US20110150892A1 - Human antibodies that bind lymphocyte activation gene-3 (lag-3) and uses thereof - Google Patents

Human antibodies that bind lymphocyte activation gene-3 (lag-3) and uses thereof Download PDF

Info

Publication number
US20110150892A1
US20110150892A1 US13/058,492 US200913058492A US2011150892A1 US 20110150892 A1 US20110150892 A1 US 20110150892A1 US 200913058492 A US200913058492 A US 200913058492A US 2011150892 A1 US2011150892 A1 US 2011150892A1
Authority
US
United States
Prior art keywords
antibody
seq
lag
chain variable
variable region
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/058,492
Other languages
English (en)
Inventor
Kent B. Thudium
Mark Selby
Kyra D. Zens
Mark Yamanaka
Alan J. Korman
Heidi N. LeBlanc
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ER Squibb and Sons LLC
Original Assignee
Medarex LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=41669613&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20110150892(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Medarex LLC filed Critical Medarex LLC
Priority to US13/058,492 priority Critical patent/US20110150892A1/en
Assigned to MEDAREX, INC. reassignment MEDAREX, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KORMAN, ALAN J., SELBY, MARK, YAMANAKA, MARK, ZENS, KYRA D., LEBLANC, HEIDI N., THUDIUM, KENT B.
Publication of US20110150892A1 publication Critical patent/US20110150892A1/en
Assigned to MEDAREX, L.L.C. reassignment MEDAREX, L.L.C. MERGER (SEE DOCUMENT FOR DETAILS). Assignors: MEDAREX, INC.
Assigned to E. R. SQUIBB & SONS, L.L.C. reassignment E. R. SQUIBB & SONS, L.L.C. MERGER (SEE DOCUMENT FOR DETAILS). Assignors: MEDAREX, L.L.C.
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • 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
    • 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
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • 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
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • 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
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • 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

  • Lymphocyte Activation Gene-3 is a member of the immunoglobulin supergene family and is structurally and genetically related to CD4. LAG-3 is not expressed on resting peripheral blood lymphocytes but is expressed on activated T cells and NK cells. LAG-3 is a membrane protein encoded by a gene located on the distal part of the short arm of chromosome 12, near the CD4 gene, suggesting that the LAG-3 gene may have evolved through gene duplication (Triebel et al. (1990) J. Exp. Med. 171:1393-1405).
  • LAG-3 has been demonstrated to interact with MHC Class II molecules but, unlike CD4, LAG-3 does not interact with the human immunodeficiency virus gp120 protein (Baixeras et al. (1992) J. Exp. Med. 176:327-337).
  • LAG-3 antibodies led to increased T cell proliferation, higher expression of activation antigens such as CD25, and higher concentrations of cytokines such as interferon-gamma and interleukin-4, supporting a role for the LAG-/MHC class II interaction in down-regulating antigen-dependent stimulation of CD4 + T lymphocytes (Huard et al. (1994) Eur. J. Immunol. 24:3216-3221).
  • LAP protein termed LAP, which is thought to be a signal transduction molecule involved in the downregulation of the CD3/TCR activation pathway (Iouzalen et al.
  • T reg CD4 + CD25 + regulatory T cells
  • T reg CD4 + CD25 + regulatory T cells
  • LAG-3 has been shown to express LAG-3 upon activation and antibodies to LAG-3 inhibit suppression by induced T reg cells, both in vitro and in vivo, suggesting that LAG-3 contributes to the suppressor activity of T reg cells (Huang, C. et al. (2004) Immunity 21:503-513).
  • LAG-3 has been shown to negatively regulate T cell homeostasis by regulatory T cells in both T cell-dependent and independent mechanisms (Workman, C. J. and Vignali, D. A. (2005) J. Immunol. 174:688-695).
  • LAG-3 also has been shown to have immunostimulatory effects.
  • LAG-3 transfected tumor cells transplanted into syngeneic mice showed marked growth reduction or complete regression as compared to untransfected tumor cells, suggesting that LAG-3 expression on the tumor cells stimulated an anti-tumor response by triggering antigen presenting cells via MHC class II molecules (Prigent et al. (1999) Eur. J. Immunol. 29:3867-3876).
  • soluble LAG-3 Ig fusion protein has been shown to stimulate both humoral and cellular immune responses when administered to mice together with an antigen, indicating that soluble LAG-3Ig can function as a vaccine adjuvant (El Mir and Triebel (2000) J. Immunol.
  • LAG-3Ig has been shown to amplify the in vitro generation of type I tumor-specific immunity (Casati et al. (2006) Cancer Res. 66:4450-4460). The functional activity of LAG-3 is reviewed further in Triebel (2003) Trends Immunol. 24:619-622. In view of the above, additional agents for modulating the activity of LAG-3 are of interest.
  • the present disclosure provides isolated monoclonal antibodies, in particular human monoclonal antibodies, that specifically bind LAG-3 and that have desirable functional properties. These properties include high affinity binding to human LAG-3, binding to human and monkey LAG-3 (e.g., cynomolgus and/or rhesus monkey LAG-3) but not to mouse LAG-3, the ability to inhibit binding of LAG-3 to major histocompatibility (MHC) Class II molecules and/or the ability to stimulate antigen-specific T cell responses.
  • the antibodies of the invention can be used, for example, to detect LAG-3 protein or to stimulate antigen-specific T cell responses, such as in a tumor-bearing subject or a virus-bearing subject.
  • the invention pertains to an isolated human monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody binds human LAG-3 and exhibits at least one of the following properties:
  • the antibody stimulates an antigen-specific T cell response, such as interleukin-2 (IL-2) production in an antigen-specific T cell response.
  • the antibody stimulates an immune response such as an anti-tumor response (e.g., inhibits tumor growth in an in vivo tumor graft model) or an autoimmune response (e.g., promotes the development of diabetes in NOD mice).
  • the antibody binds an epitope of human LAG-3 comprising the amino acid sequence PGHPLAPG (SEQ ID NO: 76).
  • the antibody binds an epitope of human LAG-3 comprising the amino acid sequence HPAPPSSW (SEQ ID NO: 77) or PAAPSSWG (SEQ ID NO: 78).
  • the antibody binds to human LAG-3 with a K D of 1 ⁇ 10 ⁇ 7 M or less, or binds to human LAG-3 with a K D of 1 ⁇ 10 ⁇ 8 M or less, or binds to human LAG-3 with a K D of 5 ⁇ 10 ⁇ 9 M or less, or binds to human LAG-3 with a K D of 1 ⁇ 10 ⁇ 9 M or less.
  • the antibody stains pituitary tissue by immunohistochemistry, whereas in another embodiment, the antibody does not stain pituitary tissue by immunohistochemistry.
  • the invention pertains to an isolated human monoclonal antibody, or antigen binding portion thereof, wherein the antibody cross-competes for binding to human LAG-3 with a reference antibody, wherein the reference antibody comprises:
  • the reference antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 43.
  • the reference antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 44.
  • the reference antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 39 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 45.
  • the reference antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 40 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 46. In another preferred embodiment, the reference antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 41 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 47. In another preferred embodiment, the reference antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 42 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 48.
  • the invention pertains to an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 3-20 gene, a human V H 4-34 gene, a human V H 3-33 gene or a human V H 1-24 gene, wherein the antibody specifically binds human
  • the invention pertains to an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L18 gene, a human V K L6 gene or a human V K A27 gene, wherein the antibody specifically binds human LAG-3.
  • the invention provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising:
  • the invention pertains to an isolated monoclonal antibody, or antigen binding portion thereof, comprising:
  • a preferred combination comprises:
  • Another preferred combination comprises:
  • Another preferred combination comprises:
  • Another preferred combination comprises:
  • Another preferred combination comprises:
  • Another preferred combination comprises:
  • the antibodies of the invention can be, for example, full-length antibodies, for example of an IgG1, IgG2 or IgG4 isotype.
  • the antibody is an IgG4 isotype.
  • the antibody is an IgG4 isotype having a serine to proline mutation in the heavy chain constant region hinge region (at a position corresponding to position 241 as described in Angal et al. (1993) Mol. Immunol. 30:105-108), such that inter-heavy chain disulfide bridge heterogeneity is reduced or abolished.
  • the antibodies can be antibody fragments, such as Fab, Fab′ or Fab′2 fragments, or single chain antibodies.
  • This disclosure also provides an immunoconjugate comprising an antibody of the invention, or antigen-binding portion thereof, linked to a therapeutic agent, e.g., a cytotoxin or a radioactive isotope.
  • a therapeutic agent e.g., a cytotoxin or a radioactive isotope.
  • This disclosure also provides a bispecific molecule comprising an antibody, or antigen-binding portion thereof, of the invention, linked to a second functional moiety having a different binding specificity than said antibody, or antigen binding portion thereof.
  • compositions comprising an antibody, or antigen-binding portion thereof, or immunoconjugate or bispecific molecule of the invention and a pharmaceutically acceptable carrier are also provided.
  • Nucleic acid molecules encoding the antibodies, or antigen-binding portions thereof, of the invention are also encompassed by this disclosure, as well as expression vectors comprising such nucleic acids and host cells comprising such expression vectors.
  • Methods for preparing anti-LAG-3 antibodies using the host cells comprising such expression vectors are also provided and can include the steps of (i) expressing the antibody in the host cell and (ii) isolating the antibody from the host cell.
  • the invention pertains to methods of stimulating immune responses using the anti-LAG-3 antibodies of the invention.
  • the invention provides a method of stimulating an antigen-specific T cell response comprising contacting said T cell with an antibody of the invention such that an antigen-specific T cell response is stimulated.
  • interleukin-2 production by the antigen-specific T cell is stimulated.
  • the invention provides a method of stimulating an immune response (e.g., an antigen-specific T cell response) in a subject comprising administering an antibody of the invention to the subject such that an immune response (e.g., an antigen-specific T cell response) in the subject is stimulated.
  • the subject is a tumor-bearing subject and an immune response against the tumor is stimulated.
  • the subject is a virus-bearing subject and an immune response against the virus is stimulated.
  • the invention provides a method for inhibiting growth of tumor cells in a subject comprising administering to the subject an antibody of the invention such that growth of the tumor is inhibited in the subject.
  • the invention provides a method for treating viral infection in a subject comprising administering to the subject an antibody of the invention such that the viral infection is treated in the subject.
  • the invention provides a method for stimulating an immune response in a subject comprising administering to the subject an anti-LAG-3 antibody and at least one additional immunostimulatory antibody, such as an anti-PD-1 antibody, an anti-PD-L1 antibody and/or an anti-CTLA-4 antibody, such that an immune response is stimulated in the subject, for example to inhibit tumor growth or to stimulate an anti-viral response.
  • the subject is administered an anti-LAG-3 antibody and an anti-PD-1 antibody.
  • the subject is administered an anti-LAG-3 antibody and an anti-PD-L1 antibody.
  • the subject is administered an anti-LAG-3 antibody and an anti-CTLA-4 antibody.
  • the anti-LAG-3 antibody is a human antibody, such as an antibody of the disclosure.
  • the anti-LAG-3 antibody can be, for example, a chimeric or humanized antibody.
  • the at least one additional immunostimulatory antibody e.g., anti-PD-1, anti-PD-L1 and/or anti-CTLA-4 antibody
  • the at least one additional immunostimulatory antibody is a human antibody.
  • the at least one additional immunostimulatory antibody can be, for example, a chimeric or humanized antibody.
  • the invention pertains to a method for preparing an anti- LAG-3 antibody.
  • the method comprises:
  • FIG. 1A shows the nucleotide sequence (SEQ ID NO: 49) and amino acid sequence (SEQ ID NO: 37) of the heavy chain variable region of the 25F7 human monoclonal antibody.
  • the CDR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 7) and CDR3 (SEQ ID NO: 13) regions are delineated and the V, D and J germline derivations are indicated.
  • FIG. 1B shows the nucleotide sequence (SEQ ID NO: 55) and amino acid sequence (SEQ ID NO: 43) of the kappa light chain variable region of the 25F7 human monoclonal antibody.
  • the CDR1 (SEQ ID NO: 19), CDR2 (SEQ ID NO: 25) and CDR3 (SEQ ID NO: 31) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 2A shows the nucleotide sequence (SEQ ID NO: 50) and amino acid sequence (SEQ ID NO: 38) of the heavy chain variable region of the 26H10 human monoclonal antibody.
  • the CDR1 (SEQ ID NO: 2), CDR2 (SEQ ID NO: 8) and CDR3 (SEQ ID NO: 14) regions are delineated and the V, D and J germline derivations are indicated.
  • FIG. 2B shows the nucleotide sequence (SEQ ID NO: 56) and amino acid sequence (SEQ ID NO: 44) of the kappa light chain variable region of the 26H10 human monoclonal antibody.
  • the CDR1 (SEQ ID NO: 20), CDR2 (SEQ ID NO: 26) and CDR3 (SEQ ID NO: 32) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 3A shows the nucleotide sequence (SEQ ID NO: 51) and amino acid sequence (SEQ ID NO: 39) of the heavy chain variable region of the 25E3 human monoclonal antibody.
  • the CDR1 (SEQ ID NO: 3), CDR2 (SEQ ID NO: 9) and CDR3 regions are delineated and the V, D and J germline derivations are indicated.
  • FIG. 3B shows the nucleotide sequence (SEQ ID NO: 57) and amino acid sequence (SEQ ID NO: 45) of the kappa light chain variable region of the 25E3 human monoclonal antibody.
  • the CDR1 (SEQ ID NO: 21), CDR2 (SEQ ID NO: 27) and CDR3 (SEQ ID NO: 33) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 4A shows the nucleotide sequence (SEQ ID NO: 52) and amino acid sequence (SEQ ID NO: 40) of the heavy chain variable region of the 8B7 human monoclonal antibody.
  • the CDR1 (SEQ ID NO: 4), CDR2 (SEQ ID NO: 10) and CDR3 (SEQ ID NO: 16) regions are delineated and the V, D and J germline derivations are indicated.
  • FIG. 4B shows the nucleotide sequence (SEQ ID NO: 58) and amino acid sequence (SEQ ID NO: 46) of the kappa light chain variable region of the 8B7 human monoclonal antibody.
  • the CDR1 (SEQ ID NO: 22), CDR2 (SEQ ID NO: 28) and CDR3 (SEQ ID NO: 34) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 5A shows the nucleotide sequence (SEQ ID NO: 53) and amino acid sequence (SEQ ID NO: 41) of the heavy chain variable region of the 11F2 human monoclonal antibody.
  • the CDR1 (SEQ ID NO: 5), CDR2 (SEQ ID NO: 11) and CDR3 (SEQ ID NO: 17) regions are delineated and the V, D and J germline derivations are indicated.
  • FIG. 5B shows the nucleotide sequence (SEQ ID NO: 59) and amino acid sequence (SEQ ID NO: 47) of the kappa light chain variable region of the 11F2 human monoclonal antibody.
  • the CDR1 (SEQ ID NO: 23), CDR2 (SEQ ID NO: 29) and CDR3 (SEQ ID NO: 35) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 6A shows the nucleotide sequence (SEQ ID NO: 54) and amino acid sequence (SEQ ID NO: 42) of the heavy chain variable region of the 17E5 human monoclonal antibody.
  • the CDR1 (SEQ ID NO: 6), CDR2 (SEQ ID NO: 12) and CDR3 (SEQ ID NO: 18) regions are delineated and the V, D and J germline derivations are indicated.
  • FIG. 6B shows the nucleotide sequence (SEQ ID NO: 60) and amino acid sequence (SEQ ID NO: 48) of the kappa light chain variable region of the 17E5 human monoclonal antibody.
  • the CDR1 (SEQ ID NO: 24), CDR2 (SEQ ID NO: 30) and CDR3 (SEQ ID NO: 36) regions are delineated and the V and J germline derivations are indicated.
  • FIG. 7 shows the alignment of the amino acid sequence of the heavy chain variable regions of 25F7 (SEQ ID NO: 37) with the human germline V H 4-34 and JH5b amino acid sequences (SEQ ID NOS: 61 and 62, respectively).
  • FIG. 8 shows the alignment of the amino acid sequence of the light chain variable region of 25F7 (SEQ ID NO: 43) with the human germline V k L6 and JK2 amino acid sequences (SEQ ID NOS: 63 and 64, respectively).
  • FIG. 9 shows the alignment of the amino acid sequence of the heavy chain variable regions of 26H10 (SEQ ID NO: 38) with the human germline V H 3-33 and JH6B amino acid sequences (SEQ ID NOS: 65 and 66, respectively).
  • FIG. 10 shows the alignment of the amino acid sequence of the light chain variable region of 26H10 (SEQ ID NO: 44) with the human germline V k A27 and JK3 amino acid sequences (SEQ ID NO: 67 and 68, respectively).
  • FIG. 11 shows the alignment of the amino acid sequence of the heavy chain variable regions of 25E3 (SEQ ID NO: 39) with the human germline V H 3-20 and JH4b amino acid sequences (SEQ ID NOS: 69 and 70, respectively).
  • FIG. 12 shows the alignment of the amino acid sequence of the light chain variable region of 25E3 (SEQ ID NO: 45) with the human germline V k L18 and JK2 amino acid sequences (SEQ ID NOS: 71 and 64, respectively).
  • FIG. 13 shows the alignment of the amino acid sequence of the heavy chain variable regions of 8B7 (SEQ ID NO: 40) with the human germline V H 4-34 and JH5b amino acid sequences (SEQ ID NOS: 61 and 62, respectively).
  • FIG. 14 shows the alignment of the amino acid sequence of the light chain variable region of 8B7 (SEQ ID NO: 46) with the human germline V k L6 and JK4 amino acid sequences (SEQ ID NOS: 63 and 72, respectively).
  • FIG. 15 shows the alignment of the amino acid sequence of the heavy chain variable regions of 11F2 (SEQ ID NO: 41) with the human germline V H 1-24 and JH4b amino acid sequences (SEQ ID NOS: 73 and 70, respectively).
