific membrane antigen and / or PSCA to target prostate cancer; HER2 and / or disialoganglioside (GD2) to target sarcoma; GD2 and / or c-Met to target melanoma; and / or carcinoembryonic antigen (CEA) and / or glypican 3 (GPC3) to target colorectal cancer.Without wanting to limit ourselves to theory, these markers are generally selected for their overexpression in tumor cells compared to normal tissues, which helps to target tumor cells while minimizing damage to normal cells. Petition 870250093142, dated 10 / 10 / 2025, pp. 86 / 819 57 / 640

[00138] As used herein, treatment or treating refers to a therapeutic intervention that improves a sign or symptom of a disease or pathological condition after its onset, and also includes the treatment of a medical condition or disease with the aim of improving or stabilizing an outcome in a mammal undergoing treatment. Treat, treating, and treatment have grammatically corresponding meanings. In the context of cancer, the terms treat or treating or treatment may, among other things, refer to the induction of apoptosis of cancer cells, the reduction in the size of a cancerous tumor, the retardation of tumor growth, or the induction or intensification of an immune response against one or more cancer cells, wherein the immune response has the effect of inducing apoptosis, reducing the size of a tumor, or similar. The terms treat, treating, treatment, therapeutically effective, prevention, etc. used herein do not necessarily imply 100% or complete treatment / prevention / etc.Instead, there are varying degrees that a specialist in the field recognizes as having a potential benefit or therapeutic effect. In this sense, membranous vesicles, enveloped viral particles, recombinant viral vectors, etc., as described herein, and the methods described herein can provide any amount or level of treatment. Furthermore, the treatment provided by the described method may include the treatment of one or more conditions or symptoms of the disease or condition being treated.

[00139] In some respects, a treatment method comprises administering a composition, as described herein, or a retroviral vector expression system, as described herein, comprising a rhabdoviral G glycoprotein or a functional fragment or derivative thereof, or a recombinant fusion protein thereof, and subsequently administering a composition, as described herein, or a retroviral vector expression system, as Petition 870250093142, dated 10 / 10 / 2025, pp. 87 / 819 58 / 640 described herein, comprising a different rhabdoviral G glycoprotein, or a functional fragment or derivative thereof, or a recombinant fusion protein thereof. Subsequent administration may occur within hours, days, months, or years after the first administration, with the schedule to be determined by the patient's needs. Multiple rounds of subsequent administrations may be performed, using the same or different rhabdoviral G glycoproteins, as determined by the patient's needs. Without limiting ourselves to theory, it is believed that the administration of a different rhabdoviral G glycoprotein, or a functional fragment or derivative thereof, reduces the likelihood of decreased efficacy due to any immune response directed against the first rhabdoviral G glycoprotein, or a functional fragment or derivative thereof.A rhabdoviral G glycoprotein or functional fragment or derivative thereof or recombinant fusion protein described herein may be administered first, and a rhabdoviral G glycoprotein or functional fragment or derivative thereof or recombinant fusion protein as described herein that has a rhabdoviral G glycoprotein different from the first rhabdoviral G glycoprotein or functional fragment or derivative thereof or recombinant fusion protein may be the rhabdoviral G glycoprotein or functional fragment or derivative thereof or recombinant fusion protein administered subsequently. This sequence of events may be termed redosing.

[00140] In some respects, the composition is administered intravenously. In other respects, the composition is administered intraperitoneally.

[00141] Grhabdoviral glycoproteins can associate into trimers on the surface of a native virus, an enveloped delivery vehicle as described herein, a membranous vesicle as described herein, an enveloped viral particle as described herein, or a vector. Petition 870250093142, dated 10 / 10 / 2025, pages 88 / 819 59 / 640 recombinant viral, as described herein. As used herein, a mixed rhabdoviral G glycoprotein trimer comprises, essentially consists of, or consists of three rhabdoviral G glycoproteins or functional fragments or derivatives thereof (where each is optionally within a recombinant fusion protein), wherein (a) at least one of the rhabdoviral G glycoproteins or functional fragments or derivatives thereof in the trimer is within a recombinant fusion protein comprising, essentially consisting of, or consisting of a rhabdoviral G glycoprotein or a functional fragment or derivative thereof designed to reduce or abolish natural receptor binding specificity and a polypeptide antibody construct, wherein the polypeptide antibody construct has the ability to bind to human CD3,(b) at least one of the rhabdoviral G glycoproteins or functional fragments or derivatives thereof in the trimer is not within a recombinant fusion protein and does not have a polypeptide antibody construct.

[00142] Trimers of rhabdoviral G glycoproteins or functional fragments or derivatives thereof may have one, two, or three polypeptide antibody constructs, wherein the polypeptide antibody construct has the ability to bind to human CD3. The number of polypeptide antibody constructs in the trimer is the trimer occupancy, wherein the trimer may have full occupancy (three polypeptide antibody constructs in the trimer), partial occupancy (polypeptide antibody constructs in less than all of the rhabdoviral G glycoproteins or functional fragments or derivatives thereof in the trimer, for example, two or one polypeptide antibody construct), or no occupancy (no polypeptide antibody construct in the trimer).

[00143] In some respects, the present invention provides a method for producing a mixed trimer of rhabdoviral G glycoprotein, the Petition 870250093142, dated 10 / 10 / 2025, pages 89 / 819 60 / 640 method comprising, essentially consisting of, or comprising: a) transfecting or transducing a packaging host cell with a retroviral vector expression system, as described herein; and b) recovering the mixed trimer of rhabdoviral G glycoprotein. The mixed trimers may be prepared using any suitable method.

[00144] In aspects, the present invention provides a method for reducing the inactivation of a rhabdoviral G glycoprotein or a functional or derivative fragment thereof by serum, LDL or vLDL, the method comprising, essentially consisting of, or consisting of producing the rhabdoviral G glycoprotein or functional or derivative fragment thereof as a recombinant fusion protein, and exposing the recombinant fusion protein to serum, LDL or vLDL, wherein the inactivation by serum, LDL or vLDL is reduced.

[00145] In some respects, the present invention provides a method for reducing the inactivation of a rhabdoviral G glycoprotein or a functional or derivative fragment thereof (e.g., reducing rhabdoviral G glycoprotein-mediated fusion inactivation) by serum, LDL, or vLDL (e.g., lipoproteins containing ApoB-100), the method comprising, essentially consisting of, or consisting of producing a rhabdoviral G glycoprotein or a functional or derivative fragment thereof as a recombinant fusion protein, as described herein, and exposing the recombinant fusion protein to serum, LDL, or vLDL, wherein the inactivation by serum, LDL, or vLDL is reduced. In some respects, the recombinant fusion protein is inactivated to a lesser degree by serum, LDL, or vLDL compared to a rhabdoviral G glycoprotein without the polypeptide antibody construct.The reduction in inhibition can be of any magnitude, for example, reduced by 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 2%, 1%, or any interval between these percentages. Petition 870250093142, dated 10 / 10 / 2025, page 90 / 819 61 / 640 In some aspects, the production of vectors, as described here in a cell that expresses CD55 (or overexpresses CD55), can increase resistance to complement inactivation.

[00148] In some respects, the present invention provides a method of activating lymphocytes by means of lymphocyte contact with a composition, a virus, a membranous vesicle, an enveloped delivery vehicle, an enveloped viral particle or a recombinant viral vector, as described herein. Lymphocytes include, for example, T cells and natural killer cells. The T cell may be, for example, a CD8+ T cell.

[00149] In aspects, the present invention provides a nucleic acid construct comprising, consisting essentially of, or consisting of a nucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 221.

[00150] In aspects, the present invention provides a nucleic acid construct comprising, consisting essentially of, or consisting of a nucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 222.

[00151] International Common Property Patent Application No. PCT / US2024 / 024511, entitled MODULAR REDIRECTION OF RHABDOVIRICAL (G) GLYCOPROTEINS FROM THEIR NATURAL RECEPTORS, filed on April 12, 2024, and with Process Number 770398, is incorporated herein by reference in its entirety.

[00152] International Patent Application No. PCT / US2024 / 013058, entitled MODIFIED RHABDOVIRUS GLYCOPROTEINS AND THEIR USES, filed on January 26, 2024, is incorporated herein by reference in its entirety.

[00153] The following are some aspects of the invention.

[00154] 1. A recombinant fusion protein comprising, consisting essentially of, or consisting of (a) a glycoprotein Petition 870250093142, dated 10 / 10 / 2025, pages 813 / 819 62 / 640 rabdoviral G-in or a functional fragment or derivative thereof and (b) a polypeptide antibody construct, wherein the polypeptide antibody construct has the ability to bind to human CD3.

[00155] 2. The recombinant fusion protein of aspect 1, wherein the antibody polypeptide construct is N-terminal to the rhabdoviral glycoprotein G or a functional fragment or derivative thereof.

[00156] 3. The recombinant fusion protein of aspect 1 or 2, wherein the fusion protein comprises a linker between the antibody polypeptide construct and the rhabdoviral glycoprotein G or a functional fragment or derivative thereof.

[00157] 4. The recombinant fusion protein of aspect 3, in which the ligand is flexible.

[00158] 5. The recombinant fusion protein of aspect 4, in which the ligand is AAASGGSGGGGSGGGGSGP (SEQ ID NO: 130), AAASGGSGGGGSGGGGS (SEQ ID NO: 131), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 132), GGGGSGGGGSGGGGS (SEQ ID NO: 36), GGGGSGGGGS (SEQ ID NO: 133), GGGGS (SEQ ID NO: 134), GGGGGGGG (SEQ ID NO: 135), GGGGGG (SEQ ID NO: 136), GSAGSAAGSGEF (SEQ ID NO: 137) and VPGVGVGVG (SEQ ID NO: 138).

[00159] 6. The recombinant fusion protein of aspect 3, in which the ligand is rigid.

[00160] 7. The recombinant fusion protein of aspect 6, in which the ligand is PAPAP (SEQ ID NO: 139), EAAAKAAAKAAAK (SEQ ID NO: 140), Petition 870250093142, dated 10 / 10 / 2025, pp. 814 / 819 63 / 640 EAAAKEAAAK (SEQ ID NO: 141), EAAAK (SEQ ID NO: 142) AEAAAKEAAAAKEAAAKAAAKALEEAAAAKEAAAKAAAKAAAKA (SEQ ID NO: 143), AEAAAKEAAAKA (SEQ ID NO: 144), ESKYGPPCPPCP (SEQ ID NO: 145), CPPCPAPELLGGPSVF (SEQ ID NO: 146) and repeated alanine-proline (AP) for a total of 10 to 34 amino acids (SEQ ID NO: 147).

[00159] 8. The recombinant fusion protein of aspect 3, in which the ligand comprises an IgG1 hinge region.

[00160] 9. The recombinant fusion protein of aspect 8, where IgG1 is human IgG1

[00161] 10. Recombinant fusion protein of aspect 8, where the ligand comprises SEQ ID NO: 175.

[00162] 11. The recombinant fusion protein of any of aspects 11 to 0, wherein the rhabdoviral G glycoprotein or functional fragment or derivative thereof is of a Flanders virus glycoprotein (FLAV-G) (SEQ ID NO: 13), a Chandipura virus glycoprotein (CHPV-G) (SEQ ID NO: 14), a Perinet virus glycoprotein (PERV-G) (SEQ ID NO: 15), a Piry virus glycoprotein (PIRYVG) (SEQ ID NO: 16), a Fukuoka virus glycoprotein (FUKV-G) (SEQ ID NO: 17), a Joinjakaka virus glycoprotein (JOIV-G) (SEQ ID NO: 18), a Kumasi virus glycoprotein (KRV-G) (SEQ ID NO: 19), a Keuraliba virus glycoprotein (KEUV-G) (SEQ ID NO: 20), an Isfahan glycoprotein (ISFV-G), a Jurona glycoprotein (JURV-G), a Mediterranean bat glycoprotein (MBV-G), a Malpais Spring glycoprotein (MSPV-G), a Radi glycoprotein (RADV-G), a Rhinolophus affinis glycoprotein-G, a Yug Bugdanavoc glycoprotein (YBV-G), a Yinshui bat glycoprotein Petition 870250093142, dated 10 / 10 / 2025, page 93 / 819 64 / 640 (YSBV-G), a Kimberley glycoprotein (KIMV-G), a Kanyawara glycoprotein (KYAV-G), a La Joya glycoprotein (LJV-G), a Mosquiero glycoprotein (MQOV-G), a Parry Creek glycoprotein (PCVG), a Bas Congo glycoprotein (BASV-G), a bovine ephemeral fever glycoprotein (BEFV-G), a Curionopolis glycoprotein (CURVG), a Drosophila melanogaster Sigmavirus glycoprotein (DMelSVG), a Niakha glycoprotein (NIAV-G), a Puerto Almandras glycoprotein (PTAMV-G), or a Tupaia rhabdovirus glycoprotein (TUPTVG).

[00163] 12. The recombinant fusion protein of any of aspects 1 to 10, wherein the rhabdoviral G glycoprotein or a functional fragment or derivative thereof is a vesiculovirus glycoprotein or a functional fragment or derivative thereof.

[00164] 13. The recombinant fusion protein of any of aspects 1 to 10, wherein the rhabdoviral G glycoprotein or functional fragment or derivative thereof is from Vesiculovirus indiana, Vesiculovirus newjersey, Vesiculovirus carajas or Vesiculovirus alagoas.

[00165] 14. The recombinant fusion protein of aspect 13, wherein the rhabdoviral G glycoprotein or functional fragment or derivative thereof is from Vesiculovirus indiana (SEQ ID NO: 21).

[00166] 15. The recombinant fusion protein of aspect 13, wherein the rhabdoviral G glycoprotein or functional fragment or derivative thereof is from Vesiculovirus newjersey (SEQ ID NO: 22).

[00167] 16. The recombinant fusion protein of any of aspects 1 to 15, in which the rhabdoviral G glycoprotein is substantially intact.

[00168] 17. The recombinant fusion protein of any of aspects 1 to 15, wherein the rhabdoviral glycoprotein G is a functional fragment or derivative thereof.

[00169] 18. The recombinant fusion protein of aspect 17, in Petition 870250093142, dated 10 / 10 / 2025, page 94 / 819 65 / 640 that the cytoplasmic tail of the glycoprotein is truncated, deleted, or replaced by another sequence.

[00170] 19. A recombinant fusion protein of any of aspects 1 to 18, in which the rhabdoviral G glycoprotein is engineered to reduce or abolish its binding specificity to the natural receptor.

[00171] 20. The recombinant fusion protein of aspect 19, in which the rhabdoviral G glycoprotein is engineered to have a mutation to reduce or abolish its binding specificity to the natural receptor.

[00172] 21. The recombinant fusion protein of aspect 20, in which the rhabdoviral G glycoprotein comprises a mutation at one or more positions corresponding to H8, K47, Y209 and K354 in the Indian Vesiculovirus glycoprotein (SEQ ID NO: 21).

[00173] 22. The recombinant fusion protein of aspect 20 or 21, wherein the mutation is a substitution.

[00174] 23. The recombinant fusion protein of aspect 22, wherein the substitution is with a Q.

[00175] 24. The recombinant fusion protein of aspect 22 or 23, in which the mutation is a substitution at two or more positions.

[00176] 25. The recombinant fusion protein of aspect 20 or 21, wherein the mutation is a deletion.

[00177] 26. The recombinant fusion protein of aspect 25, wherein the mutation is a single deletion at the position corresponding to K47 in the Indian Vesiculovirus glycoprotein (SEQ ID NO: 21)

[00178] 27. The recombinant fusion protein of any of aspects 1 to 26, wherein the recombinant fusion protein is inactivated to a lesser degree by serum, LDL, or vLDL compared to a rhabdoviral G glycoprotein without the polypeptide antibody construct.

[00179] 28. The recombinant fusion protein of any of aspects 1 to 27, wherein the polypeptide antibody construct is a CD3 agonist. Petition 870250093142, dated 10 / 10 / 2025, page 95 / 819 66 / 640

[00180] 29. The recombinant fusion protein of any of aspects 1 to 28, wherein the polypeptide antibody construct comprises a single-chain variable fragment (scFv).

[00181] 30. The recombinant fusion protein of aspect 29, in which scFv has the N-terminal VL for VH.

[00182] 31. The recombinant fusion protein of aspect 29, in which scFv has the N-terminal VH to VL.

[00183] 32. The recombinant fusion protein of aspect 29, wherein scFv is UCHT1, HuM291, OKT3 or TR66.

[00184] 33. The recombinant fusion protein of aspect 32, wherein scFv is a humanized UCHT1.

[00185] 34. The recombinant fusion protein of aspect 33, wherein scFv comprises a variable heavy chain (VH) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 46 and a variable light chain (VL) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 45.

[00186] 35. The recombinant fusion protein of aspect 34, in which VH and VL are separated by a flexible linker.

[00187] 36. The recombinant fusion protein of aspect 35, wherein the flexible ligand is SEQ ID NO: 36.

[00188] 37. The recombinant fusion protein of aspect 32, wherein scFv is TR66 and wherein TR66 is codon-optimized for human expression, and wherein scFv comprises a variable heavy chain (VH) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 44 and a variable light chain (VL) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 43.

[00189] 38. The recombinant fusion protein of aspect 32, wherein scFv is UCHT1 and wherein scFv comprises a heavy chain Petition 870250093142, dated 10 / 10 / 2025, page 96 / 819 67 / 640 of the variable (VH) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 46 and a variable light chain (VL) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 45.

[00190] 39. The recombinant fusion protein of aspect 32, wherein the scFv is HuM291 and wherein the scFv comprises a variable heavy chain (VH) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 38 and a variable light chain (VL) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 37.

[00191] 40.The recombinant fusion protein of aspect 32, wherein the scFv is OKT3 and wherein the scFv comprises a variable heavy chain (VH) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 40 and a variable light chain (VL) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 39.

[00192] 41. The recombinant fusion protein of aspect 32, wherein the scFv is TR66 and wherein the scFv comprises a variable heavy chain (VH) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 42 and a variable light chain (VL) comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 41.

[00193] 42. The recombinant fusion protein of either aspect 1-41, wherein the recombinant fusion protein comprises a signal peptide N-terminal for the polypeptide antibody construct.

[00194] 43. The recombinant fusion protein of aspect 42, wherein the signal peptide comprises the amino acid sequence of SEQ ID NO: 60.

[00195] 44. The recombinant fusion protein of aspect 42 or 43, Petition 870250093142, dated 10 / 10 / 2025, p. 97 / 819 68 / 640 where the signal sequence is cleaved.

[00196] 45. A membranous vesicle comprising, consisting essentially of, or consisting of recombinant fusion protein of any of aspects 1 to 44.

[00197] 46. The membranous vesicle of aspect 45, wherein the vesicle is a gesicle or an exosome.

[00198] 47. The membranous vesicle of aspect 45 or 46, wherein the membranous vesicle comprises a mixed trimer, wherein the mixed trimer comprises (a) at least one recombinant fusion protein and (b) at least one rhabdoviral G glycoprotein or functional fragment or derivative thereof that is not within a recombinant fusion protein.

[00199] 48. The membranous vesicle of aspect 47, wherein the membranous vesicle comprises an unmixed trimer, wherein the unmixed trimer comprises only rhabdoviral G glycoprotein or a functional fragment or derivative thereof that is not within a recombinant fusion protein.

[00200] 49. The membranous vesicle of aspect 48, wherein the membranous vesicle comprises the maximum number of recombinant fusion proteins that can be accommodated within the membrane of the membranous vesicle.

[00201] 50. An enveloped viral particle comprising, consisting essentially of, or consisting of the recombinant fusion protein of any of aspects 1 to 44.

[00202] 51. The enveloped viral particle of aspect 50, wherein the enveloped viral particle comprises a mixed trimer, wherein the mixed trimer comprises (a) at least one recombinant fusion protein and (b) at least one rhabdoviral G glycoprotein or functional fragment or derivative thereof that is not within a recombinant fusion protein. Petition 870250093142, dated 10 / 10 / 2025, pp. 98 / 819 69 / 640

[00203] 52. The enveloped viral particle of aspect 51, wherein the enveloped viral particle comprises an unmixed trimer, wherein the unmixed trimer comprises only the rhabdoviral glycoprotein G or a functional fragment or derivative thereof that is not within a recombinant fusion protein.

[00204] 53. The enveloped viral particle of aspect 52, wherein the enveloped viral particle comprises the maximum number of recombinant fusion proteins that can be accommodated within the membrane of the enveloped viral particle.

[00205] 54. A recombinant viral vector comprising, consisting essentially of, or consisting of a nucleotide encapsulated by the membranous vesicle of either aspect 45 to 49 or by the enveloped viral particle of either aspect 50 to 53.

[00206] 55. A composition comprising, consisting essentially of, or comprising a pharmaceutically acceptable vehicle and the membranous vesicle of any of aspects 45-49, the enveloped viral particle of any of aspects 50-53, or the recombinant viral vector of aspect 54.

[00207] 56. A method of delivering a payload to a cell T, the method comprising, consisting essentially of, or comprising, placing the T cell in contact with the membranous vesicle of any of aspects 45 to 49, the enveloped viral particle of any of aspects 50 to 53, the recombinant viral vector of aspect 54, or the composition of aspect 55.

[00208] 57. The method of aspect 56, in which the T cell in vitro or ex vivo.

[00209] 58. The method of aspect 56, in which the T cell in vivo.

[00210] 59. The method of any of the aspects 56 to 58, wherein the payload is a nucleotide sequence encoding a re Petition 870250093142, dated 10 / 10 / 2025, pp. 99 / 819 70 / 640 chimeric antigen receptor (CAR) comprising, consisting essentially of, or comprising an antigen-binding domain, a transmembrane domain and an intracellular signaling domain.

[00211] 60. The method of aspect 59, in which CAR has antigenic specificity for CD19 or BCMA.

[00212] 61. The 59 or 60 aspect method, wherein CAR comprises a hinge domain, wherein the hinge domain is the hinge domain of CD28α or CD8α.

[00213] 62. The method of either of aspects 59 to 61, wherein the transmembrane domain is the transmembrane domain of CD28 or CD8.

[00214] 63. The method of any of the aspects 59 to 62, in which the intracellular signaling domain comprises a co-stimulatory domain and an activating domain.

[00215] 64. The aspect 63 method, in which the co-stimulatory domain is 4 - 1BB.

[00216] 65. The aspect 63 method, in which the activation domain is CD3zeta.

[00217] 66. The method of any of the aspects 56-58, wherein the payload is a transgene or gene editing system.

[00218] 67. A retroviral vector expression system comprising, consisting essentially of, or consisting of one or more nucleotide sequences encoding the recombinant fusion protein of any of aspects 1 to 44.

[00219] 68. The retroviral vector expression system aspect 67, in which the retroviral vector expression system comprises a vector construct and auxiliary constructs, each residing on separate plasmids.

[00220] 69. The retroviral vector expression system aspect Petition 870250093142, dated 10 / 10 / 2025, page 100 / 819 71 / 640 or 68, where the retroviral vector expression system is a lentirival vector expression system.

[00221] 70. The retroviral vector expression system of any of aspects 67 to 69, comprising, consisting essentially of, or consisting of a nucleotide sequence encoding a chimeric antigen receptor (CAR) comprising, consisting essentially of, or consisting of an antigen-binding domain, a transmembrane domain and an intracellular signaling domain.

[00222] 71. The retroviral vector expression system aspect 70, wherein the CAR has antigenic specificity for CD19 or BCMA.

[00223] 72. The retroviral vector expression system of aspect or 71, wherein the CAR comprises a hinge domain, wherein the hinge domain is the hinge domain of CD28a or CD8a.

[00224] 73. The retroviral vector expression system of any of aspects 70 to 72, wherein the transmembrane domain is the transmembrane domain of CD28 or CD8.

[00225] 74. The retroviral vector expression system of any of the aspects 70 to 73, in which the intracellular signaling domain comprises a co-stimulatory domain and an activating domain.

[00226] 75. The retroviral vector expression system aspect 74, in which the co-stimulatory domain is 4-1BB.

[00227] 76. The retroviral vector expression system aspect 74, where the activation domain is CD3zeta.

[00228] 77. The retroviral vector expression system of any of aspects 67 to 69, comprising, consisting essentially of, or consisting of one or more nucleotide sequences encoding a transgene or gene editing system.

[00229] 78. A method for producing a membranous vesicle, Petition 870250093142, dated 10 / 10 / 2025, page 101 / 819 72 / 640 an enveloped viral particle or a recombinant viral vector, the method comprising, consisting essentially of, or consisting of: a) transfect or transduce a packaging host cell with the retroviral vector expression system of any of the aspects 67 to 77; and b) to recover the membranous vesicle, enveloped viral particle, or recombinant viral vector produced by the transfected or transduced packaging host cell.

[00230] 79. A plasmid comprising, consisting essentially of, or consisting of one or more nucleotide sequences encoding the recombinant fusion protein of any of aspects 1 to 44.

[00231] 80. The composition of aspect 55 or the retroviral vector expression system of any of aspects 61 to 71 for use in the treatment of a disease in a mammal.

[00232] 81. The aspect ratio method 80, in which the mammal is a human.

[00233] 82. The 80 or 81 aspect method, in which the disease is a genetic disease.

[00234] 83. The 80 or 81 aspect method, in which the disease is cancer.

[00235] 84. The method of any of the aspects 80 to 83, in which the composition is administered intravenously.

[00236] 85. The method of any of the aspects 80 to 83, in which the composition is administered intraperitoneally.

[00237] 86. A method for producing a mixed rhabdoviral G glycoprotein trimer, the method comprising, consisting essentially of, or consisting of: a) to transfect or transduce a host cell into Petition 870250093142, dated 10 / 10 / 2025, page 102 / 819 73 / 640 packaging with the retroviral vector expression system of any of the aspects 67 to 77; and (b) recovering the mixed rhabdoviral G glycoprotein trimer.

[00238] 87. A method for reducing the inactivation of a rhabdoviral G glycoprotein or a functional or derivative fragment thereof by serum, LDL or vLDL, the method comprising, essentially consisting of, or consisting of producing the rhabdoviral G glycoprotein or a functional or derivative fragment thereof as a recombinant fusion protein, and exposing the recombinant fusion protein to serum, LDL or vLDL, wherein the inactivation by serum, LDL or vLDL is reduced.

[00239] 88.A method for reducing the inactivation of a rhabdoviral G glycoprotein or a functional or derivative fragment thereof by serum, LDL or vLDL, the method comprising, essentially consisting of, or consisting of producing the rhabdoviral G glycoprotein or a functional or derivative fragment thereof as the recombinant fusion protein of any of aspects 1-44, and exposing the recombinant fusion protein to serum, LDL or vLDL, wherein the inactivation by serum, LDL or vLDL is reduced.

[00240] 89. A method of activating T lymphocytes through contact of the T lymphocyte with the composition of aspect 55.

[00241] 90. A nucleic acid construct comprising, consisting essentially of, or consisting of a nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 221.

[00242] 91. A nucleic acid construct comprising, consisting essentially of, or consisting of a nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 222.

[00243] It should be noted that the above items are merely examples of aspects of the invention. Other exemplary aspects are Petition 870250093142, dated 10 / 10 / 2025, page 103 / 819 74 / 640 evident from the totality of the description presented here. It will also be understood by someone with common knowledge in the area that each of these aspects can be used in various combinations with the other aspects presented here.

[00244] The following examples further illustrate aspects of the invention, but, of course, should not be interpreted as limiting its scope. EXAMPLE 1

[00245] This example demonstrates the development of expression vectors encoding Indian Vesiculovirus G glycoprotein (VSIV-G) constructs with reduced binding to the low-density lipoprotein receptor (LDLR) fused to a CD3 targeting molecule for use in lentiviruses.

[00246] To develop a recombinant fusion protein comprising a VSIV-G with reduced or abolished LDLR binding fused to anti-CD3 scFvs for use in lentivirus constructs, the following were designed according to Figure 3. The constructs were designed using a pCG-4MC11 expression vector with sequences encoding a VSIV-G signal peptide, one of the anti-CD3 scFvs UCHT1 (SEQ ID NOs: 45 and 46), HuM291 (SEQ ID NOs: 37 and 38), OKT3 (SEQ ID NOs: 39 and 40), scFv TR66 (SEQ ID NOs: 41 and 42) or TR66-opt (SEQ ID NOs: 43 and 44), a flexible 19-amino acid linker (SEQ ID NO: 130) or an IgG1 hinge C2 linker (SEQ ID NO: 175) and a VSIV-G with Q substitutions at residues K47 and R354 (VSIV-G-QQ) (SEQ ID NO: 25).The anti-CD3 scFvs of plasmids version 1 (SEQ ID NOs: 179-183) and version 2 (SEQ ID NOs: 184-188) are oriented with the N-terminal of the heavy chain (VH) towards the light chain (VL), while plasmids of version 3 (SEQ ID NOs: 189-193) are oriented with the N-terminal of the VL towards the VH, except for constructs containing scFv UCHT1 which had opposite orientations. Petition 870250093142, dated 10 / 10 / 2025, page 104 / 819 75 / 640 VH and VL.

[00247] HEK-293T packaging cells were transfected with transfer plasmid, packaging plasmid, and envelope plasmids of versions 1, 2, or 3 (FIG. 4). After 24 hours, the medium for the HEK-293T cells was removed and replaced with fresh medium. 72 hours after transfection, the virus was collected, clarified, and concentrated. 72 hours after transfection for lentivirus production, cell lysates were collected and subjected to Western blotting with anti-VSV-G and anti-GAPDH polyclonal antibodies (FIG. 5), and Western blotting was also performed on lentivirus particles with the same antibodies (FIG. 6).Cell lysates from HEK-293T cells transfected with an envelope plasmid encoding a recombinant human stem cell factor (hSCF) fusion protein (SEQ ID NO: 52), a 19-amino acid ligand (SEQ ID NO: 130), and VSIV-G (SEQ ID NO: 21), and lentiviral particles pseudotyped with the same were used as controls to show the effect of the cleavable ligand on partial G cleavage. In the cell lysate, only the scFv anti-CD3 version 3 plasmids with 19aaL (SEQ ID NO: 130) and scFv UCHT1 (SEQ ID NOs: 45 and 46) showed partial G cleavage. Western blots of version 1 lentivirus particles were performed using pre- and post-concentrated lentivirus particles, while for version 2 and 3 lentivirus particles, only concentrated samples were used. used. The incorporation of antiCD3 scFvs into virions is less efficient in pre-concentrated samples compared to post-concentrated samples.In the samples from version 1, the scFv TR66-opt (SEQ ID NOs: 43 and 44) ​​was detected at slightly higher levels than the other scFvs. All scFvs were detected at similar levels in the samples from versions 2 and 3.

[00248] The collected lentivirus particles were titrated using Petition 870250093142, dated 10 / 10 / 2025, page 105 / 819 76 / 640 ELISA for p24 and quantified as shown in Tables 2 to 4. Lentiviruses were lysed in the buffer provided in the Takara Kit and the ELISA for p24 was performed according to the manufacturer's instructions, with p24 levels then converted to TCID50 / ml. Table 2 Virus Name p24 ELISA Titer: Conversion to (TCID50 / ml) Pre-concentration p24 ELISA Titer: Conversion to (TCID50 / ml) Post-concentration LV-SFFV-eGFP: pseudo-WTG # out of range 1.24E+08 LV-SFFV-eGFP: pseudo-GQQ 2.18E+07 # out of range LV-SFFV-eGFP: Pseudo-aCD3-UCHT119aaL-G-QQ 1.21E+07 8.77E+07 LV-SFFV-eGFP: Pseudo-aCD3HUM291-19aaL-G-QQ 8.91E+06 9.97E+07 LV-SFFV-eGFP: Pseudo-aCD3-OKT319aaL-G-QQ 2.20E+07 2.43E+08 LV-SFFV-eGFP: Pseudo-aCD3TR66opt-19aaL-G-QQ 1.27E+07 1.25E+08 LV-SFFV-eGFP: Pseudo-aCD3-TR6619aaL-G-QQ 1.30E+07 1.20E+08 Petition 870250093142, dated 10 / 10 / 2025, page 106 / 819 77 / 640 Table 3 Virus Name p24 Titer ELISA: conversion to (TCID50 / ml) LV-SFFV-eGFP: pseudo-WTG 3.15E+06 LV-SFFV-eGFP: pseudo-GQQ 1.73E+07 LV-SFFV-eGFP: Pseudo-HuM291 -19aaliganteG-QQ <1.56e5 LV-SFFV-eGFP: Pseudo-aCD3-OKT319aaligante-G-QQ 9.78E+05 LV-SFFV-eGFP: Pseudo-aCD3-TR6619aaligante-G-QQ 8.45E+05 LV-SFFV-eGFP: Pseudo-aCD3-TR66opt19aaligante-G-QQ 2.43E+05 Table 4 p24 Virus Name ELISA Title: Conversion to (TCID50 / ml) LV-SFFV-eGFP: pseudo-WTG 5.31E+08 LV-SFFV-eGFP: pseudo-GQQ 4.43E+08 LV-SFFV-eGFP: Pseudo-aCD3-UCHT1-19aaLG-QQ 2.73E+06 LV-SFFV-eGFP: Pseudo-aCD3-HUM29119aaL-G-QQ 5.27E+08 LV-SFFV-eGFP: Pseudo-aCD3-OKT3-19aaLG-QQ 1.16E+07 LV-SFFV-eGFP: Pseudo-aCD3-TR66opt19aaL-G-QQ 7.15E+07 LV-SFFV-eGFP: Pseudo-aCD3-TR66-19aaLG-QQ 1.32E+07

[00249] Jurkat cells, which are a CD3-expressing T cell lineage, were transduced with 10 μL of lentivirus pseudotyped with VSIV-G (SEQ ID NO: 21), VSIV-G-QQ (SEQ ID NO: 25) or Petition 870250093142, dated 10 / 10 / 2025, page 107 / 819 78 / 640 with an anti-CD3 scFv fused to VSIV-G-QQ of each virion construct from versions 1, 2, and 3. Five days after transduction, phase-contrast (bottom) and fluorescence (top) images were taken using a Nikon microscope with a 10x objective lens (FIG. 7). The VSIV-G pseudotyped positive control lentivirus (SEQ ID NO: 21) was able to transduce Jurkat cells, but among the anti-CD3 constructs, only the lentivirus pseudotyped with the recombinant fusion protein version 3 with scFv UCHT1 (SEQ ID NOs: 45 and 46), which exhibited partial G cleavage, was able to transduce Jurkat cells. This suggests that partial G cleavage in the chimeric protein is necessary to achieve T cell targeting. EXAMPLE 2

[00250] This example demonstrates the targeting specificity of the pseudotyped lentivirus with blind LDLR VSIV-G fused to a CD3 targeting molecule.

[00251] To further test the targeting specificity of the pseudotyped lentivirus with the version 3 constructs, Jurkat cells, which are CD3 positive, and Nalm6 cells, which are CD3 negative, were seeded in 96-well plates at 5 and 4 cells per well and transduced with pseudotyped lentivirus with VSIV-G (SEQ ID NO: 21), VSIV-G-QQ (SEQ ID NO: 25) or a recombinant fusion protein of an N-terminal scFv anti-CD3 to a 19 amino acid N-linker (SEQ ID NO: 130) for VSIV-G-QQ (SEQ ID NO: 25) at a multiplicity of infection (MOI) of 2. 72 hours after transduction, fluorescence images were obtained by Nikon microscope with 10x objective lens and an exposure of 50 ms or 300 ms (FIG. 8A). Only the scFv anti-CD3 UCHT1 (SEQ ID NOs: 45 and 46) was able to specifically transduce Jurkat cells. Fluorescent images were obtained by CELIGO for cytometric measurements of Jurkat and Nalm6 cells, as well as K562 parental cells, which are CD3 Petition 870250093142, dated 10 / 10 / 2025, p. 108 / 819 79 / 640 negative, transduced under the same conditions as Jurkat and Nalm6 cells (FIG. 8B). Cytometric quantification showed that, of lentiviruses pseudotyped with recombinant fusion proteins of an N-terminal scFv anti-CD3 to a 19-amino acid N-linker (SEQ ID NO: 130) for VSIV-G-QQ (SEQ ID NO: 25), only scFv UCHT1 (SEQ ID NOs: 45 and 46) showed transduction in Jurkat cells (FIG. 8C). This suggests that scFv UCHT1 (SEQ ID NOs: 45 and 46) in the version 3 construct is the best candidate among those tested to target lentiviruses to CD3-expressing cells. Along with the results of the Western analysis, these data also suggest that the partially cleaved G can be mixed with the recombinant scFv UCHT1 fusion protein (SEQ ID NOs: 45 and 46) (chimeric) to form a mixed trimer displayed on the lentivirus surface, which induces CD3 receptor-mediated entry. EXAMPLE 3

[00252] This example demonstrates the increased infectivity of lentivirus pseudotyped with LDLR-blind VSIV-G fused to a CD3 targeting molecule when mixed with lentivirus pseudotyped only with LDLR-blind VSIV-G.

