WO2024039672A2 - Anticorps anti-mlsn et leurs méthodes d'utilisation - Google Patents
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001166—Adhesion molecules, e.g. NRCAM, EpCAM or cadherins
- A61K39/001168—Mesothelin [MSLN]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Definitions
- MSLN can exist in two forms, bound to the cell membrane via a GPI linker, and in a soluble/shed form.
- the heavy chain comprises a CDR1 comprising GYTLTTNG (SEQ ID NO: 31), GGTFSSDT (SEQ ID Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 NO: 35), GFTFDDYA (SEQ ID NO: 38), GFKFTDYY (SEQ ID NO: 46), or GYTFTHYA (SEQ ID NO: 49), CDR2 comprising VSPYNGHI (SEQ ID NO: 32), VNPYNGHI (SEQ ID NO: 34), INPNSGGT (SEQ ID NO: 36), ISWNSGSI (SEQ ID NO: 39), ISWNNGSI (SEQ ID NO: 41), ISWNSGNI (SEQ ID NO: 43), INTSSNHI (SEQ ID NO: 47), or IHAGNGNS (SEQ ID NO: 50), CDR3 comprising ARVNRANYYGMDV ,(SEQ ID NO: 33), ARESALGGSYPLSF (SEQ ID NO: 37), AKDP
- the sequences have been determined using IMGT numbering scheme.
- the mesothelin protein is a human mesothelin protein.
- the antibody is fully human or humanized.
- the antibody is monospecific, bispecific, or multispecific.
- the antibody is an IgG.
- the antibody is an IgG1, IgG2, IgG3, or IgG4 antibody.
- the antibody is a single chain antibody, bispecific antibody, or bispecific T cell engager.
- the antibody has a binding affinity of at least 1.0 x10-9 M.
- the antibody further comprising a heavy chain constant region, a light chain constant region, an Fc region, or a combination thereof. Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 [0015]
- the antibody comprises Gly3-1-H10, TEA2-E10, TEA1-D3, Gly3-2-C1, TEA1-D2, Gly2-2-F7, Gly1-2-H4, Gly1-2-D4, TEA1-E5, Gly3-2-C10, Gly2-1- F2, Gly2-2-B6, Gly1-2-E10, TEA2-C9, or TEA1-E8.
- the antibody competes with binding of Gly3-1-H10, TEA2-E10, TEA1-D3, Gly3-2-C1, TEA1-D2, Gly2-2-F7, Gly1-2-H4, Gly1-2-D4, TEA1-E5, Gly3-2- C10, Gly2-1-F2, Gly2-2-B6, Gly1-2-E10, TEA2-C9, or TEA1-E8.
- the antibody competes with binding of Gly3-1-H10, TEA2-E10, TEA1-D3, Gly3-2-C1, TEA1-D2, Gly2-2-F7, Gly1-2-H4, Gly1-2-D4, TEA1-E5, Gly3-2- C10, Gly2-1-F2, Gly2-2-B6, Gly1-2-E10, TEA2-C9, or TEA1-E8.
- the antibody or fragment is linked to a therapeutic agent.
- the antibody is a single chain fragment, a bispecific antibody, or a bispecific T cell engager (BiTE).
- the antibody comprises: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 31, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 32, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 33, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 52, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 54; or (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 31, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 32, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 33, a VL CDR1 comprising the amino acid sequence of SEQ
- the antibody comprises: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 31, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 32, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 33, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 52, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 54; or (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 31, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 32, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 33, a VL CDR1 comprising the amino acid sequence of
- the sequences have been determined using IMGT numbering scheme.
- the invention comprises an isolated antibody or fragment thereof that binds to a human mesothelin protein comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29, or a sequence at least 90% identical thereto.
- the invention comprises an isolated antibody or fragment thereof that binds to a human mesothelin protein comprising a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30, or a sequence at least 90% identical thereto.
- the invention comprises an isolated antibody or fragment thereof that binds to a human mesothelin protein comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30, or a sequence at least 90% identical thereto.
- the invention comprises an isolated scFv that binds to a human mesothelin protein comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29, or a sequence at least 90% identical thereto.
- the invention comprises an isolated scFv that binds to a human mesothelin protein comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30, or a sequence at least 90% identical thereto.
- the invention comprises an isolated scFv that binds to a human mesothelin protein comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30, or a sequence at least 90% identical thereto.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 1, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 2.
- the invention comprises an isolated scFv that binds to a human mesothelin protein comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 1, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 2.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 3, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 4.
- the invention comprises an isolated scFv antibody that binds to a human mesothelin protein comprising a heavy chain, a light chain, or a combination thereof, Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 3, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 4.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 5, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 6.
- the invention comprises an isolated scFv that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 5, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 6.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 7, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 8.
- the invention comprises an isolated scFv antibody that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 7, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 8.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 9, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 10.
- the invention comprises an isolated scFv antibody that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 9, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 10.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 11, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 12.
- the invention comprises an isolated scFv antibody that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 11, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 12.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 13, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 14.
- the invention comprises an isolated scFv antibody that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 13, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 14.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 15, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 16.
- the invention comprises an isolated scFv that binds to a human mesothelin protein comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 15, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 16.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 amino acid sequence about 95% identical to SEQ ID NO: 17, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 18.
- the invention comprises an isolated scFv antibody that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 17, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 18.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 19, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 20.
- the invention comprises an isolated scFv antibody that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 19, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 20.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 21, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 22.
- the invention comprises an isolated scFv antibody that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 21, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 22.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 23, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 24.
- the invention comprises an isolated scFv antibody that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 23, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 24.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 25, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 26.
- the invention comprises an isolated scFv antibody that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 25, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 26.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 27, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 28.
- the invention comprises an isolated scFv that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 27, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 28.
- the invention comprises an isolated monoclonal antibody or antigen-binding fragment thereof that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 29, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 30.
- the invention comprises an isolated scFv antibody that binds to a human mesothelin protein, comprising a heavy chain, a light chain, or a combination thereof, wherein the heavy chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 29, and the light chain comprises an amino acid sequence about 95% identical to SEQ ID NO: 30.
- Aspects of the invention are also drawn towards an isolated bispecific antibody, comprising the antibody fragment as described herein and a second antigen-binding fragment having specificity to a molecule on an immune cell.
- the molecule is selected from the group consisting of CCR4, B7H3, B7H4, CD27, CD28, CD40, CD40L, CD47, CD122, CTLA-4, GITR, GITRL, ICOS, ICOSL, LAG-3, LIGHT, OX-40, OX40L, PD-1, TIM3, 4-1BB, TIGIT, VISTA, HEVM, BTLA, and KIR.
- the fragment and the second fragment each is independently selected from a Fab fragment, a single-chain variable fragment (scFv), or a single-domain antibody.
- the bispecific antibody further comprises a Fc fragment.
- the BiTE comprises: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 31, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 32, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 33, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 52, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 54; or (b) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 31, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 32, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 33, a VL CDR1 comprising the amino acid sequence of SEQ ID NO:
- the sequences have been determined using IMGT numbering scheme.
- aspects of the invention are drawn towards a bispecific T cell engager (BiTE) that binds to a human mesothelin protein, comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29, or a sequence at least 90% identical thereto.
- BiTE bispecific T cell engager
- BiTE bispecific T cell engager
- a human mesothelin protein comprising a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30, or a sequence at least 90% identical thereto.
- aspects of the invention are drawn towards a bispecific T cell engager (BiTE) that binds to a human mesothelin protein, comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30, or a sequence at least 90% identical thereto.
- Aspects of the invention are also drawn towards a nucleic acid encoding the antibody or fragment as described herein.
- aspects of the invention are also drawn towards a pharmaceutical composition comprising the antibody or fragment thereof as described herein, and a pharmaceutically acceptable carrier or excipient.
- the pharmaceutical composition further comprises at least one additional therapeutic agent.
- the therapeutic agent is a toxin, a radiolabel, a siRNA, a small molecule, or a cytokine.
- Aspects of the invention are also drawn towards an isolated cell comprising one or more polynucleotide(s) encoding an antibody or fragment as described herein.
- a vector can comprise the nucleic acid as described herein.
- a cell can comprise the vector as described herein.
- the chimeric antigen receptor comprises an extracellular ligand binding domain that is specific for an antigen on the surface of a cancer cell, wherein the antigen comprises mesothelin, wherein the extracellular ligand binding domain comprises an antibody or fragment thereof, where the antibody or fragment thereof comprises: (a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 31, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 32, a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 33, a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 52, a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 54; (b)
- the sequences have been determined using IMGT numbering scheme.
- the antibody or fragment thereof comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29, or a sequence at least 90% identical thereto.
- the antibody or fragment thereof comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30, or a sequence at least 90% identical thereto.
- the antibody or fragment thereof comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 and 29, or a sequence at least 90% identical thereto, and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30, or a sequence at least 90% identical thereto.
- the cell comprises a T cell, an NK cell, an NKT cell, an iPS cell, an iPS-derived cell, a cell line, or a B cell.
- the cell comprises a CD4+, CD8+, CD3+ pan T cells, or any combination thereof.
- the kit comprises at least one pharmaceutical composition as described herein; a syringe, needle, or applicator for administration of the at least one antibody to a subject; and instructions for use.
- aspects of the invention are drawn towards a method for detecting the presence of mesothelin in a sample.
- the method comprises contacting the sample with the monoclonal antibody as described herein and detecting the presence or absence of an antibody-antigen complex, thereby detecting the presence of mesothelin in the sample.
- contacting comprises immunohistochemistry.
- immunohistochemistry comprises precipitation, immunofluorescence, western blot, or ELISA.
- the sample comprises whole blood, a blood component, a body fluid, a biopsy, a tissue, serum or one or more cells.
- the one or more cells comprise an in vitro culture.
- the one or more cells comprise mesothelin- expressing cells.
- the sample comprises a normal sample or a cancerous sample.
- the sample is an in vitro sample.
- Embodiments can further comprise the step of obtaining a sample from a subject.
- the cancer expresses mesothelin.
- the cancer comprises an epithelial cell cancer.
- the epithelial cell cancer comprises lung cancer, mesothelioma, or ovarian cancer.
- Aspects of the invention are also drawn towards a method for treating cancer in a subject.
- the method comprises administering to the subject a pharmaceutical composition as described herein.
- the cancer comprises an epithelial cell cancer.
- the cancer comprises lung cancer, mesothelioma or ovarian cancer.
- FIG. 1 is a characterization of a set of antibodies for CASS B cell development.
- FIG. 1 provides cell binding curve for anti-MSLN (top) and anti-Muc1 (bottom) scFv-Fcs indicate that we have previously identified high affinity antibodies.
- FIG. 2 is a CASS B cell construct testing and B cell transduction.
- Panel A shows cells expressing the engineered IgG-BCR construct can bind soluble HA.
- Panel B shows lentivirus can be used to achieve high transduction efficiency using multiple DNA constructs and donors.
- Panel C shows an engineered reporter system in Jurkat cells using an NFAT/NFkB inducible response element that shows increasing levels of GFP expression with various stimulatory conditions. Embodiments as described herein can be used in the CASS B cell platform.
- FIG.3 shows 293T cells transfected with a engineered membrane bound IgG show high levels of membrane IgG binding (Panel A) and soluble HA capture (Panel B).
- FIG.4 is a schematic showing the structure of mesothelin (MSLN).
- FIG.5 is a schematic showing a protocol for whole cell panning.
- FIG.6 is a table showing Mesothelin panning results.
- FIG.7 shows representative FACS data and FACS screening summary (14 plates).
- FIG.8 shows MSLN serum levels. Adapted from Detection and Quantitation of Serum Mesothelin, a Tumor Marker for Patients with Mesothelioma and Ovarian Cancer, Hassan, Raffit, et al, Clin Cancer Res, 2006 and A prospective trial evaluating the role of mesothelin in undiagnosed pleural effusions, Hooper, Clare E.
- FIG.9 shows purified phage binding curves (MSLN).
- FIG.10 shows kinetic data (raw supernatant). scFv-Fcs were expressed in a 6 well plate using Expi293 cells. Two days after transfection, scFv-Fc concentration in the supernatant was quantified via Bethyl IgG quantification kit. These concentrations were used to normalize samples to 10ug/ml for Octet kinetic analysis.
- FIG.11 shows purified scFv-Fc binding curves.
- FIG.12 shows killing assay with 293T-MSLN-BFP cells and 293T-CLDN4- mCard cells mixed.
- FIG.13 shows killing assay with 293T-MSLN-BFP cells and 293T-CLDN4- mCard cells mixed.
- FIG.14 shows killing assay of anti-MSLN mono CAR T cells against Ovcar8 and Ovcar5 cells.
- FIG.15 and FIG.16 show anti-MSLN CAR T cells were incubated at a 5:1 ratio with a 1:1 mixture of ovarian cancer cell lines expressing high (Ov8) or low (Ov5) levels of MSLN for 48 hours. Number of Ov8 and Ov5 cells were counted at T0 and T48 using the Celigo image cytometer.
- FIG.17 shows killing assay with sorted cells. Anti-MSLN CART cells were sorted and expanded prior to killing assay. Positive numbers indicate killing, negative numbers indicate target cell growth/expansion. As demonstrated here, the anti-MSLN CAR T cells exhibit preferential killing of MSLN+ OVCAR8 cells and not MSLN- Skrc59 cells.
- FIG.18 shows CRISPR knockout MSLN in Ovcar8.
- FIG.19 shows protocol for dual CAR T E8-T4E3 killing assay.
- FIG.20 shows dual CAR T E8-T4E3 killing assay. CARTS of donors 2020030401 were sorted and CARTS of donors 2020030402 were not sorted.
- FIG.21 shows F10 nonspecific killing is cell line dependent.
- FIG.22 shows F10 nonspecific killing is donor dependent.
- FIG.23 shows killing assay of Ovcar8 MSLN negative cell line.
- FIG.24 shows killing assay of Ovcar8 MSLN negative cell line.
- FIG.25 shows COV362 binding curve.
- FIG.26 shows Ovcar8 binding curve.
- FIG.27 shows MSLN surface expression on Ovcar8 is higher than that of Cov362.
- FIG.28 shows the anti-MSLN CAR T cells exhibit preferential killing of MSLN+ OVCAR8 cells and not MSLN- Skrc59 cells. Anti-MSLN CART cells were sorted and expanded prior to killing assay. Positive numbers indicate killing, negative numbers indicate target cell growth/expansion.
- FIG.29 shows antibody competition. anti-His HIS1K sensors were used for competition. Sensors were loaded with 5ug/ml MSLN-his (Biolegend) for 60 seconds.
- FIG.30 shows killing of additional MSLN+ OvCA cell lines with anti-MSLN E8 CAR T.
- FIG.31 shows killing assay of anti-muc1 and anti-msln dual CAR T.
- CAR T tested E8-T4E3: anti-mesothelin and anti-muc1 dual CAR T; E8: anti-mesothelin mono- CAR T; T4E3: anti-MUC1 mono-CAR T; F10: anti-HA mono-CAR T as negative control.
- FIG.32 shows a schematic of anti-mesothelin CASS B cell therapy for NSCLC.
- FIG. 33 shows characterization of non-limiting, exemplary antibodies for CASS B cell development. A cell binding curve (left) and BLI based kinetic measurements (right) demonstrate that one clone (Gly1-2-H4) binds a conformational epitope only present on the GPI linked form.
- FIG.34 shows schematic of engineering strategy for dual targeting and affinity fine- tuning of anti-MUC1/anti-MSLN scFv targeting moieties to increase tumor killing efficacy and patient safety. Balanced affinity, and scFv orientation to both targets will provide the optimized DFIR CAR targeting design. [00119] FIG. 35 shows anti-MSLN CAR killing.
- Panel A provides a schematic of 71 kDa surface glycosylphosphatidylinositol (GPI)-linked glycoprotein that is processed to 31 kDa megakaryocyte potentiating factor (MPF) and the 40 kDa MSLN that remains membrane bound; Panels B & C), Killing of MSLN+ OVCAR8 cells (Panel B) but not SK59 RCC cells (Panel C) by three (H4, F2 & E8) anti-MSLN CAR-T cells; Panel D), Killing of MUC1+, MSLN+ CoV362 cells by each anti-MUC1 (T4E3) and anti-MSLN (E8) CAR-T cells and the dual targeted E8-TAE3 CAR-T cells.
- GPI surface glycosylphosphatidylinositol
- FIG. 36 shows anti-tumor effects of anti-CCR4 mAb 2-3 in vivo.
- Panel A shows mAb2-3 treatment blocks migration of human Tregs to CCL22 secreting OvCA cells.
- Panel B shows mAb2-3 treatment in vivo restores killing of IGROV-1 by depletion of Tregs.
- FIG. 37 shows schematic of DFIR CAR.
- Anti-MUC1 and anti-MLSN targeting moieties will be tested in different positions and with different lengths to optimize orientation- based access to their respective targets.
- An internal ribosomal entry site (IRES) will allow CAP independent translation of Ab payloads.
- FIG. 38 shows evaluating CAR-T cell killing in ccRCC 3D cultures.
- Panel A provides IF staining of Hoechst (in blue), Calcein and EpCAM (in green), PI and CD8 (in red), CD45, EpCAM and CAIX (in purple) on ccRCC patient derived organotypic spheroids (PDOTS).
- Panel B provides a workflow of generating ccRCC PDOTS.
- Panel C provides T cell migration and cytokine release.
- FIG. 39 shows antibody binding data. FACS binding represents cell expressed MSLN and ELISA binding represents soluble MSLN. This distinction can be important because MSLN can be shed from tumor cells, acting as a decoy for CAR T/Ab therapies; however, there is a slight conformational shift upon shedding that can allow for targeting of membrane bound MSLN only.
- FIG.40 shows amino acid sequences of anti-mesothelin antibodies.
- DETAILED DESCRIPTION [00125] Abbreviations and Definitions [00126] Detailed descriptions of one or more embodiments are provided herein. It is to be understood, however, that the present invention can be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in any appropriate manner. [00127] The singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise.
- a process involving steps a, b, and c means that the process includes at least steps a, b and c.
- the terms “a” or “an” are used, “one or more” is understood, unless such interpretation is nonsensical in context.
- the term “about” is used herein to mean approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (higher or lower).