  • FIG. 16 shows the alignment of the amino acid sequence of the light chain variable region of 11F2 (SEQ ID NO: 47) with the human germline V k L6 and JK1 amino acid sequences (SEQ ID NOS: 63 and 74, respectively).
  • FIG. 17 shows the alignment of the amino acid sequence of the heavy chain variable regions of 17E5 (SEQ ID NO: 42) with the human germline V H 3-33 and 2-2 amino acid sequences (SEQ ID NOS: 65 and 70, respectively).
  • FIG. 18 shows the alignment of the amino acid sequence of the light chain variable region of 17E5 (SEQ ID NO: 48) with the human germline V k L6 amino acid sequence (SEQ ID NOS: 63 and 75, respectively).
  • FIG. 19 shows the alignment of the protein sequence encoded by the monkey LAG-3 cDNA clone pa23-5 (SEQ ID NO: 93) with the Genbank deposited rhesus monkey LAG-3 protein sequence (SEQ ID NO: 94) (Genbank Accession No. XM — 001108923).
  • the extra loop peptide region and transmembrane domain are underlined.
  • the one amino acid difference between the two sequences is highlighted in bold.
  • the present disclosure relates to isolated monoclonal antibodies, particularly human monoclonal antibodies, which bind to human LAG-3 and that have desirable functional properties.
  • the antibodies of the invention are derived from particular heavy and light chain germline sequences and/or comprise particular structural features such as CDR regions comprising particular amino acid sequences.
  • This disclosure provides isolated antibodies, methods of making such antibodies, immunoconjugates and bispecific molecules comprising such antibodies and pharmaceutical compositions containing the antibodies, immunoconjugates or bispecific molecules of the invention.
  • This disclosure also relates to methods of using the antibodies, such as to detect LAG-3 protein, as well as to methods of using the anti-LAG-3 antibodies of the invention to stimulate immune responses, alone or in combination with other immunostimulatory antibodies. Accordingly, this disclosure also provides methods of using the anti-LAG-3 antibodies of the invention to, for example, inhibit tumor growth or treat viral infection.
  • LAG-3 refers to Lymphocyte Activation Gene-3.
  • LAG-3 includes variants, isoforms, homologs, orthologs and paralogs.
  • antibodies specific for a human LAG-3 protein may, in certain cases, cross-react with a LAG-3 protein from a species other than human.
  • the antibodies specific for a human LAG-3 protein may be completely specific for the human LAG-3 protein and may not exhibit species or other types of cross-reactivity, or may cross-react with LAG-3 from certain other species but not all other species (e.g., cross-react with monkey LAG-3 but not mouse LAG-3).
  • human LAG-3 refers to human sequence LAG-3, such as the complete amino acid sequence of human LAG-3 having Genbank Accession No. NP — 002277.
  • mouse LAG-3 refers to mouse sequence LAG-3, such as the complete amino acid sequence of mouse LAG-3 having Genbank Accession No. NP — 032505.
  • LAG-3 is also known in the art as, for example, CD223.
  • the human LAG-3 sequence may differ from human LAG-3 of Genbank Accession No. NP — 002277 by having, e.g., conserved mutations or mutations in non-conserved regions and the LAG-3 has substantially the same biological function as the human LAG-3 of Genbank Accession No. NP — 002277.
  • LAG-3 is having an epitope in the extracellular domain of LAG-3 that is specifically bound by an antibody of the instant disclosure or a biological function of human LAG-3 is binding to MHC Class II molecules.
  • monkey LAG-3 is intended to encompass LAG-3 proteins expressed by Old World and New World monkeys, including but not limited to cynomolgus monkey LAG-3 and rhesus monkey LAG-3.
  • a representative amino acid sequence for monkey LAG-3 is the rhesus monkey LAG-3 amino acid sequence shown in FIG. 19 and SEQ ID NO: 85, which is also deposited as Genbank Accession No. XM — 001108923.
  • Another representative amino acid sequence for monkey LAG-3 is the alternative rhesus monkey sequence of clone pa23-5 shown in FIG. 19 and SEQ ID NO: 84, isolated as described in Example 3A, subsection 3. This alternative rhesus sequence exhibits a single amino acid difference, at position 419, as compared to the Genbank-deposited sequence.
  • a particular human LAG-3 sequence will generally be at least 90% identical in amino acids sequence to human LAG-3 of Genbank Accession No. NP — 002277 and contains amino acid residues that identify the amino acid sequence as being human when compared to LAG-3 amino acid sequences of other species (e.g., murine).
  • a human LAG-3 can be at least 95%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to LAG-3 of Genbank Accession No. NP — 002277.
  • a human LAG-3 sequence will display no more than 10 amino acid differences from the LAG-3 sequence of Genbank Accession No. NP — 002277.
  • the human LAG-3 can display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the LAG-3 sequence of Genbank Accession No. NP — 002277. Percent identity can be determined as described herein.
  • immune response refers to the action of, for example, lymphocytes, antigen presenting cells, phagocytic cells, granulocytes, and soluble macromolecules produced by the above cells or the liver (including antibodies, cytokines, and complement) that results in selective damage to, destruction of, or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancerous cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
  • an “antigen-specific T cell response” refers to responses by a T cell that result from stimulation of the T cell with the antigen for which the T cell is specific.
  • responses by a T cell upon antigen-specific stimulation include proliferation and cytokine production (e.g., IL-2 production).
  • antibody as referred to herein includes whole antibodies and any antigen binding fragment (i.e., “antigen-binding portion”) or single chains thereof.
  • Whole antibodies are glycoproteins comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, C H 1, C H 2 and C H 3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as V L ) and a light chain constant region.
  • the light chain constant region is comprised of one domain, C L .
  • V H and V L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each V H and V L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • antibody portion refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., a LAG-3 protein). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • binding fragments encompassed within the term “antigen-binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the V L , V H , C L and C H 1 domains; (ii) a F(ab′) 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fab′ fragment, which is essentially an Fab with part of the hinge region (see, FUNDAMENTAL IMMUNOLOGY (Paul ed., 3.sup.rd ed.
  • the two domains of the Fv fragment, V L and V H are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the V L and V H regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term “antigen- binding portion” of an antibody.
  • an “isolated antibody”, as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds a LAG-3 protein is substantially free of antibodies that specifically bind antigens other than LAG-3 proteins).
  • An isolated antibody that specifically binds a human LAG-3 protein may, however, have cross-reactivity to other antigens, such as LAG-3 proteins from other species.
  • an isolated antibody can be substantially free of other cellular material and/or chemicals.
  • monoclonal antibody or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition.
  • a monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
  • human antibody is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences.
  • the human antibodies of the invention can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • the term “human antibody”, as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • human monoclonal antibody refers to antibodies displaying a single binding specificity, which have variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences.
  • the human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic nonhuman animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.
  • recombinant human antibody includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom (described further below), (b) antibodies isolated from a host cell transformed to express the human antibody, e.g., from a transfectoma, (c) antibodies isolated from a recombinant, combinatorial human antibody library, and (d) antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences.
  • Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences.
  • such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V H and V L regions of the recombinant antibodies are sequences that, while derived from and related to human germline V H and V L sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • isotype refers to the antibody class (e.g., IgM or IgG1) that is encoded by the heavy chain constant region genes.
  • an antibody recognizing an antigen and “an antibody specific for an antigen” are used interchangeably herein with the term “an antibody which binds specifically to an antigen.”
  • human antibody derivatives refers to any modified form of the human antibody, e.g., a conjugate of the antibody and another agent or antibody.
  • humanized antibody is intended to refer to antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. Additional framework region modifications can be made within the human framework sequences.
  • chimeric antibody is intended to refer to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.
  • an antibody that “specifically binds human LAG-3” is intended to refer to an antibody that binds to human LAG-3 protein (and possibly a LAG-3 protein from one or more non-human species) but does not substantially bind to non-LAG-3 proteins.
  • the antibody binds to a human LAG-3 protein with “high affinity”, namely with a K D of 1 ⁇ 10 ⁇ 7 M or less, more preferably 5 ⁇ 10 ⁇ 8 M or less, more preferably 3 ⁇ 10 ⁇ 8 M or less, more preferably 1 ⁇ 10 ⁇ 8 M or less, more preferably 5 ⁇ 10 ⁇ 9 M or less or even more preferably 1 ⁇ 10 ⁇ 9 M or less.
  • does not substantially bind to a protein or cells, as used herein, means does not bind or does not bind with a high affinity to the protein or cells, i.e. binds to the protein or cells with a K D of 1 ⁇ 10 ⁇ 6 M or more, more preferably 1 ⁇ 10 ⁇ 5 M or more, more preferably 1 ⁇ 10 ⁇ 4 M or more, more preferably 1 ⁇ 10 ⁇ 3 M or more, even more preferably 1 ⁇ 10 ⁇ -2 M or more.
  • K assoc or “K a ”, as used herein, is intended to refer to the association rate of a particular antibody-antigen interaction
  • K dis or “K d ,” as used herein, is intended to refer to the dissociation rate of a particular antibody-antigen interaction
  • K D is intended to refer to the dissociation constant, which is obtained from the ratio of K d to K a (i.e., K d /K a ) and is expressed as a molar concentration (M).
  • K D values for antibodies can be determined using methods well established in the art. A preferred method for determining the K D of an antibody is by using surface plasmon resonance, preferably using a biosensor system such as a Biacore® system.
  • high affinity for an IgG antibody refers to an antibody having a K D of 1 ⁇ 10 ⁇ 7 M or less, more preferably 5 ⁇ 10 ⁇ 8 M or less, even more preferably 1 ⁇ 10 ⁇ 8 M or less, even more preferably 5 ⁇ 10 ⁇ 9 M or less and even more preferably 1 ⁇ 10 ⁇ 9 M or less for a target antigen.
  • “high affinity” binding can vary for other antibody isotypes.
  • “high affinity” binding for an IgM isotype refers to an antibody having a K D of 10 ⁇ 6 M or less, more preferably 10 ⁇ 7 M or less, even more preferably 10 ⁇ 8 M or less.
  • subject includes any human or nonhuman animal.
  • nonhuman animal includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals are preferred, such as non-human primates, sheep, dogs, cats, cows and horses.
  • the antibodies of the invention are characterized by particular functional features or properties of the antibodies.
  • the antibodies specifically bind to human LAG-3 and may bind to LAG-3 from certain other species, e.g., monkey LAG-3 (e.g., cynomolgus monkey, rhesus monkey), but do not substantially bind to LAG-3 from certain other species, e.g., mouse LAG-3.
  • an antibody of the invention binds to human LAG-3 with high affinity.
  • an antibody of the invention binds to human LAG-3 and exhibits an ability to stimulate an antigen-specific T cell response. In other embodiments, an antibody of the invention binds to human LAG-3 but does not exhibit an ability to stimulate an antigen-specific T cell response.
  • IL-2 interleukin-2
  • Other means by which to evaluate the ability of the antibody to stimulate an immune response include the ability of the antibody to inhibit tumor growth, such as in an in vivo tumor graft model (see, e.g., Example 6) or the ability of the antibody to stimulate an autoimmune response, such as the ability to promote the development of an autoimmune disease in an autoimmune model, such as the ability to promote the development of diabetes in the NOD mouse model (see, e.g., Example 7).
  • an antibody of the invention can be tested by a flow cytometry assay in which the antibody is reacted with a cell line that expresses human LAG-3, such as CHO cells that have been transfected to express LAG-3 (e.g., human LAG-3, or monkey LAG-3 (e.g., rhesus or cynomolgus monkey) or mouse LAG-3) on their cell surface (see, e.g., Example 3A for a suitable assay).
  • a cell line that expresses human LAG-3 such as CHO cells that have been transfected to express LAG-3 (e.g., human LAG-3, or monkey LAG-3 (e.g., rhesus or cynomolgus monkey) or mouse LAG-3) on their cell surface (see, e.g., Example 3A for a suitable assay).
  • suitable cells for use in flow cytometry assays include anti-CD3-stimulated CD4 + activated T cells, which express native L
  • the binding of the antibody can be tested in BIAcore binding assays (see, e.g., Example 3B for suitable assays).
  • BIAcore binding assays see, e.g., Example 3B for suitable assays.
  • Still other suitable binding assays include ELISA assays, for example using a recombinant LAG-3 protein (see, e.g., Example 1 for a suitable assay).
  • an antibody of the invention binds to a LAG-3 protein with a K D of 5 ⁇ 10 ⁇ 8 M or less, binds to a LAG-3 protein with a K D of 2 ⁇ 10 ⁇ 8 M or less, binds to a LAG-3 protein with a K D of 5 ⁇ 10 ⁇ 9 M or less, binds to a LAG-3 protein with a K D of 4 ⁇ 10 ⁇ 9 M or less, binds to a LAG-3 protein with a K D of 3 ⁇ 10 ⁇ 9 M or less, binds to a LAG-3 protein with a K D of 2 ⁇ 10 ⁇ 9 M or less, binds to a LAG-3 protein with a K D of 1 ⁇ 10 ⁇ 9 M or less, binds to a LAG-3 protein with a K D of 5 ⁇ 10 ⁇ 10 M or less, or binds to a
  • LAG-3 protein with a K D of 1 ⁇ 10 ⁇ 10 M or less.
  • an antibody of the invention binds to LAG-3 in lymphoid tissues, such as tonsil, spleen or thymus, which can be detected by immunohistochemistry.
  • lymphoid tissues such as tonsil, spleen or thymus
  • certain anti-LAG-3 antibodies of the invention stain pituitary tissue (e.g., are retained in the pituitary) as measured by immunohistochemistry, whereas other anti-LAG-3 antibodies of the invention do not stain pituitary tissue (e.g., are not retained in the pituitary) as measured by immunohistochemistry.
  • the invention provides a human anti-LAG-3 antibody that stains pituitary tissue by immunohistochemistry, whereas in another embodiment, the invention provides a human anti-LAG-3 antibody that does not stain pituitary tissue by immunohistochemistry.
  • antibodies of the invention are human monoclonal antibodies. Additionally or alternatively, the antibodies can be, for example, chimeric or humanized monoclonal antibodies.
  • Preferred antibodies of the invention are the human monoclonal antibodies 25F7, 26H10, 25E3, 8B7, 11F2 and 17E5 isolated and structurally characterized as described in Examples 1 and 2.
  • the V H amino acid sequences of 25F7, 26H10, 25E3, 8B7, 11F2 and 17E5 are shown in SEQ ID NOs: 37-42, respectively.
  • the V K amino acid sequences of 25F7, 26H10, 25E3, 8B7, 11F2 and 17E5 are shown in SEQ ID NOs: 43-48, respectively.
  • V H and V L sequences can be “mixed and matched” to create other anti-LAG-3 binding molecules of the invention.
  • V H and V L chains are mixed and matched, a V H sequence from a particular V H /V L pairing is replaced with a structurally similar V H sequence.
  • a V L sequence from a particular V H /V L pairing is replaced with a structurally similar V L sequence.
  • this disclosure provides an isolated monoclonal antibody, or antigen binding portion thereof comprising:
  • this disclosure provides antibodies that comprise the heavy chain and light chain CDR1s, CDR2s and CDR3s of 25F7, 26H10, 25E3, 8B7, 11F2 or 17E5, or combinations thereof.
  • the amino acid sequences of the V H CDR1s of 25F7, 26H10, 25E3, 8B7, 11F2 and 17E5 are shown in SEQ ID NOs: 37-42, respectively.
  • the amino acid sequences of the V H CDR2s of 25F7, 26H10, 25E3, 8B7, 11F2 and 17E5 are shown in SEQ ID NOs: 43-48, respectively.
  • the amino acid sequences of the V H CDR3s of 25F7, 26H10, 25E3, 8B7, 11F2 and 17E5 are shown in SEQ ID NOs: 13-14, GGY and 16-18, respectively.
  • the amino acid sequences of the V K CDR1s of 25F7, 26H10, 25E3, 8B7, 11F2 and 17E5 are shown in SEQ ID NOs: 19-24 respectively.
  • the amino acid sequences of the V K CDR2s of 25F7, 26H10, 25E3, 8B7, 11F2 and 17E5 are shown in SEQ ID NOs: 25-30.
  • V K CDR3s The amino acid sequences of the V K CDR3s of 25F7, 26H10, 25E3, 8B7, 11F2 and 17E5 are shown in SEQ ID NOs: 31-36, respectively.
  • the CDR regions are delineated using the Kabat system (Kabat et al. (1991) Sequences of
  • V H CDR1, CDR2, and CDR3 sequences and V L CDR1, CDR2, and CDR3 sequences can be “mixed and matched” (i.e., CDRs from different antibodies can be mixed and match, although each antibody must contain a V H CDR1, CDR2, and CDR3 and a V L CDR1, CDR2, and CDR3) to create other anti-LAG-3 binding molecules of the invention.
  • LAG-3 binding of such “mixed and matched” antibodies can be tested using the binding assays described above and in the Examples (e.g., ELISAs, Biacore® analysis).
  • the CDR1, CDR2 and/or CDR3 sequence from a particular V H sequence is replaced with a structurally similar CDR sequence(s).
  • the CDR1, CDR2 and/or CDR3 sequence from a particular V L sequence preferably is replaced with a structurally similar CDR sequence(s).
  • V H and V L sequences can be created by substituting one or more V H and/or V L CDR region sequences with structurally similar sequences from the CDR sequences disclosed herein for monoclonal antibodies 25F7, 26H10, 25E3, 8B7, 11F2 and 17E5.
  • this disclosure provides an isolated monoclonal antibody, or antigen binding portion thereof comprising:
  • the CDR3 domain independently from the CDR1 and/or CDR2 domain(s), alone can determine the binding specificity of an antibody for a cognate antigen and that multiple antibodies can predictably be generated having the same binding specificity based on a common CDR3 sequence. See, e.g., Klimka et al., British J. of Cancer 83(2):252-260 (2000); Beiboer et al., J. Mol. Biol. 296:833-849 (2000); Rader et al., Proc. Natl. Acad. Sci. U.S.A. 95:8910-8915 (1998); Barbas et al., J. Am. Chem. Soc.