[00253] To test the effectiveness of pseudotyped CD3-targeted lentiviruses generated using a mixture of envelope plasmids encoding a recombinant VSIV-G LDLR-blind fusion protein fused to a CD3 targeting molecule and envelope plasmids encoding an LDLR-blind VSIV-G without a CD3 targeting molecule to generate lentiviruses with a mixed trimer, experiments were performed as shown in Figure 9A. HEK-293T cells were transfected with packaging plasmid, transfer plasmid, and a constant amount of envelope plasmid (SEQ ID NO: 193) (1 μg) encoding a recombinant VSIV-G-QQ fusion protein (SEQ ID Petition 870250093142, dated 10 / 10 / 2025, p. 109 / 819 80 / 640 NO: 25) fused to scFv anti-CD3 UCHT1 (SEQ ID NOs: 45 and 46) via a non-cleavable IgG1 ligand (SEQ ID NO: 175) (scFv-G-QQ) and with a plasmid (SEQ ID NO: 97) encoding a VSIV-G-QQ (SEQ ID NO: 25) without a CD3 targeting molecule (GQQ) in increasing amounts (0, 1, 2, 3, or 4 μg). After 24 hours, the medium for HEK-293T cells was removed and replaced with fresh medium. 72 hours after transfection, cell lysates were collected, clarified, and concentrated to collect lentivirus particles. 72 hours after lentivirus transfection, cell lysates were collected and subjected to western blotting with anti-VSV-G and anti-GAPDH polyclonal antibodies (FIG. 9B), and western blotting was also performed on lentivirus particles with the same antibodies (FIG. 9C).The recombinant fusion protein of scFv UCHT1 fused to VSIV-G-QQ (SEQ ID NO: 25) (aCD3 UCHT1-G-QQ) was detected at similar levels in all different plasmid ratios in the cell lysate, but in lentivirus particle samples, aCD3 UCHT1-G-QQ was detected at much lower levels when no envelope plasmid encoding VSIV-G (SEQ ID NO: 21) alone (VSV-G) was present. The collected lentivirus particles were titrated using p24 ELISA as previously described and quantified as shown in Table 5. Table 5 Sample P24 (pg / mL) Calculated Title / mL G-WT 1272400 1.53E+08 G-QQ 668980 8.03E+07 1:00 1532.3 1.84E+05 1:1 38547 4.63E+06 1:2 26375 3.17E+06 1:3 50058 6.01E+06 1:4 44652 5.36E+06 Petition 870250093142, dated 10 / 10 / 2025, page 110 / 819 81 / 640

[00254] These lentiviral particles were then used to infect Jurkat and Nalm6 cells, as described previously. Jurkat cells and Nalm6 cells treated without lentivirus (Simulation) were used as negative controls, and Jurkat cells and Nalm6 cells infected with lentivirus encoding VSIV-G (SEQ ID NO: 21) or VSIV-GG (SEQ ID NO: 25) without a CD3 targeting molecule were used as positive controls. Five days after transduction, fluorescence images were obtained using a CELIGO machine to quantify the number of GFP-positive cells (FIG. 9D). Pseudotyped lentivirus particles with recombinant scFv UCHT1 fusion protein fused to VSIV-GG (SEQ ID NO: 25) did not infect Jurkat cells and showed the highest number of GFP-positive cells when created using a mixed trimer approach (FIG. 9E).These results suggest that lentiviruses pseudotyped with mixed trimers of VSIV-G-QQ and VSIV-G-QQ fused to a target molecule, such as scFv UCHT1, are the most effective in infecting CD3-positive cells. These results also suggest that there must be a cleavable linker between the scFv and the G protein to form the mixed trimer and be displayed on the lentivirus surface. Without wanting to limit ourselves to theory, this suggests that there may be some kind of steric hindrance for VSIV-G molecules fused to scFv-sized target molecules, which decreases infectivity. EXAMPLE 4

[00255] This example demonstrates the effect of different ligands on the infectivity of the VSIV-G blinded lentivirus fused to a CD3 targeting molecule.

[00256] To test the effects of different ligands on recombinant fusion proteins that connect VSIV-G to the target molecule, Jurkat cells and Nalm6 cells were infected with second-generation lentiviruses encoding eGFP and pseudotyped with the glycoproteins Petition 870250093142, dated 10 / 10 / 2025, page 111 / 819 82 / 640 as described in Table 6. Lentiviral vectors were created as previously described and then concentrated to approximately 30 times the initial concentration using PEG8000. Jurkat cells and Nalm6 cells were seeded at 4x10⁵ cells per well and then transduced with 15 μL of the concentrated vectors. Fluorescent images were obtained 24 hours after transduction using an inverted fluorescence microscope (FIG. 10A). GFP-positive cells were then quantified using the CELIGO machine (FIG. 10B). These results demonstrated the production of functional pseudotyped lentivirus with recombinant scFv anti-CD3 TR66opt N-terminal fusion proteins fused to VSIV-G-QQ (SEQ ID NO: 25) with a 19-amino acid ligand (SEQ ID NO: 130) and an IgG1 ligand (SEQ ID NO: 175) that specifically targeted Jurkat CD3-positive cells.Vectors with a 19-amino acid ligand (SEQ ID NO: 130) showed higher levels of GFP-positive cells than vectors with IgG1 ligand (SEQ ID NO: 175). Lentivirus particles created using a 1:3, 1:6, or 1:9 mixture of plasmids encoding the recombinant scFv TR66opt fusion protein linked to VSIV-G-QQ (SEQ ID NO: 25) via the 19-amino acid ligand (SEQ ID NO: 130) to the plasmid encoding VSIV-G-QQ (SEQ ID NO: 25) alone showed similar levels of GFP-positive cells, which were higher than the number of GFP-positive cells detected when using a 1:1 or 1:0 mixture.These results suggest that lentivirus particles created using a mixed plasmid approach with a ratio of at least 1:3 of plasmid encoding the recombinant fusion protein of a CD3 targeting molecule fused to VSIV-G-QQ (SEQ ID NO: 25) via a 19-amino acid linker (SEQ ID NO: 130) to the plasmid encoding VSIV-G-QQ (SEQ ID NO: 25) without a targeting molecule would be the most effective in infecting CD3-positive cells. Petition 870250093142, dated 10 / 10 / 2025, page 112 / 819 83 / 640 Table 6 Glycoprotein Description WT-G VSIV-G wild type (SEQ ID NO: 21) G-QQ VSIV-G mutated in K47Q / R354Q (SEQ ID NO: 25) G-QQ-αEGFR VSIV-G mutated in K47Q / R354Q (SEQ ID NO: 25) linked to an ScFv αEGFR with N-terminal VH to VL via a RAAASGGS(G4S)2GP ligand (SEQ ID NO: 208) G-QQ-19aaL-UCHT1:G-QQ 1:1 mixture of VSIV-G mutated by K47Q / R354Q (SEQ ID NO: 25) linked to UCHT1 αCD3 ScFv with N-terminal VH to VL (SEQ ID NO: 46) via 19aaL (SEQ ID NO: 130) and K47Q / R354Q mutated VSIV-G (SEQ ID NO: 25) G-QQ-19aaL- TR66opt: G-QQ Mixture of K47Q / R354Q mutated VSIV-G (SEQ ID NO: 25) linked to TR66opt αCD3 ScFv with N-terminal VL (SEQ ID NO: 43) to VH (SEQ ID NO: 44) via 19aaL (SEQ ID NO: 130) and K47Q / R354Q mutated VSIV-G (SEQ ID NO: 25), with the mixture in the indicated proportions of (1:0, 1:1, 1:3,1:6 and 1:9) G-QQ-IG1- TR66opt: G-QQ Mixture of VSIV-G with K47Q / R354Q mutation (SEQ ID NO: 25) linked to ScFv αCD3 TR66opt with N-terminal VH (SEQ ID NO: 44) to VL (SEQ ID NO: 43) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G with K47Q / R354Q mutation (SEQ ID NO: 25), with the mixture in the indicated proportions of (1:0, 1:1, 1:3, 1:6 and 1:9),

[00257] A similar experiment was performed by transducing Jurkat and Nalm6 cells as described above with lentivirus pseudotyped with VSIV-G (G-WT) (SEQ ID NO: 21), an LDL-R blind VSIV-G with K47QY209QR354Q substitutions (VSIV-G-QQQ) (SEQ ID NO: 26), a 1:3 ratio of a recombinant scFv UCHT1 αCD3 fusion protein with the N-terminal fused with VL (SEQ ID NO: 45) to the N-terminal fused with VH (SEQ ID NO: 46) via a (G4S)3 ligand (SEQ ID NO: 36) via an IgG1 ligand (SEQ ID NO: Petition 870250093142, dated 10 / 10 / 2025, p. 113 / 819 84 / 640 175) to VSIV-G-QQQ (SEQ ID NO: 26) (VSIV-G-QQQ-IgG1-UCHT1) and VSIV-G-QQ (G-QQQ) (SEQ ID NO: 26), or a 1:3 ratio of a recombinant αCD3 scFv Hum291 fusion protein with the N-terminal fused from VH (SEQ ID NO: 38) to VL (SEQ ID NO: 37) via a (G4S)3 ligand (SEQ ID NO: 36) fused via an IgG1 ligand (SEQ ID NO: 175) to VSIV-G-QQQ (SEQ ID NO: 26) (VSIV-G-QQQ-IgG1-Hum291) and VSIV-G-QQ (G-QQQ) (SEQ ID NO: 26). Fluorescent images were obtained 72 hours after transduction (FIG. 10C). Lentivirus particles pseudotyped with VSIV-GQQQ-IgG1-UCHT1 or VSIV-G-QQQ-IgG1-UCHT1 infected Jurkat cells, but not Nalm6 cells. These results suggest that VSIV-GQQQ-IgG1-UCHT1 and VSIV-G-QQQ-IgG1-UCHT1 exhibit targeting specificity for CD3-positive cells. EXAMPLE 5

[00258] This example demonstrates the resistance of the VSIV-G-blind LDLR-fused pseudotyped lentivirus to a CD3 targeting molecule to serum inactivation.

[00259] To test the efficacy of lentiviruses pseudotyped with recombinant fusion proteins of CD3 targeting molecules fused with VSIV-G-QQ in vivo, experiments were performed to determine the serum stability of these lentiviruses. Table 7 shows the lentiviruses tested, prepared as previously described and concentrated using PEG. The lentiviruses in Table 7 with scFv TR66opt (SEQ ID NOs: 43 and 44) ​​were prepared using the previously described mixed envelope plasmid approach, in a ratio of 1:1, 1:3, 1:6 or 1:9. Jurkat cells were seeded at 4x10⁵ cells per well and cultured in medium alone (medium) or in medium containing human serum (serum) and transduced with the lentiviruses shown in Table 7, using 3.8 μL of LV-WT-GFP, 7.5 μL of LV-UCHT1 (19aa)-GQQ-GFP and 15 μL of the remaining TR66opt lentiviruses. Images Petition 870250093142, dated 10 / 10 / 2025, page 114 / 819 85 / 640 fluorescent images taken 48 hours after transduction were taken on an Olympus microscope (FIGs. 11A-11C). These results show that lentiviruses pseudotyped with VSIV-G (SEQ ID NO: 21) or VSIV-G-QQ (SEQ ID NO: 25) alone were not resistant to serum inactivation, but that lentiviruses pseudotyped with a recombinant fusion protein of an anti-CD3 targeting molecule fused with VSIV-G-QQ were resistant to serum inactivation. These results suggest that the CD3-targeted lentiviruses described here would be effective in infecting CD3-positive cells in vivo, since they demonstrate resistance to serum inactivation. Table 7 Virus 1 LV-WT-GFP 2 LV-GQQ-GFP 3 LV-UCHT1 (19aa)-GQQ-GFP 4 LV-TR66opt (19aa) - GQQ -GFP 1:1 5 LV-TR66opt (19aa) - GQQ -GFP 1:3 6 LV-TR66opt (19aa) - GQQ -GFP 1:6 7 LV-TR66opt (19aa) - GQQ -GFP 1:9 8 LV-TR66opt (Ig1a) - GQQ -GFP 1:1 9 LV-TR66opt (Ig1a) - GQQ -GFP 1:3 10 LV-TR66opt (Ig1a) - GQQ -GFP 1:6 11 LV-TR66opt (Ig1a) - GQQ -GFP 1:9

[00260] To also test resistance to serum inactivation, lentiviruses containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with VSIV-G (SEQ ID NO: 21) were produced in mouse HEK-293T cells and HEK293T cells expressing CD55, lentiviruses pseudotyped with VSIV-G-QQ (SEQ ID NO: 25), a recombinant UCHT1 scFv fusion protein (SEQ ID NOs: 45 and 46) fused to VSIV-G-QQ (SEQ ID NO: 25) via a 19-amino acid linker (SEQ ID NO: 130) (LV-UCHT1-19aaL-G-QQ-GFP), or Petition 870250093142, dated 10 / 10 / 2025, page 115 / 819 86 / 640 recombinant TR66opt scFv fusion protein (SEQ ID NOs: 43 and 44) ​​fused to VSIV-G-QQ (SEQ ID NO: 25) via an IgG1A ligand (SEQ ID NO: 175) (LV-TR66opt-IgG1A-G-QQ-GFP (1:6)) produced using the 1:6 ratio mixed plasmid approach, were produced in HEK-293T cells. Jurkat cells were cultured by flow cytometry in medium containing OptiMem, or 60% complement-active human or mouse serum, or 60% heat-inactivated (HI) human or mouse serum, and then transduced with the lentiviruses as previously described. 24 hours after transduction, fluorescent images were obtained using an inverted fluorescence microscope (FIG. 11D).These images show that while lentiviruses pseudotyped with VSIV-G (SEQ ID NO: 21) or VSIV-G-QQ (SEQ ID NO: 25) alone do not exhibit resistance to serum inactivation by complement-activated or heat-inactivated human and murine serum, lentiviruses LV-UCHT119aaL-G-QQ-GFP and LV-TR66opt-IgG1A-G-QQ-GFP (1:6) exhibit resistance to serum inactivation by complement-activated or heat-inactivated human and murine serum. The fold variation in the culture of GFP-positive Jurkat cells in OptiMem-containing media relative to each other culture condition was quantified in Figure 11E. A flow cytometry histogram demonstrated that HEK293T-mCD55 exhibited a higher number of CD55-positive cells compared to parental HEK-293T cells (FIG. 11F). These results suggest that elevated CD55 levels did not confer any additional resistance to serum inactivation of lentivirus particles.These results suggest that the CD3-targeted lentiviruses described here would be effective in infecting CD3-positive cells in vivo in humans and other mammals, as they demonstrate resistance to serum inactivation. EXAMPLE 6 Petition 870250093142, dated 10 / 10 / 2025, page 116 / 819 87 / 640

[00261] This example demonstrates the ability of the VSIV-G-blinded lentivirus fused or covalently linked to a CD3 targeting molecule to specifically infect CD3+ T cells in human peripheral blood mononuclear cells (PBMCs).

[00262] To test this in lentiviruses pseudotyped with VSIV-G blinded to LDLR fused to a CD3 targeting molecule, frozen human PBMCs from healthy volunteers were thawed and cultured in RPMI (ThermoFisher Sci., #A1049101) supplemented with 10% heat-inactivated fetal bovine serum (FBS) alone (Gibco) or with the cytokine interleukin 2 for T cell maintenance (50 ng / ml rhIL-2), or with the cytokines interleukin-7 (IL-7) and interleukin-15 (IL-15) for T cell activation (25 ng / ml rhIL-7 and 25 ng / ml rhIL-15). After 24 hours, PBMCs were seeded in 96-well plates at 105 cells per well in fresh medium with double the concentration of FBS and cytokines.PBMCs were then transduced with lentivirus containing a GFF expression cassette and pseudotyped with wild-type VSIV-G (G-WT) (SEQ ID NO: 21), VSIV-G-QQ (G-QQ) (SEQ ID NO: 25) or a 1:1 ratio of a recombinant fusion protein of the anti-CD3 scFvs UCHT1 (SEQ ID NOs: 45 and 46), TR66 (SEQ ID NOs: 41 and 42) or TR66opt (SEQ ID NOs: 43 and 44) ​​fused at the N-terminus to VSIV-G-QQ (SEQ ID NO: 25) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQ (SEQ ID NO: 25) (TR66opt) at a multiplicity of infection (MOI) of 10 (FIG. 12A) or an MOI of 100 (FIG. 12C). The final concentration of FBS and cytokines during infection was the same as in the original medium. Lentivirus titers were calculated based on ELISA for p24. Four days after transduction, transduction efficiency was measured based on GFP expression and analyzed in CD3-positive and negative PBMCs transduced at an MOI of 10 (FIG. 12B) or an MOI of 100. Petition 870250093142, dated 10 / 10 / 2025, p. 117 / 819 88 / 640 (FIG. 12D). These graphs showed that T cell activation increased the transduction efficiency of lentiviruses pseudotyped with VSIV-G (G-WT) (SEQ ID NO: 21) and that the G-WT pseudotyped lentivirus infected both CD3-positive and CD3-negative cells. In contrast, lentiviruses pseudotyped with the recombinant fusion protein of an anti-CD3 scFv fused to the N-terminus of VSIV-G-QQ (SEQ ID NO: 25) via an IgG1 ligand (SEQ ID NO: 175) infected only CD3-positive PBMCs (T cells), and this transduction efficiency was not affected by T cell activation.

[00263] Whole blood samples were collected from healthy human subjects. PBMCs were then isolated using density gradient medium with Ficoll. The collected PBMCs were washed with an appropriate buffer. PBMCs were then cultured in appropriate media containing hIL-2 for T cell maintenance or hIL-7 and hIL-15 for T cell activation. PBMCs were then infected with lentivirus pseudotyped with wild-type VSIV-G (G-WT) (SEQ ID NO: 21), K47Q+R354Q VSIV-G (G-QQ) substitution (SEQ ID NO: 25), K47Q+R354Q+Y209Q VSIV-G (GQQQ) substitution (SEQ ID NO: 26), or SpyTag K47Q+R354Q+Y209Q VSIV-G (ST-G-QQQ) substitution alone or linked to SpyCatcher (SEQ ID NO: 30) with UCHT1 targeting molecule (SEQ ID NOs: 45 and 46) (G-QQQ-ST-UCHT1), TR66-opt (SEQ ID NOs: 43 and 44) ​​(G-QQQ-ST-TR66-opt), or TR66 (SEQ ID NOs: 41 and 42) (GQQQ-ST-TR66) at a multiplicity of infection (MOI) of 5. Three days after infection, PBMCs cultured in media containing hIL-2 (FIG.Figs. 13A) or hIL-7 and hIL-15 (Fig. 13C) were subjected to flow analysis for human CD3 (hCD3), and the results were quantified (Figs. 13E). These results suggest that lentiviruses pseudotyped with G-WT (SEQ ID NO: 21) and, to a lesser extent, G-QQ (SEQ ID NO: 25) and G-QQQ (SEQ ID NO: 26) infected the majority of... Petition 870250093142, dated 10 / 10 / 2025, page 118 / 819 89 / 640 PBMCs, while those pseudotyped with G-QQQ-ST and a CD3 targeting molecule specifically infected T cells in PBMCs. This suggests that this system can be used in vivo to target specific cell populations, such as CD3-expressing T cells. Three days after infection, flow analysis for CD25 was performed on PBMCs cultured in media containing hIL-2 (FIG. 13B) and hIL-7 and hIL-15 (FIG. 13D), and the results were quantified (FIG. 13F). The increased percentage of CD25 in PBMCs infected with the lentivirus pseudotyped with VSIV-G-QQQ linked to a SpyCatcher with a CD3 targeting molecule, compared to the other PBMC samples, suggests that the transduced T cells are activated. Surprisingly, PBMCs transduced with lentivirus pseudotyped with VSIV-G-QQQ linked to a SpyCatcher with a target molecule against CD3 showed increased levels of CD25 compared to other PBMCs, even when cultured in media containing IL-2.These results suggest that the lentivirus pseudotyped with an anti-CD3 targeting molecule bound to VSIV-G-QQQ can induce T cell activation in the absence of activating cytokines and increase T cell activation in the presence of activating cytokines.

[00264] PBMCs from healthy volunteers were thawed and cultured in medium containing 10% heat-inactivated fetal bovine serum (FBS) alone or with 25% human serum and the cytokine interleukin-2 (50 ng / ml rhIL-2) for T cell maintenance (human serum) or with the cytokines interleukin-7 (IL-7) and interleukin-15 (IL-15) (25 ng / ml rhIL-7 and 25 ng / ml rhIL-15) for T cell activation (activated human serum cytokine). After 24 hours, the PBMCs were seeded in 96-well plates at 10⁵ cells per well in fresh medium with double the concentration of FBS and cytokines. The PBMCs were then transduced with lentivirus containing an expression cassette. Petition 870250093142, dated 10 / 10 / 2025, p. 119 / 819 90 / 640 GFP (SEQ ID NO: 176) and pseudotyped with wild-type VSIV-G (WT-G) (SEQ ID NO: 21), VSIV-G-QQ (G-QQ) (SEQ ID NO: 25) or recombinant TR66opt fusion protein (SEQ ID NOs: 45 and 46) N-terminally fused to VSIV-G-QQ (SEQ ID NO: 25) via an IgG1 ligand (SEQ ID NO: 175) made by the mixed envelope plasmid approach in a 1:1 or 1:6 ratio. Four days after transduction, PBMCs were analyzed by CELIGO imaging of GFP-positive cells (FIG. 14A) and GFP vs. CD3 intensity flow analysis (FIGs. 14B). These results showed that lentiviruses pseudotyped with a recombinant TR66opt fusion protein fused at the N-terminal to VSIV-G-QQ (SEQ ID NO: 25) via an IgG1 ligand (SEQ ID NO: 175) were resistant to human serum inactivation.These results suggest that these lentiviruses pseudotyped with an anti-CD3 scFv fused to a VSIV-G with reduced LDLR binding can be used to target CD3-expressing cells, such as T cells, in vivo, without being inactivated by serum. EXAMPLE 7

[00265] This example demonstrates the ability of lentivirus containing a plasmid encoding a VSIV-G blind LDLR pseudotyped αCD19-CAR with a CD3 targeting molecule to generate CAR-T cells in human peripheral blood mononuclear cells (PBMCs).

[00266] PBMCs were prepared as described above and then cultured in media without IL-2 or containing IL-2. The PBMCs were then transduced with lentivirus containing a plasmid encoding an αCD19-CAR (SEQ ID NO: 165) (FIG. 15A) pseudotyped with VSIV-G (G-WT) (SEQ ID NO: 21), or pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) (G-UCHT1) or a fusion protein Petition 870250093142, dated 10 / 10 / 2025, p. 120 / 819 91 / 640 recombinant scFv anti-CD3 TR66opt (SEQ ID NOs: 43 and 44) ​​(GTR66opt) N-terminally fused to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) ligand. CAR-T cells were identified by flow analysis of GFP and CD19 levels (FIG. 15B). Six days after transduction, lentivirus transduction efficiency was measured using flow analysis based on GFP expression and analyzed in CD3-positive and negative PBMCs cultured in media without IL-2 or containing IL-2 (FIG. 15C). These results showed that lentiviruses pseudotyped with G-UCHT1 or G-TR66opt were able to transduce cultured CD3-positive cells without cytokines or without activating cytokines, while lentiviruses pseudotyped only with VSIV-G (SEQ ID NO: 21) were not. Six days after transduction, T cell activation was measured using flow cytometry against CD25 and quantified as histograms (FIG. 15D).These results show that lentiviruses pseudotyped with G-UCHT1 or G-TR66opt are capable of activating T cells without any exogenous activating cytokines. The variation in the number of PBMCs on the sixth day after transduction was also measured (FIG. 15E). PBMCs without lentivirus or transduced with lentivirus pseudotyped with G-WT showed little change, while PBMCs transduced with lentivirus pseudotyped with G-UCHT1 or G-TR66opt showed a large increase in the number of cells. This suggests that T cells transduced by lentivirus pseudotyped with G-UCHT1 or G-TR66opt induce T cell proliferation, which would be beneficial for in vivo CAR-T applications. The levels of the cytokines interferon gamma (IFNy), tumor necrosis factor alpha (TNFα), and IL-2 were measured in the middle of the PBMCs 48 hours after transduction (FIG. 15F).These results show that IFNγ and TNFα levels increased in PBMCs cultured in media containing IL-2 and transduced with lentivirus pseudotyped with GPetition 870250093142, 10 / 10 / 2025, p. 121 / 819. 92 / 640 UCHT1 or G-TR66opt and IL-2 levels increased in PBMCs cultured in IL-2-free media and transduced with lentivirus pseudotyped with G-UCHT1 or G-TR66opt. None of the other PBMCs had media with high levels of these cytokines. These results suggest that T cells cultured in IL-2-free media transduced with lentivirus pseudotyped with G-UCHT1 or G-TR66opt begin to produce IL-2, and T cells cultured in IL-2-containing media become activated and begin to produce other cytokines, such as IFNγ and TNFα. This suggests that these lentiviruses would be able to transduce CD3-positive cells in vivo, even without activating the cytokines present in the serum. EXAMPLE 8

[00267] This example demonstrates the development of an expression vector encoding a chimeric antigen receptor (CAR) αCD19 and the generation of αCD19-CAR T cells via targeted administration of αCD19-CAR to CD3+ cells in whole human blood using VSIV-G blinded LDLR pseudotyped lentivirus with a CD3 targeting molecule.

[00268] The experiments were carried out as shown in Figure 16A. Whole blood samples were collected from healthy human subjects and immediately seeded and transduced with lentivirus containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with VSIV-G (SEQ ID NO: 21) or a lentivirus containing a plasmid encoding an αCD19-CAR (FIG. 16B) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) fused N-terminally to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) (G-CD3) ligand, and then incubated in a shaker for 6 hours at 120 rpm. Next, PBMCs were isolated from these transduced whole blood samples. Petition 870250093142, dated 10 / 10 / 2025, page 122 / 819 93 / 640 using density gradient medium with Ficoll. PBMCs were then cultured in IL-2-maintained T-cell medium and incubated for 4–7 days. GFP vs. CD3 flow analysis was performed on day 6 post-transduction (FIG. 16C). These dot plots showed that the G-CD3 pseudotyped lentivirus was able to transduce CD3-positive cells into whole human blood. This suggests that the G-CD3 pseudotyped lentivirus is resistant to serum inactivation and can target CD3-positive cells, such as T cells, in vivo. Additional CD8 vs. CD4 flow analyses were performed on day 6, followed by GFP vs. CD25 analysis to identify CAR-T CD8-positive and CAR-T CD4-positive cells (Fig. 16E).These results show that aCD19-CAR is expressed in both CD8-positive T cells, which are restricted to major histocompatibility complex 1 and associated with cytotoxic function, and CD4-positive T cells, which are restricted to major histocompatibility complex 2 and associated with auxiliary functions in the analyzed PBMCs. This suggests that a lentivirus containing a plasmid encoding a pseudotyped aCD19-CAR with the recombinant GCD3 fusion protein would be useful for in vivo applications in CAR-T cells. Flow analysis for CD25 levels was quantified 4 days after transduction and showed increased CD25 levels only in PBMCs transduced with the G-CD3 pseudotyped lentivirus (FIG. 16D). This result suggests that the G-CD3 pseudotyped lentivirus would be able to induce T cell activation in vivo, even in the absence of activating cytokines. EXAMPLE 9

[00269] This example demonstrates the effectiveness of CAR T cells generated in vivo in humanized mice.

[00270] Experiments to test the in vivo generation of CAR T cells in humanized mice were performed as shown Petition 870250093142, dated 10 / 10 / 2025, page 123 / 819 94 / 640 in Figure 17A. Humanized NSG mice with PBMCs were prepared so that more than 40% of their blood cells were positive for human CD45. The lentivirus was administered by intravenous (IV) injection into the caudal vein. Intravenous injection of saline solution was used as a negative control and 7,5e8 lentivirus particles containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (G-WT) (SEQ ID NO: 21) as a positive control or a 1:3 ratio of a recombinant scFv anti-CD3 TR66opt fusion protein (SEQ ID NOs: 43 and 44) ​​(GTR66opt) N-terminally fused to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) (G-TR66opt) was tested. Blood samples were collected periodically and subjected to FACS analysis to track the generation, phenotype, and persistence of CAR-T cells, and finally, samples of blood, spleen, bone marrow, and liver were collected.

[00271] GFP vs. CD3 flow analysis was performed on the blood of mice from the intravenous injection groups throughout the experiment, and a representative flow analysis is shown from day 39 post-injection (FIG. 17B). GFP-positive cells were quantified as a percentage of hCD45-positive cells (FIG. 17C). GFP vs. CD3 flow analysis was performed on mice from the intravenous injection groups throughout the experiment, and a representative flow analysis is shown from day 39 post-injection. GFP-positive cells were quantified as a percentage of hCD45-positive cells. These results showed that only the lentivirus containing a plasmid encoding an αCD19-CAR pseudotyped with G-TR66opt had more than 1% GFP-positive cells. This suggests that intravenous injection of G-TR66opt pseudotyped lentivirus was able to generate CAR-T cells in vivo. Petition 870250093142, dated 10 / 10 / 2025, page 124 / 819 95 / 640

[00272] CD19 vs. CD3 flow analysis was performed on the blood of mice from the intravenous injection groups throughout the experiment, and a representative flow analysis is shown from day 39 post-injection (FIG. 17D). The upper left quadrant indicates B cells and the lower right quadrant of the dot plot indicates T cells. CD19-positive B cells were quantified as a percentage of hCD45-positive cells (FIG. 17E). CD3-positive T cells were also quantified as a percentage of hCD45+ cells in the blood and showed that the percentage of CD3-positive T cells increased in all groups (FIG. 17F). These results showed that the appearance of αCD19-CAR-T cells in the blood coincided with the downregulation of endogenous CD19+ B cells, suggesting functional in vivo generation of CAR-T.

[00273] Flow analysis was performed on bone marrow, spleen, and liver of mice from groups IV 39 days after IV injection for GFP vs CD3 to measure αCD19-CAR T cell levels (FIG. 17G) and for CD19 vs. CD3 to measure levels of endogenous human B cells (CD19-positive cell levels (FIG. 17H)). CAR-T cells generated in vivo accompanied by the absence or reduction of CD19+ B cells were observed in all tissue samples from mice transduced with the lentivirus containing a plasmid encoding the G-TR66opt pseudotyped αCD19-CAR. No CAR-T cell generation was detected at any time in mice injected with lentivirus containing a plasmid encoding the VSIV-G pseudotyped αCD19-CAR. These results suggest that lentivirus containing a plasmid encoding the G-TR66opt pseudotyped αCD19-CAR can be used to generate CART cells in vivo that would have systemic circulation.

[00274] Additional experiments to test the generation of CAR T cells in vivo in humanized mice were performed, such as Petition 870250093142, dated 10 / 10 / 2025, page 125 / 819 96 / 640 shown in Figure 17I. Humanized NSG mice with PBMCs were prepared so that more than 40% of their blood cells were positive for human CD45. The lentivirus was administered by intravenous (IV) injection into the tail vein or by intraperitoneal (IP) injection.Intraperitoneal (IP) injection of saline solution was used as a negative control, and IP administration of 1.5 x 10⁹ lentivirus particles containing a plasmid encoding aCD19CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (SEQ ID NO: 21) (G-WT-CAR / GFP) or a 1:3 ratio of a recombinant scFv anti-CD3 TR66opt fusion protein (SEQ ID NOs: 43 and 44) ​​N-terminally fused to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) ligand (GCD3-CAR / GFP) or IP administration of 1.5 x 10⁹ or IV administration of 3.58 x 10⁹ lentivirus particles containing a GFP expression cassette (SEQ ID NO: 176) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) N-terminally fused to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) (G-CD3-GFP) ligand was tested.Blood samples were collected periodically and subjected to FACS analysis to track the generation, phenotype, and persistence of CAR-T cells.

[00275] GFP vs. CD3 flow analysis was performed on the blood of mice from each treatment group throughout the experiment, and a representative flow analysis is shown from day 24 post-injection (FIG. 17J). GFP-positive cells were quantified as a percentage of hCD45-positive cells (FIG. 17K). These results showed that only the lentivirus containing a plasmid encoding an aCD19-CAR pseudotyped with G-TR66opt presented GFP-positive cells. This suggests that IP injection of the G-TR66opt pseudotyped lentivirus was able to ge Petition 870250093142, dated 10 / 10 / 2025, page 126 / 819 97 / 640 rar CAR-T cells in vivo.

[00276] CD19 vs. CD3 flow analysis was performed on the blood of mice from each group throughout the experiment, and a representative flow analysis is shown from day 24 after saline and G-CD3-CAR / GFP injection (FIG. 17L). The upper left quadrant indicates B cells and the lower right quadrant of the dot plot indicates T cells. CD19-positive B cells were quantified as a percentage of hCD45-positive cells (FIG. 17M). CD3-positive T cells were also quantified as a percentage of hCD45+ cells in the blood, and showed that the percentage of CD3-positive T cells increased in all groups (FIG. 17N). These results showed that the appearance of αCD19-CAR-T T cells in the blood coincided with the downregulation of endogenous CD19+ B cells, suggesting functional in vivo generation of CAR-T. EXAMPLE 10

[00277] This example demonstrates the effectiveness of CAR-T cells generated in vivo in humanized mice bearing tumors.

[00278] To test the ability of in vivo generated CAR-T cells to treat tumors in humanized mice, experiments were performed as shown in Figure 18A. NSG mice were implanted with a tumor by intravenous injection of 5 x 10⁵ Nalm6 cells expressing firefly luciferase (Fluc) into the caudal vein. The mice were humanized by intraperitoneal injection of 1.5 x 10⁷ human PBMCs on day 3 or day 10 after tumor implantation. Four hours after PBMC injection, the mice were infected with 3 x 10⁹ lentivirus particles containing a plasmid encoding an aCD19-CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (SEQ ID NO: 21) (G-WT-CAR / GFP) or a lentivirus containing a plasmid encoding an aCD19-CAR (SEQ ID NO: Petition 870250093142, dated 10 / 10 / 2025, page 127 / 819 98 / 640 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) N-terminally fused to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) ligand (G-aCD3CART). Mice underwent weekly IVIS imaging and had blood samples collected for weekly flow cytometry analysis.

[00279] GFP vs. CD3 flow analysis was performed on the blood of mice from the lentivirus injection groups on day 3 and day 10, with representative scatter plots shown for days 16 and 23 after tumor implantation (FIG. 18B). The number of GFP-positive T cells per μL of blood (FIG. 18C) and the percentage of hCD45+ cells that were CAR-T cells (FIG. 18D) were also quantified. These results show that both mice from the infection groups on day 3 and day 10 generated CAR-T cells in vivo. CAR-T cells in the blood show increased levels earlier in the infection group on day 3, peaking on day 30, and later in the infection group on day 10, peaking on day 37.The percentage of hCD45-positive cells that were CAR-T cells was approximately 10% in the infection group on day 3 at day 16 after tumor implantation and continued to decrease, while in the infection group on day 10 the percentage started at approximately 0 on day 16, increasing to a peak of approximately 40% on day 30 before decreasing to approximately 10% on day 37. These results suggest that the CAR-T cells generated in vivo by these lentiviruses are transient. Additional CAR-T cell flow analyses were performed on the blood of mice from the infection group on day 10 to quantify the number of CD8 CAR-T cells vs. CD4 CAR-T cells (FIG. 18E). Both CD4 and CD8 CAR-T cells were observed, but the majority of CAR-T cells observed were CD8 CAR-T cells, which are associated with... Petition 870250093142, dated 10 / 10 / 2025, page 128 / 819 99 / 640 cytotoxic functions. Levels of human interferon gamma (hIFNγ) cytokine in the blood of mice from the day 3 and day 10 groups were also measured on days 16 and 23 after tumor implantation (FIG. 18F). The day 3 and day 10 infection groups showed low hIFNγ levels on day 16 and increased levels on day 23, although levels increased much more in the day 10 infection group. IVIS images were obtained weekly to monitor the growth of Nalm6-Fluc tumors (FIG. 18G). In the saline-treated group, tumor fluorescence was detectable in all mice on day 16 after tumor implantation and increased until the mice died. Tumor fluorescence was detected on day 16 in the day 10 infection group but decreased on day 23 and was not observed on day 30 or later. In the day 3 infection group, tumor fluorescence was never observed.These results suggest that lentivirus containing a plasmid encoding an αCD19CAR pseudotyped with the recombinant G-aCD3 fusion protein generates CAR-T cells in vivo that treat or prevent the formation of Nalm6 tumors. Without wanting to limit ourselves to theory, these results suggest that most of the CAR-T cells generated in vivo are CD8 CAR-T cells that use their cytotoxic functions to eliminate Nalm6 cancerous cells. The timing of tumor growth and elimination in the day 10 infection group also suggests that blood levels of CAR-T cells in vivo increase during tumor treatment and decrease after tumor destruction. The percent change in body weight (FIG. 18H) and survival rate (FIG. 18I) were quantified for each treatment group. Although all mice treated with saline solution died at the end of the experiment, all but one of the mice in the lentivirus-treated groups survived.None of the mice treated with lentivirus showed negative effects on the percentage change in weight. Petition 870250093142, dated 10 / 10 / 2025, page 129 / 819 100 / 640 so corporal. These results suggest that CAR-T cells generated in vivo by lentivirus have no negative impacts on health and increased the survival rate of mice bearing the Nalm6 tumor by up to 80% to 100%.