- MSLN monoclonal mesothelin
- the amino acid sequence of the monoclonal MSLN antibodies are provided herein, in addition to an exemplary wildtype IgG constant region useful in combination with the VH and VL sequences provided herein (see Tables 1-15); the amino acid sequences of the heavy and light chain complementary determining regions CDRs of the MSLN antibodies are underlined (CDR1), underlined and bolded (CDR2), or underlined, italicized, and bolded (CDR3) below: Table 1.
- CDR1 underlined
- CDR2 underlined and bolded
- CDR3 underlined, italicized, and bolded
- MSLN-WC-R3-TEA2-E10 Ab Variable Region amino acid sequences V H chain of TEA2-E10 QVQLVQSGAEVKKPGASVRVSCKASGYTLTTNGLSWVRQAPGHGLEWMGWVSPYNGHI T V Table 3.
- MSLN-WC-R3-TEA1-D3 Ab Variable Region amino acid sequences V H chain of TEA1-D3 HI T P Table 4.
- MSLN-WC-R3-Gly3-2-C1 Ab Variable Region amino acid sequences V H chain of Gly3-2-C1 I T V Table 5.
- MSLN-WC-R3-TEA1-D2 Ab Variable Region amino acid sequences V chain of TEA1-D2 I T V Table 6.
- MSLN-WC-R3-Gly2-2-F7 Ab Variable Region amino acid sequences Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 V H chain of Gly2-2-F7 QVQLVQSGAEVKKPGASVRVSCKASGYTLTTNGLSWVRQAPGHGLEWMGWVSPYNGHI SYARNLEGRITMTTDTSTNTAHMELRRLTSDDTAVYYCARVNRANYYGMDVWGQGTTVT V Table 7.
- MSLN-WC-R3-Gly1-2-H4 Ab Variable Region amino acid sequences V H chain of Gly1-2-H4 N V F Table 8.
- MSLN-WC-R3-Gly1-2-D4 Ab Variable Region amino acid sequences V H chain of Gly1-2-D4 T S Table 9.
- MSLN-WC-R3-TEA1-E5 Ab Variable Region amino acid sequences h i f TEA1 E5 T S Table 10.
- MSLN-WC-R3-Gly3-2-C10 Ab Variable Region amino acid sequences Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 EVQLVQSGGGLIQPGGSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWMSWISWNNGSIG YADSVK.GRFPISRNNPQNSLYLQMNSLKAEDTALYYCAKDPSTSWLAGAFDIWGQGTMV TVSS S V H chain of Gly2-1-F2 AA A A I IG V F Table 12. MSLN-WC-R3-Gly2-2-B6 Ab Variable Region amino acid sequences V H chain of Gly2-2-B6 G T F Table 13.
- MSLN-WC-R3-Gly1-2-E10 Ab Variable Region amino acid sequences V H chain of Gly1-2-E10 V F Table 14.
- MSLN-WC-R3-TEA2-C9 Ab Variable Region amino acid sequences Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 V H chain of TEA2-C9 EVQLVESGGGLVKAGGSLRLSCTASGFKFTDYYMSWIRQTPGKGLEWVSYINTSSNHINYA HSVKGRFTISRDNAINSLFLQMDRLTSEDTAVYYCARGASWGPLWGQGTLVTVSS S Table 15.
- MSLN-WC-R3-TEA1-E8 Ab Variable Region amino acid sequences V H chain of TEA1-E8 N S D e am no ac sequences o e eavy an g c a n comp emen ary e erm nng regions of the MSLN antibodies are shown in Table 16A-B below: Table 16A.
- VH Heavy chain (VH) complementary determining regions (CDRs) of the MSLN antibodies Sequence ID V H CDR1 V H CDR2 V H CDR3 GYTLTTNG VSPYNGHI ARVNRANYYGMDV Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 Sequence ID V H CDR1 V H CDR2 V H CDR3 GFTFDDYA ISWNNGSI AKDPSTSWLAGAFDI Table 16B.
- VL Light chain
- CDRs Light chain complementary determining regions of the MSLN antibodies
- QSADYNWLCD [ ] e amno ac sequences o te eavy an gt can ramewor regons o the MSLN antibodies are shown in Table 17A-B below: Table 17A.
- V H Heavy chain (V H ) framework regions (FRs) of the MSLN antibodies Sequence VH FR1 VH FR2 VH FR3 VH FR4 Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 Sequence VH FR1 VH FR2 VH FR3 VH FR4 ID S ) ) Table 17B.
- V L Light chain (V L ) framework regions (FRs) of the MSLN antibodies Sequence ) Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 Sequence ID VL FR1 VL FR2 VL FR3 VL FR4 ) ) ) ) ) ) ) ) ) ) ) ) ) ) [ . , e MSLN antibodies have high affinity and high specificity for MSLN.
- Some embodiments also feature antibodies that have a specified percentage identity or similarity to the amino acid or nucleotide sequences of the anti-MSLN antibodies described herein.
- “homology” or “identity” or “similarity” refers to sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence, which can be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences.
- the antibodies can have 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher amino acid sequence identity when compared to a specified region or the full length of any one of the anti-MSLN antibodies described herein.
- the antibodies can have 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher nucleic acid identity when compared to a specified region or the full length of any one of the anti-MSLN antibodies described herein.
- Sequence identity or similarity to the nucleic acids and proteins of the invention can be determined by sequence comparison and/or alignment by methods known in the art, for example, using software programs known in the art, such as those described in Ausubel et al. eds. (2007) Current Protocols in Molecular Biology.
- sequence comparison algorithms i.e., BLAST or BLAST 2.0
- manual alignment or visual inspection can be utilized to determine percent sequence identity or similarity for the nucleic acids and proteins of the invention.
- Polypeptide as used herein can encompass a singular “polypeptide” as well as plural “polypeptides,” and can refer to a molecule composed of monomers (amino acids) linearly linked by amide bonds (also known as peptide bonds).
- the term “polypeptide” can refer to any chain or chains of two or more amino acids and does not refer to a specific length of the product.
- peptides, dipeptides, tripeptides, oligopeptides, “protein,” “amino acid chain,” or any other term can be used to refer to a chain or chains of two or more amino acids, can refer to “polypeptide” herein, and the term “polypeptide” can be used instead of, or interchangeably with any of these terms.
- Polypeptide can also refer to the products of post- expression modifications of the polypeptide, including without limitation glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, or modification by non-naturally occurring amino acids.
- a polypeptide can be derived from a natural biological source or produced by recombinant technology, but is not necessarily translated from a nucleic acid sequence. It can be generated in any manner, including by chemical synthesis.
- amino acid sequences one of skill in the art will readily recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds, deletes, or substitutes a single amino acid or a small percentage of amino acids in the encoded sequence is collectively referred to herein as a "conservatively modified variant".
- the alteration results in the substitution of an amino acid with a chemically similar amino acid.
- Conservative substitution tables providing functionally similar amino acids are well known in the art.
- Such conservatively modified variants of the anti-MSLN antibodies disclosed herein can exhibit increased cross-reactivity to MSLN in comparison to an unmodified MSLN antibody.
- a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain.
- Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).
- basic side chains e.g., lysine, arginine, histidine
- acidic side chains e.g., aspartic acid
- an “antibody” or “antigen-binding polypeptide” can refer to a polypeptide or a polypeptide complex that specifically recognizes and binds to an antigen.
- An antibody can be a whole antibody and any antigen binding fragment or a single chain thereof.
- antibody can include any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule having biological activity of binding to the antigen.
- Non-limiting examples a complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework (FR) region, or any portion thereof, or at least one portion of a binding protein.
- CDR complementarity determining region
- the term “antibody” can refer to an immunoglobulin molecule and immunologically active portions of an immunoglobulin (Ig) molecule, i.e., a molecule that contains an antigen binding site that specifically binds (immunoreacts with) an antigen.
- immunoglobulin immunoglobulin
- immunoglobulin a molecule that contains an antigen binding site that specifically binds (immunoreacts with) an antigen.
- specifically binds or “immunoreacts with” is meant that the antibody reacts with one or more antigenic determinants of the antigen and does not react with other polypeptides.
- the terms “antibody fragment” or “antigen-binding fragment”, as used herein, is a portion of an antibody such as F(ab′)2, F(ab)2, Fab′, Fab, Fv, scFv and the like.
- an antibody fragment binds with the same antigen that is recognized by the intact antibody.
- antibody fragment can include aptamers (such as spiegelmers), minibodies, and diabodies.
- antibody fragment can also include any synthetic or genetically engineered protein that acts like an antibody by binding to a specific antigen to form a complex.
- Antibodies, antigen-binding polypeptides, variants, or derivatives described herein include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized or chimeric antibodies, single chain antibodies, epitope-binding fragments, e.g., Fab, Fab′ and F(ab′) 2 , Fd, Fvs, single-chain Fvs (scFv), single-chain antibodies, dAb (domain antibody), minibodies, disulfide-linked Fvs (sdFv), fragments comprising a VL or VH domain, fragments produced by a Fab expression library, and anti-idiotypic (anti-Id) antibodies.
- polyclonal, monoclonal, multispecific, human, humanized or chimeric antibodies single chain antibodies, epitope-binding fragments, e.g., Fab, Fab′ and F(ab′) 2 , Fd, Fvs, single-chain Fvs (scFv
- a “single-chain variable fragment” or “scFv” refers to a fusion protein of the variable regions of the heavy (V H ) and light chains (V L ) of immunoglobulins.
- a single chain Fv (“scFv”) polypeptide molecule is a covalently linked VH:VL heterodimer, which can be expressed from a gene fusion including VH- and VL-encoding genes linked by a peptide- encoding linker. (See Huston et al. (1988) Proc Nat Acad Sci USA 85(16):5879-5883).
- the regions are connected with a short linker peptide of ten to about 25 amino acids.
- the linker can be rich in glycine for flexibility, as well as serine or threonine for solubility, and Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 can connect the N-terminus of the VH with the C-terminus of the VL, or vice versa.
- This protein retains the specificity of the original immunoglobulin, despite removal of the constant regions and the introduction of the linker.
- a number of methods have been described to discern chemical structures for converting the naturally aggregated, but chemically separated, light and heavy polypeptide chains from an antibody V region into an scFv molecule, which will fold into a three-dimensional structure substantially similar to the structure of an antigen-binding site.
- Antibody molecules obtained from humans fall into five classes of immunoglobulins: IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule.
- immunoglobulins Those skilled in the art will appreciate that heavy chains are classified as gamma, mu, alpha, delta, or epsilon ( ⁇ , ⁇ , ⁇ , ⁇ , ⁇ ) with some subclasses among them (e.g., ⁇ 1- ⁇ 4).
- Certain classes have subclasses as well, such as IgG1, IgG2, IgG3 and IgG 4 and others.
- immunoglobulin subclasses e.g., IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgG 5 , etc. are well characterized and are known to confer functional specialization.
- IgG a standard immunoglobulin molecule comprises two identical light chain polypeptides of molecular weight approximately 23,000 Daltons, and two identical heavy chain polypeptides of molecular weight 53,000-70,000.
- the four chains are joined by disulfide bonds in a “Y” configuration wherein the light chains bracket the heavy chains starting at the mouth of the “Y” and continuing through the variable region.
- Immunoglobulin or antibody molecules described herein can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of an immunoglobulin molecule.
- Light chains are classified as kappa or lambda ( ⁇ , ⁇ ). Each heavy chain class can be bound with a kappa or lambda light chain.
- the light and heavy chains are covalently bonded to each other, and the “tail” portions of the two heavy chains are bonded to each other by covalent disulfide linkages or non-covalent linkages when the immunoglobulins are generated by hybridomas, B cells, or genetically engineered host cells.
- the amino acid sequences run from an N-terminus at the forked ends of the Y configuration to the C-terminus at the bottom of each chain. Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 [00146] Both the light and heavy chains are divided into regions of structural and functional homology. The terms “constant” and “variable” are used functionally.
- variable domains of both the light (VL) and heavy (VH) chain portions determine antigen recognition and specificity.
- the constant domains of the light chain (CL) and the heavy chain (CH1, CH2 or CH3) confer important biological properties such as secretion, transplacental mobility, Fc receptor binding, complement binding, and the like.
- the term "antigen-binding site,” or “binding portion” can refer to the part of the immunoglobulin molecule that participates in antigen binding.
- the antigen binding site is formed by amino acid residues of the N-terminal variable ("V") regions of the heavy ("H") and light (“L”) chains.
- FR framework regions
- FR can refer to amino acid sequences which are naturally found between, and adjacent to, hypervariable regions in immunoglobulins.
- the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three-dimensional space to form an antigen-binding surface.
- the antigen-binding surface is complementary to the three- dimensional surface of a bound antigen, and the three hypervariable regions of each of the heavy and light chains are referred to as "complementarity-determining regions," or "CDRs.”
- VH and VL regions which contain the CDRs, as well as frameworks (FRs) of the MSLN antibodies are shown in Table 1-Table 17.
- the six CDRs present in each antigen-binding domain are short, non-contiguous sequences of amino acids that are specifically positioned to form the antigen-binding domain as the antibody assumes its three-dimensional configuration in an aqueous environment. The remainder of the amino acids in the antigen-binding domains, the FR regions, show less inter- molecular variability.
- the framework regions largely adopt a ⁇ -sheet conformation and the CDRs form loops which connect, and in some cases form part of, the ⁇ -sheet structure.
- the framework regions act to form a scaffold that provides for positioning the CDRs in correct orientation by inter-chain, non-covalent interactions.
- the antigen-binding domain formed by the positioned CDRs provides a surface complementary to the epitope on the immunoreactive antigen, which promotes the non-covalent binding of the antibody to its cognate epitope.
- amino acids comprising the CDRs and the framework regions, respectively can be readily identified for a heavy or light chain variable region by one of ordinary skill in the art, since they have been previously defined (See, “Sequences of Proteins of Immunological Interest,” Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 Kabat, E., et al., U.S. Department of Health and Human Services, (1983); and Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987)). [00148] Where there are two or more definitions of a term which is used and/or accepted within the art, the definition of the term as used herein is intended to include such meanings unless explicitly stated to the contrary.
- CDR complementarity determining region
- Kabat numbering refers to the numbering system set forth by Kabat et al., U.S. Dept. of Health and Human Services, “Sequence of Proteins of Immunological Interest” (1983). [00150] In addition to table above, the Kabat number system describes the CDR regions as follows: CDR-H1 begins at approximately amino acid 31 (i.e., approximately 9 residues after Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 the first cysteine residue), includes approximately 5-7 amino acids, and ends at the next tryptophan residue.
- CDR-H2 begins at the fifteenth residue after the end of CDR-H1, includes approximately 16-19 amino acids, and ends at the next arginine or lysine residue.
- CDR-H3 begins at approximately the thirty third amino acid residue after the end of CDR-H2; includes 3-25 amino acids; and ends at the sequence W-G-X-G, where X is any amino acid.
- CDR-L1 begins at approximately residue 24 (i.e., following a cysteine residue); includes approximately 10-17 residues; and ends at the next tryptophan residue.
- CDR-L2 begins at approximately the sixteenth residue after the end of CDR-L1 and includes approximately 7 residues.
- CDR-L3 begins at approximately the thirty third residue after the end of CDR-L2 (i.e., following a cysteine residue); includes approximately 7-11 residues and ends at the sequence F or W-G-X- G, where X is any amino acid.
- the CDRs of an antibody can be determined according to the IMGT numbering system.
- the IMGT unique numbering has been defined to compare the variable domains whatever the antigen receptor, the chain type, or the species [Lefranc M.-P., Immunology Today 18, 509 (1997)/Lefranc M.-P., The Immunologist, 7, 132-136 (1999)/Lefranc, M.-P., Pommié, C., Ruiz, M., Giudicelli, V., Foulquier, E., Truong, L., Thouvenin-Contet, V. and Lefranc, Dev. Comp. Immunol., 27, 55-77 (2003)].
- cysteine 23 (1st-CYS), tryptophan 41 (CONSERVED-TRP), hydrophobic amino acid 89, cysteine 104 (2nd-CYS), phenylalanine or tryptophan 118 (J-PHE or J-TRP).
- the IMGT unique numbering provides a standardized delimitation of the framework regions (FR1-IMGT: positions 1 to 26, FR2-IMGT: 39 to 55, FR3-IMGT: 66 to 104 and FR4-IMGT: 118 to 128) and of the complementarity determining regions: CDR1-IMGT: 27 to 38, CDR2-IMGT: 56 to 65 and CDR3-IMGT: 105 to 117. As gaps represent unoccupied positions, the CDR-IMGT lengths (shown between brackets and separated by dots, e.g. [8.8.13]) become crucial information.
- the IMGT unique numbering is used in 2D graphical representations, designated as IMGT Colliers de Perles [Ruiz, M.
- epitopes can include any protein determinant that can specifically bind to an immunoglobulin, a scFv, or a T-cell receptor.
- variable region allows the antibody to selectively recognize and specifically bind epitopes on antigens.
- VL domain and VH domain, or subset of the complementarity determining regions (CDRs), Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 of an antibody combine to form the variable region that defines a three-dimensional antigen- binding site.
- This quaternary antibody structure forms the antigen-binding site present at the end of each arm of the Y.
- Epitopic determinants can consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and can have specific three- dimensional structural characteristics, as well as specific charge characteristics.
- antibodies can be raised against N- terminal or C-terminal peptides of a polypeptide.
- the antigen-binding site is defined by three CDRs on each of the VH and VL chains (i.e., CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3).
- the antibodies can be directed to mesothelin (MSLN) encoded by NCBI Reference No: NM_005823 and having amino acid sequence: MALPTARPLLGSCGTPALGSLLFLLFSLGWVQPSRTLAGETGQE AAPLDGVLANPPNISSLSPRQLLGFPCAEVSGLSTERVRELAVALAQKNVKLSTEQLR CLAHRLSEPPEDLDALPLDLLLFLNPDAFSGPQACTRFFSRITKANVDLLPRGAPERQ RLLPAALACWGVRGSLLSEADVRALGGLACDLPGRFVAESAEVLLPRLVSCPGPLDQD QQEAARAALQGGGPPYGPPSTWSVSTMDALRGLLPVLGQPIIRSIPQGIVAAWRQRSS RDPSWRQPERTILRPRFRREVEKTACPSGKKAREIDESLIFYKKWELEACVDAALLAT QMDRVNAIPFTYEQLDVLKHKLDELYPQGYPESVIQHLGYLFLKMSPEDIRKWNVTSL
- immunological binding can refer to the non-covalent interactions of the type which occur between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific.