  • the present disclosure provides monoclonal antibodies comprising one or more heavy and/or light chain CDR3 domains from an antibody derived from a human or non-human animal, wherein the monoclonal antibody is capable of specifically binding to human LAG-3.
  • the present disclosure provides monoclonal antibodies comprising one or more heavy and/or light chain CDR3 domain from a non-human antibody, such as a mouse or rat antibody, wherein the monoclonal antibody is capable of specifically binding to LAG-3.
  • inventive antibodies comprising one or more heavy and/or light chain CDR3 domain from a non-human antibody (a) are capable of competing for binding with; (b) retain the functional characteristics; (c) bind to the same epitope; and/or (d) have a similar binding affinity as the corresponding parental non-human antibody.
  • the present disclosure provides monoclonal antibodies comprising one or more heavy and/or light chain CDR3 domain from a human antibody, such as, e.g., a human antibody obtained from a non-human animal, wherein the human antibody is capable of specifically binding to human LAG-3.
  • a human antibody such as, e.g., a human antibody obtained from a non-human animal, wherein the human antibody is capable of specifically binding to human LAG-3.
  • the present disclosure provides monoclonal antibodies comprising one or more heavy and/or light chain CDR3 domain from a first human antibody, such as, for example, a human antibody obtained from a non-human animal, wherein the first human antibody is capable of specifically binding to human LAG-3 and wherein the CDR3 domain from the first human antibody replaces a CDR3 domain in a human antibody that is lacking binding specificity for LAG-3 to generate a second human antibody that is capable of specifically binding to human LAG-3.
  • a first human antibody such as, for example, a human antibody obtained from a non-human animal
  • the first human antibody is capable of specifically binding to human LAG-3
  • the CDR3 domain from the first human antibody replaces a CDR3 domain in a human antibody that is lacking binding specificity for LAG-3 to generate a second human antibody that is capable of specifically binding to human LAG-3.
  • inventive antibodies comprising one or more heavy and/or light chain CDR3 domain from the first human antibody (a) are capable of competing for binding with; (b) retain the functional characteristics; (c) bind to the same epitope; and/or (d) have a similar binding affinity as the corresponding parental first human antibody.
  • an antibody of the invention comprises a heavy chain variable region from a particular germline heavy chain immunoglobulin gene and/or a light chain variable region from a particular germline light chain immunoglobulin gene.
  • this disclosure provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a heavy chain variable region that is the product of or derived from a human V H 3-20 gene, a human V H 4-34 gene, a human V H 3-33 gene or a human V H 1-24 gene, wherein the antibody specifically binds human LAG-3.
  • this disclosure provides an isolated monoclonal antibody, or an antigen-binding portion thereof, comprising a light chain variable region that is the product of or derived from a human V K L18 gene, a human V K L6 gene or a human V K A27 gene, wherein the antibody specifically binds human LAG-3.
  • this disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, wherein the antibody comprises a heavy chain variable region that is the product of or derived from a human V H 3-20 gene and comprises a light chain variable region that is the product of or derived from a human V K L18 gene, wherein the antibody specifically binds human LAG-3.
  • this disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, wherein the antibody comprises a heavy chain variable region that is the product of or derived from a human V H 4-34 gene and comprises a light chain variable region that is the product of or derived from a human V K L6 gene, wherein the antibody specifically binds human LAG-3.
  • this disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, wherein the antibody comprises a heavy chain variable region that is the product of or derived from a human V H 3-33 gene and comprises a light chain variable region that is the product of or derived from a human V K A27 gene, wherein the antibody specifically binds human LAG-3.
  • this disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, wherein the antibody comprises a heavy chain variable region that is the product of or derived from a human V H 1-24 gene and comprises a light chain variable region that is the product of or derived from a human V K L6 gene, wherein the antibody specifically binds human LAG-3.
  • this disclosure provides an isolated monoclonal antibody, or antigen-binding portion thereof, wherein the antibody comprises a heavy chain variable region that is the product of or derived from a human V H 3-33 gene and comprises a light chain variable region that is the product of or derived from a human V K L6 gene, wherein the antibody specifically binds human LAG-3.
  • Such antibodies can also possess one or more of the functional characteristics described in detail above, such as high affinity binding to human LAG-3, binding to monkey LAG-3, lack of binding to mouse LAG-3, the ability to inhibit binding of LAG-3 to MHC Class II molecules and/or the ability to stimulate antigen-specific T cell responses.
  • An example of an antibody having V H and V L of V H 3-20 and V K L18, respectively, is the 25E3 antibody.
  • Examples of antibodies having V H and V L of V H 4-34 and V K L6, respectively, are the 25F7 and 8B7 antibodies.
  • An example of an antibody having V H and V L of V H 3-33 and V K A27, respectively, is the 26H10 antibody.
  • An example of an antibody having V H and V L of V H 1-24 and V K L6, respectively, is the 11F2 antibody.
  • An example of an antibody having V H and V L of V H 3-33 and V K L6, respectively, is the 17E5 antibody.
  • a human antibody comprises heavy or light chain variable regions that is “the product of” or “derived from” a particular germline sequence if the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin genes.
  • Such systems include immunizing a transgenic mouse carrying human immunoglobulin genes with the antigen of interest or screening a human immunoglobulin gene library displayed on phage with the antigen of interest.
  • a human antibody that is “the product of or “derived from” a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequences of human germline immunoglobulins and selecting the human germline immunoglobulin sequence that is closest in sequence (i.e., greatest % identity) to the sequence of the human antibody.
  • a human antibody that is “the product of” or “derived from” a particular human germline immunoglobulin sequence can contain amino acid differences as compared to the germline sequence, due to, for example, naturally-occurring somatic mutations or intentional introduction of site-directed mutation.
  • a selected human antibody typically is at least 90% identical in amino acids sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as being human when compared to the germline immunoglobulin amino acid sequences of other species (e.g., murine germline sequences).
  • a human antibody can be at least 95%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene.
  • a human antibody derived from a particular human germline sequence will display no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene.
  • the human antibody can display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the amino acid sequence encoded by the germline immunoglobulin gene.
  • an antibody of the invention comprises heavy and light chain variable regions comprising amino acid sequences that are homologous to the amino acid sequences of the preferred antibodies described herein, and wherein the antibodies retain the desired functional properties of the anti-LAG-3 antibodies of the invention.
  • this disclosure provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein:
  • the antibody can possess one or more of the following functional properties discussed above, such as high affinity binding to human LAG-3, binding to monkey LAG-3, lack of binding to mouse LAG-3, the ability to inhibit binding of LAG-3 to MHC Class II molecules and/or the ability to stimulate antigen-specific T cell responses.
  • the antibody can be, for example, a human antibody, a humanized antibody or a chimeric antibody.
  • the V H and/or V L amino acid sequences can be 85%, 90%, 95%, 96%, 97%, 98% or 99% homologous to the sequences set forth above.
  • An antibody having V H and V L regions having high (i.e., 80% or greater) homology to the V H and V L regions of the sequences set forth above can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of nucleic acid molecules encoding SEQ ID NOs: 49-54 or 55-60, followed by testing of the encoded altered antibody for retained function (i.e., the functions set forth above) using the functional assays described herein.
  • the percent homology between two amino acid sequences is equivalent to the percent identity between the two sequences.
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.
  • the percent identity between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller ( Comput. Appl. Biosci., 4:11-17 (1988)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch ( J. Mol. Biol.
  • the protein sequences of the present disclosure can further be used as a “query sequence” to perform a search against public databases to, e.g., to identify related sequences.
  • Such searches can be performed using the XBLAST program (version 2.0) of Altschul et al. (1990) J. Mol. Biol. 215:403-10.
  • Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25(17):3389-3402.
  • the default parameters of the respective programs e.g., XBLAST and NBLAST are useful. See www.ncbi.nlm.nih.gov.
  • an antibody of the invention comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences and a light chain variable region comprising CDR1, CDR2 and CDR3 sequences, wherein one or more of these CDR sequences comprise specified amino acid sequences based on the preferred antibodies described herein (e.g., 25F7, 26H10, 25E3, 8B7, 11F2, 17E5), or conservative modifications thereof, and wherein the antibodies retain the desired functional properties of the anti-LAG-3 antibodies of the invention. It is understood in the art that certain conservative sequence modification can be made which do not remove antigen binding. See, e.g., Brummell et al. (1993) Biochem 32:1180-8; de Wildt et al.
  • this disclosure provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein:
  • the antibody can possess one or more of the following functional properties described above, such as high affinity binding to human LAG-3, binding to monkey LAG-3, lack of binding to mouse LAG-3, the ability to inhibit binding of LAG-3 to MHC Class II molecules and/or the ability to stimulate antigen-specific T cell responses.
  • the heavy chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs: 7-12, and conservative modifications thereof; and the light chain variable region CDR2 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs: 25-30, and conservative modifications thereof.
  • the heavy chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs: 1-6, and conservative modifications thereof; and the light chain variable region CDR1 sequence comprises an amino acid sequence selected from the group consisting of amino acid sequences of SEQ ID NOs: 19-24, and conservative modifications thereof.
  • the antibody can be, for example, human antibodies, humanized antibodies or chimeric antibodies.
  • conservative sequence modifications is intended to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones 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.
  • amino acids with 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, tryptophan
  • nonpolar side chains e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
  • beta-branched side chains e.g., threonine, valine, isoleucine
  • aromatic side chains e.g., tyrosine, phenylalanine, tryptophan, histidine
  • amino acid residues within the CDR regions of an antibody of the invention can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested for retained function (i.e., the functions set forth above) using the functional assays described herein.
  • this disclosure provides antibodies that bind to the same epitope on LAG-3 as any of the anti-LAG-3 monoclonal antibodies of the invention (i.e., antibodies that have the ability to cross-compete for binding to human LAG-3 with any of the monoclonal antibodies of the invention).
  • the reference antibody for cross-competition studies can be the monoclonal antibodies 25F7, 26H10, 25E3, 8B7, 11F2 or 17E5.
  • cross-competing antibodies can be identified based on their ability to cross- compete with 25F7, 26H10, 25E3, 8B7, 11F2 and/or 17E5 in standard LAG-3 binding assays.
  • standard ELISA assays can be used in which a recombinant human LAG-3 protein is immobilized on the plate, one of the antibodies is fluorescently labeled and the ability of non-labeled antibodies to compete off the binding of the labeled antibody is evaluated.
  • BIAcore analysis can be used to assess the ability of the antibodies to cross-compete.
  • test antibody to inhibit the binding of, for example, 25F7, 26H10, 25E3, 8B7, 11F2 and/or 17E5, to human LAG-3 demonstrates that the test antibody can compete with 25F7, 26H10, 25E3, 8B7, 11F2 and/or 17E5 for binding to human LAG-3 and thus binds to the same epitope on human LAG-3 as 25F7, 26H10, 25E3, 8B7, 11F2 and/or 17E5.
  • the antibody that binds to the same epitope on human LAG-3 as 25E3, 25F7, 8B7, 26H10, 11F2 or 17E5 is a human monoclonal antibody.
  • Such human monoclonal antibodies can be prepared and isolated as described in the Examples.
  • the binding of 25E3, 25F7 and 8B7 to human LAG-3 has been mapped to an “extra loop” region within the first extracellular domain of human LAG-3.
  • the sequence of the extra loop region is set forth in SEQ ID NO: 79.
  • PGHPLAPG SEQ ID NO: 76
  • HPAAPSSW SEQ ID NO: 77
  • PAAPSSWG SEQ ID NO: 78
  • the invention provides an anti-LAG-3 antibody that binds an epitope of human LAG-3 comprising the amino acid sequence PGHPLAPG (SEQ ID NO: 76).
  • the invention provides an anti-LAG-3 antibody that binds an epitope of human LAG-3 comprising the amino acid sequence HPAPPSSW (SEQ ID NO: 77) or PAAPSSWG (SEQ ID NO: 78).
  • An antibody of the invention further can be prepared using an antibody having one or more of the V H and/or V L sequences disclosed herein as starting material to engineer a modified antibody, which modified antibody may have altered properties from the starting antibody.
  • An antibody can be engineered by modifying one or more residues within one or both variable regions (i.e., V H and/or V L ), for example within one or more CDR regions and/or within one or more framework regions. Additionally or alternatively, an antibody can be engineered by modifying residues within the constant region(s), for example to alter the effector function(s) of the antibody.
  • CDR grafting can be used to engineer variable regions of antibodies.
  • Antibodies interact with target antigens predominantly through amino acid residues that are located in the six heavy and light chain complementarity determining regions (CDRs). For this reason, the amino acid sequences within CDRs are more diverse between individual antibodies than sequences outside of CDRs. Because CDR sequences are responsible for most antibody-antigen interactions, it is possible to express recombinant antibodies that mimic the properties of specific naturally occurring antibodies by constructing expression vectors that include CDR sequences from the specific naturally occurring antibody grafted onto framework sequences from a different antibody with different properties (see, e.g., Riechmann et al. (1998) Nature 332:323-327; Jones et al.
  • another embodiment of the invention pertains to an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-6, SEQ ID NOs: 7-12, and SEQ ID NOs: 13-14, GGY and 16-18, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-24, SEQ ID NOs: 25-30, and SEQ ID NOs: 31-36, respectively.
  • such antibodies contain the V H and V L CDR sequences of monoclonal antibodies 25F7, 26H10, 25E3, 8B7, 11F2 or 17E5 can contain different framework sequences from these antibodies.
  • Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
  • germline DNA sequences for human heavy and light chain variable region genes can be found in the “VBase” human germline sequence database (available on the Internet at www.mrc-cpe.cam.ac.uk/vbase), as well as in Kabat et al. (1991), cited supra; Tomlinson et al. (1992) “The Repertoire of Human Germline V H Sequences Reveals about Fifty Groups of V H Segments with Different Hypervariable Loops” J. Mol. Biol. 227:776-798; and Cox et al.
  • the germline DNA sequences for human heavy and light chain variable region genes can be found in the Genbank database.
  • the following heavy chain germline sequences found in the HCo7 HuMAb mouse are available in the accompanying Genbank Accession Nos.: 1-69 (NG — 0010109, NT — 024637 & BC070333), 3-33 (NG — 0010109 & NT — 024637) and 3-7 (NG — 0010109 & NT — 024637).
  • Antibody protein sequences are compared against a compiled protein sequence database using one of the sequence similarity searching methods called the Gapped BLAST (Altschul et al. (1997), supra), which is well known to those skilled in the art.
  • Preferred framework sequences for use in the antibodies of the invention are those that are structurally similar to the framework sequences used by selected antibodies of the invention, e.g., similar to the V H 3-20 (SEQ ID NO: 69), V H 4-34 (SEQ ID NO: 61), V H 3-33 (SEQ ID NO: 65) or V H 1-24 (SEQ ID NO: 73) framework sequences and/or the V K L18 (SEQ ID NO: 71), V K L6 (SEQ ID NO: 63) or V K A27 (SEQ ID NO: 67) framework sequences used by preferred monoclonal antibodies of the invention.
  • V H CDR1, CDR2, and CDR3 sequences can be grafted onto framework regions that have the identical sequence as that found in the germline immunoglobulin gene from which the framework sequence derive, or the CDR sequences can be grafted onto framework regions that contain one or more mutations as compared to the germline sequences.
  • the CDR sequences can be grafted onto framework regions that contain one or more mutations as compared to the germline sequences.
  • variable region modification is to mutate amino acid residues within the V H and/or V L CDR1, CDR2 and/or CDR3 regions to thereby improve one or more binding properties (e.g., affinity) of the antibody of interest.
  • Site-directed mutagenesis or PCR-mediated mutagenesis can be performed to introduce the mutation(s) and the effect on antibody binding, or other functional property of interest, can be evaluated in in vitro or in vivo assays as described herein and provided in the Examples.
  • Preferably conservative modifications are introduced.
  • the mutations can be amino acid substitutions, additions or deletions, but are preferably substitutions.
  • typically no more than one, two, three, four or five residues within a CDR region are altered.
  • the instant disclosure provides isolated anti-LAG-3 monoclonal antibodies, or antigen binding portions thereof, comprising a heavy chain variable region comprising: (a) a V H CDR1 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-6, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs: 1-6; (b) a V H CDR2 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7-12, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs: 7-12; (c) a V H CDR3 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13-14, GGY and 16-18, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID
  • Engineered antibodies of the invention include those in which modifications have been made to framework residues within V H and/or V L , e.g. to improve the properties of the antibody. Typically such framework modifications are made to decrease the immunogenicity of the antibody. For example, one approach is to “backmutate” one or more framework residues to the corresponding germline sequence. More specifically, an antibody that has undergone somatic mutation can contain framework residues that differ from the germline sequence from which the antibody is derived. Such residues can be identified by comparing the antibody framework sequences to the germline sequences from which the antibody is derived.
  • Table A shows regions where a framework region amino acid position (using Kabat numbering system) differs from the germline and how this position can be backmutated to the germline by the indicated substitutions:
  • Another type of framework modification involves mutating one or more residues within the framework region, or even within one or more CDR regions, to remove T cell epitopes to thereby reduce the potential immunogenicity of the antibody. This approach is also referred to as “deimmunization” and is described in further detail in U.S. Patent Publication No. 20030153043.
  • antibodies of the invention can be engineered to include modifications within the Fc region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity.
  • an antibody of the invention can be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or be modified to alter its glycosylation, again to alter one or more functional properties of the antibody.
  • the antibody is an IgG4 isotype antibody comprising a Serine to Proline mutation at a position corresponding to position 228 (S228P; EU index) in the hinge region of the heavy chain constant region.
  • S228P Serine to Proline mutation at a position corresponding to position 228
  • This mutation has been reported to abolish the heterogeneity of inter-heavy chain disulfide bridges in the hinge region (Angal et al. supra; position 241 is based on the Kabat numbering system).