[00280] Further experiments were conducted to test the efficacy of a lentivirus containing a plasmid encoding an αCD19-CAR pseudotyped with recombinant anti-CD3 scFv UCHT1 fusion protein fused N-terminally to VSIV-G with a deletion at residue K47 (VSIV-G-ΔK47) (SEQ ID NO: 27) or Vesiculovirus newjersey G glycoprotein with a deletion at residue K47 (VSNJV-G-ΔK47) (SEQ ID NO: 29) via an IgG1 ligand (SEQ ID NO: 175), as shown in Figure 1A. NSG / KO MHC-I / II mice were implanted with a tumor by intravenous injection of 5 x 10⁵ Nalm6Fluc cells into the tail vein. Nine days later, the mice were humanized by injection of 6 x 10⁶ human PBMCs via intraperitoneal injection (IP).Twenty-four hours later, the mice received 0.2 mL of saline solution (Group 1) or 0.2 mL containing 1.16 x 10⁹ lentiviral particles containing a plasmid encoding an αCD19-CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (SEQ ID NO: 21) (Group 2, G-WT / IV), 6.92 x 10⁹ lentiviral particles containing a plasmid encoding an αCD19CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) N-terminally fused to VSIV-G with a deletion at residue K47 (VSIV-G-ΔK47) (SEQ ID NO: 27) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-ΔK47 (SEQ ID NO: 27) (Group 3, GCD3 / IV), or 1.33 x1010 lentiviral particles containing a plasmid encoding an αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv antiCD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) N-terminally fused to Vesiculovirus newjersey G glycoprotein with a deletion at residue K47. Petition 870250093142, dated 10 / 10 / 2025, p. 130 / 819 101 / 640 (VSNJV-G-ΔK47) (SEQ ID NO: 29) via IgG1 ligand (SEQ ID NO: 175) and VSNJV-G-ΔK47 (SEQ ID NO: 29) (Group 5 G-CD3NJ / IV) via IP injection or 0.85 mL of 2.94 x1010 lentiviral particles containing the αCD19-CAR encoding plasmid (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) N-terminally fused to VSIV-G with a deletion at residue K47 (VSIV-GΔK47) (SEQ ID NO: 27) via IgG1 ligand (SEQ ID NO: 175) and VSIV-G-ΔK47 (SEQ ID NO: 27) (Group 4, G-CD3 / IP). Mice underwent weekly IVIS imaging and had blood samples collected for weekly flow cytometry analysis.

[00281] The average number of human CD45-positive (hCD45+) cells per μL of blood from humanized mice implanted with Nalm6-Fluc tumors at various days post-implantation (Days PI) was quantified for each group (FIG. 19B). The same measurements are shown for individual mice in each group on day 8 (left graph) and for individual mice in group 1 throughout treatment. These results show that human PBMCs are present in the blood of all treatment groups and increase over time for most groups. The increase in group 3 and group 4 appears to be correlated with increased tumor growth. The number of GFP-positive cells per μL of blood was quantified for all groups (FIG. 19D), and for groups 3 and 4 the number of CD4 and CD8 GFP-positive cells was subsequently quantified (FIG. 19E). These results suggest that groups 3, 4, and 5 generated CAR-T cells in vivo.The increase in the number of CAR-T cells in group 3 on day 15 and in group 4 on days 22 and 29 appears to correlate with peaks in tumor growth. This suggests that CAR-T cells generated in vivo increase in the bloodstream. Petition 870250093142, dated 10 / 10 / 2025, p. 131 / 819 102 / 640 guinea during tumor treatment and decrease after tumor elimination. The levels of the cytokines IL-2 (FIG. 19G), TNFα (FIG. 19H), and IFNγ (FIG. 19I) were measured in the blood of groups 1, 2, 3, and 4. Group 3 showed increased levels of TNFα and IFNγ on days 23 and 37, and group 4 showed increased levels of IL-2, TNFα, and IFNγ on day 7, while the other groups did not show similar increases in cytokine levels. These results suggest that as the levels of in vivo-generated CAR-T cells increase in the blood, the levels of cytokines such as TNFα and IFNγ also increase in the blood.

[00282] IVIS images were taken weekly to monitor the growth of Nalm6-Fluc tumors (FIG. 19J). All groups showed detectable levels of Nalm6 tumors on day 8 after treatment. Mice in group 4 showed almost complete tumor clearance on day 15 after treatment, while mice in groups 3 and 5 showed increasing levels of bioluminescence until day 29, with decreasing levels from day 36 until the end of the experiment. Mice in groups 1 and 2 showed increasing tumor levels and all died before the end of the experiment. These results suggest that in vivo CAR-T cells generated by lentivirus increase with tumor growth and destroy or reduce tumor levels. Tumor burden was measured on day 0 (FIG. 19K) and throughout the experiment (FIG. 19L) as total flux (p / s).These results show that all groups started with approximately the same tumor burden on day 0, but then increased in all groups initially, before decreasing in group 4 on day 15 and decreasing in groups 3 and 5 on day 36. A more in-depth analysis of tumor growth in groups 3, 4, and 5 was quantified from IVIS images on days 43 to 57 (FIG. 19M), using data from dorsal and ventral views (FIG. 19N). These results do not show... Petition 870250093142, dated 10 / 10 / 2025, page 132 / 819 103 / 640 showed tumor growth in group 4.

[00283] Flow analysis was performed on bone marrow, spleen, and liver of mice from groups 1 to 5 on day 16 (GFP vs. CD3) to measure the levels of αCD19 CAR T cells (FIG. 19O) and quantified on a bar graph (FIG. 19P). Group 4 showed the highest levels of CAR T cells on day 16, with groups 3 and 5 showing low, but detectable, levels of CAR T cells on day 16 as well. Groups 1 and 2 did not show detectable CAR T cells on day 16. These results suggest that groups 3, 4, and 5 generated CAR T cells in vivo and that these CAR T cells have systemic circulation. Flow analysis of blood samples on day 36 was performed for GFP vs. CD19 to identify CAR T cells. Groups 3, 4, and 5 presented identifiable CAR-T positive cells (upper right quadrant), suggesting that GFP expression correlated with CD19-CAR expression in vivo.

[00284] CAR-T cells were subsequently studied by flow analysis for GFP vs. CD19, followed by flow analysis for CD62L vs. CD45RA, in order to identify different T cell populations observed on day 36 (FIGs. 19R-19U). The CD62L vs. CD45RA dot plots show CD3+ core memory T cells (Tcm) (upper left quadrant), CD3+ effector memory T cells (Tem) (lower left quadrant), CD3+ effector T cells (Teff) (lower right quadrant), and naive / stem cell-like T cells (upper right quadrant). The percentage of stem cell-like T cells that were CAR-T cells or non-CAR-T cells was quantified as a percentage of the total human T cells (FIG. 19V). These results show that group 4 has the highest percentage of CAR-T stem cell-like T cells, approximately 13%, with groups 3 and 5 showing approximately 5% CAR-T stem cells and groups 1 and 2 Petition 870250093142, dated 10 / 10 / 2025, page 133 / 819 104 / 640 showing 0%. These results suggest that mice from groups 3 to 5 with stem cell-like CAR-T cells will retain the ability to generate CAR-T cells, since CAR-T cells are long-lived. After the study, some of the surviving mice from groups 3 to 5 were challenged with additional tumor implants and no tumor growth was observed (data not shown). After collecting animal tissue from these mice, stem cell-like CAR-T cells were detected. These results suggest that this system can generate long-lived stem cell-like CAR-T cells in vivo and prevent tumor regrowth recurrence. EXAMPLE 11

[00285] This example further demonstrates the effectiveness of CAR-T cells generated in vivo in humanized mice.

[00286] Experiments to further test the in vivo generation of CAR T cells in humanized NSG mice with PBMCs were prepared so that more than 40% of their blood cells were positive for human CD45. The lentivirus was administered by intravenous injection into the tail vein or by intraperitoneal injection.Humanized mice were administered via IP injection with either 1.5 x 10⁹ lentivirus particles containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) (UCHT-CAR19 IP Group), or scFv anti-CD3 TR66opt (SEQ ID NOs: 43 and 44) ​​(TR66optCAR19 IP), fused at the N-terminus to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) ligand, or a lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:6:1 ratio of a recombinant scFv anti-CD3 fusion protein. Petition 870250093142, dated 10 / 10 / 2025, page 134 / 819 105 / 640 TR66opt (SEQ ID NOs: 43 and 44) ​​N-terminally fused to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175), VSIV-G-QQQ (SEQ ID NO: 26) and a recombinant human CD80 fusion protein (HuCD80-G-QQ), or administered by intravenous injection with 7.5 x 10⁸ lentivirus particles containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv antiCD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) N-terminally fused to VSIV-GQQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) (UCHT-CAR19 IV). Blood samples were collected periodically and subjected to FACS analysis to track the generation, phenotype, and persistence of CAR-T cells, and finally, samples of blood, spleen, bone marrow, and liver were collected.

[00287] GFP vs. CD3 flow analysis was performed on the blood of mice from each group throughout the experiment, and representative flow analyses are shown on days 14 and 21 after injection (FIG. 20A). GFP-positive cells were quantified as a percentage of hCD45-positive cells (FIG. 20B). These results showed that only mice that received an IP injection of the UCHT-CAR19 lentivirus exhibited increased levels of GFP-positive cells. These results showed that IP injection of the UCHT-CAR19 lentivirus generated more CAR-T cells than IV injection with the same virus. These results also suggest that the addition of HuCD80, which contributes to T cell activation, did not provide any increase in T cell activation in these experiments. This suggests that this system can generate activated CAR-T cells in vivo without the need for any additional T cell activation factors.

[00288] CD19 vs CD3 flow analysis was also performed Petition 870250093142, dated 10 / 10 / 2025, page 135 / 819 106 / 640 in the blood of mice throughout the experiment, and representative flow analyses are shown on days 14 and 21 post-injection (FIG. 20C). The upper left quadrant indicates B cells and the lower right quadrant of the scatter plot indicates T cells. CD19+ B cells were quantified as a percentage of hCD45-positive cells (FIG. 20D). These results showed that mice receiving an IP injection of the UCHTCAR19 lentivirus exhibited a greater decrease in CD19+ B cells in the blood than any other group, and this decrease coincided with increased levels of CAR-T cells. These results also showed no further decrease in CD19+ B cells in the group that received HuCD80, suggesting that the addition of T cell activation factors is not necessary for T cell activation in this system. EXAMPLE 12

[00289] This example demonstrates the safety of CAR-T cells generated in vivo in fully immunocompetent transgenic mice for the γ, δ and ε subunits of human CD3 (GDE mice).

[00290] To test the cytotoxicity of lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with VSIV-G (G-WT LV) or a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) N-terminally fused to VSIV-G-QQQ (SEQ ID NO: 26) via an IgG1 ligand (SEQ ID NO: 175) and VSIV-G-QQQ (SEQ ID NO: 26) (GCD3 LV) in mouse CD3-expressing GDE and KaLwRij mice, intravenous injections of 1.16 x109 G-WT lentiviral particles or 4.78 x109 G-CD3 lentiviral particles were administered. Blood samples were collected from GDE mice before lentivirus injection and 3, 6, and 24 hours after LV injection, according to the Petition 870250093142, dated 10 / 10 / 2025, page 136 / 819 107 / 640 experimental design (FIG. 21).

[00291] Mouse CD3 vs. human CD3 flow analysis was performed on blood samples from GDE and KaLwRij mice (FIG. 22A). These results showed that only human CD3-positive cells were detected in the blood of GDE mice and only mouse CD3-positive cells were detected in the blood of KaLwRij mice. Mouse CD69 vs. mouse CD25 flow analysis was also performed to measure T cell activation (FIG. 22B). Flow analysis showed increased levels of CD69 expression at 3, 6, and 24 hours after LV injection. Cytokine levels of interleukin 6 (IL6), TNFα, IFNγ, IL2, interleukin 4 (IL4), and macrophage inflammatory protein 1 alpha (MIP1α) were also measured in the blood, as shown in Table 8 below (ND indicates that a cytokine was not detected). No significant changes were observed in the levels of any of the cytokines.These results showed no observable cytotoxicity from the LV injection in GDE mice. These results suggest that this system would likely not induce cytotoxicity in humans and would be safe for human use. Table 8 Plasma cytokines, pg / ml IL6 TNFα IFNY IL2 IL4 MIP1a No treatment ND ND ND ND 121.1 ND No treatment ND ND ND ND 186.7 ND G-WT M1 3hpi 38.1 ND 7.7 ND 252.1 2.05 G-WT M2 6hpi ND ND ND ND 110.2 ND G-WT M1 24hpi ND ND ND ND 121.1 1.44 G-WT M2 24hpi ND ND ND ND 143.0 2.05 Petition 870250093142, dated 10 / 10 / 2025, page 137 / 819 108 / 640 Plasma cytokines, pg / ml IL6 TNFα ifny IL2 IL4 MIP1α G-CD3 M3 3hpi 52.1 5.7 18.3 4.9 230.3 3.25 G-CD3 M4 6hpi ND 4.5 18.3 ND 252.1 ND G-CD3 M3 24hpi ND ND 7.7 ND 99.2 1.44 G-CD3 M4 24hpi ND ND ND ND 164.9 ND Minimum detection level 16.03 1.17 7.72 4.93 32.90 0.98

[00292] To also test the safety of this lentivirus system in GDE mice, an experiment was performed as shown in Figure 23A. GDE mice were injected with a lentivirus containing a plasmid encoding αCD19-CAR (SEQ ID NO: 165) pseudotyped with a 1:3 ratio of a recombinant scFv anti-CD3 UCHT1 fusion protein (SEQ ID NOs: 45 and 46) fused N-terminally to VSNJV-G-ΔK47 (SEQ ID NO: 29) via an IgG1 (SEQ ID NO: 175) and VSNJV-G-ΔK47 (SEQ ID NO: 29) ligand at a dose of 2 mL containing 1.33 x10¹⁰ lentiviral particles per IV injection (Group 1) or 8.5 mL containing 5.66 x10¹⁰ per IP injection (Group 2). Blood samples were collected 2 hours and 4 days after injection. Body weight was also measured on the day of injection and 3 and 4 days after injection.