- the strength, or affinity of immunological binding interactions can be expressed in terms of the dissociation constant (Kd) of the interaction, wherein a smaller Kd represents a greater affinity.
- Immunological binding properties of selected polypeptides can be quantified using methods well known in the art. One such method entails measuring the rates of antigen- binding site/antigen complex formation and dissociation, wherein those rates depend on the concentrations of the complex partners, the affinity of the interaction, and geometric parameters that equally influence the rate in both directions.
- both the "on rate constant” (Kon) and the “off rate constant” (Koff) can be determined by calculation of the concentrations and the actual rates of association and dissociation. (See Nature 361: 186-87 (1993)).
- the ratio Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 of Koff /Kon allows for the cancellation of parameters not related to affinity, and is equal to the equilibrium binding constant, K D . (See, generally, Davies et al. (1990) Annual Rev Biochem 59:439-473).
- An antibody of the invention can specifically bind to a MSLN epitope when the equilibrium binding constant (K D ) is ⁇ 1 ⁇ M, ⁇ 10 ⁇ , ⁇ 10 nM, ⁇ 10 pM, or ⁇ 100 pM to about 1 pM, as measured by kinetic assays such as radioligand binding assays or similar assays known to those skilled in the art, such as BIAcore or Octet (BLI).
- the KD is between about 1E-12 M and a KD about 1E-11 M. In some embodiments, the KD is between about 1E-11 M and a KD about 1E-10 M.
- the KD is between about 1E-10 M and a KD about 1E-9 M. In some embodiments, the KD is between about 1E-9 M and a K D about 1E-8 M. In some embodiments, the K D is between about 1E-8 M and a K D about 1E-7 M. In some embodiments, the KD is between about 1E-7 M and a KD about 1E-6 M. For example, in some embodiments, the K D is about 1E-12 M while in other embodiments the KD is about 1E-11 M. In some embodiments, the KD is about 1E-10 M while in other embodiments the K D is about 1E-9 M.
- the K D is about 1E-8 M while in other embodiments the KD is about 1E-7 M. In some embodiments, the KD is about 1E-6 M while in other embodiments the K D is about 1E-5 M. In some embodiments, for example, the KD is about 3 E-11 M, while in other embodiments the KD is about 3E-12 M. In some embodiments, the K D is about 6E-11 M. “Specifically binds” or “has specificity to,” can refer to an antibody that binds to an epitope via its antigen-binding domain, and that the binding entails some complementarity between the antigen-binding domain and the epitope.
- an antibody is said to “specifically bind” to an epitope when it binds to that epitope, via its antigen-binding domain more readily than it can bind to a random, unrelated epitope.
- the MSLN antibody can be monovalent or bivalent, and/or can comprise a single or double chain. Functionally, the binding affinity of the MSLN antibody is within the range of 10 ⁇ 5 M to 10 ⁇ 12 M.
- the binding affinity of the MSLN antibody is from 10 ⁇ 6 M to 10 ⁇ 12 M, from 10 ⁇ 7 M to 10 ⁇ 12 M, from 10 ⁇ 8 M to 10 ⁇ 12 M, from 10 ⁇ 9 M to 10 ⁇ 12 M, from 10 ⁇ 5 M to 10 ⁇ 11 M, from 10 ⁇ 6 M to 10 ⁇ 11 M, from 10 ⁇ 7 M to 10 ⁇ 11 M, from 10 ⁇ 8 M to 10 ⁇ 11 M, from 10 ⁇ 9 M to 10 ⁇ 11 M, from 10 ⁇ 10 M to 10 ⁇ 11 M, from 10 ⁇ 5 M to 10 ⁇ 10 M, from 10 ⁇ 6 M to 10 ⁇ 10 M, from 10 ⁇ 7 M to 10 ⁇ 10 M, from 10 ⁇ 8 M to 10 ⁇ 10 M, from 10 ⁇ 9 M to 10 ⁇ 10 M, from 10 ⁇ 5 M to 10 ⁇ 9 M, from 10 ⁇ 6 M to 10 ⁇ 9 M, from 10 ⁇ 7 M to 10 ⁇ 9 M, from 10 ⁇ 8 M to 10 ⁇
- a MSLN protein, or a derivative, fragment, analog, homolog or ortholog thereof, can be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.
- a MSLN protein or a derivative, fragment, analog, homolog, or ortholog thereof, coupled to a proteoliposome can be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.
- a human monoclonal antibody has the same specificity as a human monoclonal antibody of the invention by ascertaining whether the former prevents the latter from binding to MSLN. For example, if the human monoclonal antibody being tested competes with the human monoclonal antibody of the invention, as shown by a decrease in binding by the human monoclonal antibody of the invention, then the two monoclonal antibodies bind to the same, or to a closely related, epitope.
- Another way to determine whether a human monoclonal antibody has the specificity of a human monoclonal antibody of the invention is to pre-incubate the human monoclonal antibody of the invention with the MSLN protein, with which it is normally reactive, and then add the human monoclonal antibody being tested to determine if the human monoclonal antibody being tested is inhibited in its ability to bind MSLN. If the human monoclonal antibody being tested is inhibited, then it can have the same, or functionally equivalent, epitopic specificity as the monoclonal antibody of the invention. Screening of human monoclonal antibodies of the invention can be also carried out by utilizing MSLN and determining whether the test monoclonal antibody is able to neutralize MSLN.
- Antibodies can be purified by well-known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum.
- the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, can be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Engineer, published by The Engineer, Inc., Philadelphia PA, Vol.14, No.8 (April 17, 2000), pp.25-28).
- the term “monoclonal antibody” or “mAb” or “Mab” or “monoclonal antibody composition”, as used herein, can refer to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product.
- the complementarity determining regions (CDRs) of the monoclonal antibody are identical in the molecules of the population.
- MAbs contain an antigen binding site that can immunoreact with an epitope of the antigen characterized by a unique binding affinity for it.
- Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975).
- a hybridoma method a mouse, hamster, or other appropriate host animal, is immunized with an immunizing agent to elicit lymphocytes that produce or can produce antibodies that will specifically bind to the immunizing agent.
- the lymphocytes can be immunized in vitro.
- the immunizing agent can include the protein antigen, a fragment thereof or a fusion protein thereof.
- peripheral blood lymphocytes can be used if cells of human origin are preferred, or spleen cells or lymph node cells can be used if non-human mammalian sources are preferred.
- the lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (See Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103).
- Immortalized cell lines can be transformed mammalian cells, such as myeloma cells of rodent, bovine and human origin. For example, rat or mouse myeloma cell lines are employed.
- the hybridoma cells can be cultured in a suitable culture medium that contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells.
- the culture medium for the hybridomas can include hypoxanthine, aminopterin, and thymidine ("HAT medium”), which substances prevent the growth of HGPRT-deficient cells.
- HAT medium hypoxanthine, aminopterin, and thymidine
- Immortalized cell lines that are useful are those that fuse efficiently, support stable high-level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium.
- immortalized cell lines can be murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center (San Diego, California) and the American Type Culture Collection (Manassas, Virginia).
- the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art.
- the binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980).
- the clones can be subcloned by limiting dilution procedures and grown by standard methods. (See Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103). Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.
- the monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
- Monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Patent No.4,816,567 (incorporated herein by reference in its entirety).
- DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that can bind specifically to genes encoding the heavy and light chains of murine antibodies).
- the hybridoma cells of the invention serve as a source of such DNA.
- the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells.
- the DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (See U.S. Patent No. 4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide.
- non-immunoglobulin polypeptide can be Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 substituted for the constant domains of an antibody of the invention, and/or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.
- Fully human antibodies for example, are antibody molecules in which the entire sequence of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed "human antibodies” or "fully human antibodies”.
- Human monoclonal antibodies such as fully human and humanized antibodies, can be prepared by using trioma technique; the human B-cell hybridoma technique (see Kozbor, et al, 1983 Immunol Today 4: 72); and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al, 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp.77-96). Human monoclonal antibodies can be utilized and can be produced by using human hybridomas (see Cote, et al, 1983.
- Humanized antibodies can be antibodies from a non-human species (such as mouse), whose amino acid sequences (for example, in the CDR regions) have been modified to increase their similarity to antibody variants produced in humans.
- Antibodies can be humanized by methods known in the art, such as CDR-grafting.
- humanized antibodies can be produced in transgenic plants, as an inexpensive production alternative to existing mammalian systems.
- the transgenic plant can be a tobacco plant, i.e., Nicotiania benthamiana, and Nicotiana tabaccum.
- the antibodies are purified from the plant leaves.
- Stable transformation of the plants can be achieved through the use of Agrobacterium tumefaciens or particle bombardment.
- nucleic acid expression vectors containing at least the heavy and light chain sequences are expressed in bacterial cultures, i.e., A. tumefaciens strain BLA4404, via transformation.
- Infiltration of the plants can be accomplished via injection.
- Soluble leaf extracts can be prepared by grinding leaf tissue in a mortar and by centrifugation. Isolation and purification of the antibodies can be performed by many of the methods known to the skilled artisan in the art. Other methods for antibody production in plants are described in, for example, Fischer et al., Vaccine, 2003, 21:820-5; and Ko et al, Current Topics in Microbiology and Immunology, Vol. 332, 2009, pp. 55-78.
- the invention further provides any cell or plant comprising a vector that encodes the antibody of the invention or produces the antibody of the invention.
- Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239,400; PCT publication WO 91/09967; U.S. Pat. Nos.5,225,539; 5,530,101; and 5,585,089), veneering or resurfacing (EP 592,106; EP 519,596; Padlan, Molecular Immunology 28(4/5):489-498 (1991); Studnicka et al., Protein Engineering 7(6):805-814 (1994); Roguska. et al., Proc. Natl. Sci.
- “Humanization” also called Reshaping or CDR-grafting is a well-established technique understood by the skilled artisan for reducing the immunogenicity of monoclonal antibodies (mAbs) from xenogeneic sources (such as rodent) and for improving their activation of the human immune system (See, for example, Hou S, Li B, Wang L, Qian W, Zhang D, Hong X, Wang H, Guo Y (July 2008).
- antibodies can also be produced using other techniques, including phage display libraries. (See Hoogenboom and Winter, J. Mol. Biol, 227:381 (1991); Marks et al., J. Mol. Biol, 222:581 (1991)).
- human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated.
- Human antibodies can additionally be produced using transgenic nonhuman animals which are modified to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen.
- transgenic nonhuman animals which are modified to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen.
- the endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome.
- the human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments.
- An animal which provides the preferred modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 than the full complement of the modifications.
- a non-limiting example of such a nonhuman animal is a mouse and is termed the XenomouseTM as disclosed in PCT publication nos. WO96/33735 and WO96/34096.
- This animal produces B cells which secrete fully human immunoglobulins.
- the antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies.
- the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv (scFv) molecules.
- scFv single chain Fv
- an antibody of interest such as a human antibody, is disclosed in U.S. Patent No.5,916,771.
- This method includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell.
- the hybrid cell expresses an antibody containing the heavy chain and the light chain. Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 [00177]
- a method for identifying a clinically relevant epitope on an immunogen and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity is disclosed in PCT publication No.
- the antibody of interest can also be expressed by a vector containing a DNA segment encoding the single chain antibody described herein.
- Vectors include, but are not limited to, chemical conjugates such as described in WO 93/64701, which has targeting moiety (e.g. a ligand to a cellular surface receptor), and a nucleic acid binding moiety (e.g. polylysine), viral vectors (e.g. a DNA or RNA viral vector), fusion proteins such as described in PCT/US 95/02140 (WO 95/22618), which is a fusion protein containing a target moiety (e.g. an antibody specific for a target cell) and a nucleic acid binding moiety (e.g.
- the vectors can be chromosomal, non-chromosomal or synthetic. Retroviral vectors can also be used and include moloney murine leukemia viruses. DNA viral vectors can also be used, and include pox vectors such as orthopox or avipox vectors, herpesvirus vectors such as a herpes simplex I virus (HSV) vector (See Geller, A. I. et al, J. Neurochem, 64:487 (1995); Lim, F., et al, in DNA Cloning: Mammalian Systems, D. Glover, Ed. (Oxford Univ. Press, Oxford England) (1995); Geller, A.
- HSV herpes simplex I virus
- Avipox virus vectors result in only a short-term expression of the nucleic acid.
- Adenovirus vectors, adeno- associated virus vectors, and herpes simplex virus (HSV) vectors can be used for introducing the nucleic acid into neural cells.
- the adenovirus vector results in a shorter-term expression (about 2 months) than adeno-associated virus (about 4 months), which in turn is shorter than HSV vectors.
- the vector chosen will depend upon the target cell and the condition being treated.
- the introduction can be by standard techniques, e.g., infection, transfection, transduction or transformation.
- Examples of modes of gene transfer include e.g., naked DNA, CaP04 precipitation, DEAE dextran, electroporation, protoplast fusion, lipofection, cell microinjection, and viral vectors.
- the vector can be employed to target essentially any target cell.
- stereotaxic injection can be used to direct the vectors (e.g., adenovirus, HSV) to a preferred location.
- the particles can be delivered by intracerebroventricular (icv) infusion Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 using a minipump infusion system, such as a SynchroMed Infusion System.
- a method based on bulk flow termed convection, has also proven effective at delivering large molecules to extended areas of the brain and can be useful in delivering the vector to the target cell.
- convection A method based on bulk flow, termed convection, has also proven effective at delivering large molecules to extended areas of the brain and can be useful in delivering the vector to the target cell.
- Other methods that can be used include catheters, intravenous, parenteral, intraperitoneal and subcutaneous injection, and oral or other known routes of administration.
- These vectors can be used to express large quantities of antibodies that can be used in a variety of ways. For example, to detect the presence of MSLN in a sample.
- the antibody can also be used to try to bind to and disrupt a MSLN activity.
- the antibodies described herein can be full-length antibodies, including those containing an Fc region similar to wild-type Fc regions that bind to Fc receptors.
- Techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (See e.g., U.S. Patent No.4,946,778).
- Fab expression libraries See e.g., Huse, et al, 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal Fab fragments with the preferred specificity for a protein or derivatives, fragments, analogs or homologs thereof.
- Antibody fragments that contain the idiotypes to a protein antigen can be produced by techniques known in the art including, but not limited to: (i) an F(ab')2 fragment produced by pepsin digestion of an antibody molecule; (ii) an F ab fragment generated by reducing the disulfide bridges of an F(ab')2 fragment; (iii) an Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) F v fragments.
- Heteroconjugate antibodies are also within the scope of the invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies can, for example, target immune system cells to unwanted cells (see U.S. Patent No.
- the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents.
- immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond.
- suitable reagents for this purpose include iminothiolate and methyl-4- mercaptobutyrimidate and those disclosed, for example, in U.S. Patent No.4,676,980.
- the antibody of the invention can be modified with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer.
- cysteine Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 residue(s) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region.
- the homodimeric antibody thus generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody- dependent cellular cytotoxicity (ADCC).
- ADCC antibody- dependent cellular cytotoxicity
- an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities.
- the antibody of the invention has modifications of the Fc region, such that the Fc region does not bind to the Fc receptors.
- the Fc receptor is Fc ⁇ receptor.
- Antibodies with modification of the Fc region such that the Fc region does not bind to Fc ⁇ , but still binds to neonatal Fc receptor are useful as described herein.
- an antibody of the invention can comprise an Fc variant. See, for example, WO2018/145075 and WO2019/183362, which provide Fc variant compositions for augmenting antibody mediated receptor signaling.
- the Fc variant can comprise an amino acid substitution which alters the antigen-independent effector functions of the antibody, such as the circulating half-life of the antibody.
- Such antibodies exhibit increased or decreased binding to FcRn when compared to antibodies lacking these substitutions, therefore, have an increased or decreased half-life in serum, respectively.
- Fc variants with improved affinity for FcRn can have longer serum half-lives, and such molecules have useful applications in methods of treating mammals where long half-life of the administered antibody is preferred, e.g., to treat a chronic disease or disorder.
- Fc variants with decreased FcRn binding affinity can have shorter half-lives, and such molecules are also useful, for example, for administration to a mammal where a shortened circulation time can be advantageous, e.g., for in vivo diagnostic imaging or in situations where the starting antibody has toxic side effects when present in the circulation for prolonged periods.
- Fc variants with decreased FcRn binding affinity are also less likely to cross the placenta and, thus, are also useful in the treatment of diseases or disorders in pregnant women.
- other applications in which reduced FcRn binding affinity can be preferred include those applications in which localization to the brain, kidney, and/or liver is preferred.
- the Fc variant-containing antibodies can exhibit reduced transport across the epithelium of kidney glomeruli from the vasculature. In another embodiment, the Fc variant-containing antibodies can exhibit reduced transport across the blood brain barrier (BBB) from the brain, into the vascular space.
- BBB blood brain barrier
- an antibody with altered FcRn binding comprises an Fc Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 domain having one or more amino acid substitutions within the "FcRn binding loop" of an Fc domain.
- the FcRn binding loop is comprised of amino acid residues 280-299 (according to EU numbering). Exemplary amino acid substitutions with altered FcRn binding activity are disclosed in PCT Publication No.
- the antibodies, or fragments thereof, of the invention comprise an Fc domain having one or more of the following substitutions: V284E, H285E, N286D, K290E and S304D (EU numbering).
- mutations are introduced to the constant regions of the mAb such that the antibody dependent cell-mediated cytotoxicity (ADCC) activity of the mAb is altered.
- the mutation is a LALA mutation in the CH2 domain.
- the antibody e.g., a human mAb, or a bispecific Ab
- the mAb contains mutations on one scFv unit of the heterodimeric mAb, which reduces the ADCC activity.
- the mAb contains mutations on both chains of the heterodimeric mAb, which completely ablates the ADCC activity.
- the mutations introduced into one or both scFv units of the mAb are LALA mutations in the CH2 domain.
- antibodies of the invention for use in the diagnostic and treatment methods described herein have a constant region, e.g., an IgG1 or IgG4 heavy chain constant region, which can be altered to reduce or eliminate glycosylation.