  • an anti-LAG-3 antibody of the invention can comprise the heavy chain variable region of 25F7 (SEQ ID NO: 37) or 26H10 (SEQ ID NO: 38) linked to a human IgG4 constant region in which the Serine at a position corresponding to position 241 as described in Angal et al., supra, has been mutated to Proline.
  • this mutation corresponds to an S228P mutation by the EU index.
  • the hinge region of CH1 is modified such that the number of cysteine residues in the hinge region is altered, e.g., increased or decreased. This approach is described further in U.S. Pat. No. 5,677,425.
  • the number of cysteine residues in the hinge region of CH1 is altered to, for example, facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.
  • the Fc hinge region of an antibody is mutated to decrease the biological half life of the antibody. More specifically, one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody has impaired Staphylococcyl protein A (SpA) binding relative to native Fc-hinge domain SpA binding.
  • SpA Staphylococcyl protein A
  • the antibody is modified to increase its biological half life.
  • Various approaches are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Pat. No. 6,277,375.
  • the antibody can be altered within the CH1 or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Pat. Nos. 5,869,046 and 6,121,022.
  • the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector function(s) of the antibody.
  • one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320 and 322 can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody.
  • the effector ligand to which affinity is altered can be, for example, an Fc receptor or the C1 component of complement. This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260.
  • one or more amino acids selected from amino acid residues 329, 331 and 322 can be replaced with a different amino acid residue such that the antibody has altered Clq binding and/or reduced or abolished complement dependent cytotoxicity (CDC).
  • CDC complement dependent cytotoxicity
  • one or more amino acid residues within amino acid positions 231 and 239 are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in PCT Publication WO 94/29351.
  • the Fc region is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and/or to increase the affinity of the antibody for an Fc ⁇ receptor by modifying one or more amino acids at the following positions: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 301, 303, 305, 307, 309, 312, 315, 320, 322, 324, 326, 327, 329, 330, 331, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438 or 439.
  • ADCC antibody dependent cellular cytotoxicity
  • the glycosylation of an antibody is modified.
  • an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation).
  • Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen.
  • carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence.
  • one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site.
  • Such aglycosylation may increase the affinity of the antibody for antigen. See, e.g., U.S. Pat. Nos. 5,714,350 and 6,350,861.
  • an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures.
  • altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies.
  • carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies of the invention to thereby produce an antibody with altered glycosylation.
  • the cell lines Ms704, Ms705, and Ms709 lack the fucosyltransferase gene, FUT8 ( ⁇ (1,6)-fucosyltransferase), such that antibodies expressed in the Ms704, Ms705, and Ms709 cell lines lack fucose on their carbohydrates.
  • the Ms704, Ms705, and Ms709 FUT8 ⁇ / ⁇ cell lines were created by the targeted disruption of the FUT8 gene in CHO/DG44 cells using two replacement vectors (see U.S. Patent Publication No. 20040110704 and Yamane-Ohnuki et al. (2004) Biotechnol Bioeng 87:614-22).
  • EP 1,176,195 describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation by reducing or eliminating the a-1,6 bond-related enzyme.
  • EP 1,176,195 also describes cell lines which have a low enzyme activity for adding fucose to the N-acetylglucosamine that binds to the Fc region of the antibody or does not have the enzyme activity, for example the rat myeloma cell line YB2/0 (ATCC CRL 1662).
  • PCT Publication WO 03/035835 describes a variant CHO cell line, Lec13 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields et al. (2002) J. Biol. Chem. 277:26733-26740).
  • Antibodies with a modified glycosylation profile can also be produced in chicken eggs, as described in PCT Publication WO 06/089231.
  • antibodies with a modified glycosylation profile can be produced in plant cells, such as Lemna.
  • PCT Publication WO 99/54342 describes cell lines engineered to express glycoprotein-modifying glycosyl transferases (e.g., ⁇ (1,4)-N-acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al. (1999) Nat. Biotech. 17:176-180).
  • glycoprotein-modifying glycosyl transferases e.g., ⁇ (1,4)-N-acetylglucosaminyltransferase III (GnTIII)
  • the fucose residues of the antibody can be cleaved off using a fucosidase enzyme; e.g., the fucosidase a-L-fucosidase removes fucosyl residues from antibodies (Tarentino et al. (1975) Biochem. 14:5516-23).
  • a fucosidase enzyme e.g., the fucosidase a-L-fucosidase removes fucosyl residues from antibodies (Tarentino et al. (1975) Biochem. 14:5516-23).
  • An antibody can be pegylated to, for example, increase the biological (e.g., serum) half life of the antibody.
  • the antibody, or fragment thereof typically is reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the antibody or antibody fragment.
  • PEG polyethylene glycol
  • the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer).
  • polyethylene glycol is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (C1-C10) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide.
  • the antibody to be pegylated is an aglycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies of the invention. See, e.g., EP 0 154 316 and EP 0 401 384.
  • Antibodies of this disclosure can be characterized by their various physical properties, to detect and/or differentiate different classes thereof.
  • Antibodies of the present disclosure can contain one or more glycosylation sites in either the light or heavy chain variable region. Such glycosylation sites may result in increased immunogenicity of the antibody or an alteration of the pK of the antibody due to altered antigen binding (Marshall et al (1972) Annu Rev Biochem 41:673-702; Gala and Morrison (2004) J. Immunol 172:5489-94; Wallick et al (1988) J Exp Med 168:1099-109; Spiro (2002) Glycobiology 12:43R-56R; Parekh et al (1985) Nature 316:452-7; Mimura et al. (2000) Mol Immunol 37:697-706).
  • Glycosylation has been known to occur at motifs containing an N-X-S/T sequence.
  • an anti-LAG-3 antibody that does not contain variable region glycosylation. This can be achieved either by selecting antibodies that do not contain the glycosylation motif in the variable region or by mutating residues within the glycosylation region.
  • the antibodies of the present disclosure do not contain asparagine isomerism sites.
  • the deamidation of asparagine may occur on N-G or D-G sequences and result in the creation of an isoaspartic acid residue that introduces a kink into the polypeptide chain and decreases its stability (isoaspartic acid effect).
  • Each antibody will have a unique isoelectric point (pI), which generally falls in the pH range between 6 and 9.5.
  • the pI for an IgG1 antibody typically falls within the pH range of 7-9.5 and the pI for an IgG4 antibody typically falls within the pH range of 6-8.
  • pI isoelectric point
  • an anti-LAG-3 antibody that contains a pI value that falls in the normal range. This can be achieved either by selecting antibodies with a pI in the normal range or by mutating charged surface residues.
  • each antibody will have a characteristic melting temperature, with a higher melting temperature indicating greater overall stability in vivo (Krishnamurthy R and Manning M C (2002) Curr Pharm Biotechnol 3:361-71).
  • the T M1 the temperature of initial unfolding
  • the melting point of an antibody can be measured using differential scanning calorimetry (Chen et al (2003) Pharm Res 20:1952-60; Ghirlando et al (1999) Immunol Lett 68:47-52) or circular dichroism (Murray et al. (2002) J. Chromatogr Sci 40:343-9).
  • antibodies are selected that do not degrade rapidly. Degradation of an antibody can be measured using capillary electrophoresis (CE) and MALDI-MS (Alexander A J and Hughes D E (1995) Anal Chem 67:3626-32).
  • CE capillary electrophoresis
  • MALDI-MS Alexander A J and Hughes D E (1995) Anal Chem 67:3626-32).
  • antibodies are selected that have minimal aggregation effects, which can lead to the triggering of an unwanted immune response and/or altered or unfavorable pharmacokinetic properties.
  • antibodies are acceptable with aggregation of 25% or less, preferably 20% or less, even more preferably 15% or less, even more preferably 10% or less and even more preferably 5% or less.
  • Aggregation can be measured by several techniques, including size-exclusion column (SEC), high performance liquid chromatography (HPLC), and light scattering.
  • the anti-LAG-3 antibodies having V H and V L sequences disclosed herein can be used to create new anti-LAG-3 antibodies by modifying the V H and/or V L sequences, or the constant region(s) attached thereto.
  • the structural features of an anti-LAG-3 antibody of the invention e.g. 25F7, 26H10, 25E3, 8B7, 11F2 or 17E5, are used to create structurally related anti-LAG-3 antibodies that retain at least one functional property of the antibodies of the invention, such as binding to human LAG-3.
  • one or more CDR regions of 25F7, 26H10, 25E3, 8B7, 11F2 or 17E5, or mutations thereof can be combined recombinantly with known framework regions and/or other CDRs to create additional, recombinantly-engineered, anti-LAG-3 antibodies of the invention, as discussed above.
  • the starting material for the engineering method is one or more of the V H and/or V L sequences provided herein, or one or more CDR regions thereof.
  • To create the engineered antibody it is not necessary to actually prepare (i.e., express as a protein) an antibody having one or more of the V H and/or V L sequences provided herein, or one or more CDR regions thereof. Rather, the information contained in the sequence(s) is used as the starting material to create a “second generation” sequence(s) derived from the original sequence(s) and then the “second generation” sequence(s) is prepared and expressed as a protein.
  • this disclosure provides a method for preparing an anti-LAG-3 antibody comprising:
  • Standard molecular biology techniques can be used to prepare and express the altered antibody sequence.
  • the antibody encoded by the altered antibody sequence(s) is one that retains one, some or all of the functional properties of the anti-LAG-3 antibodies described herein, which functional properties include, but are not limited to:
  • the functional properties of the altered antibodies can be assessed using standard assays available in the art and/or described herein, such as those set forth in the Examples.
  • mutations can be introduced randomly or selectively along all or part of an anti-LAG-3 antibody coding sequence and the resulting modified anti-LAG-3 antibodies can be screened for binding activity and/or other functional properties as described herein. Mutational methods have been described in the art (see, e.g., PCT Publications WO 02/092780 and WO 03/074679).
  • nucleic acid molecules that encode the antibodies of the invention.
  • the nucleic acids can be present in whole cells, in a cell lysate, or in a partially purified or substantially pure form.
  • a nucleic acid is “isolated” or “rendered substantially pure” when purified away from other cellular components or other contaminants, e.g., other cellular nucleic acids or proteins, by standard techniques, including alkaline/SDS treatment, CsCl banding, column chromatography, agarose gel electrophoresis and others well known in the art. See, Ausubel, et al., ed. (1987) Current
  • a nucleic acid of the invention can be, e.g., DNA or RNA and may or may not contain intronic sequences.
  • the nucleic acid is a cDNA molecule.
  • Nucleic acids of the invention can be obtained using standard molecular biology techniques.
  • hybridomas e.g., hybridomas prepared from transgenic mice carrying human immunoglobulin genes as described further below
  • cDNAs encoding the light and heavy chains of the antibody made by the hybridoma can be obtained by standard PCR amplification or cDNA cloning techniques.
  • an immunoglobulin gene library e.g., using phage display techniques
  • a nucleic acid encoding such antibodies can be recovered from the gene library.
  • Preferred nucleic acids molecules of the invention are those encoding the V H and V L sequences of the 25E3, 25F7, 8B7, 26H10, 11F2 and 17E5 monoclonal antibodies.
  • DNA sequences encoding the V H sequences of 25E3, 25F7, 8B7, 26H10, 11F2 and 17E5 are shown in SEQ ID NOs: 49-54, respectively.
  • DNA sequences encoding the V L sequences of 25E3, 25F7, 8B7, 26H10, 11F2 and 17E5 are shown in SEQ ID NOs: 55-60, respectively.
  • V H and V L segments are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to a scFv gene.
  • a V L - or V H -encoding DNA fragment is operatively linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker.
  • the term “operatively linked”, as used in this context, is intended to mean that the two DNA fragments are joined such that the amino acid sequences encoded by the two DNA fragments remain in-frame.
  • the isolated DNA encoding the V H region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding DNA to another DNA molecule encoding heavy chain constant regions (CH1, CH2 and CH3).
  • heavy chain constant regions CH1, CH2 and CH3
  • the sequences of human heavy chain constant region genes are known in the art (see e.g., Kabat et al. (1991), supra) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
  • the heavy chain constant region can be an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but most preferably is an IgG1 or IgG4 constant region.
  • the V H -encoding DNA can be operatively linked to another DNA molecule encoding only the heavy chain CH1 constant region.
  • the isolated DNA encoding the V L region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the V L -encoding DNA to another DNA molecule encoding the light chain constant region, CL.
  • the sequences of human light chain constant region genes are known in the art (see e.g., Kabat et al., supra) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
  • the light chain constant region can be a kappa or lambda constant region.
  • the V H - and V L -encoding DNA fragments are operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly 4 -Ser) 3 , such that the V H and V L sequences can be expressed as a contiguous single-chain protein, with the V L and V H regions joined by the flexible linker (see e.g., Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al., (1990) Nature 348:552-554).
  • a flexible linker e.g., encoding the amino acid sequence (Gly 4 -Ser) 3
  • Monoclonal antibodies (mAbs) of the present disclosure can be produced using the well-known somatic cell hybridization (hybridoma) technique of Kohler and Milstein (1975) Nature 256: 495.
  • Other embodiments for producing monoclonal antibodies include viral or oncogenic transformation of B lymphocytes and phage display techniques.
  • Chimeric or humanized antibodies are also well known in the art. See e.g., U.S. Pat. Nos. 4,816,567; 5,225,539; 5,530,101; 5,585,089; 5,693,762 and 6,180,370, the contents of which are specifically incorporated herein by reference in their entirety.
  • the antibodies of the invention are human monoclonal antibodies.
  • Such human monoclonal antibodies directed against human LAG-3 can be generated using transgenic or transchromosomic mice carrying parts of the human immune system rather than the mouse system.
  • transgenic and transchromosomic mice include mice referred to herein as the HuMAb Mouse® and KM Mouse®, respectively, and are collectively referred to herein as “human Ig mice.”
  • the HuMAb Mouse® (Medarex®, Inc.) contains human immunoglobulin gene miniloci that encode unrearranged human heavy ( ⁇ and ⁇ ) and ⁇ light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous ⁇ and ⁇ chain loci (see e.g., Lonberg et al. (1994) Nature 368(6474): 856-859). Accordingly, the mice exhibit reduced expression of mouse IgM or ⁇ , and in response to immunization, the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to generate high affinity human IgG ⁇ monoclonal antibodies (Lonberg et al.
  • human antibodies of the invention can be raised using a mouse that carries human immunoglobulin sequences on transgenes and transchomosomes, such as a mouse that carries a human heavy chain transgene and a human light chain transchromosome.
  • This mouse is referred to herein as a “KM mouse®,” and is described in detail in PCT Publication WO 02/43478.
  • a modified form of this mouse, which further comprises a homozygous disruption of the endogenous Fc ⁇ RIIB receptor gene, is also described in PCT Publication WO 02/43478 and referred to herein as a “KM/FCGR2D mouse®.”
  • mice with either the HCo7 or HCo12 heavy chain transgenes or both can be used.
  • transgenic animal embodiments include the Xenomouse (Abgenix, Inc., U.S. Pat. Nos. 5,939,598; 6,075,181; 6,114,598; 6,150,584 and 6,162,963). Further embodiments include “TC mice” (Tomizuka et al. (2000) Proc. Natl. Acad. Sci. USA 97:722-727) and cows carrying human heavy and light chain transchromosomes (Kuroiwa et al. (2002) Nature Biotechnology 20:889-894; PCT Publication WO 02/092812). The contents of these patents and publications are specifically incorporated herein by reference in their entirety.
  • human monoclonal antibodies of the invention are prepared using phage display methods for screening libraries of human immunoglobulin genes. See, e.g. U.S. Pat. Nos. 5,223,409; 5,403,484; 5,571,698; 5,427,908; 5,580,717; 5,969,108;6,172,197; 5,885,793; 6,521,404; 6,544,731; 6,555,313; 6,582,915; and 6,593,081, the contents of which are incorporated herein by reference in their entirety.
  • Human monoclonal antibodies of the invention can also be prepared using SCID mice into which human immune cells have been reconstituted such that a human antibody response can be generated upon immunization. See, e.g., U.S. Pat. Nos. 5,476,996 and 5,698,767, the contents of which are incorporated herein by reference in their entirety.
  • human anti-LAG-3 antibodies are prepared using phage display where the phages comprise nucleic acids encoding antibodies generated in transgenic animals previously immunized with LAG-3.
  • the transgenic animal is a HuMab, KM, or Kirin mouse. See, e.g. U.S. Pat. No. 6,794,132, the contents of which are incorporated herein by reference in its entirety.
  • human Ig mice are immunized with a purified or enriched preparation of a LAG-3 antigen, recombinant LAG-3 protein, or cells expressing a LAG-3 protein. See, e.g., Lonberg et al. (1994), supra; Fishwild et al. (1996), supra; PCT Publications WO 98/24884 or WO 01/14424, the contents of which are incorporated herein by reference in their entirety.
  • 6-16 week old mice are immunized with 5-50 ⁇ g of LAG-3 protein.
  • a portion of LAG-3 fused to a non-LAG-3 polypeptide is used.
  • the transgenic mice are immunized intraperitoneally (IP) or intravenously (IV) with LAG-3 antigen in complete Freund's adjuvant, followed by subsequent IP or IV immunizations with antigen in incomplete Freund's adjuvant.
  • adjuvants other than Freund's or whole cells in the absence of adjuvant are used.
  • the plasma can be screened by ELISA and cells from mice with sufficient titers of anti-LAG-3 human immunoglobulin can be used for fusions.
  • hybridomas producing human monoclonal antibodies of the invention splenocytes and/or lymph node cells from immunized mice can be isolated and fused to an appropriate immortalized cell line, such as a mouse myeloma cell line.
  • an appropriate immortalized cell line such as a mouse myeloma cell line.
  • the resulting hybridomas can be screened for the production of antigen-specific antibodies.
  • Generation of hybridomas is well-known in the art. See, e.g., Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York.