[00293] Flux analysis of CD69 in mice versus CD25 in mice was performed to measure T cell activation (FIG. 23B). Flux analysis showed only upregulation in CD69 expression 2 hours after injection into the LV. Cytokine levels of IL6, TNFα, IFNγ, IL2, IL4, and MIP1α were also measured in the blood, as shown in Table 9 below (ND indicates that no cytokines were detected). No significant changes were observed in the levels of any of the cytokines. These results showed no observable cytotoxicity from injection into the LV in GDE mice. A Petition 870250093142, dated 10 / 10 / 2025, page 138 / 819 A 109 / 640 percent change in body weight after lentivirus injection was calculated for mice in group 1 and group 2 (FIG. 23C). No significant percent change in body weight was observed. These results suggest that this system would likely not induce cytotoxicity in humans and would be safe for human use. Table 9 Cytokines, pg / ml Treatment Group Blood Collection Route of administration of LV IL6 TNF α IFN γ IL2 IL4 MIP1 α Naive GDE without injection NA ND ND ND ND 212.2± 14.6 ND 1 GDE treated 2hpi IV ND ND ND ND 205.3± 12.0 ND 2 GDE treated 2hpi IP ND ND ND ND 207.0± 9.0 ND 1 GDE treated 4dpi IV 52.5±2 6.1 ND ND ND 194.9± 15.8 ND 2 GDE treated 4dpi IP 40.4±1 8.1 ND ND ND 194.9± 21.6 ND SEQUENCES SEQ ID NO Name Sequence 1 SpyTag001 AHIVMVDAYKPTK 2 SpyTag002 VPTIVMVDAYKRYK 3 SpyTag003 RGVPHIVMVDAYKRYK 4 Isopeptag TDKDMTITFTNKKDAE 5 SnoopTag KLGDIEFIK6rVDAYKRYK KLGSIEFIKVNK 7 DogTag DIPATYEFTDGKHYITNEPIPPK 8 ST ligand 1 GLSSGSG 9 ST ligand 2 GLSGLSGS 10 ST ligand 3 GLSGLSGLSG Petition 870250093142, of 10 / 10 / 2025, p. 139 / 819 110 / 640 SEQ ID NO Sequence Name 11 ST 4 Ligand GLSGGSGLSG 12 Flexible 6aa Ligand GSGGSG 13 FLAV-G WTHDSGRSFVRQYHDPSWFDQTMVYP IECNSTWQEVNTLNLRCPKSLKIDPKNK LNFELGTVYHPLPSSRYVVNGYICHKQT WISKCEETWYFSTTETNKIENVPITPEDC REAVTIYEMGEYVNPFFPPFYCSWCST QIDKKTFVIVEPHIVKEDIYNKTFIDPLFLN GYCDQLPCKTIHPDVLWVPQELQKRKD LCNKGTWETGKVFGVLEEKLYQNGYSK DNRFGIDEQWIRSSIYGLRSLVGSCYRG VCQQFGIRFKTGEWWGLEGKDVTVWIK RIIPKCQESQYVSFHHDNSDENIAEAQL VARELVCEEFLGRAKGGDLISPFDLNYL LPLNPGLGPSYRAFKRILKRDSHGGSSP QFRLEKRDCIYSIVHNVTEKVNITNNKLAI GQLFDGSYVYINESEFSRPDYLNNSDNA SRDGWFLLSLNGMIKYGNSVYLPHGVS TGLSGIQDIVERGTLMLLDHPKSIAISNQ MDLAKNIYTSYFQMNTTSIGSKIENMIIRA KNAVSSYFSQLTNIAWWIGTGILGLLGFI VIKRFHLIQLICGKKHRNGKIKKKNNKLN NGDQEAHVYDTISNTPKTPPHGKGTGV KYFDY 14 CHPV-G SLSIAFPENTKLDWKPVTKNTRYCPMG GEWFLEPGLQEESFLSSSTPIGATPSKSD GFLCHAAKWVTTCDFRWYGPKYITHSIH NIKPTRSDCDTALASYKSGTLVSPGFPP ESCGYASVTDSEFLVIMITPHHVGVDDY RGHWVDPLFVGGECDQSYCDTIHNSSV WIPADQTKKNICGQSFTPLTVTVAYDKT KEIAAGAIVFKSKYHSHMEGARTCRLSY CGRNGIKFPNGEWVSLDVKTKIQEKPLLPLFKECPAGTEVRSTLQSDGAQVLTSEI Petition 870250093142, dated 10 / 10 / 2025, page 140 / 819 111 / 640 SEQ ID NO Nome Sequência QRILDYSLCQNTWDKVERKEPLSPLDLS YLASKSPGKGLAYTVINGTLSFAHTRYV RMWIDGPVLKEMKGKRESPSGISSDIW TQWFKYGDMEIGPNGLLKTAGGYKFPW HLIGMGIVDNELHELSEANPLDHPQLPH AQSIADDSEEIFFGDTGVSKNPVELVTG WFTSWKESLAAGVVLILVVVLIYGVLRCF PVLCTTCRKPKWKKGVERSDSFEMRIF KPNNMRARV 15 PERV-G SFQIVFPEFNNAAWLPYLKTSRYCPQSA EMEFERRVSTTLLSADVPIGVTPTKSDG YLCHAAKWVTTCDFRWYGPKYVTHSIH DLTPAQVDCHEALARYKAGTLFNPGFP PASCGYATITDSEQKVVMITPHHVGIDD YRGKWIDPIFPGGECTTNYCETLHNSSV WLPADEKIVDICAQTFRKIKVTATYPSEG AVTKETISLHSAYHPHVPGTGICRMTYC SKEGLRLPNGEWLGIFYDNRIKTTDVRT VFPACPDGLEVKSTLNSDGANTIAWETQ RMLDYALCQSTWDKVQNKEPLSAVDLS YLSARSPGKGLAYTVINGTLHFAHVRYV RTWIDGPVLKDLKGSRFDPTAAQKTLW DQWFPFGSNEIGPNGLLKTPKDFKFPLY IIGTGLVDEDLQELSEAGPIDHPQIPDAS GILPNSEQVYYGDTGVSKNPIELIEGWF ANWKETVMSIVGLVLLITIVFTVLKCIGTC RSLRRKRKIEKDIELQEIGPYQPTTYRPR 16 PIRYV-G KFQIVFPDQNELEWRPVVGDSRHCPQS SEMQFDGSRSQTILTGKAPVGITPSKSD GFICHAAKWVTTCDFRWYGPKYITHSIH HLRPTTSDCETALQRYKDGSLINLGFPP ESCGYATVTDSEAMLVQVTPHHVGVDD YRGHWIDPLFPGGECSTNFCDTVHNSSVWIPKSQKTDICAQSFKNIKMTASYPSE GALVSDRFAFHSAYHPNMPGSTVCIMD Petition 870250093142, dated 10 / 10 / 2025, page 141 / 819 112 / 640 SEQ ID NO Nome Sequência FCEQKGLRFTNGEWMGLNVEQSIREKK ISAIFPNCVAGTEIRATLESEGARTLTWE TQRMLDYSLCQNTWDKVSRKEPLSPLD LSYLSPRAPGKGMAYTVINGTLHSAHAK YIRTWIDYGEMKEIKGGRGEYSKAPELL WSQWFDFGPFKIGPNGLLHTGKTFKFP LYLIGAGIIDEDLHELDEAAPIDHPQMPD AKSVLPEDEEIFFGDTGVSKNPIELIQGW FSNWRESVMAIVGIVLLIVVTFLAIKTVR VLNCLWRPRKKRIVRQEVDVESRLNHF EMRGFPEYVKR 17 FUKV-G QQDYSYGGKTKDIIGLLPQDKKLHWKTT KLDSIKCPEMGLISNKEEHVVEKWLIERP RTTGKLRNKGKLCHLAKWITKCEYTWY FSKTVSRTIQNLEAHEDDCKQAIREYNQ GKLIPGSFPPESCYWASTNEESVIAHIIT PHEVTYDPYEDRYLDPLFVHGFCRTSF CETVYESTVWLTDSPGRQSSCKLEGDE PVEVLESYRHNKAGESKFGFWMRGSHI HHMPLSRLCKKEYCGKLGYVNQQGVW FHVTSVQWSYNESISFRHVVENCTESP DLVVLSEEFNDDDLAATLEEMMWDINCL NAVENIQKHKRASLHDLYQISQRHPGPG TAYRLKDGHLESAQANFVALYAPDEHE QNRECLGTVLDHTGDQCHAWDDWTHI ANSTYHAVNGITEVDGKIVFPEYRVLKR RWDLEYSLKHDLRQINHPVISDFVGKVH ENIVHKEIKSHSVNAGDLIGNWVTVAES KIGEFFKGFSHSFVTISVFLMVVLTIWIIIR CCQMCKREKPTKIISAKDDIPMVTSSFG 18 JOIV-G ILWDFRINRLVRNKRKTQKTKLDQIGNG VVIQPIDPKEVHYNIVKPSIQIKNQSHPVI EIDDQKEPELKLEDFDWVSGNEFEGVVNMPVNCLTNWKVINPYAIRCPTFYEHDR YGGGRTVIGTAVHPEEIEHNIIPGFMCQK Petition 870250093142, dated 10 / 10 / 2025, page 142 / 819 113 / 640 SEQ ID NO Nome Sequência QTWVTECTEAWYWSTTVKNYVESSPV VEMECLMALAKEKVGTYVDPFFPPAEC AWNANSRSSKEFVTLHPHDVRFDFYQY SKVDPLFVGGKCNEKSCPTIHQHVIWIG KNPVPLEGTCNLDRWRQSDIFALETHTS EKKVSDKVTIYLEFIESATYGMRSTKNAC WTRFCDVPGIRFNDGEWWGIKSGHNV ALDFLPECGKKSLITLHHAVNQDSEFKN RLSLKHYKCTEVLTKLISGSVITPMDISYL ISDRPGLQSYYRFSAKQKGNGPVMGGG NNYMIEQKECMYQFVLLESDRFNITKQS DQINVGMTLQGDHIYINLTDFQHTKGNK SNDINRFTMTVNGYLKTGNVLVLPVDEIT SESVDNTLYTPIGYHLIEEEEIGNYTTIGD AIEKILILDPRLNRTDIVEETVHFVNNIGKT VSSFFQGTSSLLWWGVTSVFFLVIVLLM RKCGVIDWLLKKKKPKSVERMNKYNSE SNRMVDNKTSHGNVNGGFFGNV 19 KRV-G DGTPAPVVKNETGDFLWGLGTELILPVE VISKWVEINPEDMRCPSDPVTDHVIGAIV GHTRFSRYSGFHKATQKGFLCHKMRWI TAC1 1 1 WYFSHDVQRRVEAQEPGTQEC LDQVKKRGEGTEEEGSYPPSQCAWNS VNEEAEVVIHLTVHEVRVDPYTMELLDP VFPSGRCNTTACDTVHQSVLWIEDPSK TRPSCGDRVVDEGNIIRSGWTDNVPGA YYLISQHLPPTKIDGACRLSFCGESGLLF ENGIWTHDIKLETVVANQTFQNCQADR RAGAVGPTYEIDKLRFDWEAAKEKIKCL DMIEIISATGALSFRRLHHFNPRTPGIHP VYRIVN KTLQMAKAHYVVTN NPMSHKG TRDCLGTYMDHDTRKCVAWHHWVDVG NGTEQGPNGLLVTGDKVSYPHWFIREKTWDPALHIINYLQNADHPIVSHLGRYIDN ASRDSLRKDRSENVGDAASAAVTKLAG Petition 870250093142, dated 10 / 10 / 2025, page 143 / 819 114 / 640 SEQ ID NO NAME SEQUêNCIA SIGGVFKDVWHVITTCVTVGVIIIIILIFRR MIGVFWRGREKHPLPKTPNNIYQETHEL KSFG 20 KEUV-G YPIEDQMTIPLKPGIHRTLDGDLDYNDDE HYHSPPLVLPVPNNRSWKPVNLSTLKC PESSHLGPDTHRTLEKWLIFRPKSSILTK IEGVLCHKSRWLTRCQYTWYFSKTISRK IEPIPPTFQECQEAIKLKEEGILENLGFPP PNCYWARTNDEENILIEISEHPMTYDPYL DGVIDSILVGGKCSQKECETVHDSTIWIE TQRDTRPSQCDMGTEEQLELVSGLKQI DGNKQKYQHSVFVVGTNYPFMDAKGA CKLRFCGKSGMLLSNGLWFNIAHTILPK PEANSNFWSALPDCSSDKQVGVLGEEY EIEKLQATMEDIMWDLDCFRTVDSLAHH KKVSMLDLFRLAKLTPGPGPAYKLIEGTL MMKEVQYVKARRDTKEQANPLCAAYIT ESTSNQERCIDYSNYDQNGTYKGQVMN GILVTDGVLIFPHERFHLRQWDPEFIIKH DLQQVHHPVIGNFSKKLHDSIHNSLIKDH SANLGDVMGNWVKVAASKVSGFFKEIE KFLIGLLLVVILLMVGLLCKCKCRRKPK AKNLKANSSGDEMSPNESIF 21 VSIV-G KFTIVFPHNQKGNWKNVPSNYHYCPSS SDLNWHNDLIGTAJQVKMPKSHKAIQAD GWMCHASKWVTTCCDFRWYGPKYITHSI RSFTPSVEQCKESIEQTKQGTWLNPGF PPQSCGYATVTDAEAVIVQVTPHHVLVD EYTGEWVDSQFINGKCSNYICPTVHNST TWHSDYKVKGLCDSNLISMDITFFSEDG ELSSLGKEGTGFRSNYFAYETGGKACK MQYCKHWGVRLPSGVWFEMADKDLFA AARFPECPEGSSISAPSQTSVDVSLIQD VERILDYSLCQETWSKIRAGLPISPVDLSYLAPKNPGTGPAFTIINGTLKYFETRYIR Petition 870250093142, of 10 / 10 / 2025, p. 144 / 819 115 / 640 SEQ ID NO Name Sequence VDIAAPILSRMVGMISGI 1 IERELWDDW APYEDVEIGPNGVLRTSSGYKFPLYMIG HGMLDSDLHLSSKAQVFEHPHIQDAAS QLPDDESLFFGDTGLSKNPIELVEGWFS SWKSSIASFFFIIGLIIGLFLVLRVGIHLCIK LKHTKKRQIYTDIEMNRLGK Note: J can be isoleucine or leucine.22 VSNJV-G- Variante KIEIVFPQHTTGDWKRVPHEYNYCPTSA DKNSHGTQTGIPVELTMPKGLTTHQVD GFMCHSALWMTTCDFRWYGPKYITHSI HNEEPTDYQCLEAIKAYKDGVGFNPGF PPQSCGYGTVTDAEAHIITVTPHSVKVD EYTGEWIDPHFIGGRCKGKICETVHNST KWFTSSDGESVCSQLFTLVGGTFFSDS EEITSMGLPETGIRSNYFPYISTEGICKM PFCRKPGYKLKNDLWFQITDPDLDKTVR DLPHIKDCDLSSSIITPGEHATDISLISDV ERILDYALCQNTWGKIEAGEPITPVDLSY LGPKNPGVGPVFTIINSSLHYFTSKYLRV ELESPVIPRMEGRVAGTRIVRQLWDQW FPFGEAEIGPNGVLKTKQGYKFPLHIIGT GEVDSDIKMERIVKHWEHPHIEAAQTYL KKDDTEEVIYYGDTGISKYPVELVEGWF SGWRSSIMGVVAVIIGFVILIFLIRLIGVLS SLFRPKRRPIYKSDVEMAHFR 23 VSCV-G KITISFPQSLKGDWRPVPKGYNYCPTSA DKNLHGDLIDIGLRLRAPKSFKGISADG WMCHAARWITTCDFRWYGPKYITHSIH SFRPSNDQCKEAIRLTNEGNWINPGFPP QSCGYASVTDSESVVVTVTKHQVLVDE YSGSWIDSQFPGGSCTSPICDTVHNSTL WHADHTLDSICDQEFVAMDAVLFTESG KFEEFGKPNSGIRSNYFPYESLKDVCQ MDFCKRKGFKLPSGVWFEIEDAEKSHK. Petição 870250093142, de 10 / 10 / 2025, pág. 145 / 819 116 / 640 SEQ ID NO Nome Sequência AQVELKIKRCPHGAVISAPNQNAADINLI MDVERILDYSLCQATWSKIQNKEALTPID ISYLGPKNPGPGPAFTIINGTLHYFNTRYI RVDIAGPVTKEITGFVSGTSTSRVLWDQ WFPYGENSIGPNGLLKTASGYKYPLFM VGTGVLDADIHKLGEATVIEHPHAKEAQ KVVDDSEVIFFGDTGVSKNPVEVVEGW FSGWRSSLMSIFGIILLIVCLVLIVRILIALK YCCVRHKKRTIYKEDLEMGRIPRRA 24 VSAV-G KFTIVFPQSQKGDWKDVPPNYRYCPSS ADQNWHGDLLGVNIRAKMPKVHKAIKA DGWMCHAAKWVTTCDYRWYGPQYITH SIHSFIPTKAQCEESIKQTKEGVWINPGF PPKNCGYASVSDAESIIVQATAHSVMID EYSGDWLDSQFPTGRCTGSTCETIHNS TLWYADYQVTGLCDSALVSTEVTFYSE DGLMTSIGRQNTGYRSNYFPYEKGAAA CRMKYCTHEGIRLPSGVWFEMVDKELL ESVQMPECPAGLTISAPTQTSVDVSLILD VERMLDYSLCQETWSKVHSGLPISPVDL GYIAPKNPGAGPAFTIVNGTLKYFDTRYL RIDIEGPVLKKMTGKVSGTPTKRELWTE WFPYDDVEIGPNGVLKTPEGYKFPLYMI GHGLLDSDLQKTSQAEVFHHPQIAEAV QKLPDDETLFFGDTGISKNPVEVIEGWF SNWRSSVMAIVFAILLLVITVLMVRLCVA FRHFCCQKRHKIYNDLEMNQLRR 25 VSIV-G-QQ KFTIVFPHNQKGNWKNVPSNYHYCPSS SDLNWHNDLIGTAJQVKMPQSHKAIQAD GWMCHASKWVTTCDFRWYGPKYITHSI RSFTPSVEQCKESIEQTKQGTWLNPGF PPQSCGYATVTDAEAVIVQVTPHHVLVD EYTGEWVDSQFINGKCSNYICPTVHNSTTWHSDYKVKGLCDSNLISMDITFFSEDG ELSSLGKEGTGFRSNYFAYETGGKACK Petition 870250093142, dated 10 / 10 / 2025, page 146 / 819 117 / 640 SEQ ID NO NAME SEQêNcia MQYCKHWGVRLPSGVWFEMADKDLFA AARFPECPEGSSISAPSQTSVDVSLIQD VERILDYSLCQETWSKIRAGLPISPVDLS YLAPKNPGTGPAFTIINGTLKYFETRYIR VDIAAPILSRMVGMISGT 1 TEQELWDDW APYEDVEIGPNGVLRTSSGYKFPLYMIG HGMLDSDLHLSSKAQVFEHPHIQDAAS QLPDDESLFFGDTGLSKNPIELVEGWFS SWKSSIASFFFIIGLIIGLFLVLRVGIHLCIK LKHTKKRQIYTDIEMNRLGK Note: This is the isoleucina or the leucina. 26 VSIV-G-QQQ KFTIVFPHNQKGNWKNVPSNYHYCPSS SDLNWHNDLIGTAJQVKMPQSHKAIQAD GWMCHASKWVTTCDFRWYGPKYITHSI RSFTPSVEQCKESIEQTKQGTWLNPGF PPQSCGYATVTDAEAVIVQVTPHHVLVD EYTGEWVDSQFINGKCSNYICPTVHNST TWHSDYKVKGLCDSNLISMDITFFSEDG ELSSLGKEGTGFRSNQFAYETGGKACK MQYCKHWGVRLPSGVWFEMADKDLFA AARFPECPEGSSISAPSQTSVDVSLIQD VERILDYSLCQETWSKIRAGLPISPVDLS YLAPKNPGTGPAFTIINGTLKYFETRYIR VDIAAPILSRMVGMISGI T TEQELWDDW APYEDVEIGPNGVLRTSSGYKFPLYMIG HGMLDSDLHLSSKAQVFEHPHIQDAAS QLPDDESLFFGDTGLSKNPIELVEGWFS SWKSSIASFFFIIGLIIGLFLVLRVGIHLCIK LKHTKKRQIYTDIEMNRLGK Note: It takes isoleucina or leucina.27 VSIV-GDeltaK47 KFTIVFPHNQKGNWKNVPSNYHYCPSS SDLNWHNDLIGTAJQVKMPSHKAIQADG WMCHASKWVTTCDFRWYGPKYITHSIR SFTPSVEQCKESIEQTKQGTWLNPGFP. Petition 870250093142, dated 10 / 10 / 2025, page 147 / 819 118 / 640 SEQ ID NO Sequence Name PQSCGYATVTDAEAVIVQVTPHHVLVDE YTGEWVDSQFINGKCSNYICPTVHNSTT WHSDYKVKGLCDSNLISMDITFFSEDGE LSSLGKEGTGFRSNYFAYETGGKACKM QYCKHWGVRLPSGVWFEMADKDLFAA ARFPECPEGSSISAPSQTSVDVSLIQDV ERILDYSLCQETWSKIRAGLPISPVDLSY LAPKNPGTGPAFTIINGTLKYFETRYIRV DIAAPILSRMVGMISGT 1 IERELWDDWA PYEDVEIGPNGVLRTSSGYKFPLYMIGH GMLDSDLHLSSKAQVFEHPHIQDAASQL PDDESLFFGDTGLSKNPIELVEGWFSS WKSSIASFFFIIGLIIGLFLVLRVGIHLCIKL KHTKKRQIYTDIEMNRLGK Note: J may be isoleucine or leucine.28 VSIV-GDeltaK47Y209R35 4 KFTIVFPHNQKGNWKNVPSNYHYCPSS SDLNWHNDLIGTAJQVKMPSHKAIQADG WMCHASKWVTTCDFRWYGPKYITHSIR SFTPSVEQCKESIEQTKQGTWLNPGFP PQSCGYATVTDAEAVIVQVTPHHVLVDE YTGEWVDSQFINGKCSNYICPTVHNSTT WHSDYKVKGLCDSNLISMDITFFSEDGE LSSLGKEGTGFRSNYFAETGGKACKMQ YCKHWGVRLPSGVWFEMADKDLFAAA RFPECPEGSSISAPSQTSVDVSLIQDVE RILDYSLCQETWSKIRAGLPISPVDLSYL APKNPGTGPAFTIINGTLKYFETRYIRVDI AAPILSRMVGMISG T T T EELWDDWAPY EDVEIGPNGVLRTSSGYKFPLYMIGHGM LDSDLHLSSKAQVFEHPHIQDAASQLPD DESLFFGDTGLSKNPIELVEGWFSSWK SSIASFFFIIGLIIGLFLVLRVGIHLCIKLKH TKKRQIYTDIEMNRLGK. Petição 870250093142, de 10 / 10 / 2025, pág. 148 / 819 119 / 640 SEQ ID NO Sequence Name Note: J can be isoleucine or leucine.29 VSNJV-GDeltaK47 KIEIVFPQHTTGDWKRVPHEYNYCPTSA DKNSHGTQTGIPVELTMPGLTTHQVDG FMCHSALWMTTCDFRWYGPKYITHSIH NEEPTDYQCLEAIKAYKDGVGFNPGFPP QSCGYGTVTDAEAHIITTVTPHSVKVDEY TGEWIDPHFFIGGRCKGKICETVHNSTKW FTSSDGESVCSQLFTLVGGTFFSSDSEEI TSMGLPETGIRSNYFPYISTEGICKMPFC RKPGYKLNKDLWFQITDPDLDKTVRDLP HIKDCDLSSSIITPGHEHATDISLISDVERIL DYALCQNTWGKIEAGEPITPVDLSYLGP KNPGVGPVFTIINSSLHYFTSKYLRVELE SPVIPRMEGRVAGTRIVRQLWDQWFPF GEAEIGPNWGLKTKQGYFPLHIIGTGEV DSDIKMERIVKHWEHPHIEAAQTYLKD DTEEVIYYGDTGISKYPVELVEGWFSGW RSSIMGVVAVIIGFVILILIRLIGVLSSLFR PKRRPIYKSDVEMAHFR 30 SpyCatcher001 GAMVDTLSGLSSEQGQSGDMTIEEDSA THIKFSKREDDGKELAGATMELRDSSGK TISTWISDGQVKDFYLYPGKYTFVETAA PDGYEVATAITFTVNQGQVTVNGKATK GDAHI 31 SpyCatcher002 AMVTTLSGLSGEQGPSGDMTTEEDSAT HIKFSKREDDGRELAGATMELRDSSGK TISTWISDGHVKDFYLYPGKYTFVETAA PDGYEVATAITFTVNQGQVTVNGEATK GDAHT 32 SpyCatcher003 VTTLSGLSGEQGPSGDMTTEEDSATHIK FSKRDEDDGRELAGATMELRDSSGKTIST WISDGHVKDFYLYPGKYTFVETAAPDG YEVATPIEFTVNEDGQVTVDGEATEGDA HT 33 Ktag ATHIKFSKRD. Petition 870250093142, dated 10 / 10 / 2025, p. 149 / 819 120 / 640 SEQ ID NO Nome Sequência 34 pilin-C ATTVHGETVVNGAKLTVTKNLDLVNSNA LIPNTDFTFKIEPDTTVNEDGNKFKGVAL NTPMTKVTYTNSDKGGSNTKTAEFDFS EVTFEKPGVYYYKVTEEKIDKVPGVSYD TTSYTVQVHVLWNEEQQKPVATYIVGY KEGSKVIQFKNSLDSTTLTVKKKVSGTG GDRSKDFNFGLTLKANQYYKASEKVMIE KTTKGGQAPVQTEASIDQLYHFTLKDGE SIKVTNLPVGVDYVVTEDDYKSEKYTTN VEVSPQDGAVKNIAGNSTEQETSTDKD MTI 35 SnoopCatcher KPLRGAVFSLQKQHPDYPDIYGAIDQNG TYQNVRTGEDGKLTFKNLSDGKYRLFE NSEPAGYKPVQNKPIVAFQIVNGEVRDV TSIVPQDIPATYEFTNGKHYITNEPIPPK 36 Ligante (G4S)x3 GGGGSGGGGSGGGGS 37 HuM291 scFv VL DIQMTQSPSSLSASVGDRVTITCSASSS VSYMNWYQQKPGKAPKRLIYDTSKLAS GVPSRFSGSGSGTDFTLTISSLQPEDFA TYYCQQWSSNPPTFGGGTKVEIK 38 HuM291 scFv VH QVQLVQSGAEVKKPGASVKVSCKASGY TFISYTMHWVRQAPGQGLEWMGYINPR SGYTHYNQKLKDKATLTADKSASTAYM ELSSRSEDTAVYYCARSAYYDYDGFA YWGQGTLVTVSS 39 OKT3 scFv VL QIVLTQSPAIMSASPGEKVTMTCSASSS VSYMNWYQQKSGTSPKRWIYDTSKLAS GVPAHFRGSGSGTSYSLTISGMEAEDA ATYYCQQWSSNPFTFGSGTKLEIN R 40 OKT3 scFv VH QVQLQQSGAELARPGASVKMSCKASG YTFTRYTMHWVKQRPGQGLEWIGYINP SRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLD YWGQGTTLTVSS Petition 870250093142, dated 10 / 10 / 2025, page 150 / 819 121 / 640 SEQ ID NO Nome Sequência 41 TR66 scFv VL QIVLTQSPAIMSASPGEKVTMTCRASSS VSYMNWYQQKSGTSPKRWIYDTSKVAS GVPYRFSGSGSGTSYSLTISSMEAEDAA TYYCQQWSSNPLTFGAGTKLELK 42 TR66 scFv VH QVQLQQSGAELARPGASVKMSCKTSG YTFTRYTMHWVKQRPGQGLEWIGYINP SRGYTNYNQKFKDKATLTTDKSSSTAY MQLSSLTSEDSAVYYCARYYDDHYSLD YWGQGTTLTVSS 43 TR66-opt scFv VL QIVLTQSPSSLSASLGEKVTMTCRASSS VSYMNWYQQKPGTSPKRWIYDTSKVAS GVPDRFSGSGSGTSYSLTISSMEAEDA ATYYCQQWSSNPLTFGAGTKLELK 44 TR66-opt scFv VH QVQLQQSGAELARPGASVKMSCKTSG YTFTRYTMHWVKQRPGQGLEWIGYINP SRGYTNYNQKFKDKATLTTDKSSSTAY MQLSSLTSEDSAVYYCARYYDDHYSLD YWGQGTTLTVSS 45 UCHT1 scFv VL EVQLVESGGGLVQPGGSLRLSCAASGY SFTGYTMNWVRQAPGKGLEWVALINPY KGVSTYNQKFKDRFTISVDKSKNTAYLQ MNSLRAEDTAVYYCARSGYYGDSDWY FDVWGQGTLVTVSS 46 UCHT1 scFv VH DIQMTQSPSSLSASVGDRVTITCRASQD IRNYLNWYQQKPGKAPKLLIYYTSRLES GVPSRFSGSGSGTDYTLTISSLQPEDFA TYYCQQGNTLPWTFGQGTKVEIK 47 EGFR Nanocorpo 7D12 QVKLEESGGGSVQTGGSLRLTCAASGR TSRSYGMGWFRQAPGKEREFVSGISW RGDSTGYADSVKGRFTISRDNAKNTVD LQMNSLKPEDTAIYYCAAAAGSAWYGT LYEYDYWGQGTQVTVSSALE 48 EGFRNanobody 9G8 EVQLVESGGGLVQAGGSLRLSCAASGR TFSSYAMGWFRQAPGKEREFVVAINWS Petition 870250093142, dated 10 / 10 / 2025, p. 151 / 819 122 / 640 SEQ ID NO Nome Sequência SGSTYYADSVKGRFTISRDNAKNTMYL QMNSLKPEDTAVYYCAAGYQINSGNYN FKDYEYDYWGQGTQVTVSSALE 49 EGFR scFv MAEVQLQQSGAELVKPGASVKLSCKAS GYTFTSHWMHWVKQRAGQGLEWIGEF NPSNGRTNYNEKFKSKATLTVDKSSSTA YMQLSSLTSEDSAVYYCASRDYDYDGR YFDYWGQGTTVTVSSGGGGSGGGGS GGGGSDIELTQSPAIMSASPGEKVTMTC SASSSVTYMYWYQQKPGSSPRLLIYDT SNLASGVPVRFSGSGSGTSYSLTISRME AEDAATYYCQQWSSHIFTFGSGTELEIK 50 Peptídeo Her2 27-24M NKFNKGMRGYWGALGGGNGKRGIMGY D 51 Her2 C6B1D2 scFv QVQLVQSGAEVKKPGESLKISCKGSGY SFTSYWIAWVRQMPGKGLEYMGLIYPG DSDTKYSPSFQGQVTISVDKSVSTAYLQ WSSLKPSDSAVYFCARHDVGYCTDRTC AKWPEWLGVWGQGTLVTVSSGGGGS GGGGSGGGGSQSVLTQPPSVSAAPGQ KVTISCSGSSSNIGNNYVSWYQQLPGTA PKLLIYDHTNRPAGVPDRFSGSKSGTSA SLAISGFRSEDEADYYCASWDYTLSGW VFGGGTKVTVLG 52 ligante solúvel hSCF EGICRNRVTNNVKDVTKLVANLPKDYMI TLKYVPGMDVLPSHCWISEMVVQLSDS LTDLLDKFSNISEGLSNYSIIDKLVNIVDD LVECVKENSSKDLKKSFKSPEPRLFTPE EFFRIFNRSIDAFKDFVVASETSDCVVSS TLSPEKDSRVSVTKPFMLPPVAA 53 ligante de camundongo SCF (comprimento total) KEICGNPVTDNVKDITKLVANLPNDYMITLNYVAGMDVLPSHCWLRDMVIQLSLSLT TLLDKFSNISEGLSNYSIIDKLGKIVDDLV LCMEENAPKNIKESPKRPETRSFTPEEF FSIFNRSIDAFKDFMVASDTSDCVLSSTL Petition 870250093142, dated 10 / 10 / 2025, page 152 / 819 123 / 640 SEQ ID NO Nome Sequência GPEKDSRVSVTKPFMLPPVAASSLRND SSSSNRKAAKAPEDSGLQWTAMALPALI SLVIGFAFGALYWKKKQSSLTRAVENIQI NEEDNEISMLQQKEREFQEV 54 Ligante de camundongo SCF (solúvel) KEICGNPVTDNVKDITKLVANLPNDYMIT LNYVAGMDVLPSHCWLRDMVIQLSLSLT TLLDKFSNISEGLSNYSIIDKLGKIVDDLV LCMEENAPKNIKESPKRPETRSFTPEEF FSIFNRSIDAFKDFMVASDTSDCVLS 55 Ligante TPO de camundongo SPVAPACDPRLLNKLLRDSHLLHSRLSQ CPDVDPLSIPVLLPAVDFSLGEWKTQTE QSKAQDILGAVSLLLEGVMAARGQLEPS CLSSLLGQLSGQVRLLLGALQGLLGTQL PLQGRTTAHKDPNALFLSLQQLLRGKVR FLLLVEGPTLCVRRTLPTTAVPSSTSQLL TLNKFPNRTSGLLETNFSVTARTAGPGL LSRLQGFRVKITPGQLNQTSRSPVQISG YLNRTHGPVNGTHGLFAGTSLQTLEAS DISPGAFNKGSLAFNLQGGLPPSPSLAP DGHTPFPPSPALPTTHGSPPQLHPLFPD PSTTMPNSTAPHPVTMYPHPRNLSQET 56 Ligante h-HGF (KR1+2) CIIGKGRSYKGTVSITKSGIKCQPWSSMI PHEHSFLPSSYRGKDLQENYCRNPRGE EGGPWCFTSNPEVRYEVCDIPQCSEVE CMTCNGESYRGLMDHTESGKICQRWD HQTPHRHKFLPERYPDKGFDDNYCRNP DGQPRPWCYTLDPHTRWEYCAIKTC 57 HGF NSQRKRRNTIHEFKKSAKTTLIKIDPALKI KTKKVNTADQCANRCTRNKGLPFTCKA FVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRNCIIGKGRSYKGTVSI TKSGIKCQPWSSMIPHEHSFLPSSYRGK DLQENYCRNPRGEEGGPWCFTSNPEV RYEVCDIPQCSEVECMTCNGESYRGLM DHTESGKICQRWDHQTPHRHKFLPERY Petition 870250093142, dated 10 / 10 / 2025, page 153 / 819 124 / 640 SEQ ID NO Nome Sequência PDKGFDDNYCRNPDGQPRPWCYTLDP HTRWEYCAIKTCADNTMNDTDVPLETT ECIQGQGEGYRGTVNTIWNGIPCQRWD SQYPHEHDMTPENFKCKDLRENYCRNP DGSESPWCFTTDPNIRVGYCSQIPNCD MSHGQDCYRGNGKNYMGNLSQTRSGL TCSMWDKNMEDLHRHIFWEPDASKLNE NYCRNPDDDAHGPWCYTGNPLIPWDY CPISRCEGDTTPTIVNLDHPVISCAKTKQ LRVVNGIPTRTNIGWMVSLRYRNKHICG GSLIKESWVLTARQCFPSRDLKDYEAW LGIHDVHGRGDEKCKQVLNVSQLVYGP EGSDLVLMKLARPAVLDDFVSTIDLPNY GCTIPEKTSCSVYGWGYTGLINYDGLLR VAHLYIMGNEKCSQHHRGKVTLNESEIC AGAEKIGSGPCEGDYGGPLVCEQHKMR MVLGVIVPGRGCAIPN RPGIFVRVAY YAKWIHKIILTYKVPQS 58 IGF-1 MGKISSLPTQLFKCCFCDFLKVKMHTMS SSHLFYLALCLLTFTSSATAGPETLCGAE LVDALQFVCGDRGFYFNKPTGYGSSSR RAPQTGIVDECCFRSCDLRRLEMYCAP LKPAKSARSVRAQRHTDMPKTQKYQPP STNKNTKSQRRKGWPKTHPGGEQKEG TEASLQIRGKKKEQRREIGSRNAECRGK KGK 59 Ligante EGFm123 NSYSECPPSYDGYCLHDGVCRYIEALD SYACNCVVGYAGERCQYRDLRWWGR R 60 VSIV-G SP MKCLLYLAFLFIGVNC 61 Sinal Sec METDTLLLWVLLLWVPGSTG 62 FLAG Tag DYKDDDDK 63 SC-EGFm123FLAG GAMVDTLSGLSSEQGQSGDMTIEEDSA THIKFSKRDEDGKELAGATMELRDSSGK TISTWISDGQVKDFYLYPGKYTFVETAA Petition 870250093142, dated 10 / 10 / 2025, p. 154 / 819 125 / 640 SEQ ID NO Nome Sequência PDGYEVATAITFTVNEQGQVTVNGKATK GDAHIGSGGSGNSYSECPPSYDGYCLH DGVCRYIEALDSYACNCVVGYAGERCQ YRDLRWWGRRGSGGSGDYKDDDDK 64 ST1-VSIV-G AHIVMVDAYKPTKKFTIVFPHNQKGNWK NVPSNYHYCPSSSDLNWHNDLIGTALQ VKMPKSHKAIQADGWMCHASKWVTTC DFRWYGPKYITHSIRSFTPSVEQCKESIE QTKQGTWLNPGFPPQSCGYATVTDAEA VIVQVTPHHVLVDEYTGEWVDSQFINGK CSNYICPTVHNSTTWHSDYKVKGLCDS NLISMDITFFSEDGELSSLGKEGTGFRS NYFAYETGGKACKMQYCKHWGVRLPS GVWFEMADKDLFAAARFPECPEGSSIS APSQTSVDVSLIQDVERILDYSLCQETW SKIRAGLPISPVDLSYLAPKNPGTGPAFT IINGTLKYFETRYIRVDIAAPILSRMVGMI SGI 1 IERELWDDWAPYEDVEIGPNGVL RTSSGYKFPLYMIGHGMLDSDLHLSSKA QVFEHPHIQDAASQLPDDESLFFGDTGL SKNPIELVEGWFSSWKSSIASFFFIIGLII GLFLVLRVGIHLCIKLKHTKKRQIYTDIEM NRLGK 65 ST1-L-VSIV-G AHIVMVDAYKPTKGSGGSGKFTIVFPHN QKGNWKNVPSNYHYCPSSSDLNWHND LIGTALQVKMPKSHKAIQADGWMCHAS KWVTTCDFRWYGPKYITHSIRSFTPSVE QCKESIEQTKQGTWLNPGFPPQSCGYA TVTDAEAVIVQVTPHHVLVDEYTGEWVD SQFINGKCSNYICPTVHNSTTWHSDYKV KGLCDSNLISMDITFFSEDGELSSLGKE GTGFRSNYFAYETGGKACKMQYCKHW GVRLPSGVWFEMADKDLFAAARFPECPEGSSISAPSQTSVDVSLIQDVERILDYSL CQETWSKIRAGLPISPVDLSYLAPKNPG Petition 870250093142, dated 10 / 10 / 2025, page 155 / 819 126 / 640 SEQ ID NO Nome Sequência TGPAFTIINGTLKYFETRYIRVDIAAPILSR MVGMISG 1 1 1 ERELWDDWAPYEDVEIG PNGVLRTSSGYKFPLYMIGHGMLDSDL HLSSKAQVFEHPHIQDAASQLPDDESLF FGDTGLSKNPIELVEGWFSSWKSSIASF FFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQI YTDIEMNRLGK 66 ST1-L-VSIV-GQQQ AHIVMVDAYKPTKGSGGSGKFTIVFPHN QKGNWKNVPSNYHYCPSSSDLNWHND LIGTAJQVKMPQSHKAIQADGWMCHAS KWVTTCDFRWYGPKYITHSIRSFTPSVE QCKESIEQTKQGTWLNPGFPPQSCGYA TVTDAEAVIVQVTPHHVLVDEYTGEWVD SQFINGKCSNYICPTVHNSTTWHSDYKV KGLCDSNLISMDITFFSEDGELSSLGKE GTGFRSNQFAYETGGKACKMQYCKHW GVRLPSGVWFEMADKDLFAAARFPECP EGSSISAPSQTSVDVSLIQDVERILDYSL CQETWSKIRAGLPISPVDLSYLAPKNPG TGPAFTIINGTLKYFETRYIRVDIAAPILSR MVGMISGI 1 TEQELWDDWAPYEDVEIG PNGVLRTSSGYKFPLYMIGHGMLDSDL HLSSKAQVFEHPHIQDAASQLPDDESLF FGDTGLSKNPIELVEGWFSSWKSSIASF FFIIGLIIGLFLVLRVGIHLCIKLKHTKKRQI YTDIEMNRLGK 67 SC-UCHT1FLAG GAMVDTLSGLSSEQGQSGDMTIEEDSA THIKFSKRDEDGKELAGATMELRDSSGK TISTWISDGQVKDFYLYPGKYTFVETAA PDGYEVATAITFTVNEQGQVTVNGKATK GDAHIGSGGSGEVQLVESGGGLVQPG GSLRLSCAASGYSFTGYTMNWVRQAP GKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYC ARSGYYGDSDWYFDVWGQGTLVTVSS Petition 870250093142, dated 10 / 10 / 2025, page 156 / 819 127 / 640 SEQ ID NO Nome Sequência GGGGSGGGGSGGGGSDIQMTQSPSSL SASVGDRVTITCRASQDIRNYLNWYQQ KPGKAPKLLIYYTSRLESGVPSRFSGSG SGTDYTLTISSLQPEDFATYYCQQGNTL PWTFGQGTKVEIKGSGGSGDYKDDDD K 68 ST003-VSIV-GQQQ RGVPHIVMVDAYKRYKGSGGSGKFTIVF PHNQKGNWKNVPSNYHYCPSSSDLNW HNDLIGTAJQVKMPQSHKAIQADGWMC HASKWVTTCDFRWYGPKYITHSIRSFTP SVEQCKESIEQTKQGTWLNPGFPPQSC GYATVTDAEAVIVQVTPHHVLVDEYTGE WVDSQFINGKCSNYICPTVHNSTTWHS DYKVKGLCDSNLISMDITFFSEDGELSSL GKEGTGFRSNQFAYETGGKACKMQYC KHWGVRLPSGVWFEMADKDLFAAARF PECPEGSSISAPSQTSVDVSLIQDVERIL DYSLCQETWSKIRAGLPISPVDLSYLAP KNPGTGPAFTIINGTLKYFETRYIRVDIAA PILSRMVGMISG 1 1 1 EQELWDDWAPYE DVEIGPNGVLRTSSGYKFPLYMIGHGML DSDLHLSSKAQVFEHPHIQDAASQLPDD ESLFFGDTGLSKNPIELVEGWFSSWKSS IASFFFIIGLIIGLFLVLRVGIHLCIKLKHTK KRQIYTDIEMNRLGK 69 SC003-UCHT1FLAG VTTLSGLSGEQGPSGDMTTEEDSATHIK FSKRDEDGRELAGATMELRDSSGKTIST WISDGHVKDFYLYPGKYTFVETAAPDG YEVATPIEFTVNEDGQVTVDGEATEGDA HTGSGGSGEVQLVESGGGLVQPGGSL RLSCAASGYSFTGYTMNWVRQAPGKG LEWVALINPYKGVSTYNQKFKDRFTISV DKSKNTAYLQMNSLRAEDTAVYYCARS GYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSAS Petition 870250093142, dated 10 / 10 / 2025, page 157 / 819 128 / 640 SEQ ID NO Nome Sequência VGDRVTITCRASQDIRNYLNWYQQKPG KAPKLLIYYTSRLESGVPSRFSGSGSGT DYTLTISSLQPEDFATYYCQQGNTLPWT FGQGTKVEIKGSGGSGDYKDDDDK 70 ST003-VSIV-GDeltaK47 RGVPHIVMVDAYKRYKGSGGSGKFTIVF PHNQKGNWKNVPSNYHYCPSSSDLNW HNDLIGTALQVKMPSHKAIQADGWMCH ASKWVTTCDFRWYGPKYITHSIRSFTPS VEQCKESIEQTKQGTWLNPGFPPQSCG YATVTDAEAVIVQVTPHHVLVD EYTG EW VDSQFINGKCSNYICPTVHNSTTWHSDY KVKGLCDSNLISMDITFFSEDGELSSLGK EGTGFRSNYFAYETGGKACKMQYCKH WGVRLPSGVWFEMADKDLFAAARFPE CPEGSSISAPSQTSVDVSLIQDVERILDY SLCQETWSKIRAGLPISPVDLSYLAPKN PGTGPAFTIINGTLKYFETRYIRVDIAAPIL SRMVGMISG 1 1 1 ERELWDDWAPYEDVE IGPNGVLRTSSGYKFPLYMIGHGMLDSD LHLSSKAQVFEHPHIQDAASQLPDDESL FFGDTGLSKNPIELVEGWFSSWKSSIAS FFFIIGLIIGLFLVLRVGIHLCIKLKHTKKR QIYTDIEMNRLGK 71 VSCV-G-RQQQ RITISFPQSLKGDWRPVPKGYNYCPTSA DKNLHGDLIDIGLRLRAPQSFKGISADG WMCHAARWITTCDFRWYGPKYITHSIH SFRPSNDQCKEAIRLTNEGNWINPGFPP QSCGYASVTDSESVVVTVTKHQVLVDE YSGSWIDSQFPGGSCTSPICDTVHNSTL WHADHTLDSICDQEFVAMDAVLFTESG KFEEFGKPNSGIRSNQFPYESLKDVCQ MDFCKRKGFKLPSGVWFEIEDAEKSHKAQVELKIKRCPHGAVISAPNQNAADINLI MDVERILDYSLCQATWSKIQNKEALTPID ISYLGPKNPGPGPAFTIINGTLHYFNTRYI Petition 870250093142, dated 10 / 10 / 2025, page 158 / 819 129 / 640 SEQ ID NO Nome Sequência RVDIAGPVTKEITGFVSGTSTSQVLWDQ WFPYGENSIGPNGLLKTASGYKYPLFM VGTGVLDADIHKLGEATVIEHPHAKEAQ KVVDDSEVIFFGDTGVSKNPVEVVEGW FSGWRSSLMSIFGIILLIVCLVLIVRILIALK YCCVRHKKRTIYKEDLEMGRIPRRA 72 VSAV-G-RQQQ RFTIVFPQSQKGDWKDVPPNYRYCPSS ADQNWHGDLLGVNIRAKMPQVHKAIKA DGWMCHAAKWVTTCDYRWYGPQYITH SIHSFIPTKAQCEESIKQTKEGVWINPGF PPKNCGYASVSDAESIIVQATAHSVMID EYSGDWLDSQFPTGRCTGSTCETIHNS TLWYADYQVTGLCDSALVSTEVTFYSE DGLMTSIGRQNTGYRSNQFPYEKGAAA CRMKYCTHEGIRLPSGVWFEMVDKELL ESVQMPECPAGLTISAPTQTSVDVSLILD VERMLDYSLCQETWSKVHSGLPISPVDL GYIAPKNPGAGPAFTIVNGTLKYFDTRYL RIDIEGPVLKKMTGKVSGTPTKQELWTE WFPYDDVEIGPNGVLKTPEGYKFPLYMI GHGLLDSDLQKTSQAEVFHHPQIAEAV QKLPDDETLFFGDTGISKNPVEVIEGWF SNWRSSVMAIVFAILLLVITVLMVRLCVA FRHFCCQKRHKIYNDLEMNQLRR 73 VSVNJ-G-QQQ KIEIVFPQHTTGDWKRVPHEYNYCPTSA DKNSHGTQTGIPVELTMPQGLTTHQVD GFMCHSALWMTTCDFRWYGPKYITHSI HNEEPTDYQCLEAIKAYKDGVGFNPGF PPQSCGYGTVTDAEAHIITVTPHSVKVD EYTGEWIDPHFIGGRCKGKICETVHNST KWFTSSDGESVCSQLFTLVGGTFFSDS EEITSMGLPETGIRSNQFPYISTEGICKM PFCRKPGYKLKNDLWFQITDPDLDKTVRDLPHIKDCDLSSSIITPGEHATDISLISDV ERILDYALCQNTWGKIEAGEPITPVDLSY Petition 870250093142, dated 10 / 10 / 2025, page 159 / 819 130 / 640 SEQ ID NO Nome Sequência LGPKNPGVGPVFTIINSSLHYFTSKYLRV ELESPVIPRMEGRVAGTRIVQQLWDQW FPFGEAEIGPNGVLKTKQGYKFPLHIIGT GEVDSDIKMERIVKHWEHPHIEAAQTYL KKDDTEEVIYYGDTGISKYPVELVEGWF SGWRSSIMGVVAVIIGFVILIFLIRLIGVLS SLFRPKRRPIYKSDVEMAHFR 74 ST-VSCV-GRQQQ AHIVMVDAYKPTKGSGGSGRITISFPQS LKGDWRPVPKGYNYCPTSADKNLHGDL IDIGLRLRAPQSFKGISADGWMCHAAR WITTCDFRWYGPKYITHSIHSFRPSNDQ CKEAIRLTNEGNWINPGFPPQSCGYASV TDSESVVVTVTKHQVLVDEYSGSWIDS QFPGGSCTSPICDTVHNSTLWHADHTL DSICDQEFVAMDAVLFTESGKFEEFGKP NSGIRSNQFPYESLKDVCQMDFCKRKG FKLPSGVWFEIEDAEKSHKAQVELKIKR CPHGAVISAPNQNAADINLIMDVERILDY SLCQATWSKIQNKEALTPIDISYLGPKNP GPGPAFTIINGTLHYFNTRYIRVDIAGPV TKEITGFVSGTSTSQVLWDQWFPYGEN SIGPNGLLKTASGYKYPLFMVGTGVLDA DIHKLGEATVIEHPHAKEAQKVVDDSEVI FFGDTGVSKNPVEVVEGWFSGWRSSL MSIFGIILLIVCLVLIVRILIALKYCCVRHKK RTIYKEDLEMGRIPRRA 75 ST-VSAV-GRQQQ AHIVMVDAYKPTKGSGGSGRFTIVFPQS QKGDWKDVPPNYRYCPSSADQNWHG DLLGVNIRAKMPQVHKAIKADGWMCHA AKWVTTCDYRWYGPQYITHSIHSFIPTK AQCEESIKQTKEGVWINPGFPPKNCGY ASVS DAESIIVQATAHSVMID EYSGDWL DSQFPTGRCTGSTCETIHNSTLWYADYQVTGLCDSALVSTEVTFYSEDGLMTSIG RQNTGYRSNQFPYEKGAAACRMKYCT Petition 870250093142, dated 10 / 10 / 2025, page 160 / 819 131 / 640 SEQ ID NO Nome Sequência HEGIRLPSGVWFEMVDKELLESVQMPE CPAGLTISAPTQTSVDVSLILDVERMLDY SLCQETWSKVHSGLPISPVDLGYIAPKN PGAGPAFTIVNGTLKYFDTRYLRIDIEGP VLKKMTGKVSGTPTKQELWTEWFPYDD VEIGPNGVLKTPEGYKFPLYMIGHGLLD SDLQKTSQAEVFHHPQIAEAVQKLPDDE TLFFGDTGISKNPVEVIEGWFSNWRSSV MAIVFAILLLVITVLMVRLCVAFRHFCCQ KRHKIYNDLEMNQLRR 76 ST-VSVNJ-GQQQ AHIVMVDAYKPTKGSGGSGKIEIVFPQH TTGDWKRVPHEYNYCPTSADKNSHGT QTGIPVELTMPQGLTTHQVDGFMCHSA LWMTTCDFRWYGPKYITHSIHNEEPTDY QCLEAIKAYKDGVGFNPGFPPQSCGYG TVTDAEAHIITVTPHSVKVDEYTGEWIDP HFIGGRCKGKICETVHNSTKWFTSSDGE SVCSQLFTLVGGTFFSDSEEITSMGLPE TGIRSNQFPYISTEGICKMPFCRKPGYKL KNDLWFQITDPDLDKTVRDLPHIKDCDL SSSIITPGEHATDISLISDVERILDYALCQ NTWGKIEAGEPITPVDLSYLGPKNPGVG PVFTIINSSLHYFTSKYLRVELESPVIPRM EGRVAGTRIVQQLWDQWFPFGEAEIGP NGVLKTKQGYKFPLHIIGTGEVDSDIKME RIVKHWEHPHIEAAQTYLKKDDTEEVIYY GDTGISKYPVELVEGWFSGWRSSIMGV VAVIIGFVILIFLIRLIGVLSSLFRPKRRPIY KSDVEMAHFR 77 VSIV-G (PDB 26J6) KFTIVFPHNQKGNWKNVPSNYHYCPSS SDLNWHNDLIGTAIQVKMPKSHKAIQAD GWMCHASKWVTTCDFRWYGPKYITQSI RSFTPSVEQCKESIEQTKQGTWLNPGFPPQSCGYATVTDAEAVIVQVTPHHVLVD EYTGEWVDSQFINGKCSNYICPTVHNST Petition 870250093142, dated 10 / 10 / 2025, page 161 / 819 132 / 640 SEQ ID NO Nome Sequência TWHSDYKVKGLCDSNLISMDITFFSEDG ELSSLGKEGTGFRSNYFAYETGGKACK MQYCKHWGVRLPSGVWFEMADKDLFA AARFPECPEGSSISAPSQTSVDVSLIQD VERILDYSLCQETWSKIRAGLPISPVDLS YLAPKNPGTGPAFTIINGTLKYFETRYIR VDIAAPILSRMVGMISGI 1 IERELWDDW APYEDVEIGPNGVLRTSSGYKFPLYMIG HGMLDSDLHLSSKAQVFEHPHIQDAAS QLPDDES 78 pCG-4MC11VSV-G-WTST#1 ggaattcgagctcgccccgttacataacttacggtaaat ggcccgcctggctgaccgcccaacgacccccgcccat tgacgtcaataatgacgtatgttcccatagtaacgccaat agggactttccattgacgtcaatgggtggagtatttacgg taaactgcccacttggcagtacatcaagtgtatcatatgc caagtacgccccctattgacgtcaatgacggtaaatgg cccgcctggcattatgcccagtacatgaccttatgggact ttcctacttggcagtacatctacgtattagtcatcgctatta ccatggtgatgcggttttggcagtacatcaatgggcgtg gatagcggtttgactcacggggatttccaagtctccacc ccattgacgtcaatgggagtttgttttggcaccaaaatca acgggactttccaaaatgtcgtaacaactccgccccatt gacgcaaatgggcggtaggcgtgtacggtgggaggtc tatataagcagagctcgtttagtgaaccgtcagatcgcct ggagacgccatccacgctgttttgacctccatagaaga caccgggaccgatccagcctccgggggatcgatcccc ccgatcctgagaacttcagggtgagtttggggacccttgattgttctttctttttcgctattgtaaaattcatgttatatggag ggggcaaagttttcagggtgttgtttagaatgggaagat gtcccttgtatcaccatggaccctcatgataattttgtttcttt cactttctactctgttgacaaccattgtctcctcttattttctttt cattttctgtaactttttcgttaaactttagcttgcatttgtaac gaatttttaaattcacttttgtttatttgtcagattgtaagtactt tctctaatcacttttttttcaaggcaatcagggtatattatatt gtacttcagcacagttttagagaacaattgttataattaaa Petição 870250093142, de 10 / 10 / 2025, pág. 162 / 819 133 / 640 SEQ ID NO Nome Sequence tgataaggtagaatttctgcatataaattctggctggcg tggaaatattctttattggtaaaactacatcctggtc atcatcctgcctttctttatggttacaatgatatacactgtt