- an antibody of the invention can also comprise an Fc variant comprising an amino acid substitution which alters the glycosylation of the antibody.
- the Fc variant can have reduced glycosylation (e.g., N- or O-linked glycosylation).
- the Fc variant comprises reduced glycosylation of the N-linked glycan normally found at amino acid position 297 (EU numbering).
- the antibody has an amino acid substitution near or within a glycosylation motif, for example, an N-linked glycosylation motif that contains the amino acid sequence NXT or NXS.
- the antibody comprises an Fc variant with an amino acid substitution at amino acid position 228 or 299 (EU numbering).
- the antibody comprises an IgGl or IgG4 constant region comprising an S228P and a T299A mutation (EU numbering).
- Exemplary amino acid substitutions which confer reduced or altered glycosylation are described in PCT Publication No, WO05/018572, which is incorporated by reference herein in its entirety.
- the antibodies of the invention, or fragments thereof are Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 modified to eliminate glycosylation.
- Such antibodies, or fragments thereof can be referred to as "agly” antibodies, or fragments thereof, (e.g., "agly” antibodies).
- agly antibodies, or fragments thereof can have an improved safety and stability profile in vivo.
- Exemplary agly antibodies, or fragments thereof comprise an aglycosylated Fc region of an IgG4 antibody which is devoid of Fc-effector function thereby eliminating the potential for Fc mediated toxicity to the normal vital tissues and cells that express MSLN.
- antibodies of the invention, or fragments thereof comprise an altered glycan.
- the antibody can have a reduced number of fucose residues on an N-glycan at Asn297 of the Fc region, i.e., is afucosylated.
- the antibody can have an altered number of sialic acid residues on the N-glycan at Asn297 of the Fc region.
- the invention also is directed to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).
- a cytotoxic agent such as a toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).
- Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.
- Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis- diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diis
- bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT
- a ricin immunotoxin can be prepared as described in Vitetta et al, Science 238: 1098 (1987).
- Carbon- 14-labeled l-isothiocyanatobenzyl-3- methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 conjugation of radionucleotide to the antibody. (See PCT Publication No. WO94/11026, and U.S. Patent No.5,736,137). [00193] Those of ordinary skill in the art understand that a large variety of possible moieties can be coupled to the resultant antibodies or to other molecules of the invention.
- Coupling can be accomplished by any chemical reaction that will bind the two molecules so long as the antibody and the other moiety retain their respective activities. This linkage can include many chemical mechanisms, for instance covalent binding, affinity binding, intercalation, coordinate binding, and complexation. In one embodiment, binding is, covalent binding. Covalent binding can be achieved by direct condensation of existing side chains or by the incorporation of external bridging molecules.
- bivalent or polyvalent linking agents are useful in coupling protein molecules, such as the antibodies of the invention, to other molecules.
- representative coupling agents can include organic compounds such as thioesters, carbodiimides, succinimide esters, diisocyanates, glutaraldehyde, diazobenzenes and hexamethylene diamines.
- This listing is not intended to be exhaustive of the various classes of coupling agents known in the art but, rather, is exemplary of the more common coupling agents. (See Killen and Lindstrom, Jour. Immun. 133: 1335- 2549 (1984); Jansen et al., Immunological Reviews 62: 185-216 (1982); and Vitetta et al, Science 238: 1098 (1987)).
- Non-limiting examples of linkers are described in the literature. (See, for example, Ramakrishnan, S. et al., Cancer Res. 44:201-208 (1984) describing use of MBS (M-maleimidobenzoyl-N-hydroxysuccinimide ester). See also, U.S. Patent No. 5,030,719, describing use of halogenated acetyl hydrazide derivative coupled to an antibody by way of an oligopeptide linker.
- MBS M-maleimidobenzoyl-N-hydroxysuccinimide ester
- Non-limiting examples of useful linkers that can be used with the antibodies of the invention include: (i) EDC (l-ethyl-3- (3-dimethylamino-propyl) carbodiimide hydrochloride; (ii) SMPT (4- succinimidyloxycarbonyl-alpha-methyl-alpha-(2- pridyl-dithio)-toluene (Pierce Chem. Co., Cat. (21558G); (iii) SPDP (succinimidyl-6 [3-(2- pyridyldithio) propionamido]hexanoate (Pierce Chem.
- NHS-ester containing linkers are less soluble than sulfo-NHS esters.
- the linker SMPT contains a sterically hindered disulfide bond, and can form conjugates with increased stability. Disulfide linkages, are in general, less stable than other linkages because the disulfide linkage is cleaved in vitro, resulting in less conjugate available.
- Sulfo-NHS can enhance the stability of carbodimide couplings.
- Carbodimide couplings when used in conjunction with sulfo-NHS, forms esters that are more resistant to hydrolysis than the carbodimide coupling reaction alone.
- the antibodies disclosed herein can also be formulated as immunoliposomes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al, Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al, Proc. Natl Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No.5,013,556.
- Non-limiting examples of useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the preferred diameter.
- Fab' fragments of the antibody of the invention can be conjugated to the liposomes as described in Martin et al, J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction.
- Multispecific Antibodies (Bispecific and Trispecific) [00199] Embodiments as described herein can comprise a monospecific antibody or a multispecific antibody.
- Monospecific antibodies are antibodies with one or more binding sites that specifically binds to a single antigen.
- Multispecific antibodies are antibodies that can recognize two or more different antigens.
- a bi-specific antibody (bsAb) is an antibody comprising two variable domains or scFv units such that the resulting antibody recognizes two different antigens.
- tsAb is an antibody comprising two variable domains or scFv units such that the resulting antibody recognizes three different antigens.
- multispecific antibodies such as bi-specific and trispecific antibodies, that recognize MSLN and a second antigen and/or a third antigen.
- multispecific antibodies e.g., bi-specific antibodies and trispecific antibodies
- Exemplary second and or third antigens include tumor associated antigens (e.g., LINGO1), cytokines (e.g., Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 IL-12 (IL-12A (p35 subunit) protein sequence having NCBI Reference No. NP_000873.2; IL- 12B (p40 subunit) protein sequence having NCBI Reference No.
- NP_002178.2 protein sequence having NCBI Reference no. NP_001553.1
- IL-15 protein sequence having NCBI Reference No. NP_000576.1
- IL-7 protein sequence having NCBI Reference No. NP_000871.1
- IL-2 protein sequence having NCBI Reference No. NP_000577.2
- IL-21 protein sequence having NCBI Reference No. NP_068575.1
- cytokine cognate receptors eg., IL-12R
- Non-limiting examples of second and/or third antigens include CTLA-4, CXCR4, LAG-3, CD28, CD122, 4-1BB, TIM3, OX-40, OX40L, CD40, CD40L, LIGHT, ICOS, ICOSL, GITR, GITRL, TIGIT, CD27, VISTA, B7H3, B7H4, HEVM (or BTLA), CD47 and CD73.
- the bispecific and trispecific antibodies comprise MSLN fusion proteins.
- the fusion protein comprises an antibody comprising a variable domain or scFv unit and a ligand or antigen and/or a third ligand or antigen as described herein such that the resulting antibody recognizes an antigen and binds to the ligand-specific receptor.
- Exemplary antibody compositions that are useful for the design of MSLN fusion proteins as described herein include, but are not limited to, anti-CAIX antibodies described in PCT/US2006/046350 and PCT/US2015/067178; anti-CXCR4 antibodies described in PCT/US20006/005691 and PCT/US2019/022272; anti-CCR4 antibodies described in PCT/US2008/088435, PCT/US2013/039744, and PCT/US2015/054202; anti-PD-L1 antibodies described in PCT/US2008/088435 and PCT/US2020/062815; anti-PD-1 antibodies described in PCT/US2020/037791 and PCT/US2020/037781; anti-GITR antibodies described in PCT/US2017/043504; anti-claudin-4 antibodies described in PCT/US2019/022272; and anti-MUC1 antibodies described in PCT/US2020/037783
- the fusion protein further comprises a constant region, and/or a linker as described herein.
- multispecific antibodies e.g., bispecific antibodies and trispecific antibodies such as a fusion protein comprises an antibody that recognizes MSLN and a ligand
- Ligands can be tumor associated antigens (e.g., LINGO1, ErbB2 (HER2/neu), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), MUC1, MSLN, CD19, CD20, CD30, CD40, CD22, RAGE-l, MN-CA IX, RET1, RET2 (AS), prostate specific antigen (PSA), TAG-72, PAP, p53, Ras, prostein, PSMA, survivin, 9D7, prostate-carcinoma tumor antigen-l (PCTA-1), GAGE, MAGE, mesothelin, ⁇ -catenin, TGF- ⁇ RII, BRCA1/2, SAP-1, HPV-E6, HPV-E7 (see also, PCT/US2015/067225 and PCT/US2019/022272 for additional tumor-associated surface Docket No.: 5031461-137-WO1 Date of Filing:
- each of the anti- MSLN fragment and the second antigen-specific fragment and/or the third antigen-specific fragment is each independently selected from a Fab fragment, a single-chain variable fragment (scFv), or a single-domain antibody.
- the bispecific or trispecific antibody further includes a Fc fragment (e.g., as described in PCT/US2015/021529 and PCT/US2019/023382, each of which are incorporated by reference in their entireties).
- a bispecific or trispecific antibody of the invention can comprise a heavy chain and a light chain combination or scFv of the MSLN antibodies described herein.
- Multispecific antibodies (e.g., bispecific antibodies and trispecific antibodies) of the invention (for example, an anti-MSLN-scFv fusion protein) can be constructed using methods known art.
- the bi-specific antibody is a single polypeptide wherein the two scFv fragments are joined by a long linker polypeptide, of sufficient length to allow intramolecular association between the two scFv units to form an antibody.
- the bi-specific antibody is more than one polypeptide linked by covalent or non- covalent bonds.
- the amino acid linker depicted herein (GGGGSGGGGS; “(G 4 S) 2 ”) can be generated with a longer G4S linker to improve flexibility.
- the linker can also be: “(G 4 S) 3 ” (e.g., GGGGSGGGGSGGGGS); “(G4S)4” (e.g., GGGGSGGGGSGGGGSGGGGS); “(G 4 S) 5 ” (e.g., GGGGSGGGGSGGGGSGGGGSGGGGS); “(G4S)6” (e.g., GGGGSGGGGSGGGGSGGGGSGGGGGGSGGGGS); “(G 4 S) 7 ” (e.g., GGGGSGGGGSGGGGSGGGGSGGGGSGGGGGGSGGGGS); and the like.
- use of the (G4S)5 linker can provide more flexibility to a ligand described herein and can improve expression.
- the linker can also be (GS) n , (GGS) n , (GGGS) n , (GGSG)n, (GGSGG)n, or (GGGGS)n, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- Non-limiting Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 examples of linkers known to those skilled in the art that can be used to construct the fusions described herein can be found in U.S. Patent No. 9,708,412; U.S. Patent Application Publication Nos. US 20180134789 and US 20200148771; and PCT Publication No. WO2019051122 (each of which are incorporated by reference in their entireties).
- the multispecific antibodies e.g., bispecific antibodies and trispecific antibodies such as anti-MSLN-scFv fusions
- the multispecific antibodies can be constructed using the "knob into hole” method (Ridgway et al, Protein Eng 7:617-621 (1996)).
- the Ig heavy chains of the two different variable domains are reduced to selectively break the heavy chain pairing while retaining the heavy-light chain pairing.
- the two heavy-light chain heterodimers that recognize two different antigens/ligands or three different antigens/ligands are mixed to promote heteroligation pairing, which is mediated through the engineered "knob into holes" of the CH3 domains.
- the multispecific antibodies can be constructed through exchange of heavy-light chain dimers from two or more different antibodies to generate a hybrid antibody where the first heavy-light chain dimer recognizes MSLN and the second heavy-light chain dimer recognizes a second antigen and/or third antigen.
- the mechanism for heavy-light chain dimer is similar to the formation of human IgG4, which also functions as a bispecific molecule. Dimerization of IgG heavy chains is driven by intramolecular force, such as the pairing the CH3 domain of each heavy chain and disulfide bridges.
- Presence of a specific amino acid in the CH3 domain has been shown to promote dimer exchange and construction of the IgG4 molecules. Heavy chain pairing is also stabilized further by interheavy chain disulfide bridges in the hinge region of the antibody.
- the hinge region contains the amino acid sequence Cys-Pro-Ser-Cys (in comparison to the stable IgGl hinge region which contains the sequence Cys-Pro-Pro-Cys) at amino acids 226- 230.
- This sequence difference of Serine at position 229 has been linked to the tendency of IgG4 to form intrachain disulfides in the hinge region (Van der Neut Kolfschoten, M.
- the multispecific antibodies e.g., bispecific antibodies and trispecific antibodies such as anti-MSLN-scFv fusions
- the multispecific antibodies can be created through introduction of the R409 residue in the CH3 domain and the Cys-Pro-Ser-Cys sequence in the hinge region of antibodies that recognize MSLN or a second and/or third antigen, so that the heavy-light chain dimers exchange to produce an antibody molecule with one heavy-light chain dimer recognizing MSLN and the second heavy-light chain dimer recognizing a second and/or third Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 antigen, wherein the second and/or third antigen (or ligand) is any antigen (or ligand) disclosed herein.
- IgG 4 molecules can also be altered such that the heavy and light chains recognize MSLN or a second and/or third antigen, as disclosed herein.
- Use of this method for constructing the multispecific antibodies (e.g., bispecific antibodies and trispecific antibodies such as anti-MSLN-scFv fusions) of the invention can be beneficial due to the intrinsic characteristic of IgG 4 molecules wherein the Fc region differs from other IgG subtypes in that it interacts poorly with effector systems of the immune response, such as complement and Fc receptors expressed by certain white blood cells.
- IgG 4 -based multispecific antibodies e.g., bispecific antibodies and trispecific antibodies such as anti- MSLN-scFv fusions
- the multispecific antibodies e.g., bispecific antibodies and trispecific antibodies such as anti-MSLN-scFv fusions
- the multispecific antibodies can be engineered with a non-depleting heavy chain isotype, such as IgG1-LALA or stabilized IgG4 or one of the other non-depleting variants.
- mutations are introduced to the constant regions of the bsAb such that the antibody dependent cell-mediated cytotoxicity (ADCC) activity of the bsAb is altered.
- the mutation is a LALA mutation in the CH2 domain.
- the multispecific antibody e.g., bispecific antibodies and trispecific antibodies such as anti- MSLN-scFv fusions
- the multispecific antibody e.g., bispecific antibodies and trispecific antibodies such as anti-MSLN-scFv fusions
- the mutations introduced in one or both scFv units of the multispecific antibody are LALA mutations in the CH2 domain.
- These multispecific antibodies e.g., bispecific antibodies and trispecific antibodies such as anti-MSLN-scFv fusions
- the multispecific antibodies with variable ADCC activity can be optimized such that the multi-specific antibodies exhibit maximal selective killing towards cells that express one antigen that is recognized by the multispecific antibody; however, exhibits minimal killing towards the second antigen that is recognized by the multispecific antibody.
- the multispecific antibodies (e.g., bispecific antibodies) described herein can be engineered as modular tetrameric bispecific antibodies (tBsAb).
- tetravalent antibody can be a dimer of a bispecific scFv fragment including a first binding site for a first antigen, and a second binding site for a second antigen.
- the anti- MSLN antibody can be the first binding site for a first antigen.
- the anti-MSLN antibody can be the second binding site for a second antigen. The two binding sites can be joined together via a linker domain.
- the linker domain includes an immunoglobulin hinge region (e.g., an IgGl, an IgG2, an IgG3, or an IgG4 hinge region) amino acid sequence.
- the immunoglobulin hinge region amino acid sequence can be flanked by a flexible linker amino acid sequence, e.g., having the linker amino acid sequence (GGGS)x1-6, (GGGGS)x1-6, or GSAGSAAGSGEF.
- the linker domain includes at least a portion of an immunoglobulin Fc domain, e.g., an IgGl, an IgG2, an IgG3, or an IgG4 Fc domain.
- the at least a portion of the immunoglobulin Fc domain does not include a CH2 domain.
- the at least a portion of the immunoglobulin Fc domain can be a CH2 domain.
- An exemplary CH2 domain amino acid sequence includes APELLGGPDVFLF (SEQ ID NO: [ ]).
- the Fc domain can be linked to the C-terminus of an immunoglobulin hinge region (e.g., an IgGl, an IgG2, an IgG3, or an IgG4 hinge region) amino acid sequence.
- the linker domain can include a flexible linker amino acid sequence (e.g., (GGGS)x1-6, (GGGGS)x1-6, or GSAGSAAGSGEF) at one terminus or at both termini.
- the tBsAb can be specific for MSLN, and also a target selected from the group consisting of B7H3, CXCR4, B7H4, CD27, CD28, CD40, CD40L, CD47, CD122, CCR4, CTLA-4, GITR, GITRL, ICOS, ICOSL, LAG-3, LIGHT, OX-40, OX40L, PD- L1, PD-1, TIM3, 4-1BB, TIGIT, VISTA, HEVM, BTLA, and KIR.
- the multispecific antibody can be a bi-specific T-cell engager (BiTE).
- BiTEs can refer to a single polypeptide chain molecule with two antigen binding domains, one of which binds to a T-cell antigen.
- the BiTE can comprise a MSLN antibody disclosed herein, or a functional fragment thereof, and an antibody or fragment thereof that binds to a T-cell antigen.
- the antibody or fragment thereof that binds to a T-cell antigen can be specific for CD3.
- the multispecific antibody can be a tri-specific T-cell engager (TriTE).
- TriTEs can refer to a single polypeptide chain molecule with three antigen binding domains, one or more of which binds to a T-cell antigen.
- the TriTE can comprise a MSLN antibody disclosed herein, or a functional fragment thereof, and an antibody or fragment thereof that binds to a T-cell antigen. Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023
- the antibody or fragment thereof that binds to a T-cell antigen can be specific for CD3, CD28, or both.
- the multispecific antibodies e.g., bispecific antibodies and trispecific antibodies such as anti-MSLN-scFv fusions
- the invention provides a fusion protein containing a MSLN antibody disclosed herein, or a functional fragment thereof, operably linked to a second protein.
- the second protein can be, for example, a cytokine or a growth factor.
- the cytokine is IL- 2 or TGF-beta and variants thereof.