  • Antibodies of the invention also can be produced in a host cell transfectoma using, for example, a combination of recombinant DNA techniques and gene transfection methods as is well known in the art (e.g., Morrison, S. (1985) Science 229:1202).
  • DNA encoding partial or full-length light and heavy chains obtained by standard molecular biology techniques is inserted into one or more expression vectors such that the genes are operatively linked to transcriptional and translational regulatory sequences.
  • the term “operatively linked” is intended to mean that an antibody gene is ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the antibody gene.
  • regulatory sequence is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes.
  • promoters e.g., promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes.
  • enhancers e.g., polyadenylation signals
  • polyadenylation signals e.g., polyadenylation signals
  • Preferred regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV), Simian Virus 40 (SV40), adenovirus, (e.g., the adenovirus major late promoter (AdMLP) and polyoma.
  • CMV cytomegalovirus
  • SV40 Simian Virus 40
  • AdMLP adenovirus major late promoter
  • nonviral regulatory sequences can be used, such as the ubiquitin promoter or ⁇ -globin promoter.
  • regulatory elements composed of sequences from different sources such as the SR ⁇ promoter system, which contains sequences from the SV40 early promoter and the long terminal repeat of human T cell leukemia virus type 1 (Takebe et al. (1988) Mol. Cell. Biol. 8:466-472).
  • the expression vector and expression control sequences are chosen to be compatible with the expression host
  • the antibody light chain gene and the antibody heavy chain gene can be inserted into the same or separate expression vectors.
  • the variable regions are used to create full-length antibody genes of any antibody isotype by inserting them into expression vectors already encoding heavy chain constant and light chain constant regions of the desired isotype such that the V H segment is operatively linked to the C H segment(s) within the vector and the V L segment is operatively linked to the C L segment within the vector.
  • the recombinant expression vector can encode a signal peptide that facilitates secretion of the antibody chain from a host cell.
  • the antibody chain gene can be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the antibody chain gene.
  • the signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).
  • the recombinant expression vectors of the invention can carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes.
  • the selectable marker gene facilitates selection of host cells into which the vector has been introduced (see, e.g., U.S. Pat. Nos. 4,399,216; 4,634,665 and 5,179,017).
  • the selectable marker gene confers resistance to drugs, such as G418, hygromycin or methotrexate, on a host cell into which the vector has been introduced.
  • Preferred selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr-host cells with methotrexate selection/amplification) and the neo gene (for G418 selection).
  • DHFR dihydrofolate reductase
  • the expression vector(s) encoding the heavy and light chains is transfected into a host cell by standard techniques.
  • the various forms of the term “transfection” are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like.
  • Preferred mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhff ⁇ CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R. J. Kaufman and P. A. Sharp (1982) J. Mol. Biol. 159:601-621), NSO myeloma cells, COS cells and SP2 cells.
  • Chinese Hamster Ovary CHO cells
  • dhff ⁇ CHO cells described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R. J. Kaufman and P. A. Sharp (1982) J. Mol. Biol. 159:601-621
  • another preferred expression system is the GS gene expression system disclosed in WO 87/04462, WO 89/01036 and EP 338,841.
  • the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are grown.
  • Antibodies can be recovered from the culture medium using standard protein purification methods.
  • Antibodies of the invention can be tested for binding to human LAG-3 by, for example, standard ELISA.
  • Anti-LAG-3 human IgGs can be further tested for reactivity with a LAG-3 antigen by Western blotting.
  • the binding specificity of an antibody of the invention can also be determined by monitoring binding of the antibody to cells expressing a LAG-3 protein, e.g., flow cytometry. These methods are known in the art. See, e.g., Harlow and Lane (1988), cited supra.
  • Antibodies of this invention can be conjugated to a therapeutic agent to form an immunoconjugate such as an antibody-drug conjugate (ADC).
  • Suitable therapeutic agents include antimetabolites, alkylating agents, DNA minor groove binders, DNA intercalators, DNA crosslinkers, histone deacetylase inhibitors, nuclear export inhibitors, proteasome inhibitors, topoisomerase I or II inhibitors, heat shock protein inhibitors, tyrosine kinase inhibitors, antibiotics, and anti-mitotic agents.
  • the antibody and therapeutic agent preferably are conjugated via a linker cleavable such as a peptidyl, disulfide, or hydrazone linker.
  • the linker is a peptidyl linker such as Val-Cit, Ala-Val, Val-Ala-Val, Lys-Lys, Pro-Val-Gly-Val-Val (SEQ ID NO:15), Ala-Asn-Val, Val-Leu-Lys, Ala-Ala-Asn, Cit-Cit, Val-Lys, Lys, Cit, Ser, or Glu.
  • the ADCs can be prepared as described in U.S. Pat. Nos.
  • bispecific molecules comprising an anti-LAG-3 antibody linked to at least one other functional molecule, e.g., another peptide or protein (e.g., another antibody or ligand for a receptor) to generate a bispecific molecule that binds to at least two different binding sites or target molecules.
  • bispecific molecule includes molecules that have three or more specificities.
  • the bispecific molecule comprises a first binding specificity for LAG-3 and a second binding specificity for a triggering molecule that recruits cytotoxic effector cells that can kill a LAG-3 expressing target cell.
  • suitable triggering molecules are CD64, CD89, CD16, and CD3. See, e.g., Kufer et al., TRENDS in Biotechnology, 22 (5), 238-244 (2004).
  • a bispecific molecule has, in addition to an anti-Fc binding specificity and an anti-LAG-3 binding specificity, a third specificity.
  • the third specificity can be for an anti-enhancement factor (EF), e.g., a molecule that binds to a surface protein involved in cytotoxic activity and thereby increases the immune response against the target cell.
  • EF anti-enhancement factor
  • the anti-enhancement factor can bind a cytotoxic T-cell (e.g. via CD2, CD3, CD8, CD28, CD4, CD40, or ICAM-1) or other immune cell, resulting in an increased immune response against the target cell.
  • Bispecific molecules can come in many different formats and sizes. At one end of the size spectrum, a bispecific molecule retains the traditional antibody format, except that, instead of having two binding arms of identical specificity, it has two binding arms each having a different specificity. At the other extreme are bispecific molecules consisting of two single-chain antibody fragments (scFv's) linked by a peptide chain, a so-called Bs(scFv) 2 construct. Intermediate-sized bispecific molecules include two different F(ab) fragments linked by a peptidyl linker. Bispecific molecules of these and other formats can be prepared by genetic engineering, somatic hybridization, or chemical methods.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising an antibody of the present disclosure formulated together with a pharmaceutically acceptable carrier. It may optionally contain one or more additional pharmaceutically active ingredients, such as another antibody or a drug.
  • the pharmaceutical compositions of the invention also can be administered in a combination therapy with, for example, another immunostimulatory agent, anti-cancer agent, an anti-viral agent, or a vaccine, such that the anti-LAG-3 antibody enhances the immune response against the vaccine.
  • the pharmaceutical composition can comprise any number of excipients.
  • Excipients that can be used include carriers, surface active agents, thickening or emulsifying agents, solid binders, dispersion or suspension aids, solubilizers, colorants, flavoring agents, coatings, disintegrating agents, lubricants, sweeteners, preservatives, isotonic agents, and combinations thereof.
  • the selection and use of suitable excipients is taught in Gennaro, ed., Remington: The Science and Practice of Pharmacy, 20th Ed. (Lippincott Williams & Wilkins 2003), the disclosure of which is incorporated herein by reference.
  • a pharmaceutical composition is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion).
  • the active compound can be coated in a material to protect it from the action of acids and other natural conditions that may inactivate it.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
  • an antibody of the invention can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, e.g., intranasally, orally, vaginally, rectally, sublingually or topically.
  • the pharmaceutical compounds of the invention can be in the form of pharmaceutically acceptable salts.
  • a “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects. Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N′-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
  • compositions can be in the form of sterile aqueous solutions or dispersions. They can also be formulated in a microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration and will generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.01% to about ninety-nine percent of active ingredient, preferably from about 0.1% to about 70%, most preferably from about 1% to about 30% of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions 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 subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • antibody can be administered as a sustained release formulation, in which case less frequent administration is required.
  • the dosage ranges from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg, of the host body weight.
  • dosages can be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg.
  • An exemplary treatment regime entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months.
  • Preferred dosage regimens for an anti-LAG-3 antibody of the invention include 1 mg/kg body weight or 3 mg/kg body weight via intravenous administration, with the antibody being given using one of the following dosing schedules: (i) every four weeks for six dosages, then every three months; (ii) every three weeks; (iii) 3 mg/kg body weight once followed by 1 mg/kg body weight every three weeks.
  • dosage is adjusted to achieve a plasma antibody concentration of about 1-1000 ⁇ g/ml and in some methods about 25-300 ⁇ g/ml.
  • a “therapeutically effective dosage” of an anti-LAG-3 antibody of the invention preferably results in a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • a “therapeutically effective dosage” preferably inhibits tumor growth by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects.
  • a therapeutically effective amount of a therapeutic compound can decrease tumor size, or otherwise ameliorate symptoms in a subject, which is typically a human or can be another mammal.
  • the pharmaceutical composition can be a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. See, e.g., Sustained and Controlled Release Drug Delivery Systems , J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • compositions can be administered via medical devices such as (1) needleless hypodermic injection devices (e.g., U.S. Pat. Nos. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; and 4,596,556); (2) micro-infusion pumps (U.S. Pat. No. 4,487,603); (3) transdermal devices (U.S. Pat. No. 4,486,194); (4) infusion apparati (U.S. Pat. Nos. 4,447,233 and 4,447,224); and (5) osmotic devices (U.S. Pat. No. 4,439,196 and 4,475,196); the disclosures of which are incorporated herein by reference.
  • needleless hypodermic injection devices e.g., U.S. Pat. Nos. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824;
  • the human monoclonal antibodies of the invention can be formulated to ensure proper distribution in vivo.
  • the therapeutic compounds of the invention can be formulated in liposomes, which may additionally comprise targeting moieties to enhance selective transport to specific cells or organs. See, e.g. U.S. Pat. Nos. 4,522,811; 5,374,548; 5,416,016; and 5,399,331; V. V. Ranade (1989) J. Clin. Pharmacol. 29:685; Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153:1038; Bloeman et al. (1995) FEBS Lett.
  • the antibodies, antibody compositions and methods of the present invention have numerous in vitro and in vivo utilities involving, for example, detection of LAG-3 or enhancement of immune response by blockade of LAG-3.
  • the antibodies of the present invention are human antibodies.
  • these molecules can be administered to cells in culture, in vitro or ex vivo, or to human subjects, e.g., in vivo, to enhance immunity in a variety of situations.
  • the invention provides a method of modifying an immune response in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of the invention such that the immune response in the subject is modified.
  • the response is enhanced, stimulated or up-regulated.
  • Preferred subjects include human patients in need of enhancement of an immune response.
  • the methods are particularly suitable for treating human patients having a disorder that can be treated by augmenting an immune response (e.g., the T-cell mediated immune response).
  • the methods are particularly suitable for treatment of cancer in vivo.
  • the anti-LAG-3 antibodies can be administered together with an antigen of interest or the antigen may already be present in the subject to be treated (e.g., a tumor-bearing or virus-bearing subject).
  • the two can be administered in either order or simultaneously.
  • the invention further provides methods for detecting the presence of human LAG-3 antigen in a sample, or measuring the amount of human LAG-3 antigen, comprising contacting the sample, and a control sample, with a human monoclonal antibody, or an antigen binding portion thereof, which specifically binds to human LAG-3, under conditions that allow for formation of a complex between the antibody or portion thereof and human LAG-3. The formation of a complex is then detected, wherein a difference complex formation between the sample compared to the control sample is indicative the presence of human LAG-3 antigen in the sample.
  • the anti-LAG-3 antibodies of the invention can be used to purify human LAG-3 via immunoaffinity purification.
  • the invention also provides in vitro and in vivo methods of using the antibodies of the invention to stimulate, enhance or upregulate antigen-specific T cell responses.
  • the invention provides a method of stimulating an antigen-specific T cell response comprising contacting said T cell with the antibody of the invention such that an antigen-specific T cell response is stimulated.
  • Any suitable indicator of an antigen-specific T cell response can be used to measure the antigen-specific T cell response.
  • suitable indicators include increased T cell proliferation in the presence of the antibody and/or increase cytokine production in the presence of the antibody.
  • interleukin-2 production by the antigen-specific T cell is stimulated.
  • the invention also provides a method of stimulating an immune response (e.g., an antigen-specific T cell response) in a subject comprising administering an antibody of the invention to the subject such that an immune response (e.g., an antigen-specific T cell response) in the subject is stimulated.
  • an immune response e.g., an antigen-specific T cell response
  • the subject is a tumor-bearing subject and an immune response against the tumor is stimulated.
  • the subject is a virus-bearing subject and an immune response against the virus is stimulated.
  • the invention provides a method for inhibiting growth of tumor cells in a subject comprising administering to the subject an antibody of the invention such that growth of the tumor is inhibited in the subject.
  • the invention provides a method of treating viral infection in a subject comprising administering to the subject an antibody of the invention such that the viral infection is treated in the subject.
  • Blockade of LAG-3 by antibodies can enhance the immune response to cancerous cells in the patient.
  • the present invention relates to treatment of a subject in vivo using an anti-LAG-3 antibody such that growth of cancerous tumors is inhibited.
  • An anti-LAG-3 antibody can be used alone to inhibit the growth of cancerous tumors.
  • an anti-LAG-3 antibody can be used in conjunction with other immunogenic agents, standard cancer treatments, or other antibodies, as described below.
  • the invention provides a method of inhibiting growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of an anti-LAG-3 antibody, or antigen-binding portion thereof.
  • the antibody is a human anti-LAG-3 antibody (such as any of the human anti-human LAG-3 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized anti-LAG-3 antibody.
  • Preferred cancers whose growth may be inhibited using the antibodies of the invention include cancers typically responsive to immunotherapy.
  • preferred cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer).
  • the invention includes refractory or recurrent malignancies whose growth may be inhibited using the antibodies of the invention.
  • cancers examples include bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood,
  • antibodies to LAG-3 can be combined with an immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J. Immunol. 173:4919-28).
  • an immunogenic agent such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J. Immunol. 173:4919-28).
  • tumor vaccines include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MART1 and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF (discussed further below).
  • tumors have been shown to be immunogenic such as melanomas.
  • LAG-3 blockade By raising the threshold of T cell activation by LAG-3 blockade, the tumor responses in the host can be activated.
  • LAG-3 blockade is likely to be more effective when combined with a vaccination protocol.
  • Many experimental strategies for vaccination against tumors have been devised (see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62; Logothetis, C., 2000, ASCO Educational Book Spring: 300-302; Khayat, D. 2000, ASCO Educational Book Spring: 414-428; Foon, K. 2000, ASCO Educational Book Spring: 730-738; see also Restifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 in DeVita et al. (eds.), 1997, Cancer: Principles and Practice of Oncology, Fifth Edition).
  • a vaccine is prepared using autologous or allogeneic tumor cells. These cellular vaccines have been shown to be most effective when the tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent activator of antigen presentation for tumor vaccination (Dranoff et al. (1993) Proc. Natl. Acad. Sci U.S.A. 90: 3539-43).
  • tumor specific antigens are differentiation antigens expressed in the tumors and in the cell from which the tumor arose, for example melanocyte antigens gp100, MAGE antigens, and Trp-2. More importantly, many of these antigens can be shown to be the targets of tumor specific T cells found in the host. LAG-3 blockade can be used in conjunction with a collection of recombinant proteins and/or peptides expressed in a tumor in order to generate an immune response to these proteins.
  • the tumor antigen can include the protein telomerase, which is required for the synthesis of telomeres of chromosomes and which is expressed in more than 85% of human cancers and in only a limited number of somatic tissues (Kim et al. (1994) Science 266: 2011-2013). (These somatic tissues may be protected from immune attack by various means).
  • Tumor antigen can also be “neo-antigens” expressed in cancer cells because of somatic mutations that alter protein sequence or create fusion proteins between two unrelated sequences (i.e., bcr-abl in the Philadelphia chromosome), or idiotype from B cell tumors.
  • tumor vaccines can include the proteins from viruses implicated in human cancers such a Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV).
  • HPV Human Papilloma Viruses
  • HBV Hepatitis Viruses
  • KHSV Kaposi's Herpes Sarcoma Virus
  • Another form of tumor specific antigen which can be used in conjunction with LAG-3 blockade is purified heat shock proteins (HSP) isolated from the tumor tissue itself. These heat shock proteins contain fragments of proteins from the tumor cells and these HSPs are highly efficient at delivery to antigen presenting cells for eliciting tumor immunity (Suot & Srivastava (1995) Science 269:1585-1588; Tamura et al. (1997) Science 278:117-120).
  • DC Dendritic cells
  • DC's can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle et al. (1998) Nature Medicine 4: 328-332). DCs can also be transduced by genetic means to express these tumor antigens as well. DCs have also been fused directly to tumor cells for the purposes of immunization (Kugler et al. (2000) Nature Medicine 6:332-336). As a method of vaccination, DC immunization can be effectively combined with LAG-3 blockade to activate more potent anti-tumor responses.
  • LAG-3 blockade can also be combined with standard cancer treatments. LAG-3 blockade can be effectively combined with chemotherapeutic regimes. In these instances, it may be possible to reduce the dose of chemotherapeutic reagent administered (Mokyr et al. (1998) Cancer Research 58: 5301-5304).
  • An example of such a combination is an anti-LAG-3 antibody in combination with decarbazine for the treatment of melanoma.
  • Another example of such a combination is an anti-LAG-3 antibody in combination with interleukin-2 (IL-2) for the treatment of melanoma.
  • IL-2 interleukin-2
  • LAG-3 blockade The scientific rationale behind the combined use of LAG-3 blockade and chemotherapy is that cell death, that is a consequence of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigen in the antigen presentation pathway.
  • Other combination therapies that may result in synergy with LAG-3 blockade through cell death are radiation, surgery, and hormone deprivation. Each of these protocols creates a source of tumor antigen in the host.