tgagatgataaatactctgagtccaaaccgggcc cctctgctaaccatgttcat gccttctctttttcctacagctc ctgggcaacgtgctggttattgtgctgtctcattttggc aaagaattgtaacgactcactatagggcgaattcgg atccccggtagttaatTAATACGCGTCACTAT GAAGTGCCI 1 1 IGIACHAGCHA ATTCATTGGGGTGAATTGCGCCCACAT CGTGATGGTGGACGCCTACAAGCCTA CCAAGAAGTTCACGATCG I Illi CCAC ACAACCAAAAAAGGAAACTGGAAAAATG TTCCTTCTAATTACCATTATTGCCCGTC AAGCTCAGAI I IAATTGGCATAATGA CTTACACAGATCAGTCGACTGACTGA AATGCCCAAGAGTCACAAGGCTATTCA AGCAGACGGTTGGATGTGTCATGCTT CCAAATGGGTCACTACTTGTGA IIICC GCTGGTATGGACCGAAGTATATAACAC ATTCCATCCGATCCπCACTCCATCTG TAGAACAATGCAAGGAAAGCATTGAAC AAACGAAACAAGGGACTGACTGAATCCATCTG CAGGCTTCCCTCCTCAAAGTTGTGGAT ATGCAACTGTGACGGATGCCGAAGCA GTGAπGTCCAGGTGACTCCTCACCAT GTGCTGGTTGATGAATACACAGGAGA ATGGGπGAπCACAGπCATCAACGG AAAATGCAGCAATTACATATGCCCCACCCTAGTCCATCTA TGACTATAAGGTCAAAGGGCTATGTGAπCTAACCTCA III CCAIGGACAICAC CπCπCTCAGAGGACGGAGAGCTAT CAICCCIGGGAAAGGAGGGCACAGG GTTCAGAAGTAACTAC III GCIIAIGA AACIGGAGGCAAGGCCIGCAAAAIGC Petition 870250093142, of 10 / 10 / 2025, p. 163 / 819 134 / 640 SEQ ID NO Name Sequence AATACTGCAAGCATTGGGGAGTCAGA CTCCCATCAGGTCTGGTTCGAGAT GGCTGATAAGGATCTC1 1 1 GCTGCAG CCAGATTCCCTGAATGCCCAGAAGGG TCAAGTATCTCTGCTCCATCTCAGACC TCAGTGGATGTAAGGATCTCTATTCATT GTTGAGAGGATCTTGGATTATTCCCTC TGCCAAGAAACCTGGAGCAAAATCAG AGCGGGTCTTCCAATCTCTCCAGTGG ATCTCAGCTATCTTGCTCCTAAAAACC CAGGAACCGGTCCTGC 1 1 1 CACCATAA TCAATGGTACCCTAAAATAC CTCCAATCCTCTCAAGAATGGTCGGAA TGATCAGTGGAACTACCACAGAAAGG GAACTGTGGGATGACTGGGCACCATA TGAAGACGTGGAAATTGGACCCAATG GAGTTCTGAGGACCAGTTCAGGATATA AGIIICCIIIATACATGATTGGACATG GTATGTTGTTCCATCCATCTGATTG GCTCAAAGGCTCAGGTGTTCGAACAT CCTCACATTCAAGACGCTGCTTCGCAA CπCCTGATGATGAGAG IIIAIIIIIIG GTGATACTGGGCTATCCAAAAATCCAA TCGAGCTTGTAGAAGGTTGGTTCAGTA GTTGGAAAAGCTCTATTTGCCCIIIIII TATTCTTGGTTCTCCGAGTTGGTATCC AIC III GCATTAAATTAAAGCACACCA AGAAAAGACAGAI I IAIACAGACAIAG AGATGAACCGACTTGGAAAGTAACTCA AATCCTGCTAGGTATGAAAAAAACTAA CAGAIAICACGCCIAGGACIGTgaaggttccccgttatggactcgctatctgtcaaccagatctta taccctgaagttcacctagatagcccgatagttaccaat Petition 870250093142, dated 10 / 10 / 2025, page 164 / 819 135 / 640 SEQ ID NO Nome Sequence aagatagtagccatcctggagtatgctcgactgtttaaac ctgcaggcatgcaagctgatctttttccctctgccaaaaa ttatggggacatcatgaagccccttgagcatctgacttct ggctaataaaggaaatttattcattgcaatagtgtgttgg aatttttgtctcgtcggagcatc caaatcatttaaaacatcagaatgagtatttggtttagagt ttggcaacatatgcccatatgctggctgccatgaacaaaa ggttggctataaagaggtcatcagtatatgaaacagcc ccctgctgtccattccttattccatagaaaagccttgacttg aggttagattttttttttatttttttgttttttttttcttat ccctaaaattttccttacatgttttactagccagatttttcctc ctctcctgactactcccagtcatagctgtccctcttcttat ggagatccctcgaggagctttttgcaaaagcctaggcct ccaaaaaagcctcttcactctctggaatagctcagaa gccgaggccccctctcgctagctagctag ttagtcagccatggggcggagaatgggcggaactggg cggagttaggggcgggatgggcggttaggggcgg gactatggttgctgactaattgcattaatcggcc aacgcgcggggagaggcggttgcgtattgggcgctct ccgcttccccctcctcgcgcgcgct gctgcggcgagcggtatcagctcactcaaaggcggta atacggttatccacagaatcaggggataacgcaggaa agacatgtgagcaaaaggcagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgtttttccatagg ctccgcccccctgacgagcatcacaaaaatcgacgct caagtcagaggtggcgaaacccgacaggactataaa gataccaggcgtttccccctggaagctccctcgtgcgct ctcctgttccgaccctgccgcttaccggatacctgtccgc ctttctcccttcgggaagcgtggcgctttctcatagctcac gctgtaggtatctcagttcggtgtaggtcgttcgctccaag ctgggctgtgtgcacgaaccccccgttcagcccgaccg ctgcgccttatccggtaactatcgtcttgagtccaacccg gtaagacacgacttatcgccactggcagcagccactg gtaacaggattagcagagcgaggtatgtaggcggtgct acagagttcttgaagtggtggcctaactacggctacact agaagaacagtatttggtatctgcgctctgctgaagcca Petição 870250093142, de 10 / 10 / 2025, pág. 165 / 819 136 / 640 SEQ ID NO Nome Sequência gttaccttcggaaaaagagttggtagctcttgatccggca aacaaaccaccgctggtagcggtggtttttttgtttgcaag cagcagattacgcgcagaaaaaaaggatctcaagaa gatcctttgatcttttctacggggtctgacgctcagtggaa cgaaaactcacgttaagggattttggtcatgagattatca aaaaggatcttcacctagatccttttaaattaaaaatgaa gttttaaatcaatctaaagtatatatgagtaaacttggtctg acagttaccaatgcttaatcagtgaggcacctatctcag cgatctgtctatttcgttcatccatagttgcctgactccccgt cgtgtagataactacgatacgggagggcttaccatctgg ccccagtgctgcaatgataccgcgagacccacgctca ccggctccagatttatcagcaataaaccagccagccgg aagggccgagcgcagaagtggtcctgcaactttatccg cctccatccagtctattaattgttgccgggaagctagagt aagtagttcgccagttaatagtttgcgcaacgttgttgcca ttgctacaggcatcgtggtgtcacgctcgtcgtttggtatg gcttcattcagctccggttcccaacgatcaaggcgagtt acatgatcccccatgttgtgcaaaaaagcggttagctcc ttcggtcctccgatcgttgtcagaagtaagttggccgcag tgttatcactcatggttatggcagcactgcataattctctta ctgtcatgccatccgtaagatgcttttctgtgactggtgagt actcaaccaagtcattctgagaatagtgtatgcggcgac cgagttgctcttgcccggcgtcaatacgggataataccgcgccacatagcagaactttaaaagtgctcatcattggaa aacgttcttcggggcgaaaactctcaaggatcttaccgc tgttgagatccagttcgatgtaacccactcgtgcaccca actgatcttcagcatcttttactttcaccagcgtttctgggtg agcaaaaacaggaaggcaaaatgccgcaaaaaag ggaataagggcgacacggaaatgttgaatactcatact cttcctttttcaatattattgaagcatttatcagggttattgtct catgagcggatacatatttgaatgtatttagaaaaataaa caaataggggttccgcgcacatttccccgaaaagtgcc acctgacgtctaagaaaccattattatcatgacattaacc tataaaaataggcgtatcacgaggccctttcgtctcgcg cgtttcggtgatgacggtgaaaacctctgacacatgcag ctcccggagacggtcacagcttgtctgtaagcggatgc Petição 870250093142, de 10 / 10 / 2025, pág. 166 / 819 137 / 640 SEQ ID NO Nome Sequência cgggagcagacaagcccgtcagggcgcgtcagcgg gtgttggcgggtgtcggggctggcttaactatgcggcatc agagcagattgtactgagagtgcaccattcgacgctctc ccttatgcgactcctgcattaggaagcagcccagtagta ggttgaggccgttgagcaccgccgccgcaaggaatgg tctggcttatcgaaattaatacgactcactatagggagac c 79 pCG-4MC11VSV-G-WTST#2 ggaattcgagctcgccccgttacataacttacggtaaat ggcccgcctggctgaccgcccaacgacccccgcccat tgacgtcaataatgacgtatgttcccatagtaacgccaat agggactttccattgacgtcaatgggtggagtatttacgg taaactgcccacttggcagtacatcaagtgtatcatatgc caagtacgccccctattgacgtcaatgacggtaaatgg cccgcctggcattatgcccagtacatgaccttatgggact ttcctacttggcagtacatctacgtattagtcatcgctatta ccatggtgatgcggttttggcagtacatcaatgggcgtg gatagcggtttgactcacggggatttccaagtctccacc ccattgacgtcaatgggagtttgttttggcaccaaaatca acgggactttccaaaatgtcgtaacaactccgccccatt gacgcaaatgggcggtaggcgtgtacggtgggaggtc tatataagcagagctcgtttagtgaaccgtcagatcgcct ggagacgccatccacgctgttttgacctccatagaaga caccgggaccgatccagcctccgggggatcgatcccc ccgatcctgagaacttcagggtgagtttggggacccttgattgttctttctttttcgctattgtaaaattcatgttatatggag ggggcaaagttttcagggtgttgtttagaatgggaagat gtcccttgtatcaccatggaccctcatgataattttgtttcttt cactttctactctgttgacaaccattgtctcctcttattttctttt cattttctgtaactttttcgttaaactttagcttgcatttgtaac gaatttttaaattcacttttgtttatttgtcagattgtaagtactt tctctaatcacttttttttcaaggcaatcagggtatattatatt gtacttcagcacagttttagagaacaattgttataattaaa tgataaggtagaatatttctgcatataaattctggctggcg tggaaatattcttattggtagaaacaactacatcctggtc atcatcctgcctttctctttatggttacaatgatatacactgtt Petição 870250093142, de 10 / 10 / 2025, pág. 167 / 819 138 / 640 SEQ ID NO Name Sequence tgagatgaggataaatactctgagtccaaaccgggcc cctctgctaaccatgttcattgccttctctttctctctacagctc ctgggcaacgtgctggttattgctgtctcatcatttggc aaagaattgtaatacgactcactatagggcgaatcctcGTAGGTTATGGTT GAAGTGCCI 1 1 IGIACHAGCCI Illi ATTCATTGGGGTGAATTGCAAGTTCAC GATCG I Illi CCACACAACCAAAAAGG AAACTGGAAAAATGTTCCTTCTAATTA CCATTATTGCCCGTCAAGCTCAGAI II AAATTGGCATAATGCCCACATCGGTGGGACCAGCCAGCCTAATTA ACTTAATAGGCACAGCCTTACAAGTCA AAATGCCCAAGAGTCACAAGGCTATTC AAGCAGACGGTTGGATGTGTCATGCT TCCAAATGGGTCACTACTTGTGA IIIC CGCTGGTATGGACCGAAGTATAACA CAπCCATCCGATCCπCACTCCATCT GTAGAACAGAGACAAGCAGCATTGATT CAAACGAAACAAGGAACTTGGCTGAAT CCAGGCTTCCCTCCTCAAAGTTGTGG ATATGCAACTGTGACGGATGCCGAAG CAGTGATTGTCCAGGTGACTCCTCAC CATGTGCTGGTTGATGAATACACAGGA GAATGGGπGAπCACAGπCATCAAC ACTGTCCATAACTCTACAACCTGGCAT TCTGACTATAAGGTCAAAGGGCTATGT GATTCTAACCTCA III CCAIGGACAIC ACCπCπCTCAGAGGACGGAGAGCT ATCATCCCTGGGAAAGGAGGGCACAG GGTTCAGAAGTAACTAC III GCIIAIGAAACIGGAGGCAAGGCCIGCAAAG CAATACTGCAAGCATTGGGGAGTCAG ACTCCCATCAGGTGTCTGGTTCGAGAT GGCTGATAAGGATCTC III GCIGCAG Petition 870250093142, of 10 / 10 / 2025, p. 168 / 819 139 / 640 SEQ ID NO Name Sequence CCAGATTCCCTGAATGCCCAGAAGGG TCAAGTATCTCTGCTCCATCTCAGACC TCAGTGGATGTAAGTCTAATTCAGGAC GTTGAGAGGATCTTGGATTATTCCCTC TGCCAAGAAACCTGGAGCAAATCAAG AGCGGGTCTTCCAATCTCCTTGAGTCGATTGACCTA CAGGAACCGGTCCTGC1 1 1 CACCATAA TCAATGGTACCCTAAAATAC 1 1 1 GAGA CCAGATACATCAGAGTCGATATTGCTG CTCCAATCCTCTCAAGAATGGTCGGAA TGATCAGTGGAACTACCACAGAAAGG GAACTGTGGGATGACTGGCAGACCAAGAGGATTGGATT GAGTTCTGAGGACCAGTTCAGGATATA AGIIICCIIIATACATGATTGGACATG GTATGTTGGACTCCGATCTTCATCTTA GCTCAAAGGCTCAGGTGTTCGAACAT CCTCACATTCAAGACGCTGCTTCGCAA CπCCTGATGATGAGAG IIIAIIIIIIG GTGATACCAACCAACCAACCAACCAT TCGAGCTTGTAGAAGGTTGGTTCAGTA GTTGGAAAAGCTCTATTGCCTCIIII TCI I IATCATAGGGTTAATCATTGGAC TATTCTTGGTTCTCCGAGTTGGTATCC AICI II GCATTAAATTAAAGCACACCA AGAAAAGACAGAI I IAIACAGACAIAG AGATGAACTTCAGACTGAACTCAGACTGAC AATCCTGCTAGGTATGAAAAAAACTAA CAGATATCACGCCTAGGACTAGTgtgaa atagacatcagaattaagaaaaacgtagggtccaagt ggttccccgttatggactcgctatctgtcaaccagatctta taccctgaagttcacctagatagcccgatagttaccaataagatagtagccatcctggagtatgctcgactgtttaaac ctgcaggcatgcaagctctttttccctctgccaaaa ttatggggacatcatgaagccccttgagcatctgacttct Petition 870250093142, of 10 / 10 / 2025, p. 169 / 819 140 / 640 SEQ ID NO Nome Sequência ggctaataaaggaaatttattttcattgcaatagtgtgttgg aattttttgtgtctctcactcggaaggacatatgggaggg caaatcatttaaaacatcagaatgagtatttggtttagagt ttggcaacatatgcccatatgctggctgccatgaacaaa ggttggctataaagaggtcatcagtatatgaaacagcc ccctgctgtccattccttattccatagaaaagccttgacttg aggttagattttttttatattttgttttgtgttatttttttctttaacat ccctaaaattttccttacatgttttactagccagatttttcctc ctctcctgactactcccagtcatagctgtccctcttctcttat ggagatccctcgaggagctttttgcaaaagcctaggcct ccaaaaaagcctcttcactacttctggaatagctcagaa gccgaggcggcctcggcctctgcataaataaaaaaaa ttagtcagccatggggcggagaatgggcggaactggg cggagttaggggcgggatgggcggagttaggggcgg gactatggttgctgactaattgctgcattaatgaatcggcc aacgcgcggggagaggcggtttgcgtattgggcgctctt ccgcttcctcgctcactgactcgctgcgctcggtcgttcg gctgcggcgagcggtatcagctcactcaaaggcggta atacggttatccacagaatcaggggataacgcaggaa agaacatgtgagcaaaaggccagcaaaaggccagg aaccgtaaaaaggccgcgttgctggcgtttttccatagg ctccgcccccctgacgagcatcacaaaaatcgacgct caagtcagaggtggcgaaacccgacaggactataaa gataccaggcgtttccccctggaagctccctcgtgcgctctcctgttccgaccctgccgctcggatacctgtccgc cttctccctcgggaagcgtggcgctttctcatagctcac gctgtaggtatctcgtcggtgtaggtcgtcgctccaag ctgggctgtgtgcgaacccccgttcagcccgcg ctgcgccttatccggtaactatcgtcttgagtccaacccg gtaagacacgacttatcgccactggcagcagccactg gtaacaggattagcagagcgaggtatgtaggcggtgct acagagttcttgaagtggggctaactacggctacact agaagaacagtatttttctctctcctctcgcgcg gttaccttcggaaaaagagtggtagctcttgatccggca aaaaccaccgctggtagcggtggttttttgtttgcaag cagcagattacgcgcagaaaaaaaaaaaaaaaaaaaaaaaaaaa Petition 870250093142, of 10 / 10 / 2025, p. 170 / 819 141 / 640 SEQ ID NO Nome Sequência gatcctttgatcttttctacggggtctgacgctcagtggaa cgaaaactcacgttaagggattttggtcatgagattatca aaaaggatcttcacctagatccttttaaattaaaaatgaa gttttaaatcaatctaaagtatatatgagtaaacttggtctg acagttaccaatgcttaatcagtgaggcacctatctcag cgatctgtctatttcgttcatccatagttgcctgactccccgt cgtgtagataactacgatacgggagggcttaccatctgg ccccagtgctgcaatgataccgcgagacccacgctca ccggctccagatttatcagcaataaaccagccagccgg aagggccgagcgcagaagtggtcctgcaactttatccg cctccatccagtctattaattgttgccgggaagctagagt aagtagttcgccagttaatagtttgcgcaacgttgttgcca ttgctacaggcatcgtggtgtcacgctcgtcgtttggtatg gcttcattcagctccggttcccaacgatcaaggcgagtt acatgatcccccatgttgtgcaaaaaagcggttagctcc ttcggtcctccgatcgttgtcagaagtaagttggccgcag tgttatcactcatggttatggcagcactgcataattctctta ctgtcatgccatccgtaagatgcttttctgtgactggtgagt actcaaccaagtcattctgagaatagtgtatgcggcgac cgagttgctcttgcccggcgtcaatacgggataataccg cgccacatagcagaactttaaaagtgctcatcattggaa aacgttcttcggggcgaaaactctcaaggatcttaccgc tgttgagatccagttcgatgtaacccactcgtgcacccaactgatcttcagcatcttttactttcaccagcgtttctgggtg agcaaaaacaggaaggcaaaatgccgcaaaaaag ggaataagggcgacacggaaatgttgaatactcatact cttcctttttcaatattattgaagcatttatcagggttattgtct catgagcggatacatatttgaatgtatttagaaaaataaa caaataggggttccgcgcacatttccccgaaaagtgcc acctgacgtctaagaaaccattattatcatgacattaacc tataaaaataggcgtatcacgaggccctttcgtctcgcg cgtttcggtgatgacggtgaaaacctctgacacatgcag ctcccggagacggtcacagcttgtctgtaagcggatgc cgggagcagacaagcccgtcagggcgcgtcagcgg gtgttggcgggtgtcggggctggcttaactatgcggcatc agagcagattgtactgagagtgcaccattcgacgctctc Petição 870250093142, de 10 / 10 / 2025, pág. 171 / 819 142 / 640 SEQ ID NO Nome Sequência ccttatgcgactcctgcattaggaagcagcccagtagta ggttgaggccgttgagcaccgccgccgcaaggaatgg tctggcttatcgaaattaatacgactcactatagggagac c 80 pCG-4MC11VSV-G-WTST#3 ggaattcgagctcgccccgttacataacttacggtaaat ggcccgcctggctgaccgcccaacgacccccgcccat tgacgtcaataatgacgtatgttcccatagtaacgccaat agggactttccattgacgtcaatgggtggagtatttacgg taaactgcccacttggcagtacatcaagtgtatcatatgc caagtacgccccctattgacgtcaatgacggtaaatgg cccgcctggcattatgcccagtacatgaccttatgggact ttcctacttggcagtacatctacgtattagtcatcgctatta ccatggtgatgcggttttggcagtacatcaatgggcgtg gatagcggtttgactcacggggatttccaagtctccacc ccattgacgtcaatgggagtttgttttggcaccaaaatca acgggactttccaaaatgtcgtaacaactccgccccatt gacgcaaatgggcggtaggcgtgtacggtgggaggtc tatataagcagagctcgtttagtgaaccgtcagatcgcct ggagacgccatccacgctgttttgacctccatagaaga caccgggaccgatccagcctccgggggatcgatcccc ccgatcctgagaacttcagggtgagtttggggacccttg attgttctttctttttcgctattgtaaaattcatgttatatggag ggggcaaagttttcagggtgttgtttagaatgggaagat gtcccttgtatcaccatggaccctcatgataattttgtttctttcactttctactctgttgacaaccattgtctcctcttattttctttt cattttctgtaactttttcgttaaactttagcttgcatttgtaac gaatttttaaattcacttttgtttatttgtcagattgtaagtactt tctctaatcacttttttttcaaggcaatcagggtatattatatt gtacttcagcacagttttagagaacaattgttataattaaa tgataaggtagaatatttctgcatataaattctggctggcg tggaaatattcttattggtagaaacaactacatcctggtc atcatcctgcctttctctttatggttacaatgatatacactgtt tgagatgaggataaaatactctgagtccaaaccgggcc cctctgctaaccatgttcatgccttcttctttttcctacagctc ctgggcaacgtgctggttattgtgctgtctcatcattttggc Petição 870250093142, de 10 / 10 / 2025, pág. 172 / 819 143 / 640 SEQ ID NO Name Sequence aaagaattgtaatacgactcactatagggcgaattcgg atcccccggtagttaatTAATACGCGTCACTAT GAAGTGCCI 1 1 IGIACITAGCCI Illi ATTCATTGGGGTGAATTGCAAGTTCAC GAICG IIII CCACACAACCAACTAACTGACTCATTTA CCATTATTGCCCGTCAAGCTCAGA III AAATTGGCATAATGACTTAATAGGCAC AGCCTTACAAGTCAAAATGCCCAAGAG TCACAAGGCTATTCAAGCAGACGGTT GGATGTGTCATGCTTCCAAATGGGTCA CTACTTGTGAI II CCGCIGGIAIGGAC CGAAGTATATACCACCATCATTCATTCAT CCTTCACTCCATCTGTAGAACAATGCA AGGAAAGCAIIGAACAAACGAAACAA GGAACTTGGCTGAATCCAGGCTTCCC TCCTCAAAGTTGTGGATATGCAACTGT GACGGATGCCGAAGCAGTGATTGTCC AGGTGACTCCTCACCATGTGCTGGTT GATGAATACAGGAGGAGGATTGATT TTCACAGTTCATCAACGGAAAATGCAG CAATTACATATGCCCCACTGTCCATAA CTCTACAACCTGGCATTCTGACTATAA GGTCAAAGCCCACATCGTGATGGTGG ACGCCTACAAGCCTACCAAGGGGCTA TGTGATTCTAACCTCAI I ICCAIGGAC ATCACCAGTTCGGATCGATCGATCGATC GCTATCATCCCTGGGAAAGGAGGGCA CAGGGTTCAGAAGTAACTAC III GCII AIGAAACIGGAGGCAAGGCCIGCAAA ATGCAATACTGCAAGCATTGGGGAGT CAGACTCCCATCAGGTGTCTGGTTCG AGATGGCTGATAAGGATCTC III GCIGCAGCCAGATTCCCTGAATGCCCAGAA GGGTCAAGTATCTCTGCTCCATCTCAG ACCTCAGTGGATGTAAGTCTAATTCAG Petition 870250093142, dated 10 / 10 / 2025, page 173 / 819 144 / 640 SEQ ID NO Name Sequence GACGTTGAGAGGATCTTGGATTATTCC CTCTGCCAAGAAACCTGGAGCAAAAT CAGAGCGGGTCTTCCAATCTCTCCAG TGGATCTCAGCTATCTTTGCTCCTAAAA ACCCAGGAACCGGTCCTGC1 1 1 CACC ATAATCAATGGTACCC 1 TAAAATACCC 1 1 GAGACCAGATACATCAGAGTCGATATT GCTGCTCCAATCCTCTCAAGAATGGTC GGAATGATCAGTGGAACTACCACACAGA AAGGGAACTGTGGGATGACTGGGCAC CATATGAAGACGTGGAAATTGGACCC AATGGAGTTCTGAGGACCAGTTCAGG ATATAAG IIICCTTGIIIGGAGGA CATGGTATGTTGGACTCCGATCTTCAT CTTAGCTCAAAGGCTCAGGTGTTCGAA CATCCTCACATTCAAGACGCTGCTTCG CAACTTCCTGATGATGAGAGIIIAIII III GGTGATACTGGGCTATCCAAAAAT CAATCGAGCTTGTAGAAGGTTGGTTC AGTAGTTGTAAGCTATGCCTCT IIIIICIIIATCATAGGGTTAATCATTG GACTATTCTTGGTTCTCCGAGTTGGTA TCCATCI II GCATTAAATTAAAGCACA CCAAGAAAAGACAGAI I IAIACAGACA TAGAGATGAACCGACTTGGAAAGTAAC TCAAATCCTGCTAGGTATGAAAAAAAC TAACAGATATCGATCGCTCAGTAGCAGAI gaaatagacatcagaattaagaaaaacgtagggtcca agtggttccccgttatggactcgctatctgtcaaccagat cttataccctgaagttcacctagatagcccgatagttacc aataagatagtagccatccagtatgctcgactgttta aacctgcaggcatgcaagctgatctttttccctctgccaaaaattatggggacatcatgaagccccttgagcatctgac ttctggctaataaaggaaatttattttcattgcaatagtgtgt tggaattttttgtgtctctcactcggaaggacatatgggag ggcaaatcatttaaaacatcagaatgagtatttggtttag Petição 870250093142, de 10 / 10 / 2025, pág. 174 / 819 145 / 640 SEQ ID NO Nome Sequência agtttggcaacatatgcccatatgctggctgccatgaac aaaggttggctataaagaggtcatcagtatatgaaaca gccccctgctgtccattccttattccatagaaaagccttga cttgaggttagattttttttatattttgttttgtgttatttttttcttta acatccctaaaattttccttacatgttttactagccagattttt cctcctctcctgactactcccagtcatagctgtccctcttct cttatggagatccctcgaggagctttttgcaaaagcctag gcctccaaaaaagcctcttcactacttctggaatagctca gaagccgaggcggcctcggcctctgcataaataaaaa aaattagtcagccatggggcggagaatgggcggaact gggcggagttaggggcgggatgggcggagttagggg cgggactatggttgctgactaattgctgcattaatgaatc ggccaacgcgcggggagaggcggtttgcgtattgggc gctcttccgcttcctcgctcactgactcgctgcgctcggtc gttcggctgcggcgagcggtatcagctcactcaaaggc ggtaatacggttatccacagaatcaggggataacgca ggaaagaacatgtgagcaaaaggccagcaaaaggc caggaaccgtaaaaaggccgcgttgctggcgtttttcca taggctccgcccccctgacgagcatcacaaaaatcga cgctcaagtcagaggtggcgaaacccgacaggactat aaagataccaggcgtttccccctggaagctccctcgtgc gctctcctgttccgaccctgccgcttaccggatacctgtcc g cctttctcccttcg ggaagcgtggcgctttctcatagctc acgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccgac cgctgcgccttatccggtaactatcgtcttgagtccaacc cggtaagacacgacttatcgccactggcagcagccact ggtaacaggattagcagagcgaggtatgtaggcggtg ctacagagttcttgaagtggtggcctaactacggctaca ctagaagaacagtatttggtatctgcgctctgctgaagcc agttaccttcggaaaaagagttggtagctcttgatccggc aaacaaaccaccgctggtagcggtggtttttttgtttgcaa gcagcagattacgcgcagaaaaaaaggatctcaaga agatcctttgatcttttctacggggtctgacgctcagtgga acgaaaactcacgttaagggattttggtcatgagattatc aaaaaggatcttcacctagatccttttaaattaaaaatga Petição 870250093142, de 10 / 10 / 2025, pág. 175 / 819 146 / 640 SEQ ID NO Nome Sequência agttttaaatcaatctaaagtatatatgagtaaacttggtct gacagttaccaatgcttaatcagtgaggcacctatctca gcgatctgtctatttcgttcatccatagttgcctgactcccc gtcgtgtagataactacgatacgggagggcttaccatct ggccccagtgctgcaatgataccgcgagacccacgct caccggctccagatttatcagcaataaaccagccagcc ggaagggccgagcgcagaagtggtcctgcaactttatc cgcctccatccagtctattaattgttgccgggaagctaga gtaagtagttcgccagttaatagtttgcgcaacgttgttgc cattgctacaggcatcgtggtgtcacgctcgtcgtttggta tggcttcattcagctccggttcccaacgatcaaggcgag ttacatgatcccccatgttgtgcaaaaaagcggttagctc cttcggtcctccgatcgttgtcagaagtaagttggccgca gtgttatcactcatggttatggcagcactgcataattctctt actgtcatgccatccgtaagatgcttttctgtgactggtga gtactcaaccaagtcattctgagaatagtgtatgcggcg accgagttgctcttgcccggcgtcaatacgggataatac cgcgccacatagcagaactttaaaagtgctcatcattgg aaaacgttcttcggggcgaaaactctcaaggatcttacc gctgttgagatccagttcgatgtaacccactcgtgcaccc aactgatcttcagcatcttttactttcaccagcgtttctgggt gagcaaaaacaggaaggcaaaatgccgcaaaaaa gggaataagggcgacacggaaatgttgaatactcatactcttcctttttcaatattattgaagcatttatcagggttattgt ctcatgagcggatacatatttgaatgtatttagaaaaata aacaaataggggttccgcgcacatttccccgaaaagtg ccacctgacgtctaagaaaccattattatcatgacattaa cctataaaaataggcgtatcacgaggccctttcgtctcg cgcgtttcggtgatgacggtgaaaacctctgacacatgc agctcccggagacggtcacagcttgtctgtaagcggat gccgggagcagacaagcccgtcagggcgcgtcagc gggtgttggcgggtgtcggggctggcttaactatgcggc atcagagcagattgtactgagagtgcaccattcgacgct ctcccttatgcgactcctgcattaggaagcagcccagta gtaggttgaggccgttgagcaccgccgccgcaaggaa tggtctggcttatcgaaattaatacgactcactataggga Petição 870250093142, de 10 / 10 / 2025, pág. 176 / 819 147 / 640 SEQ ID NO Nome Sequência gacc 81 pCG-4MC11VSV-G-WTST#4 ggaattcgagctcgccccgttacataacttacggtaaat ggcccgcctggctgaccgcccaacgacccccgcccat tgacgtcaataatgacgtatgttcccatagtaacgccaat agggactttccattgacgtcaatgggtggagtatttacgg taaactgcccacttggcagtacatcaagtgtatcatatgc caagtacgccccctattgacgtcaatgacggtaaatgg cccgcctggcattatgcccagtacatgaccttatgggact ttcctacttggcagtacatctacgtattagtcatcgctatta ccatggtgatgcggttttggcagtacatcaatgggcgtg gatagcggtttgactcacggggatttccaagtctccacc ccattgacgtcaatgggagtttgttttggcaccaaaatca acgggactttccaaaatgtcgtaacaactccgccccatt gacgcaaatgggcggtaggcgtgtacggtgggaggtc tatataagcagagctcgtttagtgaaccgtcagatcgcct ggagacgccatccacgctgttttgacctccatagaaga caccgggaccgatccagcctccgggggatcgatcccc ccgatcctgagaacttcagggtgagtttggggacccttg attgttctttctttttcgctattgtaaaattcatgttatatggag ggggcaaagttttcagggtgttgtttagaatgggaagat gtcccttgtatcaccatggaccctcatgataattttgtttcttt cactttctactctgttgacaaccattgtctcctcttattttctttt cattttctgtaactttttcgttaaactttagcttgcatttgtaacgaatttttaaattcacttttgtttattgtcagattgtaagtactt tctctaatcacttttttttcaaggcaatcagggtatattatatt gtacttcagcacagttttagaacaattgttataattaaa tgataaggtagaattctgcatataaattctggctggcg tggaaatattcttacttactactactactc atcatcctgcctttctcttggttacaatgatatacactgtt tgagatgaggataaaatactctgagtccaaaccgggcc cctctgctaaccatgttcatgccttctctttttcctacagctc ctgggcaacgtgctggttattgctgtctcattctgc aagaattgtatatacgatactactacgg atccccggtagttaatTAATACGCGTCACTAT GAAGTGCCI 1 1 IGIACITAGCCI Illi Petition 870250093142, of 10 / 10 / 2025, p. 177 / 819 148 / 640 SEQ ID NO Name Sequence ATTCATTGGGGTGAATTGCAAGTTCAC GATCG 1 Illi CCACACAACCAAAAAGG AAACTGGAAAAATGTTCCTTCTAATTA CCATTATTGCCCGTCAAGCTCAGAI II AAATTGGCATAATGACTTAATAGGCAC AGCCTTACAAGTCAAAGATCAGCCAGTCCAGCCAGTCAGTC GGATGTGTGTCATGCTTCCAAATGGGTCA CTACTTGTGAI II CCGCTGGTATGGAC CGAAGTATATAACACATTCCATCCGAT CCπCACTCCATCTGTAGAACAATGCA AGGAAAGCAIIGAACAAACGAAACAA GGAACπGGCTGAATCCAGGCTTCCCAAGTTCGATTGATTGATTGATT GACGGATGCCGAAGCAGTGATTGTCC AGGTGACTCCTCCACCATGTGCTGGπ GATGAATACACAGGAGAATGGGπGA TTCACAGTTCATCAACGGAAAATGCAG CAATTACATATGCCCCACTGTCCATAA CTCTACAACCTGGCAπCTGACTATAA GGTCAAGGCTGCTGCTGAG ACATCGTGATGGTGGACGCCTACAAG CCIACCAAGAACCICAI II CCAIGGAC ATCACCπCπCTCAGAGGACGGAGA GCTATCATCCCTGGGAAAGGAGGGCA CAGGGTTCAGAAGTAACTAC III GCII AIGAAACIGGAGGCAAGGCCIGCAAACTGACTAGGAGGAGTT CAGACTCCCATCAGGTGTCTGGπCG AGATGGCTGATAAGGATCTC III GCIG CAGCCAGAπCCCTGAATGCCCAGAA GGGTCAAGTATCTCTGCTCCATCTCAG ACCTCAGTGGATGTAAGTCTAATTCAG GACGTTGAGAGGATCTTGGATTATTCC CTCTGAACCTGCCAACTGGAGAATCAGAGCGGGTCTTCCAATCTCTCCAG Petition 870250093142, dated 10 / 10 / 2025, page 178 / 819 149 / 640 SEQ ID NO Name Sequence TGGATCTCAGCTATCTTGCTCCTAAAA ACCCAGGAACCGGTCCTGC1 1 1 CACC ATAATCAATGGTACCCTAAAATAC 1 1 1 GAGACCAGATACATCAGAGTCGATATT GCTGCTCCAATCCTCTCAAGAATGGTC GGAATGATCACTACCAGGAGAGA AAGGGAACTGTGGGATGACTGGGCAC CATATGAAGACGTGGAAATTGGACCC AATGGAGTTCTGAGGACCAGTTCAGG ATATAAG IIICCIIIATACATGATTGGA CATGGTATGTTGGACTCCGATCTTCAT CTTAGCTCAAAGGCTCAGGTGTTCGAA CATCCCCGATCGATCCATTTCTTCG CAACTTCCTGATGATGAGAGIIIAIII III GGTGATACTGGGCTATCCAAAAAT CCAATCGAGCTTGTAGAAGGTTGGTTC AGTAGTTGGAAAAGCTCTATTGCCTCT IIIIICIIIATCATAGGGTTAATCATTG GACTATTCTTGGTTCTCCGAGTTGGTA TCCATCIAAATCATTGGACAATCAATCAGAGAIAGCAATCAGAI IAIACAGACA TAGAGATGAACCGACTTGGAAAGTAAC TCAAATCCTGCTAGGTATGAAAAAAAC TAACAGATATCACGCCTAGGACTAGTgt gaaatagacatcagaattaagaaaaacgtagggtcca agtggttccccgttatggactcgctatctgtcaaccagat cttataccctgaagttcacccctaggactactactac aataagatagtagccatcctggagtatgctcgactgttta aacctgcaggcatgcaagctgatctttccctctgccaa aaattatggggacatcatgaagccccttgagcatctgac ttctggctaataaaggaaatttattttcattgcaatagtgtgttggaattttttgtgtctctcactcggaaggacatatgggag ggcaaatcatttaaaacatcagaatgagtatttggtttag agtttggcaacatatgcccatatgctggctgccatgaac aaaggttggctataaagaggtcatcagtatatgaaaca gccccctgctgtccattccttattccatagaaaagccttga Petição 870250093142, de 10 / 10 / 2025, pág. 179 / 819 150 / 640 SEQ ID NO Nome Sequência cttgaggttagattttttttatattttgttttgtgttatttttttcttta acatccctaaaattttccttacatgttttactagccagattttt cctcctctcctgactactcccagtcatagctgtccctcttct cttatggagatccctcgaggagctttttgcaaaagcctag gcctccaaaaaagcctcttcactacttctggaatagctca gaagccgaggcggcctcggcctctgcataaataaaaa aaattagtcagccatggggcggagaatgggcggaact gggcggagttaggggcgggatgggcggagttagggg cgggactatggttgctgactaattgctgcattaatgaatc ggccaacgcgcggggagaggcggtttgcgtattgggc gctcttccgcttcctcgctcactgactcgctgcgctcggtc gttcggctgcggcgagcggtatcagctcactcaaaggc ggtaatacggttatccacagaatcaggggataacgca ggaaagaacatgtgagcaaaaggccagcaaaaggc caggaaccgtaaaaaggccgcgttgctggcgtttttcca taggctccgcccccctgacgagcatcacaaaaatcga cgctcaagtcagaggtggcgaaacccgacaggactat aaagataccaggcgtttccccctggaagctccctcgtgc gctctcctgttccgaccctgccgcttaccggatacctgtcc g cctttctcccttcg ggaagcgtggcgctttctcatagctc acgctgtaggtatctcagttcggtgtaggtcgttcgctcca agctgggctgtgtgcacgaaccccccgttcagcccgac cgctgcgccttatccggtaactatcgtcttgagtccaacc cggtaagacacgacttatcgccactggcagcagccactggtaacaggattagcagagcgaggtatgtaggcggtg ctacagagttcttgaagtggtggcctaactacggctaca ctagaagaacagtatttggtatctgcgctctgctgaagcc agttaccttcggaaaaagagttggtagctcttgatccggc aaacaaaccaccgctggtagcggtggtttttttgtttgcaa gcagcagattacgcgcagaaaaaaaggatctcaaga agatcctttgatcttttctacggggtctgacgctcagtgga acgaaaactcacgttaagggattttggtcatgagattatc aaaaaggatcttcacctagatccttttaaattaaaaatga agttttaaatcaatctaaagtatatatgagtaaacttggtct gacagttaccaatgcttaatcagtgaggcacctatctca gcgatctgtctatttcgttcatccatagttgcctgactcccc Petição 870250093142, de 10 / 10 / 2025, pág. 180 / 819 151 / 640 SEQ ID NO Nome Sequência gtcgtgtagataactacgatacgggagggcttaccatct ggccccagtgctgcaatgataccgcgagacccacgct caccggctccagatttatcagcaataaaccagccagcc ggaagggccgagcgcagaagtggtcctgcaactttatc cgcctccatccagtctattaattgttgccgggaagctaga gtaagtagttcgccagttaatagtttgcgcaacgttgttgc cattgctacaggcatcgtggtgtcacgctcgtcgtttggta tggcttcattcagctccggttcccaacgatcaaggcgag ttacatgatcccccatgttgtgcaaaaaagcggttagctc cttcggtcctccgatcgttgtcagaagtaagttggccgca gtgttatcactcatggttatggcagcactgcataattctctt actgtcatgccatccgtaagatgcttttctgtgactggtga gtactcaaccaagtcattctgagaatagtgtatgcggcg accgagttgctcttgcccggcgtcaatacgggataatac cgcgccacatagcagaactttaaaagtgctcatcattgg aaaacgttcttcggggcgaaaactctcaaggatcttacc gctgttgagatccagttcgatgtaacccactcgtgcaccc aactgatcttcagcatcttttactttcaccagcgtttctgggt gagcaaaaacaggaaggcaaaatgccgcaaaaaa gggaataagggcgacacggaaatgttgaatactcata ctcttcctttttcaatattattgaagcatttatcagggttattgt ctcatgagcggatacatatttgaatgtatttagaaaaata aacaaataggggttccgcgcacatttccccgaaaagtg ccacctgacgtctaagaaaccattattatcatgacattaacctataaaaataggcgtatcacgaggccctttcgtctcg cgcgtttcggtgatgacggtgaaaacctctgacacatgc agctcccggagacggtcacagcttgtctgtaagcggat gccgggagcagacaagcccgtcagggcgcgtcagc gggtgttggcgggtgtcggggctggcttaactatgcggc atcagagcagattgtactgagagtgcaccattcgacgct ctcccttatgcgactcctgcattaggaagcagcccagta gtaggttgaggccgttgagcaccgccgccgcaaggaa tggtctggcttatcgaaattaatacgactcactataggga gacc 82 pCG-4MC11- ggaattcgagctcgccccgttacataacttacggtaaat Petição 870250093142, de 10 / 10 / 2025, pág. 181 / 819 152 / 640 SEQ ID NO Nome Sequência VSV-G-WTST#7 ggcccgcctggctgaccgcccaacgacccccgcccat tgacgtcaataatgacgtatgttcccatagtaacgccaat agggactttccattgacgtcaatgggtggagtatttacgg taaactgcccacttggcagtacatcaagtgtatcatatgc caagtacgccccctattgacgtcaatgacggtaaatgg cccgcctggcattatgcccagtacatgaccttatgggact ttcctacttggcagtacatctacgtattagtcatcgctatta ccatggtgatgcggttttggcagtacatcaatgggcgtg gatagcggtttgactcacggggatttccaagtctccacc ccattgacgtcaatgggagtttgttttggcaccaaaatca acgggactttccaaaatgtcgtaacaactccgccccatt gacgcaaatgggcggtaggcgtgtacggtgggaggtc tatataagcagagctcgtttagtgaaccgtcagatcgcct ggagacgccatccacgctgttttgacctccatagaaga caccgggaccgatccagcctccgggggatcgatcccc ccgatcctgagaacttcagggtgagtttggggacccttg attgttctttctttttcgctattgtaaaattcatgttatatggag ggggcaaagttttcagggtgttgtttagaatgggaagat gtcccttgtatcaccatggaccctcatgataattttgtttcttt cactttctactctgttgacaaccattgtctcctcttattttctttt cattttctgtaactttttcgttaaactttagcttgcatttgtaac gaatttttaaattcacttttgtttatttgtcagattgtaagtactt tctctaatcacttttttttcaaggcaatcagggtatattatattgtacttcagcacagttttagagaacaattgttataattaaa tgataaggtagaatttctgcatataaattctggctggcg tggaaatattctttattggtagaaaacaactacatcctggtc atcatcctgcctttctctttatggttacaatgatatacactgtt tgagatgaggatactacgacgacgaggtc cctctgctaaccatgttcat gccttcttttttcctacagctc ctgggcaacgtgctggttattgtgctgtctcattttggc aaagaattgtaacgactcactatagggcgaattcgg atccccggtagttaatTAATACGCGTCACTAT GAAGTGCCI 1 1 IGIACCTAGCCIT Illi ATTCATTGGGGTGAATTGCAAGTTCAC GATCG I Illi CCACACAACCAAAAAGG AAACTGGAAAAATGTTCCTTCTAATTA Petition 870250093142, of 10 / 10 / 2025, p. 182 / 819 153 / 640 SEQ ID NO Name Sequence CCATTATTGCCCGTCAAGCTCAGA1 1 1 AAATTGGCATAATGACTTAATAGGCAC AGCCTTACAAGTCAAAATGCCCAAGAG TCACAAGGCTATTCAAGCAGACGGTT GGATGTGTCATGCTTCCAAATGGGTCA CTACTTGTGA1 1 1 GGTGGCTGGGGAT CGAAGTATATAACACATTCCATCCGAT CCTTCACTCCATCTGTAGAACAATGCA AGGAAAGCATTGAACAAACGAAACAA GGAACTTGGCTGAATCCAGGCTTCCC TCCTCAAAGTTGTGGATATGCAACTGT GACGGATGCCGAAGCAGTGATTGTCC AGGTGACTCCTCCATCGCTGTTGTT GATGAATACACAGGAGAATGGGTTGA TTCACAGTTCATCAACGGAAAATGCAG CAATTACATATGCCCCACTGTCCATAA CTCTACAACCTGGCATTCTGACTATAA GGTCAAAGGGCTATGTGATTCTAACCT CAIII CCATGGACATCACCTTCTTCTC