- the second protein can be a therapeutic agent, such as a toxin, a detectable moiety, such as a fluorescent protein for detection, or a biological agent, such as an agent that stimulates T cells (i.e., CD3).
- the MSLN antibodies of the invention can be operably linked to more than one additional protein or peptide, for example 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional proteins or peptide sequences.
- the MSLN antibody disclosed herein, or functional fragment thereof is joined directly to the second protein.
- the MSLN antibody, or functional fragment thereof is joined to the second protein via a linker, such as a flexible polypeptide chain.
- the linker can be any suitable linker of any length, but can be at least 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 amino acids in length.
- the linker is an amino acid sequence that is naturally present in immunoglobulin molecules of the host, such that the presence of the linker cannot result in an immune response against the linker sequence by the mammal.
- Fusion proteins of the invention that include more than one additional protein to the MSLN antibody can have multiple linker sequences that join each additional protein or peptide sequence. [00215]
- the fusion proteins of the invention can be constructed by recombinant methods known to the skilled artisan.
- an expression vector containing the nucleic acid sequence encoding a MSLN antibody of the invention can be operably linked to the nucleic acid sequence encoding the second protein and can be introduced to an expression system to translate and produce the fusion protein.
- an expression vector containing the nucleic acid sequence encoding a MSLN antibody of the invention can be operably linked to the nucleic acid sequence encoding the second protein and can be introduced to an expression system to translate and produce the fusion protein.
- de nova protein synthesis techniques to produce the fusion proteins described herein.
- MSLN-associated disease or disorder includes disease states and/or symptoms associated with a disease state, where increased levels of MSLN and/or activation of cellular signaling pathways involving MSLN are found.
- Exemplary MSLN-associated diseases or disorders include, but are not limited to, diseases where T cells are suppressed, such as in cancer and infectious diseases.
- the cancer can be lung cancer, kidney cancer, ovarian cancer, prostate cancer, colon cancer, breast cancer, cervical cancer, uterine cancer, brain cancer, skin cancer, liver cancer, pancreatic cancer, or stomach cancer.
- the infectious disease is a viral disease, such as influenza.
- Antibodies of the invention can be used as therapeutic agents. Such agents can be employed to treat cancer in a subject, increase vaccine efficiency or augment a natural immune response.
- An antibody preparation for example, one having high specificity and high affinity for its target antigen, is administered to the subject and can have an effect due to its binding with the target. Administration of the antibody can abrogate or inhibit or interfere with an activity of the MSLN protein.
- Pharmaceutical Compositions [00220] Antibodies of the invention specifically binding a MSLN protein or fragment thereof can be administered for the treatment of a cancer in the form of pharmaceutical compositions.
- a specific dosage and treatment regimen for any patient will depend upon a variety of factors, including the antibodies, variant or derivative thereof used, the patient's age, body weight, general health, sex, and diet, and the time of administration, rate of excretion, drug combination, and the severity of the disease being treated. Judgment of such factors by medical caregivers is within the ordinary skill in the art. The amount will also depend on the individual patient to be treated, the route of administration, the type of formulation, the characteristics of the compound used, the severity of the disease, and the preferred effect. The amount used can be determined by pharmacological and pharmacokinetic principles well known in the art.
- a therapeutically effective amount of an antibody of the invention can be the amount needed to achieve a therapeutic objective. As noted herein, this can be a binding interaction between the antibody and its target antigen that, in certain cases, interferes with the functioning of the target.
- the amount required to be administered will furthermore depend on the binding affinity of the antibody for its specific antigen and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is administered.
- the dosage administered to a subject (e.g., a patient) of the antigen-binding polypeptides described herein is about 0.1 mg/kg to 100 mg/kg of the patient's body weight, between 0.1 mg/kg and 20 mg/kg of the patient's body weight, or 1 mg/kg to 10 mg/kg of the patient's body weight.
- Human antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible. Further, the dosage and frequency of administration of antibodies of the disclosure can be reduced by enhancing uptake and tissue penetration (e.g., into the brain) of the antibodies by modifications such as, for example, lipidation.
- Common ranges for therapeutically effective dosing of an antibody or antibody fragment of the invention can be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about 50 mg/kg body weight. Common dosing frequencies can range, for example, from twice daily to once a week.
- the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred.
- peptide molecules can be designed that retain the ability to bind the target protein sequence.
- Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. (See, e.g., Marasco et al, Proc. Natl. Acad. Sci.
- the formulation can also contain more than one active compound as necessary for the indication being treated, for example, those with complementary activities that do not adversely affect each other.
- the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine (e.g., IL-15), chemotherapeutic agent, or growth-inhibitory agent.
- cytotoxic agent e.g., IL-15
- chemotherapeutic agent e.g., chemotherapeutic agent
- growth-inhibitory agent e.g., growth-inhibitory agent
- the active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions.
- colloidal drug delivery systems for example, liposomes, Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 albumin microspheres, microemulsions, nanoparticles, and nanocapsules
- the formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.
- sustained-release preparations can be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2- hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No.
- copolymers of L-glutamic acid and ⁇ ethyl-L-glutamate copolymers of L-glutamic acid and ⁇ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid allow for release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.
- compositions suitable for administration can comprise the antibody or agent and a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier can include solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference.
- Non-limiting examples of such carriers or diluents include water, saline, ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils can also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. [00228] A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
- routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration.
- Solutions or suspensions used for parenteral, Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
- compositions suitable for injectable use can include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
- suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
- the composition is sterile and is fluid to the extent that easy syringeability exists. It can be stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
- sterile powders for the preparation of sterile injectable solutions methods of preparation are Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional preferred ingredient from a previously sterile-filtered solution thereof.
- Oral compositions can include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets.
- the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules.
- Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
- Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
- the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
- a binder such as microcrystalline cellulose, gum tragacanth or gelatin
- an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
- a lubricant such as magnesium stearate or Sterotes
- a glidant such as colloidal silicon dioxide
- the compounds can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
- a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
- Systemic administration can also be by transmucosal or transdermal means.
- penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
- Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
- the active compounds are formulated into ointments, salves, gels, or creams as known in the art.
- the compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
- the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
- compositions can be formulated in dosage unit form for ease of administration and uniformity of dosage.
- Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the preferred therapeutic effect in association with the required pharmaceutical carrier.
- the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
- the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
- Diagnostics [00239] An antibody according to the invention can be used as an agent for detecting the presence of MSLN (or a protein fragment thereof) in a sample.
- the sample can be a cancer sample or a sample from a subject at risk of having cancer.
- the cancer can be lung cancer, kidney cancer, ovarian cancer, prostate cancer, colon cancer, breast cancer, cervical cancer, uterine cancer, brain cancer, skin cancer, liver cancer, pancreatic cancer, or stomach cancer.
- the antibody can contain a detectable label.
- Antibodies can be polyclonal or monoclonal. An intact antibody, or a fragment thereof (e.g., F ab , scFv, or F (ab)2 ) can be used.
- labeled can encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled.
- indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin.
- biological sample can include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject.
- the detection method of the invention can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 in vivo.
- in vitro techniques for detection of an analyte mRNA includes Northern hybridizations and in situ hybridizations.
- In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence.
- In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. [00240] Procedures for conducting immunoassays are described, for example in "ELISA: Theory and Practice: Methods in Molecular Biology", Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, NJ, 1995; "Immunoassay”, E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, CA, 1996; and “Practice and Theory of Enzyme Immunoassays", P. Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore, in vivo techniques for detection of an analyte protein include introducing into a subject a labeled anti-analyte protein antibody.
- the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.
- Antibodies directed against a MSLN protein can be used in methods known within the art relating to the localization and/or quantitation of a MSLN protein (e.g., for use in measuring levels of the MSLN protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like).
- antibodies specific to a MSLN protein, or derivative, fragment, analog or homolog thereof, that contain the antibody derived antigen binding domain are utilized as pharmacologically active compounds (referred to herein as "therapeutics").
- An antibody of the invention specific for a MSLN protein can be used to isolate a MSLN polypeptide by standard techniques, such as immunoaffinity, chromatography or immunoprecipitation.
- Antibodies directed against a MSLN protein can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen.
- Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include, but are not limited to, various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials.
- Non-limiting examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, ⁇ -galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include 125 I, 131 I, 35 S, 32 P or 3 H.
- the invention provides methods (also referred to herein as “screening assays") for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that modulate or otherwise interfere with a MSLN activity. Also provided are methods of identifying compounds useful to treat cancer. The invention also encompasses compounds identified using the screening assays described herein. [00246] For example, the invention provides assays for screening candidate or test compounds which modulate MSLN expression and/or activity.
- test compounds of the invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including but not limited to: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the "one-bead one-compound” library method; and synthetic library methods using affinity chromatography selection.
- biological libraries are limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds. (See, e.g., Lam, 1997. Anticancer Drug Design 12: 145).
- a "small molecule” as used herein, can refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD.
- Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic or inorganic molecules.
- Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any of the assays of the invention.
- Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt, et al., 1993. Proc. Natl.
- Libraries of compounds can be presented in solution (see e.g., Houghten, 1992. Biotechniques 13: 412-421), or on beads (see Lam, 1991. Nature 354: 82-84), on chips (see Fodor, 1993. Nature 364: 555-556), bacteria (see U.S. Patent No.5,223,409), spores (see U.S. Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 Patent 5,233,409), plasmids (see Cull, et al., 1992. Proc. Natl. Acad. Sci. USA 89: 1865-1869) or on phage (see Scott and Smith, 1990.
- a candidate compound is introduced to an antibody-antigen complex and determining whether the candidate compound disrupts the antibody-antigen complex, wherein a disruption of this complex indicates that the candidate compound modulates an MSLN activity.
- at least one MSLN protein is provided, which is exposed to at least one monoclonal antibody.
- Formation of an antibody-antigen complex is detected, and one or more candidate compounds are introduced to the complex. If the antibody-antigen complex is disrupted following introduction of the one or more candidate compounds, the candidate compound is useful to treat cancer or a proliferative disease or disorder.
- Determining the ability of the test compound to interfere with or disrupt the antibody-antigen complex can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding of the test compound to the antigen or biologically active portion thereof can be determined by detecting the labeled compound in a complex.
- test compounds can be labeled with 125r, 35 S, 14C, or 3H, directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting.
- test compounds can be enzymatically labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product.
- the assay comprises contacting an antibody-antigen complex with a test compound and determining the ability of the test compound to interact with the antigen or otherwise disrupt the existing antibody-antigen complex.
- determining the ability of the test compound to interact with the antigen and/or disrupt the antibody-antigen complex comprises determining the ability of the test compound to preferentially bind to the antigen or a biologically active portion thereof, as compared to the antibody.
- the assay comprises contacting an antibody-antigen complex with a test compound and determining the ability of the test compound to modulate the antibody-antigen complex. Determining the ability of the test compound to modulate the antibody-antigen complex can be accomplished, for example, by determining the ability of the antigen to bind to or interact with the antibody, in the presence of the test compound.
- the antibody can be a MSLN antibody.
- the antigen can be a MSLN protein or a portion thereof.
- the screening methods disclosed herein can be performed as a cell-based assay or as a cell-free assay. In the case of cell-free assays comprising the membrane-bound forms of the MSLN proteins, it can be desirable to utilize a solubilizing agent such that the membrane- bound form of the proteins is maintained in solution.
- solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecy lglucoside, n-dodecy lmaltoside, octanoy 1-N-methy lglucamide, decanoyl-N-methylglucamide, Triton® X-100, Triton® X-114, Thesit®, Isotridecypoly( ethylene glycol ether )n, N-dodecy 1--N ,N-dimethy 1-3-ammonio-1-propane sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-1-propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1-propane sulfonate (CHAPSO).
- non-ionic detergents such as n-octy
- a fusion protein can be provided that adds a domain that allows one or both of the proteins to be bound to a matrix.
- GST-antibody fusion proteins or GST- antigen fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St.
- the antibody or the antigen can be immobilized utilizing conjugation of biotin and streptavidin.
- Biotinylated antibody or antigen molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well-known within the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical).
- the invention further pertains to new agents identified by any of the screening assays described herein and uses thereof for treatments as described herein.
- CAR cell therapies such as chimeric antigen receptor (CAR) cell therapies, are also provided herein.
- the cell can be a CAR T-cell or a CAR NK-cell,
- CAR cell therapies redirect a patient’s T-cells and/or NK-cells to kill tumor cells by the exogenous expression of a CAR on a T-cell or NK-cell, for example.
- a CAR can be a membrane spanning fusion protein that links the antigen recognition domain of an antibody to the intracellular signaling domains of the T-cell receptor and co-receptor or NK-cell receptor.
- monospecific CAR cells are provided.
- the anti- MSLN antibodies described herein can be used as the targeting moiety for the CAR cell.
- the MSLN antibody can have low affinity but high avidity for its antigen.
- the MSLN antibody can have high affinity but low avidity for its antigen.
- Antibodies with fewer binding sites can have high affinity and low avidity, while those with greater binding sites can have low affinity and high avidity.
- bispecific (or dual-targeted) CAR cells are provided.
- the CAR cell is an engineered cell comprising a chimeric antigen receptor, wherein the chimeric antigen receptor comprises an extracellular ligand binding domain that is specific for a first antigen and a second antigen on the surface of a cancer cell, wherein the first antigen comprises an antigen that is not MSLN and the second antigen comprises MSLN.
- the anti-MSLN antibodies or the MSLN fusion proteins described herein can be used as a payload for armored CAR-cell therapies.
- a suitable cell can be used, for example, that can secrete an anti-MSLN antibody of the invention (or alternatively engineered to express an anti-MSLN antibody as described herein to be secreted).
- the anti- MSLN “payloads” to be secreted can be, for example, minibodies, scFvs, IgG molecules, bispecific fusion molecules, and other antibody fragments as described herein.
- the cell described herein can then be introduced to a patient in need of a treatment by infusion therapies known to one of skill in the art.
- the patient can have a MSLN-associated disease or disorder as described herein, such as cancer.
- the cell e.g., a T cell
- the cell can be, for instance, T lymphocyte, a CD4+ T cell, a CD8+ T cell, or the combination thereof, without limitation.
- Exemplary CARs and CAR factories useful in aspects of the invention include those disclosed in, for example, PCT/US2015/067225 and PCT/US2019/022272, each of which are hereby incorporated by reference in their entireties.
- the MSLN antibodies discussed herein can be used in the construction of multi-specific antibodies or as the payload for a CAR-T cell or CAR NK-cell.
- the anti-MSLN antibodies discussed herein can be used for the targeting of the CARs (i.e., as the targeting moiety).
- the anti-MSLN antibodies discussed herein can be used as the targeting moiety, and a different MSLN antibody that targets a different epitope can be used as the payload.
- the payload can be an immunomodulatory antibody payload.
- TME tumor microenvironment
- the cell can then be introduced to a cancer patient in need of a treatment by infusion therapies known to one of skill in the art.
- the cancer patient can have a cancer of any of the types as disclosed herein.
- the cell e.g., a T cell
- CAR cells i.e., CAR T cells or CAR NK cells
- CAR T cells can be generated according to methods known in the art using lentivirus systems (via transduction), retrovirus systems (via transfection (electroporation)), and transposon systems (via PiggyBac).
- promoters for payloads that can be used in the generating of CAR-Ts include, for example, constitutive promoters (where the promoter is the same as for CAR-T, such as EF1a then IRES or 2A); inducible promoters (where the promoter is different from the promoter for CAR-T, such as NFAT, IL-2 prom); and genetically engineered promoters (such as a MSLN locus “knock in” of cytokine and/or a promoter that is under the control of an endogenous promoter).
- constitutive promoters where the promoter is the same as for CAR-T, such as EF1a then IRES or 2A
- inducible promoters where the promoter is different from the promoter for CAR-T, such as NFAT, IL-2 prom
- genetically engineered promoters such as a MSLN locus “knock in” of cytokine and/or a promoter that is under the control of an endogenous promote
- the MSLN antibodies or the MSLN fusion proteins discussed herein can Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 be used in the construction of multi-specific antibodies or as the payload for a CAR cell.
- the anti-MSLN antibodies or the MSLN fusion proteins discussed herein can be used for the targeting of the CARS (i.e., as the targeting moiety).
- the anti-MSLN antibodies or the MSLN fusion proteins discussed herein can be used as a payload to be secreted by a CAR cell.
- the anti-MSLN antibodies or the MSLN fusion proteins discussed herein can be used as the targeting moiety, and a different MSLN antibody that targets a different epitope can be used as the payload.
- the payload can be an immunomodulatory antibody payload.
- the MSLN antibodies or the MSLN fusion proteins as described herein for use in CAR-T compositions are not high-affinity MSLN antibodies (for example, so that the antibody does not bind strongly to its MSLN target).
- the MSLN antibodies or the MSLN fusion proteins described herein can be used as a payload secreted by the CAR cell, with the two targeting moieties (for example, tumor-associated surface antigens) selected for a specific cancer.
- a tumor-associated surface antigen include ErbB2 (HER2/neu), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), MUC1, MSLN, CD19, CD20, CD30, CD40, CD22, RAGE-l, MN-CA IX, RET1, RET2 (AS), prostate specific antigen (PSA), TAG-72, PAP, p53, Ras, prostein, PSMA, survivin, 9D7, prostate-carcinoma tumor antigen-l (PCTA-1), GAGE, MAGE, mesothelin, ⁇ -catenin, TGF- ⁇ RII, BRCA1/2, SAP-1, HPV-E
- Exemplary armored CAR-T cells are listed in the table below.
- CAR cells can be generated from cellular sources known to the skilled artisan.
- Non-limiting examples include T cells, NK cells, iPSC-derived cells (e.g., iPSC-derived T-cells and/or iPSC-derived NK cells), peripheral blood cells (e.g., peripheral blood mononuclear cells), cord blood cells, cell lines (e.g., NK92 cell line), human embryonic stem cells (hESCs) and CD34+ hematopoietic progenitor cells (HPCs).
- T cells e.g., iPSC-derived T-cells and/or iPSC-derived NK cells
- peripheral blood cells e.g., peripheral blood mononuclear cells
- cord blood cells e.g., NK92 cell line
- cell lines e.g., NK92 cell line
- hESCs human embryonic stem cells
- HPCs CD34+ hematopoietic progenitor cells
- Chimeric B-cell Receptor A modified B cell receptor called chimeric B cell receptor, such as a B cell receptor containing an antibody or antibody fragment previously selected by high affinity against a specific disease associated antigen, is a powerful new approach against diseases.