  • Angiogenesis inhibitors can also be combined with LAG-3 blockade. Inhibition of angiogenesis leads to tumor cell death which may feed tumor antigen into host antigen presentation pathways.
  • LAG-3 blocking antibodies can also be used in combination with bispecific antibodies that target Fc ⁇ or Fc ⁇ receptor-expressing effectors cells to tumor cells (see, e.g., U.S. Pat. Nos. 5,922,845 and 5,837,243).
  • Bispecific antibodies can be used to target two separate antigens.
  • anti-Fc receptor/anti tumor antigen e.g., Her-2/neu
  • bispecific antibodies have been used to target macrophages to sites of tumor. This targeting may more effectively activate tumor specific responses.
  • the T cell arm of these responses would be augmented by the use of LAG-3 blockade.
  • antigen may be delivered directly to DCs by the use of bispecific antibodies which bind to tumor antigen and a dendritic cell specific cell surface marker.
  • Tumors evade host immune surveillance by a large variety of mechanisms. Many of these mechanisms may be overcome by the inactivation of proteins which are expressed by the tumors and which are immunosuppressive. These include among others TGF- ⁇ (Kehrl et al. (1986) J. Exp. Med. 163: 1037-1050), IL-10 (Howard & O'Garra (1992) Immunology Today 13: 198-200), and Fas ligand (Hahne et al. (1996) Science 274: 1363-1365). Antibodies to each of these entities can be used in combination with anti-LAG-3 to counteract the effects of the immunosuppressive agent and favor tumor immune responses by the host.
  • Anti-CD40 antibodies are able to substitute effectively for T cell helper activity (Ridge et al. (1998) Nature 393: 474-478) and can be used in conjunction with LAG-3 antibodies (Ito et al. (2000) Immunobiology 201 (5) 527-40). Activating antibodies to T cell costimulatory molecules such as
  • CTLA-4 e.g., U.S. Pat. No. 5,811,097
  • OX-40 Weinberg et al. (2000) Immunol 164: 2160-2169
  • 4-1BB Melero et al. (1997) Nature Medicine 3: 682-685 (1997)
  • ICOS Human et al. (1999) Nature 397: 262-266
  • Bone marrow transplantation is currently being used to treat a variety of tumors of hematopoietic origin. While graft versus host disease is a consequence of this treatment, therapeutic benefit may be obtained from graft vs. tumor responses.
  • LAG-3 blockade can be used to increase the effectiveness of the donor engrafted tumor specific T cells.
  • Another aspect of the invention provides a method of treating an infectious disease in a subject comprising administering to the subject an anti-LAG-3 antibody, or antigen-binding portion thereof, such that the subject is treated for the infectious disease.
  • the antibody is a human anti-human LAG-3 antibody (such as any of the human anti-LAG-3 antibodies described herein).
  • the antibody can be a chimeric or humanized antibody.
  • antibody mediated LAG-3 blockade can be used alone, or as an adjuvant, in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens.
  • pathogens for which this therapeutic approach can be particularly useful include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to HIV, Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas aeruginosa .
  • LAG-3 blockade is particularly useful against established infections by agents such as HIV that present altered antigens over the course of the infections. These novel epitopes are recognized as foreign at the time of anti-human LAG-3 administration, thus provoking a strong T cell response that is not dampened by negative signals through LAG-3.
  • pathogenic viruses causing infections treatable by methods of the invention include HIV, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
  • herpes virus e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus
  • adenovirus e.g., influenza virus, flaviviruses, echovirus, rhinovirus, coxsacki
  • pathogenic bacteria causing infections treatable by methods of the invention include chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and gonococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lymes disease bacteria.
  • pathogenic fungi causing infections treatable by methods of the invention include Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizopus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • pathogenic parasites causing infections treatable by methods of the invention include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, Nippostrongylus brasiliensis.
  • LAG-3 blockade can be combined with other forms of immunotherapy such as cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), or bispecific antibody therapy, which provides for enhanced presentation of tumor antigens (see, e.g., Holliger (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak (1994) Structure 2:1121-1123).
  • cytokine treatment e.g., interferons, GM-CSF, G-CSF, IL-2
  • bispecific antibody therapy which provides for enhanced presentation of tumor antigens
  • Anti-LAG-3 antibodies may provoke and amplify autoimmune responses. Indeed, induction of anti-tumor responses using tumor cell and peptide vaccines reveals that many anti-tumor responses involve anti-self reactivities (van Elsas et al. (2001) J. Exp. Med. 194:481-489; Overwijk, et al. (1999) Proc. Natl. Acad. Sci. U.S.A. 96: 2982-2987; Hurwitz, (2000) supra; Rosenberg & White (1996) J. Immunother Emphasis Tumor Immunol 19 (1): 81-4).
  • anti-LAG-3 blockade in conjunction with various self proteins in order to devise vaccination protocols to efficiently generate immune responses against these self proteins for disease treatment.
  • Alzheimer's disease involves inappropriate accumulation of A ⁇ peptide in amyloid deposits in the brain; antibody responses against amyloid are able to clear these amyloid deposits (Schenk et al., (1999) Nature 400: 173-177).
  • Analogous methods as described above for the use of anti-LAG-3 antibody can be used for induction of therapeutic autoimmune responses to treat patients having an inappropriate accumulation of other self-antigens, such as amyloid deposits, including A ⁇ in Alzheimer's disease, cytokines such as TNFa, and IgE.
  • Anti-LAG-3 antibodies can be used to stimulate antigen-specific immune responses by coadministration of an anti-LAG-3 antibody with an antigen of interest (e.g., a vaccine). Accordingly, in another aspect the invention provides a method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) an anti-LAG-3 antibody, or antigen-binding portion thereof, such that an immune response to the antigen in the subject is enhanced.
  • the antibody is a human anti-human LAG-3 antibody (such as any of the human anti-LAG-3 antibodies described herein). Additionally or alternatively, the antibody can be a chimeric or humanized antibody.
  • the antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen.
  • antigens include those discussed in the sections above, such as the tumor antigens (or tumor vaccines) discussed above, or antigens from the viruses, bacteria or other pathogens described above.
  • Suitable routes of administering the antibody compositions e.g., human monoclonal antibodies, multispecific and bispecific molecules and immunoconjugates
  • the antibody compositions can be administered by injection (e.g., intravenous or subcutaneous).
  • Suitable dosages of the molecules used will depend on the age and weight of the subject and the concentration and/or formulation of the antibody composition.
  • human anti-LAG-3 antibodies of the invention can be co-administered with one or other more therapeutic agents, e.g., a cytotoxic agent, a radiotoxic agent or an immunosuppressive agent.
  • the antibody can be linked to the agent (as an immuno-complex) or can be administered separate from the agent. In the latter case (separate administration), the antibody can be administered before, after or concurrently with the agent or can be co-administered with other known therapies, e.g., an anti-cancer therapy, e.g., radiation.
  • Such therapeutic agents include, among others, anti-neoplastic agents such as doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, dacarbazine and cyclophosphamide hydroxyurea which, by themselves, are only effective at levels which are toxic or subtoxic to a patient.
  • anti-neoplastic agents such as doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, dacarbazine and cyclophosphamide hydroxyurea which, by themselves, are only effective at levels which are toxic or subtoxic to a patient.
  • Cisplatin is intravenously administered as a 100 mg/ml dose once every four weeks and adriamycin is intravenously administered as a 60-75 mg/ml dose once every 21 days.
  • Co-administration of the human anti-LAG-3 antibodies, or antigen binding fragments thereof, of the present invention with chemotherapeutic agents provides two anti-cancer agents which operate via different mechanisms which yield a cytotoxic effect to human tumor cells. Such co-administration can solve problems due to development of resistance to drugs or a change in the antigenicity of the tumor cells which would render them unreactive with the antibody.
  • kits comprising the antibody compositions of the invention (e.g., human antibodies, bispecific or multispecific molecules, or immunoconjugates) and instructions for use.
  • the kit can further contain at least one additional reagent, or one or more additional human antibodies of the invention (e.g., a human antibody having a complementary activity which binds to an epitope in LAG-3 antigen distinct from the first human antibody).
  • Kits typically include a label indicating the intended use of the contents of the kit.
  • the term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit.
  • the invention provides methods of combination therapy in which an anti-LAG-3 antibody is coadministered with one or more additional antibodies that are effective in stimulating immune responses to thereby further enhance, stimulate or upregulate immune responses in a subject.
  • the invention provides a method for stimulating an immune response in a subject comprising administering to the subject an anti-LAG-3 antibody and one or more additional immunostimulatory antibodies, such as an anti-PD-1 antibody, an anti-PD-L1 antibody and/or an anti-CTLA-4 antibody, such that an immune response is stimulated in the subject, for example to inhibit tumor growth or to stimulate an anti-viral response.
  • the subject is administered an anti-LAG-3 antibody and an anti-PD-1 antibody.
  • the subject is administered an anti-LAG-3 antibody and an anti-PD-L1 antibody.
  • the subject is administered an anti-LAG-3 antibody and an anti-CTLA-4 antibody.
  • the anti-LAG-3 antibody is a human antibody, such as an antibody of the disclosure.
  • the anti-LAG-3 antibody can be, for example, a chimeric or humanized antibody (e.g., prepared from a mouse anti-LAG-3 mAb).
  • the at least one additional immunostimulatory antibody e.g., anti-PD-1, anti-PD-L1 and/or anti-CTLA-4 antibody
  • the at least one additional immunostimulatory antibody is a human antibody.
  • the at least one additional immunostimulatory antibody can be, for example, a chimeric or humanized antibody (e.g., prepared from a mouse anti-PD-1, anti-PD-L1 and/or anti-CTLA-4 antibody).
  • the present invention provides a method for treating a hyperproliferative disease (e.g., cancer), comprising administering a LAG-3 antibody and a CTLA-4 antibody to a subject.
  • a hyperproliferative disease e.g., cancer
  • the anti-LAG-3 antibody is administered at a subtherapeutic dose
  • the anti-CTLA-4 antibody is administered at a subtherapeutic dose
  • the present invention provides a method for altering an adverse event associated with treatment of a hyperproliferative disease with an immunostimulatory agent, comprising administering an anti-LAG-3 antibody and a subtherapeutic dose of anti-CTLA-4 antibody to a subject.
  • the subject is human.
  • the anti-CTLA-4 antibody is human sequence monoclonal antibody 10D1 (described in PCT Publication WO 01/14424) and the anti-LAG-3 antibody is human sequence monoclonal antibody, such as 25F7, 26H10, 25E3, 8B7, 11F2 or 17E5 described herein.
  • Other anti-CTLA-4 antibodies encompassed by the methods of the present invention include, for example, those disclosed in: WO 98/42752; WO 00/37504; U.S. Pat. No. 6,207,156; Hurwitz et al. (1998) Proc. Natl. Acad. Sci. USA 95(17):10067-10071; Camacho et al. (2004) J. Clin.
  • the anti-CTLA-4 antibody binds to human CTLA-4 with a K D of 5 ⁇ 10 ⁇ 8 M or less, binds to human CTLA-4 with a K D of 1 ⁇ 10 ⁇ 8 M or less, binds to human CTLA-4 with a K D of 5 ⁇ 10 ⁇ 9 M or less, or binds to human CTLA-4 with a K D of between 1 ⁇ 10 ⁇ 8 M and 1 ⁇ 10 ⁇ 10 M or less.
  • the present invention provides a method for treating a hyperproliferative disease (e.g., cancer), comprising administering a LAG-3 antibody and a PD-1 antibody to a subject.
  • a hyperproliferative disease e.g., cancer
  • the anti-LAG-3 antibody is administered at a subtherapeutic dose
  • the anti-PD-1 antibody is administered at a subtherapeutic dose
  • the present invention provides a method for altering an adverse event associated with treatment of a hyperproliferative disease with an immunostimulatory agent, comprising administering an anti-LAG-3 antibody and a subtherapeutic dose of anti-PD-1 antibody to a subject.
  • the subject is human.
  • the anti-PD-1 antibody is a human sequence monoclonal antibody and the anti-LAG-3 antibody is human sequence monoclonal antibody, such as 25F7, 26H10, 25E3, 8B7, 11F2 or 17E5 described herein.
  • human sequence anti-PD-1 antibodies include 17D8, 2D3, 4H1, 5C4 and 4A11, which are described in PCT Publication WO 06/121168.
  • the anti-PD-1 antibody binds to human PD-1 with a K D of 5 ⁇ 10 ⁇ 8 M or less, binds to human PD-1 with a K D of 1 ⁇ 10 ⁇ 8 M or less, binds to human PD-1 with a K D of 5 ⁇ 10 ⁇ 9 M or less, or binds to human PD-1 with a K D of between 1 ⁇ 10 ⁇ 8 M and 1 ⁇ 10 ⁇ 10 M or less.
  • the present invention provides a method for treating a hyperproliferative disease (e.g., cancer), comprising administering a LAG-3 antibody and a PD-L1 antibody to a subject.
  • a hyperproliferative disease e.g., cancer
  • the anti-LAG-3 antibody is administered at a subtherapeutic dose
  • the anti-PD-L1 antibody is administered at a subtherapeutic dose
  • the present invention provides a method for altering an adverse event associated with treatment of a hyperproliferative disease with an immunostimulatory agent, comprising administering an anti-LAG-3 antibody and a subtherapeutic dose of anti-PD-L1 antibody to a subject.
  • the subject is human.
  • the anti-PD-L1 antibody is a human sequence monoclonal antibody and the anti-LAG-3 antibody is human sequence monoclonal antibody, such as 25F7, 26H10, 25E3, 8B7, 11F2 or 17E5 described herein.
  • human sequence anti-PD-L1 antibodies include 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 and 13G4, which are described in PCT Publication WO 07/005874.
  • the anti-PD-L1 antibody binds to human PD-L1 with a K D of 5 ⁇ 10 ⁇ 8 M or less, binds to human PD-L1 with a K D of 1 ⁇ 10 ⁇ 8 M or less, binds to human PD-L1 with a K D of 5 ⁇ 10 ⁇ 9 M or less, or binds to human PD-L1 with a K D of between 1 ⁇ 10 ⁇ 8 M and 1 ⁇ 10 ⁇ 10 M or less.
  • Blockade of LAG-3 and one or more second target antigens such as CTLA-4 and/or PD-1 and/or PD-L1 by antibodies can enhance the immune response to cancerous cells in the patient.
  • Cancers whose growth may be inhibited using the antibodies of the instant disclosure include cancers typically responsive to immunotherapy.
  • Representative examples of cancers for treatment with the combination therapy of the instant disclosure include those cancers specifically listed above in the discussion of monotherapy with anti-LAG-3 antibodies.
  • the combination of therapeutic antibodies discussed herein can be administered concurrently as a single composition in a pharmaceutically acceptable carrier, or concurrently as separate compositions with each antibody in a pharmaceutically acceptable carrier.
  • the combination of therapeutic antibodies can be administered sequentially.
  • an anti-CTLA-4 antibody and an anti-LAG-3 antibody can be administered sequentially, such as anti-CTLA-4 antibody being administered first and anti-LAG-3 antibody second, or anti-LAG-3 antibody being administered first and anti-CTLA-4 antibody second.
  • an anti-PD-1 antibody and an anti-LAG-3 antibody can be administered sequentially, such as anti-PD-1 antibody being administered first and anti-LAG-3 antibody second, or anti-LAG-3 antibody being administered first and anti-PD-1 antibody second.
  • an anti-PD-L1 antibody and an anti-LAG-3 antibody can be administered sequentially, such as anti-PD-L1 antibody being administered first and anti-LAG-3 antibody second, or anti-LAG-3 antibody being administered first and anti-PD-L1 antibody second.
  • sequential administrations can be combined with concurrent administrations, or any combination thereof.
  • the first administration of a combination anti-CTLA-4 antibody and anti-LAG-3 antibody can be concurrent
  • the second administration can be sequential with anti-CTLA-4 first and anti-LAG-3 second
  • the third administration can be sequential with anti-LAG-3 first and anti-CTLA-4 second, etc.
  • the first administration of a combination anti-PD-1 antibody and anti-LAG-3 antibody can be concurrent, the second administration can be sequential with anti-PD-1 first and anti-LAG-3 second, and the third administration can be sequential with anti-LAG-3 first and anti-PD-1 second, etc.
  • the first administration of a combination anti-PD-L1 antibody and anti-LAG-3 antibody can be concurrent, the second administration can be sequential with anti-PD-L1 first and anti-LAG-3 second, and the third administration can be sequential with anti-LAG-3 first and anti-PD-L1 second, etc.
  • Another representative dosing scheme can involve a first administration that is sequential with anti-LAG-3 first and anti-CTLA-4 (and/or anti-PD-1 and/or anti-PD-L1) second, and subsequent administrations may be concurrent.
  • the combination of anti-LAG-3 and one or more additional antibodies can be further combined with an immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al. (2004) J. Immunol. 173:4919-28).
  • an immunogenic agent such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al. (2004) J. Immunol. 173:4919-28).
  • Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MART1 and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF (discussed further below).
  • a combined LAG-3 and CTLA-4 and/or PD-1 and/or PD-L1 blockade can be further combined with a vaccination protocol, such as any of the vaccination protocols discussed in detail above with respect to monotherapy with anti-LAG-3 antibodies.
  • a combined LAG-3 and CTLA-4 and/or PD-1 and/or PD-L1 blockade can also be further combined with standard cancer treatments.
  • a combined LAG-3 and CTLA-4 and/or PD-1 and/or PD-L1 blockade can be effectively combined with chemotherapeutic regimes.
  • it is possible to reduce the dose of other chemotherapeutic reagent administered with the combination of the instant disclosure Mokyr et al. (1998) Cancer Research 58: 5301-5304).
  • An example of such a combination is a combination of anti-LAG-3 and anti-CTLA-4 antibodies and/or anti-PD-1 antibodies and/or anti-PD-L1 antibodies further in combination with decarbazine for the treatment of melanoma.