AGAGGACGGAGACCATCCGGTCTA GAAAGGCCCACATCGTGATGGTGGAC GCCTACAAGCCTACCAAGGAGGGCAC AGGGTTCAGAAGTAACTAC III GCTTA TGAAACTGGAGGCAAGGCCTGCAAAA TGCAATACTGCAAGCATTGGGGAGTC AGACTCCCATCAGGTGTCTGGTTCGA GATGGCT GATAGTCGATCGAGCGA AGCCAGATTCCCTGAATGCCCAGAAG GGTCAAGTATCTCTGCTCCATCTCAGA CCTCAGTGGATGTAAGTCTAATTCAGG ACGTTGAGAGGATCTTGGATTATTCCC TCTGCCAAGAAACCTGGAGCAAAATCA GAGCGGGTCTTCCAATCTCTCCCAGTGCACCAI AATCAATGGTACCCTAAAATAC IIIGA Petition 870250093142, dated 10 / 10 / 2025, page 183 / 819 154 / 640 SEQ ID NO Name Sequence GACCAGATACATCAGAGTCGATATTGC TGCTCCAATCCTCTCAAGAATGGTCGG AATGATCAGTGGAACTACCACAGAAAG GGAACTGTGGGATGACTGGGCACCAT ATGAAGACGTGGAAATTGGACCCAAT GGAGTTCTGAGGACCAGTTCAGTAGGACCATA III ATACATGATTGGACAT GGTATGTTGGACTCCGATCTTCATCTT AGCTCAAAGGCTCAGGTGTTCGAACA TCCTCACATTCAAGACGCTGCTTCGCA ACTTCCTGATGAGAG I IIAIIIIII GGTGATACTGGGGCTATCCAAAAATCCA ATCGAGCTTGTAGAAGGTTAGTTGTTGACTGACTGACTGACTGACTGACTGACTIIII I IATCATAGGGTTAATCATTGGA CTATTCTTGGTTCTCCGAGTTGGTATC CAICI II GCATTAAATTAAAGCACACC AAGAAAAGACAGAI I IAIACAGACAIA GAGATGAACCGACTTGGAAAGTAACT CAAATCCTGCTAGGTATGAAAAAAACT AACAGATATCACGAGCTAGCTGGTGGT aatagacatcagaattaagaaaaacgtagggtccaa gtggttccccgttatggactcgctatctgtcaaccagatct tataccctgaagttcacctagatagcccgatagttacca ataagatagtagccatggagtatgctcgactgtttaa acctgcaggcatgcaagctgatctttccctcctgccaaacatgatgac ctggctaataaaggaaatttttcattgcaatagtgtgtt ggaatttttgtgtctctccggaaggacatatgggag ggcaaatcatttaaaacatcagaatgagtatttggtttagagtttggcaacatatgcccatatgctggctgccatgaac aaaggttggctataaagaggtcatcagtatatgaaaca gccccctgctgtccattccttattccatagaaaagccttga cttgaggttagattttttttatattttgttttgtgttatttttttcttta acatccctaaaattttccttacatgttttactagccagattttt cctcctctcctgactactcccagtcatagctgtccctcttct Petição 870250093142, de 10 / 10 / 2025, pág. 184 / 819 155 / 640 SEQ ID NO Nome Sequência cttatggagatccctcgaggagctttttgcaaaagcctag gcctccaaaaaagcctcttcactacttctggaatagctca gaagccgaggcggcctcggcctctgcataaataaaaa aaattagtcagccatggggcggagaatgggcggaact gggcggagttaggggcgggatgggcggagttagggg cgggactatggttgctgactaattgctgcattaatgaatc ggccaacgcgcggggagaggcggtttgcgtattgggc gctcttccgcttcctcgctcactgactcgctgcgctcggtc gttcggctgcggcgagcggtatcagctcactcaaaggc ggtaatacggttatccacagaatcaggggataacgca ggaaagaacatgtgagcaaaaggccagcaaaaggc caggaaccgtaaaaaggccgcgttgctggcgtttttcca taggctccgcccccctgacgagcatcacaaaaatcga cgctcaagtcagaggtggcgaaacccgacaggactat aaagataccaggcgtttccccctggaagctccctcgtgc gctctcctgttccgaccctgccgcttaccggatacctgtcc g cctttctcccttcg ggaagcgtggcgctttctcatagctc acgctgtaggtatctcagttcggtgtaggtcgttcgctcca agctgggctgtgtgcacgaaccccccgttcagcccgac cgctgcgccttatccggtaactatcgtcttgagtccaacc cggtaagacacgacttatcgccactggcagcagccact ggtaacaggattagcagagcgaggtatgtaggcggtg ctacagagttcttgaagtggtggcctaactacggctaca ctagaagaacagtatttggtatctgcgctctgctgaagccagttaccttcggaaaaagagttggtagctcttgatccggc aaacaaaccaccgctggtagcggtggtttttttgtttgcaa gcagcagattacgcgcagaaaaaaaggatctcaaga agatcctttgatcttttctacggggtctgacgctcagtgga acgaaaactcacgttaagggattttggtcatgagattatc aaaaaggatcttcacctagatccttttaaattaaaaatga agttttaaatcaatctaaagtatatatgagtaaacttggtct gacagttaccaatgcttaatcagtgaggcacctatctca gcgatctgtctatttcgttcatccatagttgcctgactcccc gtcgtgtagataactacgatacgggagggcttaccatct ggccccagtgctgcaatgataccgcgagacccacgct caccggctccagatttatcagcaataaaccagccagcc Petição 870250093142, de 10 / 10 / 2025, pág. 185 / 819 156 / 640 SEQ ID NO Nome Sequência ggaagggccgagcgcagaagtggtcctgcaactttatc cgcctccatccagtctattaattgttgccgggaagctaga gtaagtagttcgccagttaatagtttgcgcaacgttgttgc cattgctacaggcatcgtggtgtcacgctcgtcgtttggta tggcttcattcagctccggttcccaacgatcaaggcgag ttacatgatcccccatgttgtgcaaaaaagcggttagctc cttcggtcctccgatcgttgtcagaagtaagttggccgca gtgttatcactcatggttatggcagcactgcataattctctt actgtcatgccatccgtaagatgcttttctgtgactggtga gtactcaaccaagtcattctgagaatagtgtatgcggcg accgagttgctcttgcccggcgtcaatacgggataatac cgcgccacatagcagaactttaaaagtgctcatcattgg aaaacgttcttcggggcgaaaactctcaaggatcttacc gctgttgagatccagttcgatgtaacccactcgtgcaccc aactgatcttcagcatcttttactttcaccagcgtttctgggt gagcaaaaacaggaaggcaaaatgccgcaaaaaa gggaataagggcgacacggaaatgttgaatactcata ctcttcctttttcaatattattgaagcatttatcagggttattgt ctcatgagcggatacatatttgaatgtatttagaaaaata aacaaataggggttccgcgcacatttccccgaaaagtg ccacctgacgtctaagaaaccattattatcatgacattaa cctataaaaataggcgtatcacgaggccctttcgtctcg cgcgtttcggtgatgacggtgaaaacctctgacacatgc agctcccggagacggtcacagcttgtctgtaagcggatgccgggagcagacaagcccgtcagggcgcgtcagc gggtgttggcgggtgtcggggctggcttaactatgcggc atcagagcagattgtactgagagtgcaccattcgacgct ctcccttatgcgactcctgcattaggaagcagcccagta gtaggttgaggccgttgagcaccgccgccgcaaggaa tggtctggcttatcgaaattaatacgactcactataggga gacc 83 pCG-4MC11VSV-G-WTST#9 ggaattcgagctcgccccgttacataacttacggtaaat ggcccgcctggctgaccgcccaacgacccccgcccat tgacgtcaataatgacgtatgttcccatagtaacgccaat agggactttccattgacgtcaatgggtggagtatttacgg Petição 870250093142, de 10 / 10 / 2025, pág. 186 / 819 157 / 640 SEQ ID NO Nome Sequência taaactgcccacttggcagtacatcaagtgtatcatatgc caagtacgccccctattgacgtcaatgacggtaaatgg cccgcctggcattatgcccagtacatgaccttatgggact ttcctacttggcagtacatctacgtattagtcatcgctatta ccatggtgatgcggttttggcagtacatcaatgggcgtg gatagcggtttgactcacggggatttccaagtctccacc ccattgacgtcaatgggagtttgttttggcaccaaaatca acgggactttccaaaatgtcgtaacaactccgccccatt gacgcaaatgggcggtaggcgtgtacggtgggaggtc tatataagcagagctcgtttagtgaaccgtcagatcgcct ggagacgccatccacgctgttttgacctccatagaaga caccgggaccgatccagcctccgggggatcgatcccc ccgatcctgagaacttcagggtgagtttggggacccttg attgttctttctttttcgctattgtaaaattcatgttatatggag ggggcaaagttttcagggtgttgtttagaatgggaagat gtcccttgtatcaccatggaccctcatgataattttgtttcttt cactttctactctgttgacaaccattgtctcctcttattttctttt cattttctgtaactttttcgttaaactttagcttgcatttgtaac gaatttttaaattcacttttgtttatttgtcagattgtaagtactt tctctaatcacttttttttcaaggcaatcagggtatattatatt gtacttcagcacagttttagagaacaattgttataattaaa tgataaggtagaatatttctgcatataaattctggctggcg tggaaatattcttattggtagaaacaactacatcctggtcatcatcctgcctttctcttggttacaatgatatacactgtt tgagatgaggataaaatactctgagtccaaaccgggcc cctctgctaaccatgttcatgccttctctttttctctacagctc ctgggcaacgtgctggttattgctgctcatcatttgc aaagaattgtatactgatactc atcccccggtagttaatTAATACGCGTCACTAT GAAGTGCCI 1 1 IGIACHAGCCI Illi ATTCATTGGGGTGAATTGCAAGTTCAC GATCG I Illi CCACACAACCAAAAAGG AAACTGGAAAAATGTTCCTTCTAATTA CCATTATTGCCCGTCAAGCTCAGAI II AAACATTGGACTGACTGAG AGCCTTACAAGTCAAAATGCCCAAGAG Petition 870250093142, of 10 / 10 / 2025, p. 187 / 819 158 / 640 SEQ ID NO Name Sequence TCACAAGGCTATTCAAGCAGACGGTT GGATGTGTCATGCTTCCAAATGGGTCA CTACTTGTGA1 1 1 CCGCTGGTATGGAC CGAAGTATATAACACATTCCATCCGAT CCTTCACTCCATCTGTAGAACAATGCA AGGAAAGCATTGAACGAACGAACGAAAA GGAACTTGGCTGAATCCAGGCTTCCC TCCTCAAAGTTGTGGATATGCAACTGT GACGGATGCCGAAGCAGTGATTGTCC AGGTGACTCCTCCACCATGTGCTGGTT GATGAATACACAGGAGAATGGGTTGA TTCACAGTTCATCAACGGAAAATGCAG CAATTACATCCATCCCCATAGCC CTCTACAACCTGGCATTCTGACTATAA GGTCAAAGGGCTATGTGATTCTAACCT CAIII CCATGGACATCACCTTCTTCTC AGAGGACGGAGAGCTATCATCCCTGG GAAAGGAGGGCACAGGGTTCAGAAGT AACTACI II GCTTATGAAACTGGAGGC AAGCCTAGCCATAGCCAACT GCATTGGGGAGTCAGACTCCCATCAG GTGTCTGGTTCGAGATGGCTGATAAG GAICICI II GCTGCAGCCAGATTCCCT GAATGCCCAGAAGGGTCAAGTATCTC TGCTCCATCTCAGACCTCAGTGGATGT AAGTCTAATTCAGGACGTTGAGAGGAT CTTGGATCACCTAGCCTTAACCTT CTGGAGCAAAATCAGAGCGGGTCTTC CAATCTCTCCAGTGGATCTCAGCTATC TTGCTCCTAAAAACCCAGGAACCGGT CCIGC III CACCATAATCAATGGTACC CIAAAAIAC III GAGACCAGAIACAIC AGAGTCGATATTGCTGCTCCAATCCTC ICAAGAAIGGICGGAAGGAIGAIGIGIGAACIACCGCCCACAICGIGAIGGIGG ACGCCIACAAGCCIACCAAGACAGAA Petition 870250093142, dated 10 / 10 / 2025, pp. 188 / 819 159 / 640 SEQ ID NO Name Sequence AGGGAACTGTGGGATGACTGGGCACC ATATGAAGACGTGGAAATTGGACCCAA TGGAGTTCTGAGGACCAGTTCAGGAT ATAAG IIICCIIIATACATGATTGGACA TGGTATGTTGGACTCCGATCTTCATCT TAGCTCAAAGGTGATCTCATTC ATCCTCACATTCAAGACGCTGCTTCGC AACTTCCTGATGATGAGAGIIIAIIIIII TGGTGATACTGGGCTATCCAAAAATCC AATCGAGCTTGTAGAAGGTTGGTTCAG TAGTTGGAAAAGCTCTATTGCCTCI II IIICIIIATCATAGGGTTAATCATTGGA CTATTCCGTTTCGTTGATTGTTIGTTGGA GCATTAAATTAAAGCACACC AAGAAAAGACAGAI I IATACAGACATA GAGATGAACCGACTTGGAAAGTAACT CAAATCCTGCTAGGTATGAAAAAAACT AACAGATATCACGCCTAGGACTAGTgtg aaatagacatcagaattaagaaaaacgtagggtccaa gtggttccccgttatc tataccctgaagttcacctagatagcccgatagttacca ataagatagtagccatcctggagtatgctcgactgtttaa acctgcaggcatgcaagctgatctttttccctctgccaaa aattatggggacatcatgaagccccttgagcatctgactt ctggctaataaaggaaatttatttcattgcaatagtgtggttgttgttgttctctctctc ggcaaatcatttaaaacatcagaatgagtatttggtttag agtttggcaacatatgcccatatgctggctgccatgaac aaaggttggctataaagaggtcatcagtatatgaaacagccccctgctgtccattccttattccatagaaaagccttga cttgaggttagattttttttatattttgttttgtgttatttttttcttta acatccctaaaattttccttacatgttttactagccagattttt cctcctctcctgactactcccagtcatagctgtccctcttct cttatggagatccctcgaggagctttttgcaaaagcctag gcctccaaaaaagcctcttcactacttctggaatagctca gaagccgaggcggcctcggcctctgcataaataaaaa Petição 870250093142, de 10 / 10 / 2025, pág. 189 / 819 160 / 640 SEQ ID NO Nome Sequência aaattagtcagccatggggcggagaatgggcggaact gggcggagttaggggcgggatgggcggagttagggg cgggactatggttgctgactaattgctgcattaatgaatc ggccaacgcgcggggagaggcggtttgcgtattgggc gctcttccgcttcctcgctcactgactcgctgcgctcggtc gttcggctgcggcgagcggtatcagctcactcaaaggc ggtaatacggttatccacagaatcaggggataacgca ggaaagaacatgtgagcaaaaggccagcaaaaggc caggaaccgtaaaaaggccgcgttgctggcgtttttcca taggctccgcccccctgacgagcatcacaaaaatcga cgctcaagtcagaggtggcgaaacccgacaggactat aaagataccaggcgtttccccctggaagctccctcgtgc gctctcctgttccgaccctgccgcttaccggatacctgtcc g cctttctcccttcg ggaagcgtggcgctttctcatagctc acgctgtaggtatctcagttcggtgtaggtcgttcgctcca agctgggctgtgtgcacgaaccccccgttcagcccgac cgctgcgccttatccggtaactatcgtcttgagtccaacc cggtaagacacgacttatcgccactggcagcagccact ggtaacaggattagcagagcgaggtatgtaggcggtg ctacagagttcttgaagtggtggcctaactacggctaca ctagaagaacagtatttggtatctgcgctctgctgaagcc agttaccttcggaaaaagagttggtagctcttgatccggc aaacaaaccaccgctggtagcggtggtttttttgtttgcaa gcagcagattacgcgcagaaaaaaaggatctcaagaagatcctttgatcttttctacggggtctgacgctcagtgga acgaaaactcacgttaagggattttggtcatgagattatc aaaaaggatcttcacctagatccttttaaattaaaaatga agttttaaatcaatctaaagtatatatgagtaaacttggtct gacagttaccaatgcttaatcagtgaggcacctatctca gcgatctgtctatttcgttcatccatagttgcctgactcccc gtcgtgtagataactacgatacgggagggcttaccatct ggccccagtgctgcaatgataccgcgagacccacgct caccggctccagatttatcagcaataaaccagccagcc ggaagggccgagcgcagaagtggtcctgcaactttatc cgcctccatccagtctattaattgttgccgggaagctaga gtaagtagttcgccagttaatagtttgcgcaacgttgttgc Petição 870250093142, de 10 / 10 / 2025, pág. 190 / 819 161 / 640 SEQ ID NO Nome Sequência cattgctacaggcatcgtggtgtcacgctcgtcgtttggta tggcttcattcagctccggttcccaacgatcaaggcgag ttacatgatcccccatgttgtgcaaaaaagcggttagctc cttcggtcctccgatcgttgtcagaagtaagttggccgca gtgttatcactcatggttatggcagcactgcataattctctt actgtcatgccatccgtaagatgcttttctgtgactggtga gtactcaaccaagtcattctgagaatagtgtatgcggcg accgagttgctcttgcccggcgtcaatacgggataatac cgcgccacatagcagaactttaaaagtgctcatcattgg aaaacgttcttcggggcgaaaactctcaaggatcttacc gctgttgagatccagttcgatgtaacccactcgtgcaccc aactgatcttcagcatcttttactttcaccagcgtttctgggt gagcaaaaacaggaaggcaaaatgccgcaaaaaa gggaataagggcgacacggaaatgttgaatactcata ctcttcctttttcaatattattgaagcatttatcagggttattgt ctcatgagcggatacatatttgaatgtatttagaaaaata aacaaataggggttccgcgcacatttccccgaaaagtg ccacctgacgtctaagaaaccattattatcatgacattaa cctataaaaataggcgtatcacgaggccctttcgtctcg cgcgtttcggtgatgacggtgaaaacctctgacacatgc agctcccggagacggtcacagcttgtctgtaagcggat gccgggagcagacaagcccgtcagggcgcgtcagc gggtgttggcgggtgtcggggctggcttaactatgcggc atcagagcagattgtactgagagtgcaccattcgacgctctcccttatgcgactcctgcattaggaagcagcccagta gtaggttgaggccgttgagcaccgccgccgcaaggaa tggtctggcttatcgaaattaatacgactcactataggga gacc 84 pCG-4MC11VSV-G-WTST#11 ggaattcgagctcgccccgttacataacttacggtaaat ggcccgcctggctgaccgcccaacgacccccgcccat tgacgtcaataatgacgtatgttcccatagtaacgccaat agggactttccattgacgtcaatgggtggagtatttacgg taaactgcccacttggcagtacatcaagtgtatcatatgc caagtacgccccctattgacgtcaatgacggtaaatgg cccgcctggcattatgcccagtacatgaccttatgggact Petição 870250093142, de 10 / 10 / 2025, pág. 191 / 819 162 / 640 SEQ ID NO Nome Sequência ttcctacttggcagtacatctacgtattagtcatcgctatta ccatggtgatgcggttttggcagtacatcaatgggcgtg gatagcggtttgactcacggggatttccaagtctccacc ccattgacgtcaatgggagtttgttttggcaccaaaatca acgggactttccaaaatgtcgtaacaactccgccccatt gacgcaaatgggcggtaggcgtgtacggtgggaggtc tatataagcagagctcgtttagtgaaccgtcagatcgcct ggagacgccatccacgctgttttgacctccatagaaga caccgggaccgatccagcctccgggggatcgatcccc ccgatcctgagaacttcagggtgagtttggggacccttg attgttctttctttttcgctattgtaaaattcatgttatatggag ggggcaaagttttcagggtgttgtttagaatgggaagat gtcccttgtatcaccatggaccctcatgataattttgtttcttt cactttctactctgttgacaaccattgtctcctcttattttctttt cattttctgtaactttttcgttaaactttagcttgcatttgtaac gaatttttaaattcacttttgtttatttgtcagattgtaagtactt tctctaatcacttttttttcaaggcaatcagggtatattatatt gtacttcagcacagttttagagaacaattgttataattaaa tgataaggtagaatatttctgcatataaattctggctggcg tggaaatattcttattggtagaaacaactacatcctggtc atcatcctgcctttctctttatggttacaatgatatacactgtt tgagatgaggataaaatactctgagtccaaaccgggcc cctctgctaaccatgttcatgccttcttctttttcctacagctcctgggcaacgtgctggttattgtgctgtctcatcattttggc aaagaattgtaatacgactcactatagggcgaattcgg atcccccggtagttaatTAATACGCGTCACTAT GAAGTGCCI 1 1 IGIACHAGCCI Illi ATTCATTGGGGTGAATTGCAAGTTCAC ICCACAGAACCAACCAA AAACTGGAAAAATGTTCCTTCTAATTA CCATTATTGCCCGTCAAGCTCAGAI II AAATTGGCATAATGACTTAATAGGCGC CCACATCGTGATGGTGGACGCCTACA AGCCTACCAAGACAGCCTTACAAGTCA AAATGCCCAAGAGTCAAGGCTATTC AAGCAGACGGTTGGGATGTCGCTGCT Petition 870250093142, of 10 / 10 / 2025, p. 192 / 819 163 / 640 SEQ ID NO Name Sequence TCCAAATGGGTCACTACTTGTGAIIIC CGCTGGTATGGACCGAAGTATATAACA CATTCCATCCGATCCTTCCACTCCATCT GTAGAACAATGCAAGGAAAGCATTGAA CAAACGAAACAAGGAACTTGGCTGAAT CCAGGCTTCCCCTCAAAGGTTGATTGGTTGATTGGATTGAAT CAGTGATTGTCCAGGTGACTCCTCAC CATGTGCTGGTTGATGAATACACAGGA GAATGGGTTGATTCACAGTTCATCAAC GGAAAATGCAGCAATTACATATGCCCC ACTGTCCATAACTCTACAACCTGGCAT TCTGACTATAAGGTCAAAGGGCTATGT GATTCTAACCTCAICATGA IICCATGTCGA ACCTTCTTCTCAGAGGACGGAGAGCT ATCATCCCTGGGAAAGGAGGGCACAG GGπCAGAAGTAACTAC III GCIIAIG AAACTGGAGGCAAGGCCTGCAAAATG CAATACTGCAAGCATTGGGGAGTCAG ACTCCCATCAGGTGTCTGGTTCGAGAT GGCTGATAGGAGTCAGTC CCAGATTCCCTGAATGCCCAGAAGGG TCAAGTATCTCTGCTCCATCTCAGACC TCAGTGGATGTAAGTCTAATTCAGGAC GTTGAGAGGATCTTGGATTATTCCCTC TGCCAAGAAACCTGGAGCAAAATCAG AGCGGGTCTTCCAATCTCTCCCAGTGG CACCAIAA TCAATGGTACCCTAAAATAC III GAGA CCAGATACATCAGAGTCGATATTGCTG CTCCAATCCTCTCAAGAATGGTCGGAA TGATCAGTGGAACTACCACAGAAAGG GAACTGTGGGATGACTGGGCACCATATGAAGACGTGGAAATTGGACCCAATG GAGTTCTGAGGACCAGTTCAGGATATA Petition 870250093142, dated 10 / 10 / 2025, page 193 / 819 164 / 640 SEQ ID NO Name Sequence AGIIICCIIIAIACATGATTGGACATG GTATGTTGGACTCCGATCTTCATCTTA GCTCAAAGGCTCAGGTGTTCGAACAT CCTCACATTCAAGACGCTGCTTCGCAA CTTCCTGATGAGAG IIIAIIIIIIG GTGATACTGAAGGATCCATCCATCCAA TCGAGCTTGTAGAAGGTTGGTTCAGTA GTTGGAAAAGCTCTTATTGCCTC IIIT TCI I IATCATAGGGTTAATCATTGGAC TATTCTTGGTTCTCCGAGTTGGTATCC ATCI II GCATTAAATTAAAGCACACCA AGAAAAGACAGAI I IATACAGACATAG AGATGAACGACTGACTGACTGACTGACTCATTGGAC AATCCTGCTAGGTATGAAAAAAACTAA CAGATATCACGCCTAGGACTAGTgtgaa atagacatcagaattaagaaaaaacgtagggtccaagt ggttccccgttatggactcgctatctgtcaaccagatctta taccctgaagttcacctagatagcccgatagttaccaat aagatagtagccatcctgagctgactgacttacttactta ctgcaggcatgcaagctgatctttttccctctgccaaaaa tttggggacatcatgaagccccttgagcatctgacttct ggctaataaaggaaatttattcattgcaatagtgtgttgg aatttttgtgtctctccggaaggacatatgggaggg caaatcatttaaaacattcgaattgagttagagt ttggcaacatatgcccatatgctggctgccatgaacaaaa ggttggctataaagaggtcatcagtatatgaaacagcc ccctgctgtccattccttattccatagaaaagccttgacttg aggttagattttttattatttttgttttgtgttatttttctttaacatccctaaaattttccttacatgttttactagccagatttttcctc ctctcctgactactcccagtcatagctgtccctcttctcttat ggagatccctcgaggagctttttgcaaaagcctaggcct ccaaaaaagcctcttcactacttctggaatagctcagaa gccgaggcggcctcggcctctgcataaataaaaaaaa ttagtcagccatggggcggagaatgggcggaactggg cggagttaggggcgggatgggcggagttaggggcgg gactatggttgctgactaattgctgcattaatgaatcggcc Petição 870250093142, de 10 / 10 / 2025, pág. 194 / 819 165 / 640 SEQ ID NO Nome Sequência aacgcgcggggagaggcggtttgcgtattgggcgctctt ccgcttcctcgctcactgactcgctgcgctcggtcgttcg gctgcggcgagcggtatcagctcactcaaaggcggta atacggttatccacagaatcaggggataacgcaggaa agaacatgtgagcaaaaggccagcaaaaggccagg aaccgtaaaaaggccgcgttgctggcgtttttccatagg ctccgcccccctgacgagcatcacaaaaatcgacgct caagtcagaggtggcgaaacccgacaggactataaa gataccaggcgtttccccctggaagctccctcgtgcgct ctcctgttccgaccctgccgcttaccggatacctgtccgc ctttctcccttcgggaagcgtggcgctttctcatagctcac gctgtaggtatctcagttcggtgtaggtcgttcgctccaag ctgggctgtgtgcacgaaccccccgttcagcccgaccg ctgcgccttatccggtaactatcgtcttgagtccaacccg gtaagacacgacttatcgccactggcagcagccactg gtaacaggattagcagagcgaggtatgtaggcggtgct acagagttcttgaagtggtggcctaactacggctacact agaagaacagtatttggtatctgcgctctgctgaagcca gttaccttcggaaaaagagttggtagctcttgatccggca aacaaaccaccgctggtagcggtggtttttttgtttgcaag cagcagattacgcgcagaaaaaaaggatctcaagaa gatcctttgatcttttctacggggtctgacgctcagtggaa cgaaaactcacgttaagggattttggtcatgagattatca aaaaggatcttcacctagatccttttaaattaaaaatgaagttttaaatcaatctaaagtatatatgagtaaacttggtctg acagttaccaatgcttaatcagtgaggcacctatctcag cgatctgtctatttcgttcatccatagttgcctgactccccgt cgtgtagataactacgatacgggagggcttaccatctgg ccccagtgctgcaatgataccgcgagacccacgctca ccggctccagatttatcagcaataaaccagccagccgg aagggccgagcgcagaagtggtcctgcaactttatccg cctccatccagtctattaattgttgccgggaagctagagt aagtagttcgccagttaatagtttgcgcaacgttgttgcca ttgctacaggcatcgtggtgtcacgctcgtcgtttggtatg gcttcattcagctccggttcccaacgatcaaggcgagtt acatgatcccccatgttgtgcaaaaaagcggttagctcc Petição 870250093142, de 10 / 10 / 2025, pág. 195 / 819 166 / 640 SEQ ID NO Nome Sequência ttcggtcctccgatcgttgtcagaagtaagttggccgcag tgttatcactcatggttatggcagcactgcataattctctta ctgtcatgccatccgtaagatgcttttctgtgactggtgagt actcaaccaagtcattctgagaatagtgtatgcggcgac cgagttgctcttgcccggcgtcaatacgggataataccg cgccacatagcagaactttaaaagtgctcatcattggaa aacgttcttcggggcgaaaactctcaaggatcttaccgc tgttgagatccagttcgatgtaacccactcgtgcaccca actgatcttcagcatcttttactttcaccagcgtttctgggtg agcaaaaacaggaaggcaaaatgccgcaaaaaag ggaataagggcgacacggaaatgttgaatactcatact cttcctttttcaatattattgaagcatttatcagggttattgtct catgagcggatacatatttgaatgtatttagaaaaataaa caaataggggttccgcgcacatttccccgaaaagtgcc acctgacgtctaagaaaccattattatcatgacattaacc tataaaaataggcgtatcacgaggccctttcgtctcgcg cgtttcggtgatgacggtgaaaacctctgacacatgcag ctcccggagacggtcacagcttgtctgtaagcggatgc cgggagcagacaagcccgtcagggcgcgtcagcgg gtgttggcgggtgtcggggctggcttaactatgcggcatc agagcagattgtactgagagtgcaccattcgacgctctc ccttatgcgactcctgcattaggaagcagcccagtagta ggttgaggccgttgagcaccgccgccgcaaggaatgg tctggcttatcgaaattaatacgactcactatagggagac c 85pCG-4MC11VSV-G-WT-STL#1 ggaattcgagctcgccccgttacataacttacggtaaat ggcccgcctggctgaccgcccaacgacccccgcccat tgacgtcaataatgacgtatgttcccatagtaacgccaat agggactttccattgacgtcaatgggtggagtatttacgg taaactgcccacttggcagtacatcaagtgtatcatatgc caagtacgccccctattgacgtcaatgacggtaaatgg cccgcctggcattatgcccagtacatgaccttatgggact ttcctacttggcagtacatctacgtattagtcatcgctatta ccatggtgatgcggttttggcagtacatcaatgggcgtg gatagcggtttgactcacggggatttccaagtctccacc Petição 870250093142, de 10 / 10 / 2025, pág. 196 / 819 167 / 640 SEQ ID NO Nome Sequência ccattgacgtcaatgggagtttgttttggcaccaaaatca acgggactttccaaaatgtcgtaacaactccgccccatt gacgcaaatgggcggtaggcgtgtacggtgggaggtc tatataagcagagctcgtttagtgaaccgtcagatcgcct ggagacgccatccacgctgttttgacctccatagaaga caccgggaccgatccagcctccgggggatcgatcccc ccgatcctgagaacttcagggtgagtttggggacccttg attgttctttctttttcgctattgtaaaattcatgttatatggag ggggcaaagttttcagggtgttgtttagaatgggaagat gtcccttgtatcaccatggaccctcatgataattttgtttcttt cactttctactctgttgacaaccattgtctcctcttattttctttt cattttctgtaactttttcgttaaactttagcttgcatttgtaac gaatttttaaattcacttttgtttatttgtcagattgtaagtactt tctctaatcacttttttttcaaggcaatcagggtatattatatt gtacttcagcacagttttagagaacaattgttataattaaa tgataaggtagaatatttctgcatataaattctggctggcg tggaaatattcttattggtagaaacaactacatcctggtc atcatcctgcctttctctttatggttacaatgatatacactgtt tgagatgaggataaaatactctgagtccaaaccgggcc cctctgctaaccatgttcatgccttcttctttttcctacagctc ctgggcaacgtgctggttattgtgctgtctcatcattttggc aaagaattgtaatacgactcactatagggcgaattcgg atcccccggtagttaatTAATACGCGTCACTAT GAAGTGCCI 11 IGIACHAGCCI Illi ATTCATTGGGGTGAATTGCGCCCACAT CGTGATGGTGGATGCCTATAAACCAA CAAAGGGCAGCGGCGGCTCCGGAAA GTTCACGATCGI IlliCCACACCAACCA AAAAGGAAACTGGAAAAATGTTCCTTC TAATTACCATTATTCAAGCCGTGATTGAATTAGTCATTAGACTATTAGCCTA GGCACAGCCTTACAAGTCAAAATGCC CAAGAGTCACAAGGCTATTCAAGCAG ACGGTTGGATGTGTCATGCTTCCAAAT GGGTCACTACTTGTGAI II CCGCIGGI ATGGACCGAAGTATATAACACATTCCA Petition 870250093142, of 10 / 10 / 2025, p. 197 / 819 168 / 640 SEQ ID NO Nome Sequência TCCGATCCTTCACTCCATCTGTAGAAC AATGCAAGGAAAGCATTGAACAAACGA AACAAGGAACTTGGCTGAATCCAGGC TTCCCTCCTCAAAGTTGTGGATATGCA ACTGTGACGGATGCCGAAGCAGTGAT TGTCCAGGTGACTCCTCACCATGTGCT GGTTGATGAATACACAGGAGAATGGG TTGATTCACAGTTCATCAACGGAAAAT GCAGCAATTACATATGCCCCACTGTCC ATAACTCTACAACCTGGCATTCTGACT ATAAGGTCAAAGGGCTATGTGATTCTA ACCTCA1 1 1 CCATGGACATCACCTTCT TCTCAGAGGACGGAGAGCTATCATCC CTGGGAAAGGAGGGCACAGGGTTCAG AAGTAACTAC1 1 1 GCTTATGAAACTGG AGGCAAGGCCTGCAAAATGCAATACT GCAAGCATTGGGGAGTCAGACTCCCA TCAGGTGTCTGGTTCGAGATGGCTGA TAAGGATCTC 1 1 1 GCTGCAGCCAGATT CCCTGAATGCCCAGAAGGGTCAAGTA TCTCTGCTCCATCTCAGACCTCAGTGG ATGTAAGTCTAATTCAGGACGTTGAGA GGATCTTGGATTATTCCCTCTGCCAAG AAACCTGGAGCAAAATCAGAGCGGGT CTTCCAATCTCTCCAGTGGATCTCAGC TATCTTGCTCCTAAAAACCCAGGAACC GGTCCTGC 1 1 1 CACCATAATCAATGGT ACCCTAAAATAC 1 1 1 GAGACCAGATAC ATCAGAGTCGATATTGCTGCTCCAATC CTCTCAAGAATGGTCGGAATGATCAGT GGAACTACCACAGAAAGGGAACTGTG GGATGACTGGGCACCATATGAAGACG TGGAAATTGGACCCAATGGAGTTCTGA GGACCAGTTCAGGATATAAG 1 1 1 CCTTTATACATGATTGGACATGGTATGTTGG ACTCCGATCTTCATCTTAGCTCAAAGG Petition 870250093142, dated 10 / 10 / 2025, pp. 198 / 819 169 / 640 SEQ ID NO Name Sequence CTCAGGTGTTCGAACATCCTCACATTC AAGACGCTGCTTCGCAACTTCCTGATG ATGAGAG IIIAIIIIII GGTGATACTG GGCTATCCAAAAATCCAATCGAGCTTG TAGAAGGTTGGTTCAGTAGTTGGAAAAA GTCTATTGCCTCIIICCIIIACATG AGGGTTAATCATTGGACTATTCTTGGT TCTCCGAGTTGGTATCCATCI II GCAI TAAATTAAAGCACACCAAGAAAAGACA ACTTGGAAAGTAACTCAAATCCTGCTA GGTATGAAAAAACTAACAGATATCAC aagaaaaacgtagggtccaagtggttccccgttatgga ctcgctatctgtcaaccagatcttataccctgaagttcacc tagatagcccgatagttaccaataagatagtagccatcc tggagtatgctcgactgtttaaacctgcaggcatgcaag ctgatctttccctctgccaaaaattatggcatcatg aagccccttgagcatctgacttctggctaataaaaaa tttattttcattgcaatagtgtgttggaatttttgtgtctctcac tcggaaggacatatgggagggcaaatcatttaaaacat cagaatgagtatttggttagagtttggcaacatatgccc atatgctggctgccatgac ggtcatcagtatatgaaacagccccctgctgtccattcctt attccatagaaaagccttgacttgaggttagatttttttatta tttgttttgtgttatttttctttaacatccctaaaattttccttac atgttttactagccagatttttcctctctcagtcatagctgtccctctctcttatggagatccctcgagg agctttttgcaaaagcctaggcctccaaaaaagcctct cactacttctggaatagctcagaagccgaggcggcctc ggcctctgcataaataaaaaaaaaataggcgcgcgcgc ggatgggcggagttaggggcgggactatggttgctgac taattgctgcattaatgaatcggccaacgcgcgggg aggcggtttgcgtattgggcctctcgcttcgctca ctgactcgctgcgctcggtcgttcggcgcgcggcgg Petition 870250093142, of 10 / 10 / 2025, p. 199 / 819 170 / 640 SEQ ID NO Nome Sequence tatcagctcactcaaaggcggtaatacggttatccacag aatcaggggataacgcaggaaagaacatgtgagcaa aaggccagcaaaaggccaggaaccgtaaaaggcc gcgttgctggcg ttttccata ggctccgccccccgcg agcatcacaaaaatcgacgctcaagtcagaggtggcg aaacccgacaggactataaagataccaggggtttccc cctggaagctccctcgtgcgctctctgttccgaccctgc cgcttaccggatacctgtccgccttctctccttcgggaag cgtggcgcttctcctcctctcgttagtt cggtgtaggtcgttcgctccaagctgggctgtgtgcacg aaccccgttcagcccgaccgctgcgccttatccggta actatcgtcttgagtccaacccggtaagacacgacttat cgccactggcagcactggtaacaggattagcag agcgaggtatgtaggcggtcgagctg gtggcctaactacggctacactagaagaacagtatttgg tatctcgctctgctgaagccagttaccttcggaaaaag agttggtagctcttgatcggcaaaaaaccaccgctg gtagcggtggttttttgtttgcaagcagcagattacgcgc agaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaccaccgcgcgcaagcagattacgcgc cggggtctgacgctcagtggaacgaaaactcacgttaa gggattttggtcatgagattatcaaaaaggatcttcacct agatccttttaaattaaaaatgaagttttaaatcaatctaa agtatatatgagtaaacttggtctgacagttaccaatgctt aatcagtgaggcacctatctcgctctcgattctcgttcatccatagttgcctgactccccgtcgtgtagataactac gatacgggagggcttaccatctggccccagtgctgcaa tgataccgcgagacccacgctcaccggctccagatttat cagcaataaaccagccagccggaagggccgagcgc agaagtggtcctgcaactttatccgcctccatccagtctat taattgttgccgggaagctagagtaagtagttcgccagtt aatagtttgcgcaacgttgttgccattgctacaggcatcgt ggtgtcacgctcgtcgtttggtatggcttcattcagctccg gttcccaacgatcaaggcgagttacatgatcccccatgt tgtgcaaaaaagcggttagctccttcggtcctccgatcgt tgtcagaagtaagttggccgcagtgttatcactcatggtt atggcagcactgcataattctcttactgtcatgccatccgt Petição 870250093142, de 10 / 10 / 2025, pág. 200 / 819 171 / 640 SEQ ID NO Nome Sequência aagatgcttttctgtgactggtgagtactcaaccaagtcat tctgagaatagtgtatgcggcgaccgagttgctcttgccc ggcgtcaatacgggataataccgcgccacatagcaga actttaaaagtgctcatcattggaaaacgttcttcggggc gaaaactctcaaggatcttaccgctgttgagatccagttc gatgtaacccactcgtgcacccaactgatcttcagcatct tttactttcaccagcgtttctgggtgagcaaaaacaggaa ggcaaaatgccgcaaaaaagggaataagggcgaca cggaaatgttgaatactcatactcttcctttttcaatattattg aagcatttatcagggttattgtctcatgagcggatacatat ttgaatgtatttagaaaaataaacaaataggggttccgc gcacatttccccgaaaagtgccacctgacgtctaagaa accattattatcatgacattaacctataaaaataggcgta tcacgaggccctttcgtctcgcgcgtttcggtgatgacgg tgaaaacctctgacacatgcagctcccggagacggtc acagcttgtctgtaagcggatgccgggagcagacaag cccgtcagggcgcgtcagcgggtgttggcgggtgtcgg ggctggcttaactatgcggcatcagagcagattgtactg agagtgcaccattcgacgctctcccttatgcgactcctgc attaggaagcagcccagtagtaggttgaggccgttgag caccgccgccgcaaggaatggtctggcttatcgaaatt aatacgactcactatagggagacc 86 pCG-4MC11VSV-G-WT-STL#2 ggaattcgagctcgccccgttacataacttacggtaaat ggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaat agggactttccattgacgtcaatgggtggagtatttacgg taaactgcccacttggcagtacatcaagtgtatcatatgc caagtacgccccctattgacgtcaatgacggtaaatgg cccgcctggcattatgcccagtacatgaccttatgggact ttcctacttggcagtacatctacgtattagtcatcgctatta ccatggtgatgcggttttggcagtacatcaatgggcgtg gatagcggtttgactcacggggatttccaagtctccacc ccattgacgtcaatgggagtttgttttggcaccaaaatca acgggactttccaaaatgtcgtaacaactccgccccatt gacgcaaatgggcggtaggcgtgtacggtgggaggtc Petição 870250093142, de 10 / 10 / 2025, pág. 201 / 819 172 / 640 SEQ ID NO Nome Sequência tatataagcagagctcgtttagtgaaccgtcagatcgcct ggagacgccatccacgctgttttgacctccatagaaga caccgggaccgatccagcctccgggggatcgatcccc ccgatcctgagaacttcagggtgagtttggggacccttg attgttctttctttttcgctattgtaaaattcatgttatatggag ggggcaaagttttcagggtgttgtttagaatgggaagat gtcccttgtatcaccatggaccctcatgataattttgtttcttt cactttctactctgttgacaaccattgtctcctcttattttctttt cattttctgtaactttttcgttaaactttagcttgcatttgtaac gaatttttaaattcacttttgtttatttgtcagattgtaagtactt tctctaatcacttttttttcaaggcaatcagggtatattatatt gtacttcagcacagttttagagaacaattgttataattaaa tgataaggtagaatatttctgcatataaattctggctggcg tggaaatattcttattggtagaaacaactacatcctggtc atcatcctgcctttctctttatggttacaatgatatacactgtt tgagatgaggataaaatactctgagtccaaaccgggcc cctctgctaaccatgttcatgccttcttctttttcctacagctc ctgggcaacgtgctggttattgtgctgtctcatcattttggc aaagaattgtaatacgactcactatagggcgaattcgg atcccccggtagttaatTAATACGCGTCACTAT GAAGTGCCI 1 1 IGIACUAGCCI Illi ATTCATTGGGGTGAATTGCAAGTTCAC GATCG I Illi CCACACAACCAAAAAGG AAACTGGAAAAATGTTCCTTCTAATTACCATTATTGCCCGTCAAGCTCAGAI II AAATTGGCATAATGGCAGCGGCGGAA GCGGCGCCCACATTTGTGATGGTGGAT GCCTATAAACCAACAAAAGGCTCCGG AGGCTCTGGAGACTTAATAGGCACAG CCTTACAAGTCAAATGCCCAAGAGTC ACAAGGTATTCAAGGCCGGGAG ATGTGTCATGCTTCCAAATGGGTCACT ACIIGIGAI II CCGCIGGIAIGGACCG AAGTATATAACACATTCCATCCGATCC TTCACTCCATCTGTAGAACAATGCAAG GAAAGCAIIGAACAAACGAAACAAGG Petition 870250093142, of 10 / 10 / 2025, p. 202 / 819 173 / 640 SEQ ID NO Name Sequence AACTTGGCTGAATCCAGGCTTCCCTCC TCAAAGTTGTGGATATGCAACTGTGAC GGATGCCGAAGCAGTGATTGTCCAGG TGACTCCTCACCATGTGCTGGTTGATG AATACACAGGAGAATGGGTTGATTCAC AGTTCATCAACGAGCAGGATAATGATTCAC ACATATGCCCCACTGTCCATAACTCTA CAACCTGGCATTCTGACTATAAGGTCA AAGGGCTATGTGATTCTAACCTCA1 1 1 CCATGGACATCACCTTCTTCAGAGG ACGGAGAGCTATCATCCCTGGGAAAG GAGGGCACAGGGTTCAGAAGTAACTA Clll GAACTGACTGGGACTGAGGTTCA CCTGCAAAATGCAATACTGCAAGCATT GGGGAGTCAGACTCCCATCAGGTGTC TGGTTCGAGATGGCTGATAAGGATCT Clll GCTGCAGCCAGATTCCCTGAATG CCCAGAAGGGTCAAGTATCTCTGCTC CATCTCAGACCTCAGTGGATGTAAGTC attattccctctgccaagaaacctgga gcaaaatcagagcgggtcttccaatct ctccagtggatctcagctatcttgctc ctaaaaacccaggaaccggtcctgct ttcaccataatcaatggtaccctaaaaa TAC lll gagaccagatacatcagagtc gatattgctgctgaccatcctcgcgc cacagaaagggaactgtgggatgact gggcaccatatgaagacgtggaaatt ggacccaatggagttctgaggaccag ttcaggatataag iiicciii atacatg attggacatggtatgttggactccgat cttcatcttagctcaaaggctcaggtgttcgaacatcctcacattcaagacgct gcttcgcaacttcctgatgatgagagt Petition 870250093142, dated 10 / 10 / 2025, page 203 / 819 174 / 640 SEQ ID