- B cells serve as professional antigen presenting cells, they can process and present antigens on MHC class II molecules, enhancing immune cell recognition of the tumor and assisting in neoantigen spreading.
- a key component of immunologic memory, chimeric antibody signaling and secreting (CASS) B cells will simultaneously recruit a wide range of immune cells and reverse tumor infiltrating lymphocyte exhaustion, providing a robust and lifelong surveillance program protecting against tumor metastasis and recurrence.
- the B cell can include a receptor that is chimeric, non-natural and engineered at least in part by the hand of man.
- the engineered chimeric B cell receptor has one, two, three, four, or more components, and in some embodiments the one or more components facilitate targeting or binding of the B cell to one or more antigen-comprising cells.
- Aspects of the invention include genetically engineered B cells that are modified to express and bear on its surface a chimeric B cell receptor.
- the genetically Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 modified B cell can comprise a single chimeric B cell receptor targeting one antigen, such as MSLN, or a single chimeric B cell receptor targeting two or more antigens (e.g., a bi-specific chimeric B cell receptor, or a multispecific chimeric B cell receptor).
- the cells comprise a split chimeric B cell receptor, such as two different scFvs expressed on the B cell surface with different co-stimulation domains. Further, some embodiments comprise a fine-tuned chimeric B cell receptor.
- the chimeric B cell receptor comprises an extracellular domain, a transmembrane domain, and an intracellular signaling domain; such that the polypeptides assemble together to form a chimeric B cell receptor.
- the extracellular ligand-binding domain can be chosen to recognize a ligand, such as MSLN, that acts as a cell surface marker on target cells associated with a disease state.
- the disease state can be cancer
- the target ligand can be a cancer associated antigen, such as MSLN.
- the extracellular ligand-binding domain can comprise an antigen binding domain or antigen recognition domain derived from an antibody against an antigen of the target, such as an anti-MSLN antibody described herein.
- the extracellular ligand-binding domain can comprise an antibody or fragment thereof described herein.
- the transmembrane domain comprises a stalk region.
- the stalk region can be derived from all or part of naturally occurring molecules, such as from all or part of the extracellular region of CD8, CD4 or CD28, or from all or part of an antibody constant region (such as CH1, CH2, CH3, or both CH2 and CH3 for an IgG antibody, or CH1, CH2, CH3, CH4, or any combination thereof for an IgM antibody).
- the stalk region can be a synthetic sequence that corresponds to a naturally occurring stalk sequence or can be an entirely synthetic stalk sequence. In an embodiment said stalk region is a part of human CD8 alpha chain.
- the signal transducing domain or intracellular signaling domain of the chimeric B cell receptor of the invention is responsible for intracellular signaling following the binding of extracellular ligand binding domain to the target resulting in the activation of the immune cell and immune response. In other words, the signal transducing domain is responsible for the activation of at least one of the normal function of the B cell in which the chimeric B cell receptor is expressed.
- the term "signal transducing domain” can refer to the portion of a protein which directs the cell to perform a specialized function, such as early activation of Lyn and Syk and late activation of NFAT and NF ⁇ B as examples.
- the chimeric B cell receptor can comprise native transmembrane and intracellular domains. In native B cells, engagement of the B cell receptor leads to rapid tyrosine phosphorylation of the intracellular domains and calcium ion polarization, resulting in downstream activation of NFAT and NF-kB.
- transmembrane polypeptides comprise the ability to be expressed at the surface of an immune cell, such as B cells, and to interact together for directing cellular response of immune cell against a predefined target cell.
- the different transmembrane polypeptides of the chimeric B cell receptor comprising an extracellular ligand- binding domain and/or a signal transducing domain interact together to take part in signal transduction following the binding with a target ligand and induce an immune response.
- the transmembrane domain can be derived from a natural or from a synthetic source.
- the transmembrane domain can be derived from any membrane-bound or transmembrane protein.
- Methods of Treatment refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an unsought physiological change or disorder, such as the progression of cancer.
- Beneficial or preferred clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
- Treatment can refer to prolonging survival as compared to expected survival if not receiving treatment.
- Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
- the invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a cancer (for example, if an early detection cancer biomarker is identified in such a subject), or other cell proliferation-related diseases or disorders.
- diseases or disorders include but are not limited to, e.g., those diseases or disorders associated with aberrant expression of MSLN and/or aberrant activation of cellular signaling pathways involving MSLN.
- diseases or disorders are included in MSLN associated diseases or disorders.
- the methods are used to treat, prevent, or alleviate a symptom of cancer.
- the methods are used to treat, prevent, or alleviate a symptom of a solid tumor.
- Non-limiting examples of other tumors that can be Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 treated by compositions described herein comprise lung cancer, breast, ovarian cancer, prostate cancer, colon cancer, cervical cancer, brain cancer, skin cancer, liver cancer, pancreatic cancer, or stomach cancer. Additionally, the methods of the invention can be used to treat hematologic cancers such as leukemia and lymphoma. Alternatively, the methods can be used to treat, prevent, or alleviate a symptom of a cancer that has metastasized.
- cancers that can be treated or prevented or for which symptoms can be alleviated include B-cell chronic lymphocytic leukemia (CLL), non-small-cell lung cancer, melanoma, ovarian cancer, lymphoma, or renal-cell cancer.
- CLL B-cell chronic lymphocytic leukemia
- cancers that can also be treated or prevented or for which symptoms can be alleviated include those solid tumors with a high mutation burden and WBC in filtrate.
- the invention provides methods for preventing, treating, or alleviating a symptom cancer or a cell proliferative disease or disorder in a subject by administering to the subject a monoclonal antibody, scFv antibody or bi- specific antibody of the invention.
- an anti-MSLN antibody can be administered in therapeutically effective amounts.
- Subjects at risk for cancer or cell proliferation-related diseases or disorders can include patients who have a family history of cancer or a subject exposed to a known or suspected cancer-causing agent. Administration of a prophylactic agent can occur prior to the manifestation of cancer such that the disease is prevented or, alternatively, delayed in its progression.
- tumor cell growth is inhibited by contacting a cell with an anti- MSLN antibody of the invention.
- the cell can be any cell that expresses MSLN.
- the invention further provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a chronic or acute viral, bacterial, or parasitic infection.
- the invention also provides for therapeutic methods for both prophylactic and therapeutic methods of treating a subject at risk of a disease or disorder or condition associated with T-cell exhaustion or a risk of developing T-cell exhaustion.
- the invention also provides for therapeutic methods for both prophylactic and therapeutic methods of treating a subject at risk of a disease or disorder or condition associated with T-cell exhaustion or a risk of developing T-cell exhaustion.
- diseases or disorder include, but are not limited to HIV, AIDS, and chronic or acute bacterial, viral or parasitic infections.
- Other such chronic infections include those caused by, for example, hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus 1 (HSV-1), H.
- pylori or Toxoplasma gondii.
- Other acute infections included are those caused by, for example, microorganisms, such as a Gram-positive Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 bacterium, a Gram-negative bacterium, a protozoan, or a fungus, as described herein.
- a non- limiting example of an infection comprises an influenza infection.
- Also included in the invention are methods of increasing or enhancing an immune response to an antigen. An immune response is increased or enhanced by administering to the subject a monoclonal antibody, scFv antibody, or bi-specific antibody of the invention.
- the immune response is augmented for example by augmenting antigen specific T effector function.
- the antigen is a viral (e.g., HIV), bacterial, parasitic or tumor antigen.
- the immune response is a natural immune response.
- natural immune response is meant an immune response that is a result of an infection.
- the infection can be an influenza infection.
- the infection is a chronic infection.
- Increasing or enhancing an immune response to an antigen can be measured by a number of methods known in the art.
- an immune response can be measured by measuring any one of the following: T cell activity, T cell proliferation, T cell activation, production of effector cytokines, and T cell transcriptional profile.
- the immune response is a response induced due to a vaccination.
- the invention provides a method of increasing vaccine efficiency by administering to the subject a monoclonal antibody or scFv antibody of the invention and a vaccine.
- the antibody and the vaccine are administered sequentially or concurrently.
- the vaccine is a tumor vaccine a bacterial vaccine or a viral vaccine.
- Combinatory Methods [00290] Compositions of the invention as described herein can be administered in combination with a chemotherapeutic agent.
- Chemotherapeutic agents that can be administered with the compositions of the disclosure include, but are not limited to, antibiotic derivatives (e.g., doxorubicin, bleomycin, daunorubicin, and dactinomycin); antiestrogens (e.g., tamoxifen); antimetabolites (e.g., fluorouracil, 5-FU, methotrexate, floxuridine, interferon alpha-2b, glutamic acid, plicamycin, mercaptopurine, and 6-thioguanine); cytotoxic agents (e.g., carmustine, BCNU, lomustine, CCNU, cytosine arabinoside, cyclophosphamide, estramustine, hydroxyurea, procarbazine, mitomycin, busulfan, cis-platin, and vincristine sulfate); hormones (e.g., medroxyprogesterone, estramustine phosphate sodium, e
- compositions of the invention as described herein can be administered in combination with cytokines.
- Cytokines that can be administered with the compositions include, but are not limited to, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-10, IL- 12, IL-13, IL-15, anti-CD40, CD40L, and TNF- ⁇ .
- the compositions described herein can be administered in combination with other therapeutic or prophylactic regimens, such as, for example, radiation therapy.
- compositions described herein can be administered in combination with other immunotherapeutic agents.
- immunotherapeutic agents include synthetic sirolimus, abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab,
- the invention provides for methods of treating cancer in a patient by administering two antibodies that bind to the same epitope of the MSLN protein or, alternatively, two different epitopes of the MSLN protein.
- the cancer can be treated by administering a first antibody that binds to MSLN and a second antibody that binds to a protein other than MSLN.
- the cancer can be treated by administering a bispecific antibody that binds to MSLN and that binds to a protein other than MSLN.
- the other protein other than MSLN can include, but is not limited to, IL-12, IL-12R, IL-2, IL-2R, IL-15, IL-15R, IL-7, IL-7R, IL-21, or IL-21R.
- the other protein Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 other than MSLN is a tumor-associated antigen; the other protein other than MSLN can also be a cytokine.
- Non-limiting examples of the other protein other than MSLN includes CTLA-4, CXCR4, LAG-3, CD28, CD122, 4-1BB, TIM3, OX-40, OX40L, CD40, CD40L, LIGHT, ICOS, ICOSL, GITR, GITRL, TIGIT, CD27, VISTA, B7H3, B7H4, HEVM (or BTLA), CD47 and CD73.
- the invention provides for the administration of an anti-PD- 1 antibody alone or in combination with an additional antibody that recognizes another protein other than MSLN, with cells that can effect or augment an immune response.
- these cells can be peripheral blood mononuclear cells (PBMC), or any cell type that is found in PBMC, e.g., cytotoxic T cells, macrophages, and natural killer (NK) cells.
- PBMC peripheral blood mononuclear cells
- NK natural killer cells
- the invention provides administration of an antibody that binds to the MSLN protein and an anti-neoplastic agent, such as a small molecule, a growth factor, a cytokine or other therapeutic including biomolecules such as peptides, peptidomimetics, peptoids, polynucleotides, lipid-derived mediators, small biogenic amines, hormones, neuropeptides, and proteases.
- Small molecules include, but are not limited to, inorganic molecules and small organic molecules.
- Suitable growth factors or cytokines include an IL-2, GM-CSF, IL-12, and TNF-alpha. Small molecule libraries are known in the art. (See, Lam, Anticancer Drug Des., 12: 145, 1997.) [00297] Diagnostic Assays [00298]
- the anti-MSLN antibodies can be used diagnostically to, for example, monitor the development or progression of cancer as part of a clinical testing procedure to, e.g., determine the efficacy of a given treatment and/or prevention regimen.
- the anti-MSLN antibody of the invention is linked to a detectable moiety, for example, so as to provide a method for detecting a cancer cell in a subject at risk of or suffering from a cancer.
- the detectable moieties can be conjugated directly to the antibodies or fragments, or indirectly by using, for example, a fluorescent secondary antibody. Direct conjugation can be accomplished by standard chemical coupling of, for example, a fluorophore to the antibody or antibody fragment, or through genetic engineering. Chimeras, or fusion proteins can be constructed which contain an antibody or antibody fragment coupled to a fluorescent or bioluminescent protein. For example, Casadei, et al, (Proc Natl Acad Sci U S A.
- labeled with regard to the probe or antibody, can encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled.
- Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin.
- biological sample is intended to include tissues, cells and biological fluids isolated from a subject (such as a biopsy), as well as tissues, cells and fluids present within a subject. That is, the detection method of the invention can be used to detect cells that express MSLN in a biological sample in vitro as well as in vivo.
- in vitro techniques for detection of MSLN include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence.
- in vivo techniques for detection of MSLN include introducing into a subject a labeled anti-MSLN antibody.
- the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.
- targeting moiety a molecule or feature designed to localize the conjugate within a subject or animal at a certain site or sites
- localization can refer to a state when an equilibrium between bound, "localized", and unbound, "free” entities within a subject has been essentially achieved. The rate at which such equilibrium is achieved depends upon the route of administration.
- a conjugate administered by intravenous injection can achieve localization within minutes of injection.
- a conjugate administered orally can take hours to achieve localization.
- localization can simply refer to the location of the entity within the subject or animal at selected time periods after the entity is administered.
- localization is achieved when an moiety becomes distributed following administration.
- a reasonable estimate of the time to achieve localization can be made by one skilled in the art.
- the state of localization as a function of time can be followed by imaging the detectable moiety (e.g., a light-emitting conjugate) according to the methods of the invention, such as with a photodetector device.
- the "photodetector device” used can have a high enough sensitivity to allow for the imaging of faint light from within a mammal in a reasonable amount of time, and to use the signal from such a device to construct an image.
- a pair of "night- vision" goggles or a standard high- sensitivity video camera such as a Silicon Intensified Tube (SIT) camera (e.g., from Hammamatsu Photonic Systems, Bridgewater, N.J.), can be used.
- SIT Silicon Intensified Tube
- At least two types of photodetector devices can detect individual photons and generate a signal which can be analyzed by an image processor.
- Reduced-Noise Photodetection devices achieve sensitivity by reducing the background noise in the photon detector, as opposed to amplifying the photon signal. Noise is reduced primarily by cooling the detector array.
- the devices include charge coupled device (CCD) cameras referred to as "backthinned", cooled CCD cameras. In the more sensitive instruments, the cooling is achieved using, for example, liquid nitrogen, which brings the temperature of the CCD array to approximately -120°C.
- “Backthinned” refers to an ultra- thin backplate that reduces the path length that a photon follows to be detected, thereby increasing the quantum efficiency.
- a sensitive backthinned cryogenic CCD camera is the "TECH 512", a series 200 camera available from Photometries, Ltd. (Tucson, Ariz.).
- "Photon amplification devices” amplify photons before they hit the detection screen.
- This class includes CCD cameras with intensifiers, such as microchannel intensifiers.
- a microchannel intensifier contains a metal array of channels perpendicular to and co-extensive with the detection screen of the camera. The microchannel array is placed between the sample, subject, or animal to be imaged, and the camera. Most of the photons entering the channels of the array contact a side of a channel before exiting. A voltage applied across the array results in the release of many electrons from each photon collision.
- Image processors process signals generated by photodetector devices which count photons to construct an image which can be, for example, displayed on a monitor or printed on a video printer. Such image processors are sold as part of systems which include the sensitive photon-counting cameras described herein, and accordingly, are available from the same sources.
- the image processors can be connected to a personal computer, such as an IBM- compatible PC or an Apple Macintosh (Apple Computer, Cupertino, Calif), which can or cannot be included as part of a purchased imaging system.
- a personal computer such as an IBM- compatible PC or an Apple Macintosh (Apple Computer, Cupertino, Calif)
- image processing programs such as "ADOBE PHOTOSHOP", Adobe Systems, Adobe Systems, Mt. View, Calif.
- the biological sample contains protein molecules from the test subject.
- One exemplary biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject.
- the invention also encompasses kits for detecting the presence of MSLN or a TIGIT- expressing cell in a biological sample.
- the kit can comprise: a labeled compound or agent that can detect a cancer or tumor cell (e.g., an anti-MSLN scFv or monoclonal antibody) in a biological sample; means for determining the amount of MSLN in the sample; and means for comparing the amount of MSLN in the sample with a standard.
- the standard is, in some embodiments, a non-cancer cell or cell extract thereof.
- the compound or agent can be packaged in a suitable container.
- the kit can further comprise instructions for using the kit to detect cancer in a sample.
- Other Embodiments [00313] While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. [00314] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 EXAMPLES [00315] Examples are provided below to facilitate a more complete understanding of the invention.
- EXAMPLE 1 [00316] We have identified a series of anti-Mesothelin (MSLN) antibodies via whole cell panning. Panning rounds were completed using transduced cells (293T-MSLN or Cf2Th- MSLN) or tumor cell lines that are naturally high in MLSN (OVCAR8). A total of 118 unique antibodies were identified and the lead clones were identified based on binding to OvCar8 and/or Cf2Th cells. See, FIG. 39.
- MSLN anti-Mesothelin
- MSLN has been identified as a tumor associated antigen for a wide variety of cancers, including lung and ovarian cancers. MSLN can exist in two forms, bound to the cell membrane via a GPI linker, and in a soluble/shed form.
- scFvs can be developed as monoclonal antibodies for therapeutic or diagnostic purposes. Additionally, they have potential as a targeting moiety for CAR T cells against cancers that overexpress MSLN.
- B cells are a critical component of a patients’ natural immunity and while other immune cells including T cells, NK cells, and myeloid cells have been engineered with Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 Chimeric Antigen Receptors (CAR), B cells have largely been ignored.
- the main role of B cells is to recognize foreign invaders via a membrane bound antibody (B cell receptor, BCR) and eliminate them by producing antibodies that bind and clear the threat.
- the target binding domain will be designed to recognize a tumor associated antigen and upon binding will lead to the secretion of a trispecific T cell engaging antibody that effectively stimulates recruited T cells and brings them into contact with tumor cells further enhancing tumor cell lysis.