  • Another example is a combination of anti-LAG-3 and anti-CTLA-4 antibodies and/or anti-PD-1 antibodies and/or anti-PD-L1 antibodies further in combination with interleukin-2 (IL-2) for the treatment of melanoma.
  • IL-2 interleukin-2
  • the scientific rationale behind the combined use of LAG-3 and CTLA-4 and/or PD-1 and/or PD-L1 blockade with chemotherapy is that cell death, which is a consequence of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigen in the antigen presentation pathway.
  • Other combination therapies that may result in synergy with a combined LAG-3 and CTLA-4 and/or PD-1 and/or PD-L1 blockade through cell death include radiation, surgery, or hormone deprivation.
  • Angiogenesis inhibitors can also be combined with a combined LAG-3 and CTLA-4 and/or PD-1 and/or PD-L1 blockade. Inhibition of angiogenesis leads to tumor cell death, which can be a source of tumor antigen fed into host antigen presentation pathways.
  • a combination of LAG-3 and CTLA-4 and/or PD-1 and/or PD-L1 blocking antibodies can also be used in combination with bispecific antibodies that target Fc ⁇ or Fc ⁇ receptor-expressing effector cells to tumor cells (see, e.g., U.S. Pat. Nos. 5,922,845 and 5,837,243).
  • Bispecific antibodies can be used to target two separate antigens. The T cell arm of these responses would be augmented by the use of a combined LAG-3 and CTLA-4 and/or PD-1 and/or PD-L1 blockade.
  • anti-neoplastic antibodies such as Rituxan® (rituximab), Herceptin® (trastuzumab), Bexxar® (tositumomab), Zevalin® (ibritumomab), Campath® (alemtuzumab), Lymphocide® (eprtuzumab), Avastin® (bevacizumab), and Tarceva® (erlotinib), and the like.
  • a treatment of a hyperproliferative disease can include an anti-cancer antibody in combination with anti-LAG-3 and anti-CTLA-4 and/or anti-PD-1 and/or anti-PD-L1 antibodies, concurrently or sequentially or any combination thereof, which can potentiate an anti-tumor immune responses by the host.
  • Tumors evade host immune surveillance by a large variety of mechanisms. Many of these mechanisms may be overcome by the inactivation of proteins, which are expressed by the tumors and which are immunosuppressive. These include, among others, TGF- ⁇ (Kehrl et al. (1986) J. Exp. Med. 163: 1037-1050), IL-10 (Howard & O'Garra (1992) Immunology Today 13: 198-200), and Fas ligand (Hahne et al. (1996) Science 274: 1363-1365).
  • antibodies to each of these entities can be further combined with an anti-LAG-3 and anti-CTLA-4 and/or anti-PD-1 and/or anti-PD-L1 antibody combination to counteract the effects of immunosuppressive agents and favor anti-tumor immune responses by the host.
  • Anti-CD40 antibodies can be used in conjunction with an anti-LAG-3 and anti-CTLA-4 and/or anti-PD-1 and/or anti-PD-L1 combination (Ito et al., supra).
  • Other activating antibodies to T cell costimulatory molecules Weinberg et al., supra, Melero et al. supra, Hutloff et al., supra) may also provide for increased levels of T cell activation.
  • a combined LAG-3 and CTLA-4 and/or PD-1 and/or PD-L1 blockade can be used to increase the effectiveness of the donor engrafted tumor specific T cells.
  • the present invention provides a method for altering an adverse event associated with treatment of a hyperproliferative disease (e.g., cancer) with an immunostimulatory agent, comprising administering a anti-LAG-3 antibody and a subtherapeutic dose of anti-CTLA-4 and/or anti-PD-1 and/or anti-PD-L1 antibody to a subject.
  • a hyperproliferative disease e.g., cancer
  • the methods of the present invention provide for a method of reducing the incidence of immunostimulatory therapeutic antibody-induced colitis or diarrhea by administering a non-absorbable steroid to the patient. Because any patient who will receive an immunostimulatory therapeutic antibody is at risk for developing colitis or diarrhea induced by such an antibody, this entire patient population is suitable for therapy according to the methods of the present invention.
  • steroids have been administered to treat inflammatory bowel disease (IBD) and prevent exacerbations of IBD, they have not been used to prevent (decrease the incidence of) IBD in patients who have not been diagnosed with IBD.
  • IBD inflammatory bowel disease
  • a combination LAG-3 and CTLA-4 and/or PD-1 and/or PD-L1 blockade i.e., immunostimulatory therapeutic antibodies anti-LAG-3 and anti-CTLA-4 and/or anti-PD-1 antibodies and/or anti-PD-L1 antibodies
  • a “non-absorbable steroid” is a glucocorticoid that exhibits extensive first pass metabolism such that, following metabolism in the liver, the bioavailability of the steroid is low, i.e., less than about 20%.
  • the non-absorbable steroid is budesonide.
  • Budesonide is a locally-acting glucocorticosteroid, which is extensively metabolized, primarily by the liver, following oral administration.
  • ENTOCORT EC® (Astra-Zeneca) is a pH- and time-dependent oral formulation of budesonide developed to optimize drug delivery to the ileum and throughout the colon.
  • ENTOCORT EC® is approved in the U.S. for the treatment of mild to moderate Crohn's disease involving the ileum and/or ascending colon.
  • the usual oral dosage of ENTOCORT EC® for the treatment of Crohn's disease is 6 to 9 mg/day.
  • ENTOCORT EC® is released in the intestines before being absorbed and retained in the gut mucosa.
  • ENTOCORT EC® is extensively metabolized by the cytochrome P450 system in the liver to metabolites with negligible glucocorticoid activity. Therefore, the bioavailability is low (about 10%).
  • the low bioavailability of budesonide results in an improved therapeutic ratio compared to other glucocorticoids with less extensive first-pass metabolism.
  • Budesonide results in fewer adverse effects, including less hypothalamic-pituitary suppression, than systemically-acting corticosteroids.
  • chronic administration of ENTOCORT EC® can result in systemic glucocorticoid effects such as hypercorticism and adrenal suppression. See PDR 58 th ed. 2004; 608-610.
  • a combination LAG-3 and CTLA-4 and/or PD-1 and/or PD-L1 blockade i.e., immunostimulatory therapeutic antibodies anti-LAG-3 and anti-CTLA-4 and/or anti-PD-1 and/or anti-PD-L1 antibodies
  • a non-absorbable steroid in conjunction with a non-absorbable steroid can be further combined with a salicylate.
  • Salicylates include 5-ASA agents such as, for example: sulfasalazine (AZULFIDINE®, Pharmacia & UpJohn); olsalazine (DIPENTUM®, Pharmacia & UpJohn); balsalazide (COLAZAL®, Salix Pharmaceuticals, Inc.); and mesalamine (ASACOL®, Procter & Gamble Pharmaceuticals; PENTASA®, Shire US; CANASA®, Axcan Scandipharm, Inc.; ROWASA®, Solvay).
  • 5-ASA agents such as, for example: sulfasalazine (AZULFIDINE®, Pharmacia & UpJohn); olsalazine (DIPENTUM®, Pharmacia & UpJohn); balsalazide (COLAZAL®, Salix Pharmaceuticals, Inc.); and mesalamine (ASACOL®, Procter & Gamble Pharmaceuticals; PENTASA®, Shire US; CANASA®, Axcan Scandipharm
  • a salicylate administered in combination with anti-LAG-3 and anti-CTLA-4 and/or anti-PD-1 and/or anti-PD-L1 antibodies and a non-absorbable steroid can includes any overlapping or sequential administration of the salicylate and the non-absorbable steroid for the purpose of decreasing the incidence of colitis induced by the immunostimulatory antibodies.
  • methods for reducing the incidence of colitis induced by the immunostimulatory antibodies according to the present invention encompass administering a salicylate and a non-absorbable concurrently or sequentially (e.g., a salicylate is administered 6 hours after a non-absorbable steroid), or any combination thereof.
  • a salicylate and a non-absorbable steroid can be administered by the same route (e.g., both are administered orally) or by different routes (e.g., a salicylate is administered orally and a non-absorbable steroid is administered rectally), which may differ from the route(s) used to administer the anti-LAG-3 and anti-CTLA-4 and/or anti-PD-1 and/or anti-PD-L1 antibodies.
  • Anti-LAG-3 human monoclonal antibodies were generated using transgenic mice that express human antibody genes, as follows.
  • Recombinant human LAG-3 fusion proteins were used as the immunogen to raise anti-human LAG-3 antibodies.
  • a fusion protein comprising the entire extracellular region (domains 1-4) of human LAG-3 fused to a human immunoglobulin Fc domain (R&D Systems, Catalog #2319-L3) (D1-D4 hFc) or a mouse immunoglobulin Fc domain (D1-D4 mFc) was used as the immunogen.
  • a fusion protein comprising only the first two extracellular domains of human LAG-3 fused to a mouse immunoglobulin Fc domain (D1-D2 mFc) was used as the immunogen.
  • the LAG-3 fusion proteins were prepared using standard recombinant DNA techniques.
  • Fully human monoclonal antibodies to human LAG-3 were prepared using mice of the transgenic transchromosomic KM MouseTM and KM/FCGR2D MouseTM strains, which expresses human antibody genes.
  • the endogenous mouse kappa light chain gene has been homozygously disrupted as described in Chen et al. (1993) EMBO J. 12:811-820 and the endogenous mouse heavy chain gene has been homozygously disrupted as described in Example 1 of PCT Publication WO 01/09187.
  • this mouse strain carries a human kappa light chain transgene, KCo5, as described in Fishwild et al., supra.
  • the strain also contains the SC20 transchromosome, which carries the human Ig heavy chain locus, as described in PCT Publication WO 02/43478.
  • the KM/FCGR2D MouseTM strain is the same as the KM MouseTM strain except that its genome also comprises a homozygous disruption of the endogenous Fc ⁇ RIIB gene.
  • the KM MouseTM and KM/FCGR2D MouseTM strains are also described in detail in U.S. Application Publication No. 20020199213.
  • mice of the KM MouseTM and KM/FCGR2D MouseTM strains were immunized with one of the three different recombinant LAG-3 fusion protein described above (D1-D4 hFc, D1-D4 mFc, D1-D2, mFc).
  • LAG-3 fusion protein described above
  • General immunization schemes are described in Lonberg et al. (1994) supra; Fishwild et al., supra and PCT Publication WO 98/24884.
  • the mice were 6-16 weeks of age upon the first infusion of antigen. Mice were immunized intraperitoneally (IP) and/or subcutaneously (SC).
  • mice were immunized biweekly four times with 10 ⁇ g of the recombinant LAG-3 fusion protein, followed by immunization twice with 20 ⁇ g of the same immunogen in Ribi as an adjuvant.
  • the immune response was monitored by retroorbital bleeds.
  • the plasma was screened by ELISA (as described below), and mice with sufficient titers of anti-LAG-3 human immunoglobulin were used for fusions.
  • the mice Prior to sacrifice and removal of the spleens, the mice were boosted intravenously and intraperitoneally with 20 ⁇ g of antigen followed by a subsequent intravenous boost with 20 ⁇ g of antigen.
  • mice producing antibodies that bound LAG-3 protein were tested by a modified ELISA as originally described by Fishwild et al. (1996). Briefly, microtiter plates were coated with purified recombinant LAG-3 fusion protein at 1 ⁇ g/ml in PBS, 50 ⁇ wells incubated 4° C. overnight, then blocked with 200 ⁇ l/well of 5% BSA in PBS. Dilutions of plasma from LAG-3-immunized mice were added to each well and incubated for 1-2 hours at ambient temperature.
  • the plates were washed with PBS/Tween and then incubated with a goat-anti-human kappa light chain polyclonal antibody conjugated with Horse Radish Peroxidase (HRP) for 1 hour at room temperature. After washing, the plates were developed with ABTS substrate and analyzed by spectrophotometer at OD 405.
  • HRP Horse Radish Peroxidase
  • mice immunized with the D1-D4 mFc or D1-D2 mFc fusion proteins sera from these mice with were tested by indirect ELISA using goat anti-mouse IgG to coat the plates for one hour prior to coating with the antigen to eliminate nonspecific binding to the mouse Fc part. Then the same ELISA steps as described above were carried out.
  • mice that developed the highest titers of anti-LAG-3 antibodies were used for fusions. Fusions were performed as described below and hybridoma supernatants were tested for anti-LAG-3 activity by ELISA.
  • mice The mouse splenocytes, isolated from the KM or KM/FCGR2D mice, were fused by electric field based electrofusion using a Cyto Pulse large chamber cull fusion electroporator (Cyto Pulse Sciences, Inc., Glen Burnie, Md.) to a mouse myeloma cell line. The resulting hybridomas were then screened for the production of antigen-specific antibodies. Single cell suspensions of splenic lymphocytes from immunized mice were fused to one-fourth the number of P3 ⁇ 63 Ag8.6.53 (ATCC CRL 1580) nonsecreting mouse myeloma cells.
  • Cells were plated at approximately 1 ⁇ 10 5 /well in flat bottom microtiter plate, followed by about two week incubation in selective medium containing 10% fetal calf serum, supplemented with origen (IGEN) in RPMI, L-glutamine, sodium pyruvate, HEPES, penicillin, streptamycin, gentamycin, 1 ⁇ HAT, and ⁇ -mercaptoethanol. After 1-2 weeks, cells were cultured in medium in which the HAT was replaced with HT. Individual wells were then screened by ELISA (described above) for human anti-LAG-3 monoclonal IgG antibodies. Once extensive hybridoma growth occurred, medium was monitored usually after 10-14 days.
  • IGEN origen
  • the antibody secreting hybridomas were replated, screened again and, if still positive for human IgG, anti-LAG-3 monoclonal antibodies were subcloned at least twice by limiting dilution. The stable subclones were then cultured in vitro to generate small amounts of antibody in tissue culture medium for further characterization.
  • Hybridoma clones 25F7, 26H10, 25E3, 8B7, 11F2 and 17E5 were selected for further analysis and sequencing.
  • V-regions of each antibody were amplified using a 3′ human-specific constant region primer, paired with the 5′ RACE universal primer mix.
  • PCR products containing the V-region were cloned into the pCR4-TOPO vector (Invitrogen, Carlsbad, Calif.) and transformed into E. coli strain TOP10 (Invitrogen, Carlsbad, Calif.).
  • Either miniprep DNA or Templiphi GE Healthcare Biosciences, Piscataway, N.J., USA
  • samples were prepared, and subjected to DNA sequencing (Sequetech, Mountain View, Calif.). The resultant DNA sequences were analyzed for in-frame rearrangements and other antibody characteristics.
  • the expressed proteins were characterized by standard protein chemistry analysis.
  • the 25E3, 25F7 and 26H10 clones were found to express an antibody comprising an IgG1 heavy chain and a kappa light chain, whereas the 8B7 and 17E5 clones were found to express an antibody comprising an IgG4 heavy chain and a kappa light chain and the 11F2 clone was found to express an antibody comprising an IgG2 heavy chain and a kappa light chain.
  • the nucleotide and amino acid sequences of the heavy chain variable region of 25F7 are shown in FIG. 1A and in SEQ ID NO: 49 and 37, respectively.
  • the nucleotide and amino acid sequences of the kappa light chain variable region of 25F7 are shown in FIG. 1B and in SEQ ID NO: 55 and 43, respectively.
  • Comparison of the 25F7 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences ( FIG. 7 ) showed that the 25F7 heavy chain utilizes a V H segment from human germline V H 4-34 (SEQ ID NO:61), and a JH segment from human germline JH5b (SEQ ID NO:62).
  • the nucleotide and amino acid sequences of the heavy chain variable region of 26H10 are shown in FIG. 2A and in SEQ ID NO: 50 and 38, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 26H10 are shown in FIG. 2B and in SEQ ID NO: 56 and 44, respectively.
  • Comparison of the 26H10 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences ( FIG. 9 ) showed that the 26H10 heavy chain utilizes a V H segment from human germline V H 3-33 (SEQ ID NO:65), and a JH segment from human germline JH 6B (SEQ ID NO:66).
  • the nucleotide and amino acid sequences of the heavy chain variable region of 25E3 are shown in FIG. 3A and in SEQ ID NO: 51 and 39, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 25E3 are shown in FIG. 3B and in SEQ ID NO: 57 and 45, respectively.
  • Comparison of the 25E3 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences ( FIG. 11 ) showed that the 25E3 heavy chain utilizes a V H segment from human germline V H 3-20 (SEQ ID NO:69), and a JH segment from human germline JH 4b (SEQ ID NO:70).
  • the nucleotide and amino acid sequences of the heavy chain variable region of 8B7 are shown in FIG. 4A and in SEQ ID NO: 52 and 40, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 8B7 are shown in FIG. 4B and in SEQ ID NO: 58 and 46, respectively.
  • Comparison of the 8B7 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences ( FIG. 13 ) showed that the 8B7 heavy chain utilizes a V H segment from human germline V H 4-34 (SEQ ID NO:61), and a JH segment from human germline JH 5B (SEQ ID NO:62).
  • the nucleotide and amino acid sequences of the heavy chain variable region of 11F2 are shown in FIG. 5A and in SEQ ID NO: 53 and 41, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 11F2 are shown in FIG. 5B and in SEQ ID NO: 59 and 47, respectively.
  • Comparison of the 11F2 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences ( FIG. 15 ) showed that the 11F2 heavy chain utilizes a V H segment from human germline V H 1-24 (SEQ ID NO:73), a D segment from the human germline 2-15, and a JH segment from human germline JH 4B (SEQ ID NO:70).
  • the nucleotide and amino acid sequences of the heavy chain variable region of 17E5 are shown in FIG. 6A and in SEQ ID NO: 54 and 42, respectively.
  • the nucleotide and amino acid sequences of the light chain variable region of 17E5 are shown in FIG. 6B and in SEQ ID NO: 60 and 48, respectively.