NO Name Sequence TTAIIIIIIGGI GATACTGGGCTATCC AAAAATCCAATCGAGCTTGTAGAAGGT TGGTTCAGTAGTTGGAAAAGCTCTATT GCCICIIIIIICIIIATCATAGGGTTAA TCAπGGACTAπcπGGπCTCCGAG IIGGIAICCAAICTAAITAAITAAITAA GCACACCAAGAAAAGACAGAI I IAIAC AGACAIAGAGAIGAACCGACIIGGAA AGTAACTCAAATCCTGCTAGGTATGAA AAAAACTAACAGATATCACGCCTAGGA CIAGIgtgaaatagacatcagaattaagaaaaacg tagggtccaagtggttccccgtatcgctatc atagttaccaataagatagtagccatcctggagtatgctc gactgtttaaacctgcaggcatgcaagctgatcttttccc tctgccaaaaattatggggacatcatgaagccccttgag catctgacttctggctaataaaggaaatttattcattgca atagtgtgttggaatttttttgtgtctcctc tatgggagggcaaatcatttaaaacatcagaatgagtat ttggtttagagtttggcaacatatgcccatatgctggctgc catgaacaaaggttggctataaagaggtcatcagtatat gaaacagccccctgctgtccattccttattccatagaaaa gccttgacttgaggttagattttttttt tttctttaacatccctaaaatttccttacatgttttactagcc agatttttcctctctctgactactcccagtcatagctgtc cctctctcttatggagatccctcgaggag cttttg caaaagcctaggcctccaaaaaagcctcttcactacttctgga atagctcagaagccgaggcggcctcggcctctctgcata aataaaaaaattagtcagccatggggcggagaatgg gcggaactgggcggagttaggggcgggatgggcgga gttaggggcgggactatggttgctgactaattgctgcatt aatgaatcggccaacgcgcggggagaggcggtttgcg tattgggcgctcttccgcttcctcgctcactgactcgctgc gctcggtcgttcggctgcggcgagcggtatcagctcact caaaggcggtaatacggttatccacagaatcagggga taacgcaggaaagaacatgtgagcaaaaggccagc Petition 870250093142, dated 10 / 10 / 2025, page 204 / 819 175 / 640 SEQ ID NO Nome Sequência aaaaggccaggaaccgtaaaaaggccgcgttgctgg cgtttttccataggctccgcccccctgacgagcatcaca aaaatcgacgctcaagtcagaggtggcgaaacccga caggactataaagataccaggcgtttccccctggaagc tccctcgtgcgctctcctgttccgaccctgccgcttaccgg atacctgtccgcctttctcccttcgggaagcgtggcgcttt ctcatagctcacgctgtaggtatctcagttcggtgtaggtc gttcgctccaagctgggctgtgtgcacgaaccccccgtt cagcccgaccgctgcgccttatccggtaactatcgtcttg agtccaacccggtaagacacgacttatcgccactggca gcagccactggtaacaggattagcagagcgaggtatg taggcggtgctacagagttcttgaagtggtggcctaact acggctacactagaagaacagtatttggtatctgcgctct gctgaagccagttaccttcggaaaaagagttggtagctc ttgatccggcaaacaaaccaccgctggtagcggtggttt ttttgtttgcaagcagcagattacgcgcagaaaaaaag gatctcaagaagatcctttgatcttttctacggggtctgac gctcagtggaacgaaaactcacgttaagggattttggtc atgagattatcaaaaaggatcttcacctagatccttttaa attaaaaatgaagttttaaatcaatctaaagtatatatga gtaaacttggtctgacagttaccaatgcttaatcagtgag gcacctatctcagcgatctgtctatttcgttcatccatagtt gcctgactccccgtcgtgtagataactacgatacggga gggcttaccatctggccccagtgctgcaatgataccgcgagacccacgctcaccggctccagatttatcagcaataa accagccagccggaagggccgagcgcagaagtggt cctgcaactttatccgcctccatccagtctattaattgttgc cgggaagctagagtaagtagttcgccagttaatagtttg cgcaacgttgttgccattgctacaggcatcgtggtgtcac gctcgtcgtttggtatggcttcattcagctccggttcccaac gatcaaggcgagttacatgatcccccatgttgtgcaaaa aagcggttagctccttcggtcctccgatcgttgtcagaag taagttggccgcagtgttatcactcatggttatggcagca ctgcataattctcttactgtcatgccatccgtaagatgctttt ctgtgactggtgagtactcaaccaagtcattctgagaata gtgtatgcggcgaccgagttgctcttgcccggcgtcaat Petição 870250093142, de 10 / 10 / 2025, pág. 205 / 819 176 / 640 SEQ ID NO Nome Sequência acgggataataccgcgccacatagcagaactttaaaa gtgctcatcattggaaaacgttcttcggggcgaaaactct caaggatcttaccgctgttgagatccagttcgatgtaacc cactcgtgcacccaactgatcttcagcatcttttactttcac cagcgtttctgggtgagcaaaaacaggaaggcaaaat gccgcaaaaaagggaataagggcgacacggaaatg ttgaatactcatactcttcctttttcaatattattgaagcattta tcagggttattgtctcatgagcggatacatatttgaatgtat ttagaaaaataaacaaataggggttccgcgcacatttcc ccgaaaagtgccacctgacgtctaagaaaccattattat catgacattaacctataaaaataggcgtatcacgaggc cctttcgtctcgcgcgtttcggtgatgacggtgaaaacct ctgacacatgcagctcccggagacggtcacagcttgtct gtaagcggatgccgggagcagacaagcccgtcaggg cgcgtcagcgggtgttggcgggtgtcggggctggcttaa ctatgcggcatcagagcagattgtactgagagtgcacc attcgacgctctcccttatgcgactcctgcattaggaagc agcccagtagtaggttgaggccgttgagcaccgccgc cgcaaggaatggtctggcttatcgaaattaatacgactc actatagggagacc 87 pCG-4MC11VSV-G-WT-STL#3 ggaattcgagctcgccccgttacataacttacggtaaat ggcccgcctggctgaccgcccaacgacccccgcccat tgacgtcaataatgacgtatgttcccatagtaacgccaat agggactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgc caagtacgccccctattgacgtcaatgacggtaaatgg cccgcctggcattatgcccagtacatgaccttatgggact ttcctacttggcagtacatctacgtattagtcatcgctatta ccatggtgatgcggttttggcagtacatcaatgggcgtg gatagcggtttgactcacggggatttccaagtctccacc ccattgacgtcaatgggagtttgttttggcaccaaaatca acgggactttccaaaatgtcgtaacaactccgccccatt gacgcaaatgggcggtaggcgtgtacggtgggaggtc tatataagcagagctcgtttagtgaaccgtcagatcgcct ggagacgccatccacgctgttttgacctccatagaaga Petição 870250093142, de 10 / 10 / 2025, pág. 206 / 819 177 / 640 SEQ ID NO Name Sequence caccgggaccgatccagcctccgggggatcgatcccc ccgatcctgaacttcagggtgagtttggggacccttg attgttctttctttcgctattgtaaaattcatgttatatggag ggggcaaagttttcaggttgttgttagaatgggaagat cactttctactctgttgacaccattgtctcctctttattcttttt cattttctgtaactttttcgttaaactttagcttgcatttgtaac gaatttttaaattcactttttgtttgtcagattgtaagtactt tctctaatcactttttttcaaggcaatcagggtatattatt gtacttcagcacagttttagagaacaattgttataattaaaa tgataaggtagaatattctgcatataaattctggctggcg tggaaatattctttattggtagaaaacaactacatcctggtc atcatcctgcctttctctttatggttacaatgatatacactgtt tgagatgagac cctctgctaaccatgttcat gccttctctttttcctacagctc ctgggcaacgtgctggttattgtgctgtctcattttggc aaagaattgtaacgactcactatagggcgaattcgg atccccggtagttaatTAATACGCGTCACTAT GAAGTGCCI 1 1 IGIACHAGCHA ATTCATTGGGGTGAATTGCAAGTTCAC GATCG I Illi CCACACAACCAAAGG AAACTGGAAAAATGTTCCTTCTAATTA CCATTATTGCCCGTCAAGCTCAGAI II AAATTGGCATAATGACTTAATAGGCAC AGCCTTACAAGTCAAATGCCCAAGAGTCACAAGGCTATTCAAGCAGACGGTT GGATGTGTCATGCπCCAAATGGGTCA CTACTTGTGA III CCGCIGGIAIGGAC CGAAGTATATAACACATTCCATCCGAT CCπCACTCCATCTGTAGAACAATGCA AGGAAAGCAIIGAACAAACGAAACAA GGAACTTGGGCTGACCATCCGCT TCCTCAAAGTTGTGGATATGCAACTGT GACGGATGCCGAAGCAGTGATTGTCC AGGTGACTCTCCACCATGTGCTGGTT GATGAATACACAGGAGAATGGGTTGA Petition 870250093142, of 10 / 10 / 2025, p. 207 / 819 178 / 640 SEQ ID NO Name Sequence TTCACAGTTCATCAACGGAAAATGCAG CAATTACATATGCCCCACTGTCCATAA CTCTACAACCTGGCATTCTGACTATAA GGTCAAAGGCAGCGGCGGAAGCGGC GCCCACATTGTGATGGTGGATGCCTA TAAACCAACAAAAGGCCACATTGTGATGGTGGATGCCTA 1 1 CCATGGACATCACCTTCTTCTCAG AGGACGGAGAGCTATCATCCCTGGGA AAGGAGGGCACAGGGTTCAGAAGTAA CTAC1 1 1 GCTTATGAAACTGGAGGCAA GGCCTGCAAAATGCAATACTGCAAGC ATTGGGGAGTCAGACTCCAGTCGGTGGTTGGTC 1 1 GCTGCAGCCCAGATTCCCTGA ATGCCCAGAAGGGTCAAGTATCTCTG CTCCATCTCAGACCTCAGTGGATGTAA GTCTAATTCAGGACGTTGAGAGGATCT TGGATTATTCCCTCTGCCAAGAAACCT GGAGCAAAATCAGAGCGGGTCTTCCA GCTCCTAAAAACCCAGGAACCGGTCC TGC 1 1 1 CACCATAATCAATGGTACCCT AAAATAC 1 1 1 GAGACCAGATACATCAG AGTCGATATTGCTGCTCCAATCCTCTC AAGAATGGTCGGAATGATCAGTGGAA CTACCACACAGAAAGGGAACTGGGGACTGGACTGGAGGAGGACCGGACCTC AATTGGACCCAATGGAGTTCTGAGGA CCAGTTCAGGATATAAG IIICCIIIAT ACATGATTGGACATGGTATGTTGGACT CCGATCTTCATCTTAGCTCAAAGGCTC AGGTGTTCGAACATCCTCACATTCAAG ACGCTGCTTCGCAACTTCCTGATGATG AGAGI IIAIIIIIIIGGTGATACTGGGC TATCCAAAAATCCAATCGAGCTTGTAG Petition 870250093142, dated 10 / 10 / 2025, p. 208 / 819 179 / 640 SEQ ID NO Name Sequence AAGGTTGGTTCAGTAGTTGGAAAAGCT CTATTGCCTCI IIIIICIIIATCATAGG GTTAATCATTGGACTATTCTTGGTTCT CCGAGTTGGTATCCATCI II GCAIIAA ATTAAAGCACCAAGAAAAGACAGAT TTATACAGACATAGACTGACCAGTACTGACTGACTGACTGACTATCATCI ATGAAAAAAACTAACAGATATCACGCC TAGGACTAGTtgaatagacatcagaattaaga aaaacgtagggtccaagtggttccccgtatggactcgc tatctgtcaaccagatcttataccctgaagttcacctagat agcccgatagttaccaataagatagtagccatcgatggtatgctcgactgtggttagcctgcagcagcagcat cttttccctctgccaaaattatggggacatcatgaagc cccttgagcatctgacttctggctaataaaggaaatttattt tcattgcaatagtgtgttggaatttttgtgtctctcactcgg aaggacatatgggagggcaaatcatttaaacatcag aatgagtatttggtttagagtcattggcaatgcccat gctggctgccatgaacaaaggttggctataaagaggtc atcagtatatgaaacagccccctgctgtccattccttattc catagaaaagccttgacttgaggttagattttttattatttg ttttgtgttatttttctttaacatccctaaaattttccttacatgt tttactagccagattccccctcctcctctc atagctgtccctcttcttatggagatccctcgaggagct tttgcaaaagcctaggcctccaaaaagcctcttcact acttctggaatagctcagaagccgaggcggcctcggcctctgcataaataaaaaaattagtcagccatggggcg gagaatgggcggaactgggcggagttaggggcggga tgggcggagttaggggcgggactatggttgctgactaat tgctgcattaatgaatcggccaacgcgcggggagagg cggtttgcgtattgggcgctcttccgcttcctcgctcactga ctcgctgcgctcggtcgttcggctgcggcgagcggtatc agctcactcaaaggcggtaatacggttatccacagaat caggggataacgcaggaaagaacatgtgagcaaaa ggccagcaaaaggccaggaaccgtaaaaaggccgc gttgctggcgtttttccataggctccgcccccctgacgag Petition 870250093142, dated 10 / 10 / 2025, page 209 / 819 180 / 640 SEQ ID NO Nome Sequência catcacaaaaatcgacgctcaagtcagaggtggcgaa acccgacaggactataaagataccaggcgtttccccct ggaagctccctcgtgcgctctcctgttccgaccctgccgc ttaccggatacctgtccgcctttctcccttcgggaagcgtg gcgctttctcatagctcacgctgtaggtatctcagttcggt gtaggtcgttcgctccaagctgggctgtgtgcacgaacc ccccgttcagcccgaccgctgcgccttatccggtaacta tcgtcttgagtccaacccggtaagacacgacttatcgcc actggcagcagccactggtaacaggattagcagagcg aggtatgtaggcggtgctacagagttcttgaagtggtgg cctaactacggctacactagaagaacagtatttggtatct gcgctctgctgaagccagttaccttcggaaaaagagttg gtagctcttgatccggcaaacaaaccaccgctggtagc ggtggtttttttgtttgcaagcagcagattacgcgcagaa aaaaaggatctcaagaagatcctttgatcttttctacggg gtctgacgctcagtggaacgaaaactcacgttaaggga ttttggtcatgagattatcaaaaaggatcttcacctagatc cttttaaattaaaaatgaagttttaaatcaatctaaagtata tatgagtaaacttggtctgacagttaccaatgcttaatca gtgaggcacctatctcagcgatctgtctatttcgttcatcc atagttgcctgactccccgtcgtgtagataactacgatac gggagggcttaccatctggccccagtgctgcaatgata ccgcgagacccacgctcaccggctccagatttatcagc aataaaccagccagccggaagggccgagcgcagaagtggtcctgcaactttatccgcctccatccagtctattaatt gttgccgggaagctagagtaagtagttcgccagttaata gtttgcgcaacgttgttgccattgctacaggcatcgtggtg tcacgctcgtcgtcgattggtatggcttcattcgctcggttc cacgatccgcgcatcgctcgctc aaaaaagcggttagctccttcggtcctccgatcgttgtca gaagtaagttggccgcgttatcactcatgttatggc agcactgcataatctctctgtcatgccatccgtaagat gcttttctgtgactggtgagtactcaaccaagtcattctga gaatagtgtatgcggcggccgcgcgcgcg tcaatacgggataataccgcccacatagcagaacttt aaaagtgctcatcattggaaaacgttcttcggggcgaa Petition 870250093142, of 10 / 10 / 2025, p. 210 / 819 181 / 640 SEQ ID NO Nome Sequência aactctcaaggatcttaccgctgttgagatccagttcgat gtaacccactcgtgcacccaactgatcttcagcatctttta ctttcaccagcgtttctgggtgagcaaaaacaggaagg caaaatgccgcaaaaaagggaataagggcgacacg gaaatgttgaatactcatactcttcctttttcaatattattga agcatttatcagggttattgtctcatgagcggatacatattt gaatgtatttagaaaaataaacaaataggggttccgcg cacatttccccgaaaagtgccacctgacgtctaagaaa ccattattatcatgacattaacctataaaaataggcgtatc acgaggccctttcgtctcgcgcgtttcggtgatgacggtg aaaacctctgacacatgcagctcccggagacggtcac agcttgtctgtaagcggatgccgggagcagacaagcc cgtcagggcgcgtcagcgggtgttggcgggtgtcgggg ctggcttaactatgcggcatcagagcagattgtactgag agtgcaccattcgacgctctcccttatgcgactcctgcatt aggaagcagcccagtagtaggttgaggccgttgagca ccgccgccgcaaggaatggtctggcttatcgaaattaat acgactcactatagggagacc 88 pCG-4MC11VSV-G-WT-STL#4 ggaattcgagctcgccccgttacataacttacggtaaat ggcccgcctggctgaccgcccaacgacccccgcccat tgacgtcaataatgacgtatgttcccatagtaacgccaat agggactttccattgacgtcaatgggtggagtatttacgg taaactgcccacttggcagtacatcaagtgtatcatatgc caagtacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggact ttcctacttggcagtacatctacgtattagtcatcgctatta ccatggtgatgcggttttggcagtacatcaatgggcgtg gatagcggtttgactcacggggatttccaagtctccacc ccattgacgtcaatgggagtttgttttggcaccaaaatca acgggactttccaaaatgtcgtaacaactccgccccatt gacgcaaatgggcggtaggcgtgtacggtgggaggtc tatataagcagagctcgtttagtgaaccgtcagatcgcct ggagacgccatccacgctgttttgacctccatagaaga caccgggaccgatccagcctccgggggatcgatcccc ccgatcctgagaacttcagggtgagtttggggacccttg Petição 870250093142, de 10 / 10 / 2025, pág. 211 / 819 182 / 640 SEQ ID NO Name Sequence attgttctttcttttcgctattgtaaaattcatgttatatggag ggggcaaagtttcagggtgttgtttagaatgggaagat gtcccttgtatcaccatggaccctcatgat cattttctgtaacttttcgttaaactttagcttgcatttgtaac gaatttttaaattcactttttgtttttgtcaaggcaatcagggtatattatat gtacttcagcacagttttagaacaattgtataattaaaa tgaattactactgc tggaaatattctttattggtagaaacaactacatcctggtc atcatcctgcctctctttatggttacaatgatatacactgtt tgagatgaggataaaatactctgagtccaaaccgggcc cctctgctaaccatgttcatgccttctctttttcctacagctc ctgggcaacgtgctctctctctgctc aaagaattgtaatacgactcactatagggcgaattcgg atcccccggtagttaatTAATACGCGTCACTAT GAAGTGCCI 1 1 IGIACHAGCCI Illi ATTCATTGGGGTGAATTGCAAGTTCAC GATCGI IlliCCACACAACCAAAAAGG AAACTGGAAAATTAGTCCCATCCATCCATCAGTTATTAGTTATTA AAATTGGCATAATGACTTAATAGGCAC AGCCTTACAAGTCAAAAATGCCCAAGAG TCACAAGGCTATTCAAGCAGACGGTT GGATGTGTCATGCπCCAAATGGGTCA CTACTTGTGA III CCGCIGGIAIGGACCGAAGTATATAACACATTCCATCCGAT CCπCACTCCATCTGTAGAACAATGCA AGGAAAGCAIIGAACAAACGAAACAA GGAACTTGGCTGAATCCAGGCTTCCC TCCTCAAAGTTGTGGATATGCAACTGT GACGGATGCCGAAGCAGTGATTGTCC AGGTGACTCCTCACCATGTGCTGGTT GATGAATACACAGGAGAATGGGTTGA TTCACAGTTCATCAACGGAAAATGCAG CAATTACATATGCCCCACTGTCCATAA Petição 870250093142, de 10 / 10 / 2025, pág. 212 / 819 183 / 640 SEQ ID NO Name Sequence CTCTACAACCTGGCATTCTGACTATAA GGTCAAAGGGCTATGTGATTCTGGCA GCGGCGGAAGCGGCGCCCACATGT GATGGTGGATGCCTATAAACCAACAAA AGGCTCCGGAGGCTCTGGAAACCTCA 1 1 1 CCATGGACTTCTCTCAGCAG AGGACGGAGAGCTATCATCCCTGGGA AAGGAGGGCACAGGGTTCAGAAGTAA CTAC1 1 1 GCTTATGAAACTGGAGGCAA GGCCTGCAAAATGCAATACTGCAAGC ATTGGGGAGTCAGACTCCCATCAGGT GTCTGGTTCGAGATGGCTGATAAGGA 1 GTCGATTGATTGATT ATGCCCAGAAGGGTCAAGTATCTCTG CTCCATCTCAGACCTCAGTGGATGTAA GTCTAATTCAGGACGTTGAGAGGATCT TGGATTATTCCCTCTGCCAAGAAACCT GGAGCAAAATCAGAGCGGGTCTTCCA ATCTCTCCAGTGGATCCAGCTATCCTT GCTCCTAAAACCGAGGGATCCC11 CACCATAATCAATGGTACCCT AAAATAC1 1 1 GAGACCAGATACATCAG AGTCGATATTGCTGCTCCAATCCTCTC AAGAATGGTCGGAATGATCAGTGGAA CTACCACAGAAAGGGAACTGTGGGAT GACTGGGCACCATATGAAGGGAACTGTGGGAT GACTGGGCACCATATGAAGACGTGGA AATTGGACCCATTGATTGGATCGAGGAGGGAG IIICCIIIAT ACATGATTGGACATGGTATGTTGGACT CCGATCTTCATCTTAGCTCAAAGGCTC AGGTGTTCGAACATCCTCACATTCAAG ACGCTGCTTCGCAACTTCCTGATGATG AGAGI IIAIIIIII IGGTGATACTGGGC TATCCAAAAATCCAATCGAGCTTGTAGAAGGTTGGTTCAGTAGTTGGAAAAGCT CIAIIGCCIC IIIIIICIIIAICAIAGG Petition 870250093142, dated 10 / 10 / 2025, p. 213 / 819 184 / 640 SEQ ID NO Name Sequence GTTAATCATTGGACTATTCTTGGTTCT CCGAGTTGGTATCCATC1 1 1 GCATTAA ATTAAAGCACACCAAGAAAAGACAGAT TTATACAGACATAGAGATGAACCGACT TGGAAAGTAACTCAAATCCTGCTAGGT ATGAAAAAACTAACTAACTACCAGCC TAGGACTAGTgtgaaatagacatcagaattaaga aaaacgtagggtccaagtggttccccgttatggactcgc tatctgtcaaccagatcttataccctgaagttcacctagat agcccgatagttaccaataagatagtagccatcctgga gtatgctcgactgtttaaacctgcaggcatgcaagctgat cttttcccacctcctccatcattagg cccttgagcatctgacttctggctaataaaggaaatttatt tcattgcaatagtgtgttggaatttttgtgtctctcactcgg aaggacatatgggagggcaaatcatttaaaacatcag aatgagtatttggttagagtttggcaacatatgcccat gctggctgccatgaacaaaggtataaggc atcagtatatgaaacagccccctgctgtccattccttattc catagaaaagccttgacttgaggttagattttttattatttg ttttgtgttatttttttctttaacatccctaaaattttccttacatgt tttactagccagatttcctcctcctgactactcccagtc atagctgtccctcctcctcgatgact ttttgcaaaagcctaggcctccaaaaaagcctcttcact acttctggaatagctcagaagccgaggcggcctcggc ctctgcataaataaaaaaatagtcagccatggggcggagaatgggcggaactgggcggagttaggggcggga tgggcggagttaggggcgggactatggttgctgactaat tgctgcattaatgaatcggccaacgcgcggggagagg cggtttgcgtattgggcgctcttccgcttcctcgctcactga ctcgctgcgctcggtcgttcggctgcggcgagcggtatc agctcactcaaaggcggtaatacggttatccacagaat caggggataacgcaggaaagaacatgtgagcaaaa ggccagcaaaaggccaggaaccgtaaaaaggccgc gttgctggcgtttttccataggctccgcccccctgacgag catcacaaaaatcgacgctcaagtcagaggtggcgaa acccgacaggactataaagataccaggcgtttccccct Petition 870250093142, dated 10 / 10 / 2025, pp. 214 / 819 185 / 640 SEQ ID NO Nome Sequência ggaagctccctcgtgcgctctcctgttccgaccctgccgc ttaccggatacctgtccgcctttctcccttcgggaagcgtg gcgctttctcatagctcacgctgtaggtatctcagttcggt gtaggtcgttcgctccaagctgggctgtgtgcacgaacc ccccgttcagcccgaccgctgcgccttatccggtaacta tcgtcttgagtccaacccggtaagacacgacttatcgcc actggcagcagccactggtaacaggattagcagagcg aggtatgtaggcggtgctacagagttcttgaagtggtgg cctaactacggctacactagaagaacagtatttggtatct gcgctctgctgaagccagttaccttcggaaaaagagttg gtagctcttgatccggcaaacaaaccaccgctggtagc ggtggtttttttgtttgcaagcagcagattacgcgcagaa aaaaaggatctcaagaagatcctttgatcttttctacggg gtctgacgctcagtggaacgaaaactcacgttaaggga ttttggtcatgagattatcaaaaaggatcttcacctagatc cttttaaattaaaaatgaagttttaaatcaatctaaagtata tatgagtaaacttggtctgacagttaccaatgcttaatca gtgaggcacctatctcagcgatctgtctatttcgttcatcc atagttgcctgactccccgtcgtgtagataactacgatac gggagggcttaccatctggccccagtgctgcaatgata ccgcgagacccacgctcaccggctccagatttatcagc aataaaccagccagccggaagggccgagcgcagaa gtggtcctgcaactttatccgcctccatccagtctattaatt gttgccgggaagctagagtaagtagttcgccagttaatagtttgcgcaacgttgttgccattgctacaggcatcgtggtg tcacgctcgtcgtttggtatggcttcattcagctccggttcc caacgatcaaggcgagttacatgatcccccatgttgtgc aaaaaagcggttagctccttcggtcctccgatcgttgtca gaagtaagttggccgcagtgttatcactcatggttatggc agcactgcataattctcttactgtcatgccatccgtaagat gcttttctgtgactggtgagtactcaaccaagtcattctga gaatagtgtatgcggcgaccgagttgctcttgcccggcg tcaatacgggataataccgcgccacatagcagaacttt aaaagtgctcatcattggaaaacgttcttcggggcgaa aactctcaaggatcttaccgctgttgagatccagttcgat gtaacccactcgtgcacccaactgatcttcagcatctttta Petição 870250093142, de 10 / 10 / 2025, pág. 215 / 819 186 / 640 SEQ ID NO Nome Sequência ctttcaccagcgtttctgggtgagcaaaaacaggaagg caaaatgccgcaaaaaagggaataagggcgacacg gaaatgttgaatactcatactcttcctttttcaatattattga agcatttatcagggttattgtctcatgagcggatacatattt gaatgtatttagaaaaataaacaaataggggttccgcg cacatttccccgaaaagtgccacctgacgtctaagaaa ccattattatcatgacattaacctataaaaataggcgtatc acgaggccctttcgtctcgcgcgtttcggtgatgacggtg aaaacctctgacacatgcagctcccggagacggtcac agcttgtctgtaagcggatgccgggagcagacaagcc cgtcagggcgcgtcagcgggtgttggcgggtgtcgggg ctggcttaactatgcggcatcagagcagattgtactgag agtgcaccattcgacgctctcccttatgcgactcctgcatt aggaagcagcccagtagtaggttgaggccgttgagca ccgccgccgcaaggaatggtctggcttatcgaaattaat acgactcactatagggagacc 89 pCG-4MC11VSV-G-WT-STL#7 ggaattcgagctcgccccgttacataacttacggtaaat ggcccgcctggctgaccgcccaacgacccccgcccat tgacgtcaataatgacgtatgttcccatagtaacgccaat agggactttccattgacgtcaatgggtggagtatttacgg taaactgcccacttggcagtacatcaagtgtatcatatgc caagtacgccccctattgacgtcaatgacggtaaatgg cccgcctggcattatgcccagtacatgaccttatgggact ttcctacttggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggcagtacatcaatgggcgtg gatagcggtttgactcacggggatttccaagtctccacc ccattgacgtcaatgggagtttgttttggcaccaaaatca acgggactttccaaaatgtcgtaacaactccgccccatt gacgcaaatgggcggtaggcgtgtacggtgggaggtc tatataagcagagctcgtttagtgaaccgtcagatcgcct ggagacgccatccacgctgttttgacctccatagaaga caccgggaccgatccagcctccgggggatcgatcccc ccgatcctgagaacttcagggtgagtttggggacccttg attgttctttctttttcgctattgtaaaattcatgttatatggag ggggcaaagttttcagggtgttgtttagaatgggaagat Petição 870250093142, de 10 / 10 / 2025, pág. 216 / 819 187 / 640 SEQ ID NO Name Sequence gtcccttgtatcaccatggaccctcatgataatttgtttcttt cactttctactcttttgacaccattgtctcctctttattcttttt cattttctgtaactttttcgttaaactttagcttgcatttgtaac gaatttttaaattcactttttgttattgtgtagtactt tctctaatcacttttttttcaaggcaatcagggtatattatat gtacttcagcagttttagagaacaattgttataattaaa tgataaggtagaatatttctgcatataaattggctggcg tggaaatattctttattggtagaaaacaactacatcctggtc atcatcctgccttctc tgagatgaggataaaatactctgagtccaaaccgggcc cctctgctaaccatgttcatgccttctctttttttcctacagctc ctgggcaacgtgctggttattgctgtctcatttggc aaagaattgtaatacgactcactatagggcgaattcgg atccccggttac IGIACITAGCCI Illi ATTCATTGGGGTGAATTGCAAGTTCAC GAICG IIIIII CCACACAACCAAAAAGG AAACTGGAAAAATGTTCCTTCTAATTA CCATTATTGCCCGTCAAGCTCAGA III AAATTGGCATAATGACTTAATAGGCAC AGCCTTACAAGTCAAATGCCAGCAAGCAGCAGCAGTTCAGATT GGATGTGTCATGCπCCAAATGGGTCA CTACTTGTGA III CCGCIGGIAIGGAC CGAAGTATATAACACATTCCATCCGAT CCπCACTCCATCTGTAGAACAATGCA AGGAAAGCAIIGAACAAACGAAACAAGGAACTTGGCTGAATCCAGGCTTCCC TCCTCAAAGTTGTGGATATGCAACTGT GACGGATGCCGAAGCAGTGATTGTCC AGGTGACTCCTCACCATGTGCTGGTT GATGAATACACAGGAGAATGGGTTGA TTCACAGTTCATCAACGGAAAATGCAG CAATTACATATGCCCCACTGTCCATAA CTCTACAACCTGGCATTCTGACTATAA GGTCAAAGGGCTATGTGATTCTAACCT Petição 870250093142, de 10 / 10 / 2025, pág. 217 / 819 188 / 640 SEQ ID NO Name Sequence CATTT CCATGGACATCACCTTCTCTTCTC AGAGGACGGAGAGCTATCATCCCTGG GAAAGGGCAGCGGCGGAAGCGGCGC CCACATTGTGATGGTGGATGCCTATAA ACCAACAAAAGGCTCCGGAGGCTCTG GAGAGGGCACAGGGAGGAGTTACTA GCTTATGAAACTGGAGGCAAG GCCTGCAAAATGCAATACTGCAAGCAT TGGGGAGTCAGACTCCCATCAGGTGT CTGGTTCGAGATGGCTGATAAGGATC TCTTT GCTGCAGCCCAGATTCCCTGAAT GCCCAGAAGGGTCAAGTATCTCTGCT CCATTCAGTCCAGTGAGTGAGTGGCT CTAATTCAGGACGTTGAGAGGATCTTG GATTATTCCCTCTGCCAAGAAACCTGG AGCAAAATCAGAGCGGGTCTTCCAAT CTCTCCAGTGGATCTCAGCTATCTTGC TCCTAAAAACCCAGGAACCGGTCCTG Cm CACCATAATCAATGGTACCCTAA AATAC TTT GAGACCAGGATCCATTCCTATCCATTTCTT GAATGGTCGGAATGATCAGTGGAACT ACCACAGAAAGGGAACTGTGGGATGA CTGGGCACCATATGAAGACGTGGAAA TTGGACCCAATGGAGTTCTGAGGACC AGTTCAGGATATAAG TTTCCTTT ATACA TGATTGGACATGGTATGTTGGACTCCATGATCTAGTCTAGTCTT TGTTCGAACATCCTCACATTCAAGACG CTGCTTCGCAACTTCCTGATGATGAGA GTTTATTTTTT GGTGATACTGGGCTAT CCAAAAATCCAATCGAGCTTGTAGAAG GTTGGTTCAGTAGTTGGAAAAGCTCTA TTGCCTCT TTTTTCTT TATCATAGGGTTAATCATTGGACTATTCTTGGTTCTCCG AGTTGGTATCCATC TTT GCATTAAATTA Petition 870250093142, of 10 / 10 / 2025, p. 218 / 819 189 / 640 SEQ ID NO Name Sequence AAGCACACCAAGAAAAGACAGATTTAT ACAGACATAGAGATGAACCGACTTGG AAAGTAACTCAAATCCTGCTAGGTATG AAAAAAACTAACAGATATCACGCCTAG GACTAGTgtgaatagacatcagaattaagaaaaa acgtagggtccaagtggttcccccgctcgt tgtcaaccagatcttataccctgaagttcacctagatagc ccgatagttaccaataagatagtagccatcctggagtat gctcgactgtttaaacctgcaggcatgcaagctgatcttt tccctctgccaaaaattatggggacatcatgaagcccct tgagcatctgacttctggctaataaaggaattattat tgcaatagtgtgttggaatttttgtgtctctcactcggaag gacatatgggaggggcaaatcatttaaacatcagaatg agtatttggtttagagtggcaacatatgcccatatgctg gctgccatgaacaaaggttggctataaagaggtcatca gtatatgaaacagccccctgctctcctcggaag gaaaagccttgacttgaggttagatttttttattttgttttgt gttattttttctttaacatccctaaaatttccttacatgttttac tagccagatttttcctctctctgactactcccagtcatag ctgtccctctctcttatggagatccctcgaggag cttttg c aaaaaccctaggcactactcctcctc ggaatagctcagaagccgaggcggcctcggcctctgc ataaataaaaaaaatagtcagccatggggcggagaa tgggcggaactgggcggagttaggcgggatgggc ggagttaggggcgggactatgttgctgactaattgctgcattaatgaatcggccaacgcgcggggagaggcggttt gcgtattgggcgctcttccgcttcctcgctcactgactcgc tgcgctcggtcgttcggctgcggcgagcggtatcagctc actcaaaggcggtaatacggttatccacagaatcaggg gataacgcaggaaagaacatgtgagcaaaaggcca gcaaaaggccaggaaccgtaaaaaggccgcgttgct ggcg tttttccata ggctccgcccccctgacgagcatca caaaaatcgacgctcaagtcagaggtggcgaaaccc gacaggactataaagataccaggcgtttccccctggaa gctccctcgtgcgctctcctgttccgaccctgccgcttacc ggatacctgtccg cctttctcccttcg ggaagcgtggcgc Petition 870250093142, dated 10 / 10 / 2025, page 219 / 819 190 / 640 SEQ ID NO Nome Sequência tttctcatagctcacgctgtaggtatctcagttcggtgtagg tcgttcgctccaagctgggctgtgtgcacgaaccccccg ttcagcccgaccgctgcgccttatccggtaactatcgtctt gagtccaacccggtaagacacgacttatcgccactggc agcagccactggtaacaggattagcagagcgaggtat gtaggcggtgctacagagttcttgaagtggtggcctaac tacggctacactagaagaacagtatttggtatctgcgctc tgctgaagccagttaccttcggaaaaagagttggtagct cttgatccggcaaacaaaccaccgctggtagcggtggt ttttttgtttgcaagcagcagattacgcgcagaaaaaaa ggatctcaagaagatcctttgatcttttctacggggtctga cgctcagtggaacgaaaactcacgttaagggattttggt catgagattatcaaaaaggatcttcacctagatccttttaa attaaaaatgaagttttaaatcaatctaaagtatatatga gtaaacttggtctgacagttaccaatgcttaatcagtgag gcacctatctcagcgatctgtctatttcgttcatccatagtt gcctgactccccgtcgtgtagataactacgatacggga gggcttaccatctggccccagtgctgcaatgataccgcg agacccacgctcaccggctccagatttatcagcaataa accagccagccggaagggccgagcgcagaagtggt cctgcaactttatccgcctccatccagtctattaattgttgc cgggaagctagagtaagtagttcgccagttaatagtttg cgcaacgttgttgccattgctacaggcatcgtggtgtcac gctcgtcgtttggtatggcttcattcagctccggttcccaacgatcaagcgagttacatgatcccccatgttgtgcaaaa aagcggttagctccttcggtcctccgatcgttgtcagaag tagttggccgcagtgttatcactcatcatgcagca ctgcataattctctctgtcatgccatccgtaagatgctttt ctgtgacttggctccgctcgacat gtgtatgcggcgaccgagttgctcttgcccggcgtcaat acgggataataccgcgccacatagcagaactttaaaaa gtgctcatcattggaaacgttcttcggggcgaaaactct caaggatcttaccgctgttgagatccagttcgatgtaacc cactcgtgcaccctctcatccatc cagcgtttctgggtgagcaaaaacaggaaggcaaaat gccgcaaaaaagggaataagggcgacggaaatg Petition 870250093142, of 10 / 10 / 2025, p. 220 / 819 191 / 640 SEQ ID NO Nome Sequência ttgaatactcatactcttcctttttcaatattattgaagcattta tcagggttattgtctcatgagcggatacatatttgaatgtat ttagaaaaataaacaaataggggttccgcgcacatttcc ccgaaaagtgccacctgacgtctaagaaaccattattat catgacattaacctataaaaataggcgtatcacgaggc cctttcgtctcgcgcgtttcggtgatgacggtgaaaacct ctgacacatgcagctcccggagacggtcacagcttgtct gtaagcggatgccgggagcagacaagcccgtcaggg cgcgtcagcgggtgttggcgggtgtcggggctggcttaa ctatgcggcatcagagcagattgtactgagagtgcacc attcgacgctctcccttatgcgactcctgcattaggaagc agcccagtagtaggttgaggccgttgagcaccgccgc cgcaaggaatggtctggcttatcgaaattaatacgactc actatagggagacc 90 pCG-4MC11VSV-G-WT-STL#9 ggaattcgagctcgccccgttacataacttacggtaaat ggcccgcctggctgaccgcccaacgacccccgcccat tgacgtcaataatgacgtatgttcccatagtaacgccaat agggactttccattgacgtcaatgggtggagtatttacgg taaactgcccacttggcagtacatcaagtgtatcatatgc caagtacgccccctattgacgtcaatgacggtaaatgg cccgcctggcattatgcccagtacatgaccttatgggact ttcctacttggcagtacatctacgtattagtcatcgctatta ccatggtgatgcggttttggcagtacatcaatgggcgtg gatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggagtttgttttggcaccaaaatca acgggactttccaaaatgtcgtaacaactccgccccatt gacgcaaatgggcggtaggcgtgtacggtgggaggtc tatataagcagagctcgtttagtgaaccgtcagatcgcct ggagacgccatccacgctgttttgacctccatagaaga caccgggaccgatccagcctccgggggatcgatcccc ccgatcctgagaacttcagggtgagtttggggacccttg attgttctttctttttcgctattgtaaaattcatgttatatggag ggggcaaagttttcagggtgttgtttagaatgggaagat gtcccttgtatcaccatggaccctcatgataattttgtttcttt cactttctactctgttgacaaccattgtctcctcttattttctttt Petição 870250093142, de 10 / 10 / 2025, pág. 221 / 819 192 / 640 SEQ ID NO Name Sequence cattttctgtaacttttcgttaaactttagcttgcatttgtaac gaatttttaaattcactttttttttttcaaggcaatcagggtatattatt gtacttcagcacagttttagacaattaattaa tgataaggtagaatttctgcatataaattctggctggcg tggaaatattcttattggtagaaaacaactacatcctggtc atcatcctgcctctctttatggttacaatgatatacactgtt tgagatgaggataaatactctgagtccaaaccgcc cctgctaaccattgctctctcttctt ctgggcaacgtgctggttattgtgctgtctcatcattttggc aaagaattgtaatacgactcactatagggcgaattcgg atcccccggtagttaatTAATACGCGTCACTAT GAAGTGCCI 1 1 IGIACITAGCCI Illi ATTCATTGGGGTGAATTGCAAGTTCACCCACGATCAACCAACCAACCAA AAACTGGAAAAATGTTCCTTCTAATTA CCATTATTGCCCGTCAAGCTCAGAI II AAATTGGCATAATGACTTAATAGGCAC AGCCTTACAAGTCAAAATGCCCAAGAG TCACAAGGCTATTCAAGCAGACGGTT GGATGTGTCATGCTTCCAAATGGGTCA CTACTTGTGA III CCCGAGCIGG CGAAGTATATAACACATTCCATCCGAT CCπCACTCCATCTGTAGAACAATGCA AGGAAAGCAIIGAACAAACGAAACAA GGAACTTGGCTGAATCCAGGCTTCCC TCCTCAAAGTTGTGGATATGCAACTGT GACGGATGCCGAAGCAGTGATTGTCCAGGTGACTCCTCCACCATGTGCTGGTT GATGAATACACAGGAGAATGGGTTGA TTCACAGTTCATCAACGGAAAATGCAG CAATTACATATGCCCCACTGTCCATAA CTCTACAACCTGGCATTCTGACTATAA GGTCAAAGGGCTATGTGATTCTAACCT CAIII CCATGGACCTTCATCATTCATTCAT AGAGGACGGAGAGCTATCATCCCTGG Petition 870250093142, of 10 / 10 / 2025, p. 222 / 819 193 / 640 SEQ ID NO Name Sequence GAAAGGAGGGCACAGGGTTCAGAAGT AACTAC1 1 1 GCTTATGAAACTGGAGGC AAGGCCTGCAAAATGCAATACTGCAA GCATTGGGGAGTCAGACTCCCATCAG GTGTCTGGTTCGAGATGGCTGATAAG GATCTC1 1 GCCCCAGGCCGATT GAATGCCCAGAAGGGTCAAGTATCTC TGCTCCATCTCAGACCTCAGTGGATGT AAGTCTAATTCAGGACGTTGAGAGGAT CTTGGATTATTCCCTCTGCCAAGAAAC CTGGAGCAAATCAGAGCGGTCTTC CAATCTCTCCAGTGGATCTCAGCTATC TTGCTCGAGACCTAAAGCCCT11 CACCATAATCAATGGTACC CTAAAATAC1 1 1 GAGACCAGATACATC AGAGTCGATATTGCTGCTCCAATCCTC TCAAGAATGGTCGGAATGATCAGTGG AACTACCGGCAGCGGCGGAAGCGGC GCCCACATTGTGATGGTGGATGCCTA TAAACCAACAAAAGGCGAGCTGCTGCT CTGGAACAGAAAGGGAACTGTGGGAT GACTGGGCACCATATGAAGACGTGGA AATTGGACCCAATGGAGTTCTGAGGA CCAGTTCAGGATAAG IIICCIIIAT ACATGATTGGACATGGTATGTTGGACT CCGATCTTCATCTTAGCTCAAAGGCATGTCGACCATCCATTCATTCATTC ACGCTGCTTCGCAACTTCCTGATGATG AGAGI IIAIIIIII IGGTGATACTGGGC TATCCAAAAATCCAATCGAGCTTGTAG AAGGTTGGTTCAGTAGTTGGAAAAGCT CTATTGCCTC IIIIIICIIIAICAIAGG GTTAATCATTGGACTATTCTTGGTTCTGGATGATGIIIGGAICAGGAIIAAAGCACACCAAGAAAAGACAGAI TTATACAGACATAGAGATGAACCGACT Petition 870250093142, dated 10 / 10 / 2025, p. 223 / 819 194 / 640 SEQ ID NO Nome Sequência TGGAAAGTAACTCAAATCCTGCTAGGT ATGAAAAAAACTAACAGATATCACGCC TAGGACTAGTgtgaaatagacatcagaattaaga aaaacgtagggtccaagtggttccccgttatggactcgc tatctgtcaaccagatcttataccctgaagttcacctagat agcccgatagttaccaataagatagtagccatcctgga gtatgctcgactgtttaaacctgcaggcatgcaagctgat ctttttccctctgccaaaaattatggggacatcatgaagc cccttgagcatctgacttctggctaataaaggaaatttattt tcattgcaatagtgtgttggaattttttgtgtctctcactcgg aaggacatatgggagggcaaatcatttaaaacatcag aatgagtatttggtttagagtttggcaacatatgcccatat gctggctgccatgaacaaaggttggctataaagaggtc atcagtatatgaaacagccccctgctgtccattccttattc catagaaaagccttgacttgaggttagattttttttatattttg ttttgtgttatttttttctttaacatccctaaaattttccttacatgt tttactagccagatttttcctcctctcctgactactcccagtc atagctgtccctcttctcttatggagatccctcgaggagct ttttgcaaaagcctaggcctccaaaaaagcctcttcact acttctggaatagctcagaagccgaggcggcctcggc ctctgcataaataaaaaaaattagtcagccatggggcg gagaatgggcggaactgggcggagttaggggcggga tgggcggagttaggggcgggactatggttgctgact...