- a second major function of B cells is to present foreign protein as MHC-II fragments to T cells and the formation of immune cell clusters, leading to their activation and the further recruitment of various anti-tumor immune cells.
- CASS B cells play a key role in immunologic memory and CASS B cells will provide a lifelong anti-tumor surveillance network protecting patients from metastasis and reoccurrence after the initial tumor is eliminated.
- HGSOC high grade serous ovarian cancer
- Aim 1 will validate the engineering of the CASS B cell, first by building the synthetic B cell receptor to recognize Muc1.
- Aim 2 will use 2D and 3D tissue culture experiments to validate CASS B cell engineering and to demonstrate both the efficacy of the CASS B cell, and the ability of the trispecific antibody to stimulate and engage T cells.
- Aim 3 will use humanized mice to validate the effectiveness of the CASS B cell platform in vivo and allow for detailed molecular characterization of the anti-tumor immune response. In embodiments, we can study HGSOC.
- TILs tumor infiltrating lymphocytes
- embodiments herein comprise Chimeric Antibody Secreting and Signaling (CASS) B cells, a new and innovative cellular immunotherapy platform.
- CASS B cells take advantage their ability to present antigens on MHC class II molecules, enhancing tumor cell recognition and neoantigen spreading while also relying on their role in the formation and function of tertiary lymphoid structures (TLS) to secrete chemokines that recruit various immune cell subsets to the HGSOC tumor site 8,9 .
- TLS tertiary lymphoid structures
- TAA tumor associated antigen
- BCR B cell receptor
- mucin-1 MSLN
- mesothelin MSLN
- the combination of anti-CD3xCD28 on the trispecific antibody will allow for efficient stimulation of both CD4 and CD8 T cells, and the anti-MSLN domain homes the activated T cells towards the tumor, facilitating potent tumor cell lysis 16 .
- the trispecific antibody developed here is designed to enhance T cell mediated cytotoxicity, it will not directly inhibit the immunosuppressive signals generated in the TME.
- CASS B cell platform is unique in the cell therapy space, as CASS B cells have the power to both initiate a robust anti-tumor response and to augment the activity of the recruited immune cells.
- Anti-Muc1 targeted CASS B cells secreting an anti-CD3xCD28xMSLN T cell engaging Ab for HGSOC are described herein.
- CASS B cells allow for easy targeting of other TAAs and the secreted payload can be adjusted to target the relevant immunologic axis, allowing for the adaptation of CASS B cells to a wide variety of cancers.
- B cells are long lived and an important part of immunologic memory
- CASS B cells continuously deliver the therapeutic payload at the tumor and after the primary tumor has been Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 eradicated, provides a lifelong immunosurveillance system against metastasis and reoccurrence.
- CASS B cells will remodel the HGSOC tumor microenvironment via innate antigen presenting capabilities while the formation of tertiary lymphoid structures (TLS) will result in the recruitment and activation of a wide subset of immune cells.
- TLS tertiary lymphoid structures
- CASS B cells engineered to secrete an anti-CD3xCD28xMSLN trispecific T cell engaging antibody will further restore anti-tumor immunity, enhancing T cell activation, tumor recognition, and cytotoxic activity.
- Non-Limiting Aim 1 Engineering and optimization of CASS B cell constructs and trispecific Ab payload - The appropriate Abs (anti-MSLN, Muc1, CD3, CD28) will be selected for CASS B cell development followed by optimization of the signaling domains and inducible response element (RE).
- Abs anti-MSLN, Muc1, CD3, CD28
- Non-Limiting Aim 2 In vitro evaluation of CASS B and trispecific T cell engager - In vitro characterization will be performed to identify activation thresholds and quantify Ab secretion levels.3D organoid cultures will be used for an in-depth molecular and functional characterization of both the CASS B cell and the T cell engaging payload.
- Non-Limiting Aim 3 In vivo efficacy using HLA matched, humanized HGSOC mouse models - Final evaluation of the optimized CASS B cell construct with and without systemic anti-PD1 combination therapy will be tested in vivo using a cell line derived xenograft (CDX) model in humanized mice.
- CDX cell line derived xenograft
- Non-Limiting Aim 1 Engineering and optimization of CASS B cell constructs and trispecific Ab payload: [00336]
- Non-Limiting Aim 1A Antibody discovery and trispecific T cell engager engineering - In this sub aim we will develop the four antibodies; an anti-Muc1 for IgG-BCR Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 targeting and anti-CD3, CD28, MSLN for the trispecific T cell engager. Affinity modulation and epitope mapping will be performed to further characterize these antibodies.
- Non-Limiting Aim 1B CASS B cell vector design and engineering -
- the CASS B cell lentiviral vector will be designed using an engineered IgG-BCR targeting construct and an NFAT/ NF ⁇ B inducible reporter system.
- We will validate the ability of the IgG-BCR to induce expression of a fluorescent protein via the engineered transcription factor response elements (RE), including various NFAT and NF ⁇ B formats with minimal promoters 27–30 .
- RE transcription factor response elements
- Non-Limiting Aim 1C Optimization of transduction and exponential expansion of primary B cells -
- primary B cells require an array of cytokines and stimulatory signals
- a 3T3-msCD40L feeder cell line to express IL-2, 15, and 21 to support maximal B cell growth 31,32 .
- Lentiviral transduction of primary B cells will be optimized by testing different envelope proteins (VSVG, BaEV, GaLV) for lentivirus encapsulation and promoters (Ef1 ⁇ , SFFV) to drive expression of the IgG-BCR 33–36 .
- Non-Limiting Aim 2 In vitro validation of CASS B cells and the trispecific T cell engager
- Non-Limiting Aim 2A In vitro functional validation of anti-Muc1 CASS B cells -
- the CASS B cell construct will be assembled using the trispecific T cell engager developed in Non-Limiting Aim 1. Characterization will be performed using soluble, crosslinked Muc1 to determine the CASS B cell threshold of activation and to quantify levels of trispecific Ab expression.
- Non-Limiting Aim 2B In vitro efficacy of CASS B cell in 3D culture utilizing HGSOC tumor spheroids – Muc1/MSLN positive HGSOC cell lines will engrafted in HLA matched, humanized mice. Tumors harvested from these mice will be used with microfluidic chips to generate a 3D organoid model of HGSOC in vitro 37–40 . This will allow us to validate CASS B cell homing to the tumor spheroid and cytokine analysis of the TME will allow for detailed validation of the effect of the T cell engaging payload.
- Non-Limiting Aim 3 In vivo efficacy using HLA matched, humanized HGSOC mouse models
- Non-Limiting Aim 3A Validate the anti-tumor efficacy and persistence of anti- Muc1 CASS B cells in humanized NSG-SGM3 mice bearing CDX tumors - HLA matched, humanized NSG-SGM3 mice will be used to generate a HGSOC model using a Muc1/MSLN Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 positive HGSOC cell line.
- Non-Limiting Aim 3B Validate efficacy of CASS B cells in combination with systemic anti-PD1 therapy – HGSOC CDX models described in Non-Limiting Aim 3A will be used to test CASS B cell efficacy in combination with anti-PD1 therapy.
- Moran’s Index will be used to quantify spatial autocorrelation of proteins on the segmented RNAscope ISH image, and Gabriel graphs will be used to evaluate spatial patterns correlated to response. Multivariate spatial associations between proteins will be assessed using simple Moran's eigenvector maps and spatial Principal Component Analysis. Additional statistical analysis will be provided by consultation with the Dana-Farber Biostatistics Core. [00346] In embodiments, further engineering can be performed by modification or replacement of the IgG-BCR signaling domains. We have experience with humanized mice and cohorts will be generated assuming a 20% dropout rate due to animal death or lack of CD34 engraftment.
- Immunotherapy though anti-PD1/PDL1 blockade represents an important advance in the cancer field, and is a front-line or standard therapeutic option for various cancers, including non-small-cell lung cancer, melanoma, colorectal cancer, and renal cell carcinoma (1-3).
- 1-3 non-small-cell lung cancer
- melanoma melanoma
- colorectal cancer melanoma
- renal cell carcinoma 1-3
- TCR T cell receptor
- CAR chimeric antigen receptor
- embodiments herein comprise a new form of cellular therapy called Chimeric Antibody Signaling and Secreting (CASS) B cells that will utilize B cells of the humoral immune system to do what they do best - secrete high levels of antibodies.
- CASS B cells will be engineered to recognize tumor associated antigens (TAA) through an engineered B cell receptor (BCR), which upon TAA engagement will activate the CASS B cell and induce the production of high levels of an immunomodulatory bispecific antibody (BsAb) at the tumor site.
- TAA tumor associated antigens
- BCR engineered B cell receptor
- BsAb immunomodulatory bispecific antibody
- BsAb secretion can be conditionally expressed only upon CASS B cell engagement with TAAs, and largely localized to the tumor site. Without wishing to be bound by theory, this is a step toward a new cellular therapy where locally secreted monoclonal antibodies are devoted to changing the tumor microenvironment and restoring local anti-tumor immunity.
- Monoclonal antibody (mAb) drugs that directly kill cancer cells, act as immune checkpoint blockade inhibitors or disrupt tumor vasculature are among the most promising anti-cancer therapeutics under development.
- the idea of engineering human B cells to seek out cancer cells and secrete these mAbs at the tumor site in vivo is new and can provide a powerful new way to treat both primary and metastatic tumors.
- B cells can also provide a lifelong anti-tumor immune surveillance system to prevent cancer reoccurrence and achieve “CURES”.
- a role of B cells in our immune system is to recognize foreign invaders and eliminate them by production of antibodies that bind and clear the threat whether a microbe or cancer cell.
- They Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 accomplish this by expressing a membrane bound antibody that acts as a B cell Receptor (BCRs) that bind the tumor antigen, causing the B cell to switch from a BCR expressing cell to an antibody secreting cell.
- BCRs B cell Receptor
- Anti-PD1/PDL1 therapy has had a transformative effect on the treatment of NSCLC, for example, becoming a frontline therapy for many patients.
- NSCLC an experimental model utilizing anti-PD1/anti- TIGIT bispecific antibodies under development in our lab.
- MSLN mesothelin
- the plasmid will also contain a second cassette driven by a NFAT or NF-kB responsive element that drives secretion of an anti-TIGIT/anti-PD1 BsAb.
- BsAb expression Upon localization to the tumor site and BCR activation, BsAb expression will be induced by the native signaling pathway upon BCR engagement of MSLN on NSCLC. Since this will be an inducible expression system, there will be a localized area of high antibody concentration at the tumor site, significantly decreasing on-target, off- tumor effects. [00395]
- the CASS B cell will be designed in two parts. We will successfully transfer the engineered BCR into the B cell.
- lentivirus particles will be pseudotyped with Gibbon-ape leukemia virus (GALV) or engineered baboon envelope glycoproteins and in the transfer vector BCR expression will be driven from a spleen focus- forming virus (SFFV) or human elongation factor-1 alpha (EF1 ⁇ ) promotor (8).
- SFFV spleen focus- forming virus
- EF1 ⁇ human elongation factor-1 alpha
- Raji cells and primary B cells will be transduced with the engineered anti-MSLN BCR and NFAT/NF- kB inducible GFP lentiviral vector, and soluble, biotinylated MSLN will be added to the culture media with streptavidin to cross-link BCRs. GFP expression will then be measured to Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 determine the optimal response element.
- Fig. 3 shows that our memIgG construct expresses at high levels and is functionally active as it is able to bind soluble HA.
- CASS B cells will be constructed by lenvtivirus transduction with the vector encoding the tumor specific anti-MSLN BCR and an inducible BsAb replacing GFP.
- CASS B cells secretion of anti-TIGIT/PD1 BsAb will be quantified, first using soluble biotinylated MSLN+streptavidin to induce expression, followed by co-incubation with MSLN+ A549 NSCLC cells. Secondary experiments will test for in vitro inhibition of exhaustion by co-culturing CASS B cells with CD3+ T cells and A549 cells expressing various combinations of PDL1 and CD155 (ligand of TIGIT).
- Chimeric Antibody Secreting and Signaling (CASS) B cells which express an engineered, tumor targeting B cell receptor and upon engagement, will secrete high levels of a dual-targeted bispecific CBI antibody locally at the tumor site.
- B cells also serve as professional antigen presenting cells, they can process and present antigens on MHC class II molecules, further enhancing immune cell recognition of the tumor and assisting in neoantigen spreading.
- CASS B cells will simultaneously recruit a wide range of immune cells and reverse tumor infiltrating lymphocyte exhaustion, providing a surveillance program protecting against tumor metastasis and recurrence.
- NSCLC Non-small cell lung cancer
- bsAb immunomodulatory anti-PD1/TIGIT bispecific antibody
- Aim 2 in vitro characterization and efficacy testing will be performed, resulting in a clear understanding of the linkage between CASS B cell activation and bsAb secretion, while providing critical analysis of CASS B cell efficacy in comparison to CAR T cells at both a functional and molecular level.
- Aim 3 will execute in vivo experiments using cell line derived and patient derived NSCLC models in humanized mice. Multiparameter flow cytometry, single cell RNA sequencing, and immunohistochemistry will provide a detailed assessment of the molecular and mechanistic efficacy of the immunomodulatory bsAb and the CASS B cell platform.
- B cells act as professional antigen presenting (APC) cells and can enhance tumor cell recognition and assist in neoantigen spreading, thereby leading to both reversal of tumor infiltrating lymphocyte (TIL) exhaustion and induction of a broader and more robust anti-tumor immune response.
- APC professional antigen presenting
- TIL tumor infiltrating lymphocyte
- MSLN mesothelin
- the first objective comprises the construction and optimization of the engineered anti-MSLN IgG-BCR, the anti-PD1/TIGIT bsAb to be delivered at the tumor site, and the inducible response element (RE) that drives bsAb expression.
- Panels of anti-MSLN, anti-PD1, and anti-TIGIT antibodies were identified by our lab and functional assays will identify lead candidates. Concurrent efforts will focus on the development of the inducible response elements and optimization of B cell transduction conditions.
- the second objective is the functional validation of the anti-MSLN CASS B cell in vitro. Activation assays will be used to quantify bsAb and cytokine secretion levels.
- PDOTS Patient-derived organotypic tumor spheroids
- scRNAseq single cell RNA sequencing
- Another objective will be to utilize HLA matched, humanized mice to generate cell line derived (CDX) and patient derived xenograft (PDX) models of NSCLC to test CASS B cell efficacy. Models will be paired with various analytical techniques (IHC, flow cytometry, scRNAseq) to further interrogate the effects of CASS B cell therapy on the surrounding TME.
- CBI Checkpoint blockade inhibitor
- mAbs monoclonal antibodies
- TEE immunosuppressive tumor microenvironment
- NK-CAR natural killer cells
- CAR-M macrophages
- the Chimeric Antibody Secreting and Signaling (CASS) B cell platform is a unique B cell based cellular therapy that does not rely upon direct cytotoxicity but utilizes two intrinsic capabilities of B cells; the ability to secrete high levels of CBI antibodies to reverse the immunosuppressive TME and the ability to process and present antigens on MHC class II molecules, resulting in the recruitment of CD4+ T cells and allowing for enhanced tumor cell recognition and neoantigen spreading. While inducible, targeted delivery of the CBI will decrease irAEs, the ability to serve as a professional APC makes the CASS B cell platform unique in the cell therapy space, as CASS B cells have the power to initiate a robust anti-tumor response.
- MHC class II neoantigens that play a key function in innate anti-tumor responses 16,17 .
- MSLN+ targeted CASS B cells secreting an anti- PD1/TIGIT bsAb for NSCLC the modular design of CASS B cells allow for easy targeting of other TAAs and the secreted payload can be adjusted to target the relevant immunologic axis, allowing for the adaptation of CASS B cells to a wide variety of cancers.
- CASS B cells continuously deliver the therapeutic payload at the tumor and after the primary tumor has been eradicated, provides a lifelong immunosurveillance system against metastasis and reoccurrence.
- biologic therapies such as cardiovascular and autoimmune diseases and neurological disorders, which can require long term disease maintenance and rapid administration of therapeutics to treat acute symptoms.
- B cell engineering is a more recent accomplishment and has mainly focused on creating B cells that secrete neutralizing, anti-pathogenic antibodies against RSV and HIV 21– 23 .
- the B cells described in these works focus on systemic production of antibodies to neutralize viral infection and utilize CRISPR/Cas9 to insert the recombinant mAb into the Ig locus of the B cell. This has the added benefit of allowing the antibody to continue to undergo affinity maturation, a requirement for combating infectious diseases but not for targeting immune markers.
- Aim 1 Engineering and optimization of CASS B cell constructs - The appropriate scFvs (anti-MSLN, PD1, TIGIT) will be selected for CASS B cell development followed by optimization of the signaling domains and inducible response element 25–28 . Protocols for high efficiency transduction and exponential expansion of primary B cells will also be optimized utilizing various lentivirus envelope proteins and culture conditions 29–32 .
- IgG-BCR construct Our engineered IgG-BCR is built using an scFv fused to a membrane bound IgG1 hinge-Fc that expresses at high levels and binds the target antigen 42 .
- Initial transduction experiments using primary B cells demonstrate high titer Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 transduction for multiple donors and DNA constructs.
- a fluorescent protein will be used in place of the secreted bsAb.
- Aim 2 will provide an in-depth understanding of CASS B cell activation and validate an optimal anti-MSLN scFv for selective targeting of MSLN+ tumors.
- PDOTs will provide a comprehensive data set of CASS B cell efficacy via cytokine secretion and transcriptional profiles, and that anti-MSLN CASS B cells will traffic to the tumor and the secreted bsAb will reverse the suppression of immune cells. Additionally, we will see greater epitope spreading and bystander immune cell activation with the CASS B cell compared to CAR T cell therapy.
- Milestones The first milestone in Aim 2 will be the generation of activation curves for CASS B cells and quantification of bsAb secretion. The next milestone will be establishment of the PDOTS, and efficacy testing of the bsAb systemically and as a CASS B cell payload. Another milestone will be comparing CASS B cell and CAR T cell therapy and the generation of immune profiles for each therapy via IHC and scRNAseq.
- Aim 3 In vivo efficacy using HLA matched, humanized NSCLC mouse models - in vivo experiments will be performed on a cell line derived xenograft (CDX) model in humanized mice.
- CDX cell line derived xenograft
- PDX patient derived xenograft
- the use of a validated patient derived xenograft (PDX) model from a publicly available repository for final testing will improve tumor integrity and phenotypic characteristics while accurately mimicking the TME of in vivo tumors.
- Experimental design and procedures [00439] Establishment of an NSCLC CDX and PDX model in humanized mice: NSCLC cell lines and PDX models will be screened for PDL1 and CD155 expression levels prior to luciferization 49 .
- Chimeric Antigen Receptor (CAR) T cell therapy is a new type of “living drug”.
- the CAR contains a single chain variable antibody fragment (scFv) linked to an intracellular signaling block that includes a CD3- ⁇ (z) activation domain (1st generation), with a CD28 or 41BB costimulatory domain (2nd generation), or both CD3- ⁇ and a costimulatory domain (3rd generation) 6.
- scFv single chain variable antibody fragment linked to an intracellular signaling block that includes a CD3- ⁇ (z) activation domain (1st generation), with a CD28 or 41BB costimulatory domain (2nd generation), or both CD3- ⁇ and a costimulatory domain (3rd generation) 6.
- scFv single chain variable antibody fragment linked to an intracellular signaling block that includes a CD3- ⁇ (z) activation domain (1st generation), with a CD28 or 41BB costimulatory domain (2nd generation), or both CD3- ⁇ and a costimulatory domain (3
- MUC1 anti-mucin 1
- MSLN anti-mesothelin
- the second arm of the BsAb is targeted to CCR4 which is overexpressed on regulatory T cells (Tregs) and are elevated in the tumor infiltrating lymphocyte population in OvCA 15-18.
- Tregs regulatory T cells
- the CAR-T cells can be additionally engineered to secrete a bispecific antibody (BsAb) that targets two of the major immunosuppressive pathways that are operative in HGSOC.
- BsAb bispecific antibody
- the locally secreted BsAb will be directed to TIGIT which is present on exhausted T cells, Tregs and NK cells and CCR4, which is upregulated on Tregs and plays a key role in chemotaxis. Without wishing to be bound by theory, simultaneously blocking these two pathways will reverse immunosuppression and restore local anti-tumor immunity.
- Specific Aims [00514] Aim 1 –Validate OvCA cell killing efficacy by anti-MUC1/MSLN DFIR CAR- T cells that constitutively secrete anti-CCR4/TIGIT BsAb locally at the tumor site using in vitro studies. Subtasks will include validation of reversal of T-cell exhaustion and restoration of cytokine secretion.
- DFIR CAR-T cells will be designed to have high killing efficacy of single antigen positive OvCA cells (MUC1 or MSLN) and double positive (MUC1 and MSLN) which we term “and/or” gating. Fine-tuning of the binding affinities will be achieved by validating different affinity anti-MUC1 and anti-MSLN scFvs as mono-CARs for ability to only kill tumor cells that overexpress either of these two antigens but not healthy cells that can express physiologic (lower) levels of these antigens.
- MUC1 or MSLN single antigen positive OvCA cells
- MUC1 and MSLN double positive
- Fine-tuning of the binding affinities will be achieved by validating different affinity anti-MUC1 and anti-MSLN scFvs as mono-CARs for ability to only kill tumor cells that overexpress either of these two antigens but not healthy cells that can express physiologic (lower) levels of these antigens.
- DFIR CAR-T cell antibody payloads have been determined by mining scRNAseq data from publicly available HGSOC patient samples to identify “public” signatures Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 of two nonoverlapping dysfunctional pathways of tumor infiltrating immune cells that we can use for therapeutic intervention.
- PDOTS Patient-derived organotypic tumor spheroids
- Antibody engineering techniques will allow us to fine-tune the affinity of the MUC1 and MSLN scFv targeting moieties to achieve high efficacy tumor cell killing.
- Design of new anti-CCR4/TIGIT BsAb will serve as a checkpoint control inhibitor of the TIGIT/CD155 axes on Tregs, cytotoxic T cells and NK cells, and as an antagonist against chemotaxis of Tregs to tumor cell that secrete the chemokines CCL17/CCL22.
- Improved CAR Efficacy and Safety Solid tumors can show phenotypic and genotypic heterogeneity. This is due to inherent properties effecting critical pathways such as DNA repair and replication that lead to uncontrolled tumor growth.
- dual-targeting can provide an “and/or” gating strategy whereby CAR-T cells can target and kill singly positive tumor cells and/or double positive with the latter showing synergistic binding and killing due to increased avidity 19-21.
- T4E3 scFvFc (5.26) is circa 10-fold higher than 3D1 scFvFc (57.02 nM) thereby providing us with a good therapeutic range to evaluate the effects of binding affinity and MUC1 target density on tumor cell killing as well as on-target off-tumor killing of healthy cells expressing low density of MUC-1 shows efficient killing of MUC1+ COV263 cells (bottom) even at low E:T (0.8:1) ratios (% survival at 48hrs) whereas control MUC1- HCT116v cells (top) were not killed. [00522] A similar discovery campaign was performed to identify anti-MSLN scFvs.
- IR CAR-T cells change the TME: Changing the TME is critically important for CAR-T cell therapy to both reverse immune cell exhaustion at the tumor site and to prevent the newly arrived CAR-T cells at the tumor site from becoming exhausted. We have spent considerable effort in analyzing published scRNAseq data to identify the targets for which we can develop a BsAb that can act as a potent ICI and reverse immunosuppression at the tumor site.
- TIGIT and CCR4 were chosen. Binding data for anti-TIGIT mAbs and their competition with its immunosuppressing ligand CD155 was performed. This Ab mediated blockade of CD155 binding to TIGIT can block the immunosuppression through this axis.
- CCR4 is a chemokine receptor present on immunosuppressive Tregs that migrate to the OvCA tumor site. Our lead anti-CCR4 antibody is mAb2-322-24.
- This antibody blocks the in vivo migration of human Tregs to the OvCA cells that secrete chemokines CCL17 and CCL22 (FIG 36, panel A) and restores in vivo tumor cell killing (FIG 36, panel B) [00525]
- Research plan We will validate individual anti-MUC1 and anti-MSLN CARs for killing against OVCAR8, CoV362 and MUC1 or MSLN transduced 293 T cells We will perform additional in vitro CAR-T cell killing studies of OVCAR8 and CoV362 cells that express different densities of MUC1 and MSLN as well as negative control MUC1-MSLN- SK59 cells and other low density MSLN+ or MUC1+ cell lines.
- DF CAR-T cells will be constructed using the lead anti-MUC1 and anti-MSLN scFvs in both orientations (proximal versus distal to T cell membrane) and different inter-scFv linker lengths (GGGGS) 1-3 (FIG. 34 and FIG. 37).
- Anti-CAIX G36 CAR-T cells significantly migrated from side channel to the middle channel with ccRCC spheroids and secreted CXCL10 after 6-days co-incubation (FIG. 38, panel C).
- CAR-T migration will be measured by co-transducing CAR-T cells with lentivirus expressing ZsGreen and viability by PI staining. Cytokine release profiles will be measured by Luminex.
- Luminex Cytokine release profiles
- anti-MUC1/MSLN DF CAR- T cells can be engineered to selectively kill OvCA cells that overexpress MUC1 and/or MSLN but not healthy cells that express physiologic (low) levels or are negative for these TAAs. Further, anti-MUC1/MSLN DFIR CAR-T cells that secrete anti-CCR4/TIGIT BsAbs will show enhanced killing compared to anti-MUC1/MSLN DF CAR-T cells that do not secrete ICI payloads.
- DFIR CAR-T cells that secrete anti-CCR4/TIGIT BsAbs will show greater reversal/prevention of TIL/CAR-T exhaustion than DFIR CAR-T cells that secrete only anti-TIGIT or anti-CCR4 Abs because of dual ICI pathway blockade.
- the mechanism(s) of action of our BsAb secreting DFIR CAR-T cells will be by both preventing CAR-T cell exhaustion and restoring anti-tumor immunity to the TILs.
- the outcomes to be monitored by FACS include reversal of upregulated exhaustion markers (PD1, TIM3, LAG3) in TIL/CAR-T cells and increase in TIL/CAR-T survival and by Luminex, increase in pro-inflammatory cytokine secretion.
- PD1, TIM3, LAG3 upregulated exhaustion markers
- Luminex increase in pro-inflammatory cytokine secretion.
- Cytokine ELISA Data will be analyzed in GraphPad Prism and two-way ANOVA accounting for multiple comparisons will be used for statistical analysis [00532] Aim 2 – Perform in vivo studies validating CAR-T cell efficacy in humanized mice (NSG-SGM3) bearing HLA matched ovarian tumors. Studies will be designed with appropriate control groups to separately assess the effects of anti-MUC1/anti-MSLN DFIR CAR-T cells and their anti-CCR4/TIGIT BsAb payloads. Subtasks will include analysis of TILs by scRNASeq, multiparameter FACS analysis and cytokine secretion profiles from plasma.
- the CAR was constructed with an affinity fine-tuned anti-CAIX scFv and the secreted Ab payload is an anti-PDL1 or irrelevant anti- SARS antibody. As can be seen there is markedly improved anti-tumor efficacy of the anti- CAIX CAR secreting anti-PDL1 Ab that acts as an ICI for this cancer.
- Research plan [00537] Primary OvCA PDX models from tumor cells that arose from HGSOC ascites have been established 27. Fourteen of these cell lines had growth kinetics suitable for robust in vivo experiments.
- CAR-T cells from the same donor will be injected via tail vein. Mice will be monitored by weekly BLI imaging and will be sacrificed at an appropriate time based on tumor growth. Ascites will be harvested and processed for determination of tumor cell counts. CAR-T cells and TILs will be processed for FACS staining of T cell subset and myeloid lineage and exhaustion markers (PD1, TIM3 and LAG3) and for scRNASeq to characterize changes in the TME.
- PD1, TIM3 and LAG3 myeloid lineage and exhaustion markers
- bioinformatic pipelines for this project will comprise a combination of tools including alAkazam 28; Shazam 29; Seurat 30; Cumulus 31.
- alAkazam 28; Shazam 29; Seurat 30; Cumulus 31 We will validate differences in transcriptional states, metabolic state and evolutionary patterns between different CAR-T treatments. Some overlap between subsets will be seen. We will compare these different treatments to validate whether there are phenotypic and functional properties that distinguish anti-MUC1/MSLN DFIR CAR-T cells secreting anti- CCR4/TIGIT BsAbs from other treatments and whether there are differences between the T cell donors.
- results Without wishing to be bound by theory, anti-MUC1/anti-MSLN DFIR CAR-T secreting anti-TIGIT/anti-CCR4 BsAb will show the greatest anti-tumor activity compared to other groups, followed by anti-MUC1/anti-MSLN DFIR CAR-T secreting irrelevant BsAb. Further, an irrelevant DFIR CAR-T secreting anti-TIGIT/anti-CCR4 BsAb will not have much of a clinical effect since that DFIR CAR-T cells are not targeted and will not undergo expansion. The other two animal groups will show uncontrolled tumor cell growth.
- T-cell exhaustion profiles from both FACS staining Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 and scRNASeq will correlate with the anti-tumor activity and support the contribution of the secreted anti-CCR4/TIGIT BsAb on restoring anti-tumor molecular and functional signatures.
- Tumor growth Data will be analyzed in GraphPad Prism. BLI will be analyzed using Living Image software.
- Flow Cytometry Flow Cytometry data will be analyzed using FlowJo.
- PBMC and peripheral blood mononuclear (PMN) cells are stained with each individual marker to appropriately compensate for colors.
- 10X Genomics provides a comprehensive analysis suite for data processing (Cell Ranger) and visualization (Loupe Cell Browser). Furthermore, programs in R like Seurat can further analyze the data output from Cell Ranger.
- Tumor growth trajectories will be summarized by averaging tumor growth at each time point across the repeated experiments, for each of the four types of CAR-T therapies and the control therapy (untransduced T cells) within each of the two PDX models. The most promising CAR-T therapy will have the greatest decrease in tumor growth in both PDX models.
- PubMed PMID 12928003.PMCID: PMC747367 4. Disis ML, Rivkin S. Future directions in the management of ovarian cancer. Hematol Oncol Clin North Am.2003;17(4):1075-85. Epub 2003/03/10. doi: 10.1016/s0889-8588(03)00054-6. PubMed PMID: 12959192.
- PMCID NA 5. Borella F, Ghisoni E, Giannone G, Cosma S, Benedetto C, Valabrega G, Katsaros D.
- Ovarian cancer is the fifth leading cause of cancer deaths in American women. Due to the absence of specific symptoms or signs and the lack of trustworthy screening for early detection, the majority of women with OvCA (60-65%) are diagnosed at a late stage when the cancer has spread beyond the confines of the ovary. Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 Currently, the standard treatment of OvCA is surgical intervention followed by platinum- containing chemotherapy, such as carboplatin plus paclitaxel. Treatment for stage III or IV disease is rarely curative, with 5-year survival rates under 20%.
- Chimeric Antigen Receptor (CAR) T cell therapy is a new type of “living drug”.
- the FDA approval of 2 nd generation CAR-T cell therapies have ushered this new type of cellular immunotherapy into mainstream cancer therapy for hematologic malignancies.
- these results have not been readily translatable to solid tumors. Indeed, several major hurdles have been recognized that limit our ability to achieve “cures” of solid tumors using CAR-T cells.
- TAA tumor associated antigen
- TME immunosuppressive tumor microenvironment
- one arm of the BsAb is directed against TIGIT which is over expressed on tumor antigen-specific CD8+ T cells and CD8+ tumor infiltrating lymphocytes (TILs) from individuals with high-grade serous ovarian cancer and the second arm is against CCR4 which is overexpressed on regulatory T cells (Tregs) that are elevated in the TILs in OvCA.
- TIGIT tumor antigen-specific CD8+ T cells and CD8+ tumor infiltrating lymphocytes
- CCR4 regulatory T cells
- Regs regulatory T cells
- the DF CAR-T cells can be additionally engineered to secrete a bispecific antibody (BsAb) that targets two of the major immunosuppressive pathways that are operative in HGSOC.
- BsAb bispecific antibody
- the locally secreted BsAb will be directed to TIGIT which is present on exhausted T cells, regulatory T cells (Tregs) and NK cells and CCR4, which is highly expressed on Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 Tregs.
- Aim 1 in vitro studies on OvCA cell killing efficacy by anti-MUC1/MSLN DFIR CAR T cells that constitutively secrete anti-TIGIT/CCR4 BsAb at the tumor site and to document reversal of T cell exhaustion.
- Aim 2 in vivo studies testing DFIR CAR-T cell efficacy in humanized mice (NSG-SGM3) bearing HLA-matched ovarian tumors. Studies will be designed with appropriate control groups to separately assess the effects of anti-MUC1/anti-MSLN DFIR CAR-T cells and their anti-TIGIT/CCR4 BsAb payloads.
- DFIR CAR-T treatment studies in humanized mice will validate that this treatment “cures” the HGSOC tumors.
- Humanized mice are mice that are engineered to carry a human immune system.
- Our analyses will also be aimed at understanding the mechanism by which the DFIR CAR-T cells work to restore anti-tumor immunity and is an important part of our studies.
- DFIR CAR-T cells can remain in the patient for life where they can constantly monitor by a process we call “immune surveillance” to prevent new HGSOC cells from arising.
- This cellular combination immunotherapy is formulated to be administered as a one-time, single agent, which can also decrease the burden on the patient, clinician, and payer.
- this DFIR CAR-T therapy offers a treatment of our warfighters and military who deserve the very best.
- Impact Statement [00567] Ovarian cancer is often diagnosed late, and treatment for stage III or IV disease is rarely curative, with 5-year survival rates under 20%. The disease strikes women in the US, including active and retired women of the military who deserve the very best treatment that we can offer in return for their valiant service to our country. However no effective therapy is available for relapsed or metastatic disease that has failed first-line therapy.
- Chimeric Antigen Receptor (CAR) T cell therapy is a new type of “living drug” that holds promise for the “Cure” of OvCA. This therapy takes advantage of our own Docket No.: 5031461-137-WO1 Date of Filing: August 15, 2023 immune cells and engineers them to recognize and kill cancer cells.
- CAR-T therapies have shown clinically meaningful results for the treatment of hematologic malignancies which has resulted in 3 FDA approved drugs, however, these findings have not been readily translated to solid tumors.
- Several major hurdles have been recognized that limit our ability to achieve “cures” of solid tumors using CAR-T cells.
- TAA tumor associated antigen
- TME immunosuppressive tumor microenvironment
- the TME has “public” signatures that are common to women with OvCA that can be targetable with immune checkpoint blockade inhibitors (ICIs).
- Our DFIR CAR-T cells will be able to kill a heterogeneous tumor cell population because of our “and/or” gating strategy that is allowed for by dual anti-MUC1 and anti-MSLN CAR-T targeting. Specifically, dual targeting will promote killing of both singly (MUC1 or MSLN) positive tumor cells and doubly (MUC1 and MSLN1) positive tumor cells.
- Our DFIR CAR-T cells are also anti- TIGIT/CCR4 BsAb secreting cells.
- TIGIT and CCR4 are targetable checkpoint molecules and are found to be highly expressed on TILs and tumor associated lymphocytes (TALs).
- blocking TIGIT/CD155 interactions will reverse cytotoxic T cell exhaustion, block Treg immunosuppressive function and restore NK killing function.
- Blocking CCR4 interaction will also prevent the accumulation of Tregs at the OvCA site through their blockade of binding of the CCL17/CCL22 chemokines that are secreted by the tumor cells.
- Our project involves both in vitro and in vivo studies in humanized mice and utilizes the most up-to-date technologies to evaluate our new therapy.
- this cellular combination immunotherapy is formulated to be administered as a one-time, single agent, which can also decrease the burden on the patient, clinician, and payer.
- the anti-TIGIT/CCR4 BsAb that acts as a ICIs is delivered directly to the tumor site to maximize the effects in the TME while minimizing any systemic toxicity.
- the CAR-T cells do not disappear after they kill the tumor cells, rather, they stay on to live in the patient to stop any chance of a disease recurrence.
Abstract
La présente invention comprend des anticorps humains qui se lient à la protéine mésothéline (MSLN). Les anticorps peuvent être utilisés pour traiter le cancer.
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