Claims

1. Recombinant fusion protein, characterized in that it comprises (a) a rhabdoviral G glycoprotein or a functional fragment or derivative thereof and (b) a polypeptide antibody construct, wherein the polypeptide antibody construct has the ability to bind to human CD3.

2. Recombinant fusion protein, according to claim 1, characterized in that the polypeptide antibody construct is N-terminal to the rhabdoviral G glycoprotein or a functional fragment or derivative thereof.

3. Recombinant fusion protein, according to claim 1 or 2, characterized in that the fusion protein comprises a linker between the polypeptide antibody construct and the rhabdoviral G glycoprotein or a functional fragment or derivative thereof.

4. Recombinant fusion protein, according to claim 3, characterized in that the linker is flexible.

5. Recombinant fusion protein, according to claim 4, characterized in that the linker is AAASGGSGGGGSGGGGSGP (SEQ ID NO: 130), AAASGGSGGGGSGGGGS (SEQ ID NO: 131), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 132), GGGGSGGGGSGGGGS (SEQ ID NO: 36), GGGGSGGGGS (SEQ ID NO: 133), GGGGS (SEQ ID NO: 134), GGGGGGGG (SEQ ID NO: 135), GGGGGG (SEQ ID NO: 136), GSAGSAAGSGEF (SEQ ID NO: 137) and VPGVGVGVG (SEQ ID NO: 138)).

6. Recombinant fusion protein, according to claim 3, characterized in that the linker is rigid.

7. Recombinant fusion protein, according to claim 6, characterized in that the linker is PAPAP (SEQ ID NO: 139), EAAAKEAAAKEAAAK (SEQ ID NO: 140), EAAAKEAAAK (SEQ ID NO: 141), EAAAK (SEQ ID NO: 142), AEAAAKEAAAKEAAAKEAAAKALEEAAAAKEAAAKEAAAKEAAAKA (SEQ ID NO: 143), AEAAAKEAAAKA (SEQ ID NO: 144), ESKYGPPCPPCP (SEQ ID NO: 145), CPPCPAPELLGGPSVF (SEQ ID NO: 146) and repeated alanine-proline (AP) for a total of 10 to 34 amino acids (SEQ ID NO: 147).

8. Recombinant fusion protein, according to claim 3, characterized in that the linker comprises an IgG1 hinge region.

9. Recombinant fusion protein, according to claim 8, characterized in that IgG1 is human IgG1.

10. Recombinant fusion protein, according to claim 8, characterized in that the linker comprises SEQ ID NO:

175.

11. Recombinant fusion protein, according to any one of claims 1 to 10, characterized in that the rhabdoviral glycoprotein G or a functional fragment or derivative thereof is a Flanders virus glycoprotein (FLAV-G) (SEQ ID NO: 13), a Chandipura virus glycoprotein (CHPV-G) (SEQ ID NO: 14), a Perinet virus glycoprotein (PERV-G) (SEQ ID NO: 15), a Piry virus glycoprotein (PIRYV-G) (SEQ ID NO: 16), a Fukuoka virus glycoprotein (FUKV-G) (SEQ ID NO: 17), a glycoprotein Petition 870250093142, dated 10 / 10 / 2025, p. 672 / 819 3 / 14 Joinjakaka virus protein (JOIV-G) (SEQ ID NO: 18), a Kumasi virus glycoprotein (KRV-G) (SEQ ID NO: 19), a Keuraliba virus glycoprotein (KEUV-G) (SEQ ID NO: 20), an Isfahan glycoprotein (ISFV-G), a Jurona glycoprotein (JURV-G), a Mediterranean bat glycoprotein (MBV-G), a Malpais Spring glycoprotein (MSPV-G), a Radi glycoprotein (RADV-G), a Rhinolophus affinis-G,a Yug Bugdanavoc glycoprotein (YBV-G), a Yinshui bat glycoprotein (YSBV-G), a Kimberley glycoprotein (KIMV-G), a Kanyawara glycoprotein (KYAV-G), a La Joya glycoprotein (LJV-G), a Mosquiero glycoprotein (MQOV-G), a Parry Creek glycoprotein (PCV-G), a Bas Congo glycoprotein (BASV-G), a bovine ephemeral fever glycoprotein (BEFV-G), a Curionopolis glycoprotein (CURV-G), a Drosophila melanogaster sigmavirus glycoprotein (DMelSV-G), a Niakha glycoprotein (NIAV-G), a Puerto Almandras glycoprotein (PTAMV-G), or a Tupaia rhabdovirus (TUPTV-G).

12. Recombinant fusion protein, according to any one of claims 1 to 10, characterized in that the rhabdoviral G glycoprotein or a functional fragment or derivative thereof is a vesiculovirus glycoprotein or a functional fragment or derivative thereof.

13. Recombinant fusion protein, according to any one of claims 1 to 10, characterized in that the rhabdoviral G glycoprotein or a functional fragment or derivative thereof is from Vesiculovirus indiana, Vesiculovirus newjersey, Vesiculovirus carajas or Vesiculovirus alagoas.

14. Recombinant fusion protein according to claim 13, characterized in that the rhabdoviral glycoprotein G or a functional fragment or derivative thereof is from the Indian Vesiculovirus (SEQ ID NO: 21). Petition 870250093142, dated 10 / 10 / 2025, pp. 673 / 819 4 / 14 15. Recombinant fusion protein, according to claim 13, characterized in that the rhabdoviral G glycoprotein or a functional fragment or derivative thereof is from Vesiculovirus new jersey (SEQ ID NO: 22).

16. Recombinant fusion protein, according to any one of claims 1 to 15, characterized in that the rhabdoviral G glycoprotein is substantially intact.

17. Recombinant fusion protein, according to any one of claims 1 to 15, characterized in that the rhabdoviral glycoprotein G is a functional fragment or derivative thereof.

18. Recombinant fusion protein, according to claim 17, characterized in that the cytoplasmic tail of the glycoprotein is truncated, deleted, or replaced by another sequence.

19. Recombinant fusion protein, according to any one of claims 1 to 18, characterized in that the rhabdoviral G glycoprotein is designed to reduce or abolish its natural receptor-binding specificity.

20. Recombinant fusion protein, according to claim 19, characterized in that the rhabdoviral G glycoprotein is engineered to have a mutation to reduce or abolish its natural receptor-binding specificity.

21. Recombinant fusion protein according to claim 20, characterized in that the rhabdoviral G glycoprotein comprises a mutation at one or more positions corresponding to H8, K47, Y209 and K354 in the Indian Vesiculovirus glycoprotein (SEQ ID NO: 21) 22. Recombinant fusion protein, according to claim 20 or 21, characterized in that the mutation is a substitution.

23. Recombinant fusion protein, according to claim 22, characterized in that the substitution is with a Q.

24. Recombinant fusion protein, according to claim 22 or 23, characterized in that the mutation is a substitution at two or more positions.

25. Recombinant fusion protein, according to claim 20 or 21, characterized in that the mutation is a deletion.

26. Recombinant fusion protein, according to claim 25, characterized in that the mutation is a single deletion at the position corresponding to K47 in the Indian Vesiculovirus glycoprotein (SEQ ID NO: 21).

27. Recombinant fusion protein, according to any one of claims 1 to 26, characterized in that the recombinant fusion protein is inactivated to a lesser degree by serum, LDL or vLDL compared to a rhabdoviral G glycoprotein without the polypeptide antibody construct.

28. Recombinant fusion protein, according to any one of claims 1 to 27, characterized in that the polypeptide antibody construct is a CD3 agonist.

29. Recombinant fusion protein, according to any one of claims 1 to 28, characterized in that the polypeptide antibody construct comprises a single-chain variable fragment (scFv).

30. Recombinant fusion protein, according to claim 29, characterized in that scFv has the N-terminal VL to VH.

31. Recombinant fusion protein, according to claim 29 of Petition 870250093142, dated 10 / 10 / 2025, page 675 / 819 6 / 14, characterized in that scFv has the N-terminal VH to VL.

32. Recombinant fusion protein, according to claim 29, characterized in that scFv is UCHT1, HuM291, OKT3 or TR66.

33. Recombinant fusion protein, according to claim 32, characterized in that scFv is a humanized UCHT1.

34. Recombinant fusion protein, according to claim 33, characterized in that the scFv comprises a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO: 46 and a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO: 45 35. Recombinant fusion protein, according to claim 34, characterized in that the VH and VL are separated by a flexible linker.

36. Recombinant fusion protein, according to claim 35, characterized in that the flexible linker is SEQ ID NO:

130.

37. Recombinant fusion protein, according to claim 32, characterized in that scFv is TR66 and in that TR66 is codon-optimized for expression in humans and in that scFv comprises a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO: 44 and a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO:

43.

38. Recombinant fusion protein, according to claim 32, characterized in that scFv is UCHT1 and wherein scFv comprises a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO: 46 and a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO:

45.

39. Recombinant fusion protein, according to claim 32, characterized in that scFv is HuM291 and in which scFv comprises a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO: 38 and a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO:

37.

40. Recombinant fusion protein, according to claim 32, characterized in that scFv is OKT3 and in that scFv comprises a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO: 40 and a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO:

39.

41. Recombinant fusion protein, according to claim 32, characterized in that scFv is TR66 and in that scFv comprises a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO: 42 and a variable light chain (VL) comprising the amino acid sequence of SEQ ID NO:

41.

42. Recombinant fusion protein, according to any one of claims 1 to 41, characterized in that the recombinant fusion protein comprises an N-terminal signal peptide to the polypeptide antibody construct.

43. Recombinant fusion protein, according to claim 42, characterized in that the signal peptide comprises the amino acid sequence of SEQ ID NO:

60.

44. Recombinant fusion protein, according to claim 42 or 43, characterized in that the signal sequence is cleaved. Petition 870250093142, dated 10 / 10 / 2025, pp. 677 / 819 8 / 14 45. Membranous vesicle, characterized in that it comprises recombinant fusion protein as defined in any one of claims 1 to 44.

46. ​​Membranous vesicle, according to claim 45, characterized in that the vesicle is a gesicle or an exosome.

47. Membranous vesicle, according to claim 45 or 46, characterized in that the membranous vesicle comprises a mixed trimer, wherein the mixed trimer comprises (a) at least one recombinant fusion protein and (b) at least one rhabdoviral G glycoprotein or functional fragment or derivative thereof that is not within a recombinant fusion protein.

48. Membranous vesicle, according to claim 47, characterized in that the membranous vesicle comprises an unmixed trimer, wherein the unmixed trimer comprises only rhabdoviral G glycoprotein or a functional fragment or derivative thereof that is not within a recombinant fusion protein.

49. Membranous vesicle, according to claim 48, characterized in that the membranous vesicle comprises the maximum number of recombinant fusion proteins that can be accommodated within the membrane of the membranous vesicle.

50. Enveloped viral particle, characterized in that it comprises recombinant fusion protein as defined in any one of claims 1 to 44.

51. Enveloped viral particle, according to claim 50, characterized in that the enveloped viral particle comprises a mixed trimer, wherein the mixed trimer comprises (a) at least one recombinant fusion protein and (b) at least one rhabdoviral G glycoprotein or functional fragment or derivative thereof that is not within a recombinant fusion protein.

52. Enveloped viral particle, according to claim 51, characterized in that the enveloped viral particle comprises an unmixed trimer, wherein the unmixed trimer comprises only rhabdoviral glycoprotein G or a functional fragment or derivative thereof that is not within a recombinant fusion protein.

53. Enveloped viral particle, according to claim 52, characterized in that the enveloped viral particle comprises the maximum number of recombinant fusion proteins that can be accommodated within the membrane of the enveloped viral particle.

54. Recombinant viral vector, characterized in that it comprises a nucleotide encapsulated by a membranous vesicle, as defined in any one of claims 45 to 49, or by an enveloped viral particle, as defined in any one of claims 50 to 53.

55. Composition, characterized in that it comprises a pharmaceutically acceptable vehicle and the membranous vesicle, as defined in any one of claims 45 to 49, the enveloped viral particle, as defined in any one of claims 50 to 53, or the recombinant viral vector, as defined in claim 54.

56. Method for delivering a payload to a T cell, characterized in that it comprises bringing the T cell into contact with the membranous vesicle, as defined in any one of claims 45 to 49, the enveloped viral particle, as defined in any one of claims 50 to 53, the recombinant viral vector, as defined in claim 54, or the composition, as defined in claim 55. Petition 870250093142, dated 10 / 10 / 2025, pp. 679 / 819 10 / 14 57. Method according to claim 56, characterized in that the T cell is treated in vitro or ex vivo.

58. Method according to claim 56, characterized in that the T cell in vivo.

59. A method according to any one of claims 56 to 58, characterized in that the payload is a nucleotide sequence encoding a chimeric antigen receptor (CAR) comprising an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain.

60. Method according to claim 59, characterized in that the CAR has antigenic specificity for CD19 or BCMA.

61. Method, according to claim 59 or 60, characterized in that the CAR comprises a hinge domain, wherein the hinge domain is the hinge domain of CD28α or CD8α.

62. Method, according to any one of claims 59 to 61, characterized in that the transmembrane domain is the transmembrane domain of CD28 or CD8.

63. Method, according to any one of claims 59 to 62, characterized in that the intracellular signaling domain comprises a co-stimulatory domain and an activating domain.

64. Method, according to claim 63, characterized in that the co-stimulatory domain is 4 - 1BB.

65. Method according to claim 63, characterized in that the activation domain is CD3zeta.

66. Method, according to any one of claims 56 to 58, characterized in that the payload is a transgene or gene editing system. Petition 870250093142, dated 10 / 10 / 2025, pp. 680 / 819 11 / 14 67. Retroviral vector expression system, characterized in that it comprises one or more nucleotide sequences encoding recombinant fusion protein, as defined in any one of claims 1 to 44.

68. Retroviral vector expression system, according to claim 67, characterized in that the retroviral vector expression system comprises a vector construct and auxiliary constructs, each residing on separate plasmids.

69. Retroviral vector expression system, according to claim 67 or 68, characterized in that the retroviral vector expression system is a lentirival vector expression system.

70. Retroviral vector expression system, according to any one of claims 67 to 69, characterized in that it comprises a nucleotide sequence encoding a chimeric antigen receptor (CAR) comprising an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain.

71. Retroviral vector expression system, according to claim 70, characterized in that the CAR has antigenic specificity for CD19 or BCMA.

72. Retroviral vector expression system, according to claim 70 or 71, characterized in that the CAR comprises a hinge domain, wherein the hinge domain is the hinge domain of CD28a or CD8a.

73. Retroviral vector expression system, according to any one of claims 70 to 72, characterized in that the transmembrane domain is the transmembrane domain of CD28 or CD8.

74. Retroviral vector expression system, according to Petition 870250093142, dated 10 / 10 / 2025, pp. 681 / 819 12 / 14 with any of claims 70 to 73, characterized in that the intracellular signaling domain comprises a co-stimulatory domain and an activator domain.

75. Retroviral vector expression system, according to claim 74, characterized in that the costimulatory domain is 4-1BB.

76. Retroviral vector expression system, according to claim 74, characterized in that the activation domain is CD3zeta.

77. Retroviral vector expression system, according to any one of claims 67 to 69, characterized in that it comprises one or more nucleotide sequences encoding a transgene or gene editing system.

78. Method for producing a membranous vesicle, an enveloped viral particle or a recombinant viral vector, the method characterized in that it comprises: a) transfecting or transducing a packaging host cell with a retroviral vector expression system, as defined in any one of claims 67 to 77; and b) recovering the membranous vesicle, the enveloped viral particle or the recombinant viral vector produced by the transfected or transduced packaging host cell.

79. Plasmid, characterized in that it comprises one or more nucleotide sequences encoding recombinant fusion protein, as defined in any one of claims 1 to 44.

80. Composition according to claim 55 or retroviral vector expression system according to any one of claims 61 to 71, characterized in that it is for use in the treatment of a disease in a mammal. Petition 870250093142, dated 10 / 10 / 2025, pp. 682 / 819 13 / 14 81. Method according to claim 80, characterized in that the mammal is a human being.

82. Method, according to claim 80 or 81, characterized in that the disease is a genetic disease.

83. Method according to claim 80 or 81, characterized in that the disease is a cancer.

84. Method, according to any one of claims 80 to 83, characterized in that the composition is administered intravenously.

85. Method, according to any one of claims 80 to 83, characterized in that the composition is administered intraperitoneally.

86. Method for producing a mixed rhabdoviral G glycoprotein trimer, characterized in that it comprises: a) transfecting or transducing a packaging host cell with a retroviral vector expression system, as defined in any one of claims 67 to 77; and b) recovering the mixed rhabdoviral G glycoprotein trimer.

87. Method for reducing the inactivation of a rhabdoviral G glycoprotein or a functional fragment or derivative thereof by serum, LDL or vLDL, the method characterized in that it comprises producing the rhabdoviral G glycoprotein or a functional fragment or derivative thereof as a recombinant fusion protein and exposing the recombinant fusion protein to serum, LDL or vLDL, wherein inactivation by serum, LDL or vLDL is reduced.

88. Method for reducing the inactivation of a rhabdoviral G glycoprotein or a functional fragment or derivative thereof by serum, LDL or vLDL, the method characterized in that it comprises producing the rhabdoviral G glycoprotein or a functional fragment or derivative thereof as the recombinant fusion protein, as defined in any one of claims 1 to 44, and exposing the recombinant fusion protein to serum, LDL or vLDL, wherein the inactivation by serum, LDL or vLDL is reduced.

89. Method for activating T lymphocytes by means of contact of the T lymphocyte with the composition, as defined in claim 55.

90. Nucleic acid construct, characterized in that it comprises a nucleotide sequence that encodes the amino acid sequence of SEQ ID NO:

221.

91. Nucleic acid construct, characterized in that it comprises a nucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 222.

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