  • Comparison of the 17E5 heavy chain immunoglobulin sequence to the known human germline immunoglobulin heavy chain sequences ( FIG. 17 ) showed that the 17E5 heavy chain utilizes a V H segment from human germline V H 3-33 (SEQ ID NO:65), a D segment from the human germline 2-2, and a JH segment from human germline JH 4B (SEQ ID NO:70).
  • the 25F7, 26H10, 25E3, 8B7, 11F2 and 17E5 variable regions can be converted to full-length antibodies of any desired isotype using standard recombinant DNA techniques.
  • DNA encoding the V H and V L regions can be cloned into an expression vector that carries the heavy and light chain constant regions such that the variable regions are operatively linked to the constant regions.
  • separate vectors can be used for expression of the full-length heavy chain and the full-length light chain.
  • Non-limiting examples of expression vectors suitable for use in creating full-length antibodies include the pIE vectors described in U.S. Patent Publication No. 20050153394.
  • LAG-3 human, monkey and mouse LAG-3
  • flow cytometry Furthermore, binding kinetics to LAG-3 were analyzed by BIACORE analysis. Still further epitope mapping was conducted using a peptide scan experiment.
  • the antibodies were incubated with a CHO cell line that had been transfected to express human LAG-3 on the cell surface.
  • the 25F7, 26H10, 25E3, 8B7, 11F2 and 17E5 monoclonal antibodies were serially diluted with cold 1 ⁇ PFAE buffer (1 ⁇ PBS+2% FBS, 0.02% sodium azide, 2mM Na EDTA).
  • 1 ⁇ PFAE buffer 1 ⁇ PBS+2% FBS, 0.02% sodium azide, 2mM Na EDTA.
  • 50 ⁇ l of diluted antibody solution was added to a 50 ⁇ l cell suspension containing 2 ⁇ 10 5 cells and the mixture was incubated on ice for 30 minutes. The cells were then washed two times with 1 ⁇ PFAE buffer.
  • FITC-labeled goat anti-human kappa light chain antibody (Bethyl Laboratories, Inc., Cat. #A80-115F) was added and the mixture was incubated for 30 minutes at 4° C., followed by washing twice with cold 1 ⁇ PFAE buffer. After the final wash, 150 ⁇ l of cold 1 ⁇ PFAE containing 10 ⁇ g/mL propidium iodide (Roche Applied Science, Cat #1 — 348 — 639) was added to each solution and analysis of antibody binding was carried out by flow cytometry using a FACScalibur flow cytometer (BD Bioscience).
  • CD4 + T cells were isolated from purified peripheral blood mononuclear cells and subjected to three days of stimulation with a combination of anti-CD3 and anti-CD28 antibodies affixed to polystyrene beads.
  • the 25F7, 8B7 and 26H10 monoclonal antibodies were serially diluted with cold 1 ⁇ PFAE buffer (1 ⁇ PBS+2% FBS, 0.02% sodium azide, 2 mM Na EDTA).
  • 50 ⁇ l of diluted antibody solution was mixed with 50 ⁇ l of PE-labeled anti-human CD4 (BD Bioscience, Cat # 555347).
  • Activated T cells were processed by the same protocol described above. The analysis of antibody binding was conducted as described above.
  • a cDNA sequence was cloned by RT-PCR from a preparation of pooled cDNA prepared by reverse transcription of RNAs from a collection of cynomolgus and rhesus monkey tissue samples.
  • the sequence was first amplified from the cDNA pool using primers (5′ forward primer: 5Mcyn1408; 5′-atgtgggaggctcagttcctg-3′ (SEQ ID NO: 91) & 3′ reverse primer: 3Mcyn1408a; 5′-gtcagagctgctccggctc-3′ (SEQ ID NO: 92)) using a GC-rich PCR amplification system (Roche) and was cloned into a recipient TOPO cloning vector (Invitrogen) for sequence analysis.
  • Clones matching the reference Genbank rhesus monkey LAG-3 sequence (Genbank Accession No. XM — 001108923) were subsequently re-amplified from the TOPO-cloning vector DNA utilizing a second set of primers that incorporated restriction enzyme sites for directional cloning in a mammalian cell expression vector.
  • Monkey LAG-3 clone pa23-5 was isolated and sequenced. The isolated monkey sequence exhibited 99.6% identity to the reference Genbank rhesus monkey LAG-3 sequence.
  • a comparison of the amino acid sequence of cDNA clone pa23-3 (SEQ ID NO: 93) with rhesus monkey LAG-3 (SEQ ID NO: 94) from Genbank (Accession No. XM — 001108923) is shown in FIG. 19 .
  • cDNA clone pa23-5 represents the rhesus LAG-3 gene sequence.
  • the cDNA of clone pa23-5 was inserted into an expression construct, which was transfected into CHO-S suspension cells by nucleofection (Amaxa). Rhesus LAG-3 expression by sorted, selection drug-resistant clones was verified by FACS analysis. This clonal CHO cell line over-expressing rhesus LAG-3 was used in similar FACS assays to those described above to measure antibody cross reactivity to the monkey protein. Briefly, the 25F7, 8B7 and 26H10 monoclonal antibodies were serially diluted with cold 1 ⁇ PFAE buffer (1 ⁇ PBS+2% FBS, 0.02% sodium azide, 2 mM Na EDTA).
  • the antibodies were tested for binding to cynomolgus monkey LAG-3 using activated cynomolgus monkey T cells.
  • In vitro activation of these monkey T cells was achieved through anti-CD3/anti-CD28 treatment of the T cells by essentially the same protocol described above for the in vitro activation of human T cells, followed by flow cytometry analysis performed as described above for staining of in vitro activated human CD4 + T cells.
  • mice T cell hybridoma cell line (3A9) that had been transfected to express mouse LAG-3 on its cell surface, followed by FACS analysis to detect antibody binding.
  • the binding of the 25E3, 25F7, 8B7, 26H10 and 17E5 antibodies to recombinant LAG-3 protein was examined by BIAcoreTM using a capture method.
  • the 25E3, 25F7, 8B7, 26H10 and 17E5 antibodies each were captured using anti-CH1, a reagent antibody that is specific towards the heavy chain constant region 1 of human antibody (Zymed, Clone HP6045, Stock conc. 1.0 mg/mL).
  • Anti-CH1 was coated on a CM5 chip (BR-1000-14, Research Grade) at high density (9700-11500RUs). The coating was carried out based on the standard immobilization procedure recommended by the manufacturer.
  • the antigen was allowed to dissociate for 7.5 minutes.
  • the chip surface was regenerated after each cycle with 25 ⁇ L of 25 mM NaOH followed by 30 ⁇ L of HBS-EP wash. Isotype controls were run on the chip, and the data used to subtract non-specific binding.
  • the immunoglobulin-like first domain of the extracellular region contains an exposed “extra loop” having the amino acid sequence: GPPAAAPGHPLAPGPHPAAPSSWGPRPRRY (SEQ ID NO: 79).
  • extra loop having the amino acid sequence: GPPAAAPGHPLAPGPHPAAPSSWGPRPRRY (SEQ ID NO: 79).
  • microtiter plates pre-coated with streptavidin (Sigma-Aldrich, Cat # M5432) were used to capture the biotinylated loop peptide-conjugates applied in a 100 ⁇ l volume at a concentration of 2 ⁇ g/mL and incubated 18 hours at 4° C., after which the plates were washed 3 times and blocked at room temperature for 1 hour with blocking buffer (1 ⁇ PBS+10% FBS).
  • human anti-LAG-3 antibodies serially diluted 3-fold in blocking buffer from 10 ⁇ g/mL were applied and the plates were incubated at room temperature for 2 hours and then washed three times.
  • HRP-conjugated goat anti-human kappa light chain antibody (Bethyl Laboratories, Cat #A80-115P) was diluted to 1 ⁇ g/mL in blocking buffer and applied to assay wells for 1 hour followed by three washes and application of TMB substrate (eBioscience, Cat #00-4201-56). Optical density readings at 650 nm wavelength were made on a Spectramax 340PC spectrophotometer (Molecular Dynamics, Inc.). The results of the peptide scan experiment are summarized below in Table 5.
  • the peptide scan results indicate that the 25E3, 25F7 and 8B7 antibodies bind to different although closely located epitopes within human LAG-3.
  • antibodies 25E3, 25F7 and 8B7 are capable of recognizing the human LAG-3 extra loop peptide region. Moreover, antibodies 25F7 and 8B7 also bind to the rhesus LAG-3 extra loop peptide region, albeit less well compared to the human sequence, which may be due to the species sequence divergence in this polypeptide. The results also confirm that the 26H10 antibody is not capable of recognizing the LAG-3 extra loop peptide.
  • LAG-3 fusion protein comprising human LAG-3 extracellar domain fused to mouse Fc (hLAG-3-mlg)
  • Daudi cells which express human MHC Class II molecules.
  • 25E3, 25F7, 8B7 and 26H10 were serially diluted from 20 ⁇ g/mL in PFAE buffer and to these serial dilutions was added 1 ⁇ g/ml of hLAG-3-mlg fusion protein. This mixture was incubated for 20 minutes at room temperature prior to adding to 2 ⁇ 10 5 1 ⁇ PFAE-washed Daudi cells. The mixture was applied to Daudi cells and incubated at 4° C. for 30 minutes.
  • the cells were pelleted (three minutes, 400 ⁇ g), washed once with 1 ⁇ PFAE buffer and re-pelleted, and binding of hLAG-3-mlg to the Daudi cells was detected using a recombinant PE-labeled anti-mIgG Fc ⁇ secondary reagent. Analysis of LAG-3-mIg binding was carried out with the FACScalibur flow cytometer (BD Bioscience). The results are summarized in Table 7 below, which shows IC 50 values in nM.
  • a mouse T cell hybridoma, 3A9, specific for the peptide HEL 48-62 was used as the responder T cell.
  • the responder 3A9 T cell was retrovirally transduced to express either human LAG-3 or mouse LAG-3 on its cell surface.
  • the antigen presenting cell (APC) used to present the HEL 48-62 peptide antigen to the 3A9 cells was the mouse MHC Class II positive cell line LK35.2.
  • IL-2 interleukin-2
  • ELISA mouse IL-2 OptEIA kit, BD Bioscience, Cat #555148 according to manufacturer's recommendations.
  • the APC (2.5 ⁇ 10 4 cells) was first preincubated with the antigenic peptide (200 nM) for 30 minutes at 37° C. and the 3A9 T cells (5.0 ⁇ 10 4 cells expressing either mLAG-3, hLAG-3 or control cells) were preincubated with an anti-hLAG-3 antibody (25E3, 25F7, 8B7, 26H10, 11F2, 17E5), serially diluted in three fold dilution from 25 ⁇ g/mL) for 15 minutes at 37° C. The 3A9 T cells were then added to the antigen-pulsed APCs and the culture incubated for 24 hours at 37° C. The supernatants were then harvested and measured for production of mouse IL-2. The results for the 3A9 T cells expressing human LAG-3 are in Table 8, which shows IC 50 values in nM.
  • the first model used murine Sa1N fibrosarcoma cells.
  • the second model used the murine MC38 colon cancer cell line.
  • mice (A/J strain) were each implanted with 2 ⁇ 10 6 Sa1N fibrosarcoma cells on day 0 and the tumor cells were allowed to grow for seven days.
  • the mice On day 7, day 10 and day 12 post-implantation, the mice were treated with 10 mg/kg of either an anti-LAG-3 mAb alone (the rat anti-mouse LAG-3 mAb C9B7W; eBioscience, Cat. No. 14-2231), an anti-PD-L1 antibody alone (an anti-mouse PD-L1 mAb 14D8), the anti-LAG-3 and anti-PD-L1 antibodies in combination, or an IgG1 isotype control antibody.
  • the 14D8 mAb is a rat anti-mouse PD-L1 antibody that has been chimerized to contain the mouse IgG1 and mouse kappa constant regions.
  • mice Tumor volumes in the mice were measured for over 50 days post-implantation and mean and median tumor volumes were determined. Mean tumor growth inhibition was calculated (based on treatment with the isotype control IgG1 antibody being 0% inhibition). The results for day 24 post-implantation are summarized below in Table 9:
  • anti-LAG3 antibody alone, or anti-PD-L1 antibody treatment alone resulted in tumor growth inhibition, while the combination of both antibodies led to even greater tumor growth inhibition.
  • the results were that 4 of 10 mice treated with anti-LAG3 alone became tumor free, whereas only 1 of 10 mice treated with the control IgG1 antibody became tumor free.
  • 4 of 11 mice treated with anti-PD-L1 alone were rendered tumor free.
  • Treatment of mice with the combination of anti-LAG3 and anti-PD-L1 resulted in 9 of 10 mice becoming tumor free; the remaining mouse not tumor free had an indolent tumor that remained small throughout the study.
  • mice implanted with cells of the murine MC38 colon cancer cell line Two additional studies used mice implanted with cells of the murine MC38 colon cancer cell line.
  • C57B1/6 mice were each implanted with 2 ⁇ 10 6 MC38 cells on day 0, and were treated on day 7, day 10 and day 12 post-implantation with 200 ⁇ g/dose of anti-LAG-3 alone (C9B7W mAb), anti-PD-1 alone (the 4H2 mAb) or anti-LAG-3 and anti-PD-1 in combination.
  • the 4H2 mAb is a rat anti-mouse PD-1 antibody that has been chimerized to contain the mouse IgG1 and mouse kappa constant regions.
  • C57B1/6 mice were each implanted with 2 ⁇ 10 6 MC38 cells on day 0, and were treated on day 5, day 8 and day 11 post-implantation with 200 ⁇ g/dose of test antibody and/or 400 ⁇ g/dose control IgG antibody, as follows: (i) an anti-IgG1 control antibody; (ii) an anti-LAG-3 mAb (C9B7W mAb) together with the control IgG1; (iii) an anti-PD-1 antibody (4H2) together with the control IgG1; (iv) an anti-CTLA-4 antibody (the 9D9 mouse anti-mouse CTLA-4 mAb) together with the control IgG1; (v) the anti-LAG-3 mAb together with the anti-PD-1 mAb; or (vi) the anti-LAG-3 mAb together with the anti-CTLA-4 mAb.
  • the 9D9 mAb is a mouse anti-mouse CTLA-4 antibody that was raised in
  • mice treated with the combination of anti-LAG-3 and anti-CTLA-4 3 of 10 mice were tumor free at the end of the experiment and for the mice treated with the combination of anti-LAG-3 and anti-PD-1, 8 of 10 mice were tumor free at the end of the experiment.
  • NOD mice are known to be prone to developing autoimmune diabetes. Progression of diabetes can be followed in female NOD mice by measuring serum glucose. Thus, the effect of anti-LAG-3 treatment, alone or in combination with either immunostimulatory antibodies, on the development of diabetes in female NOD mice was examined.
  • mice Female NOD mice were treated on day 0, day 2 and day 5 with 250 ⁇ g/dose of either: (i) an IgG1 isotype control antibody; (ii) anti-LAG-3 mAb alone (C9B7W mAb); (iii) anti-PD-1 mAb alone (4H2 mAb); (iv) anti-CTLA-4 mAb alone (9D9 mAb); (v) anti-LAG-3 mAb together with anti-PD-1 mAb; or (vi) anti-LAG-3 mAb together with anti-CTLA-4.
  • the results demonstrated with anti-LAG-3 treatment alone or anti-PD-1 treatment alone (but not anti-CTLA-4 treatment alone) increased the number of mice converting to the diabetic phenotype.
  • the combination treatment of anti-LAG-3 plus anti-PD-1, or anti-LAG-3 plus anti-CTLA-4 was even more effective in converting mice to the diabetic phenotype.
  • fluorescently-labeled anti-LAG-3 human antibodies were used in immunohistochemistry experiments.
  • LAG-3 transfected CHO cells also were used as a control. Acetone-fixed cryostat sections were used.
  • the sections were stained with FITC-labeled anti-LAG-3 antibody (0.2-5 ⁇ g/ml), followed by staining with a rabbit anti-FITC antibody as a bridge antibody and then visualization using the rabbit EnVisionTM+System Kit (Dako USA, Carpinteria, Calif.). The results are summarized below in Table 10.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Hematology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
US13/058,492 2008-08-11 2009-08-11 Human antibodies that bind lymphocyte activation gene-3 (lag-3) and uses thereof Abandoned US20110150892A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/058,492 US20110150892A1 (en) 2008-08-11 2009-08-11 Human antibodies that bind lymphocyte activation gene-3 (lag-3) and uses thereof

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US18854808P 2008-08-11 2008-08-11
US13/058,492 US20110150892A1 (en) 2008-08-11 2009-08-11 Human antibodies that bind lymphocyte activation gene-3 (lag-3) and uses thereof
PCT/US2009/053405 WO2010019570A2 (en) 2008-08-11 2009-08-11 Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/053405 A-371-Of-International WO2010019570A2 (en) 2008-08-11 2009-08-11 Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US15/730,363 Division US10344089B2 (en) 2008-08-11 2017-10-11 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US16/722,296 Continuation US20200231671A1 (en) 2008-08-11 2019-12-20 Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof

Publications (1)

Publication Number Publication Date
US20110150892A1 true US20110150892A1 (en) 2011-06-23

Family

ID=41669613

Family Applications (13)

Application Number Title Priority Date Filing Date
US13/058,492 Abandoned US20110150892A1 (en) 2008-08-11 2009-08-11 Human antibodies that bind lymphocyte activation gene-3 (lag-3) and uses thereof
US15/730,363 Active US10344089B2 (en) 2008-08-11 2017-10-11 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US16/419,940 Abandoned US20190276539A1 (en) 2008-08-11 2019-05-22 Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
US16/419,938 Active US10988535B2 (en) 2008-08-11 2019-05-22 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US16/722,296 Abandoned US20200231671A1 (en) 2008-08-11 2019-12-20 Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
US16/999,488 Active US11001630B2 (en) 2008-08-11 2020-08-21 Human antibodies that bind lymphocyte activation Gene-3 (LAG-3), and uses thereof
US16/999,463 Active US10988536B2 (en) 2008-08-11 2020-08-21 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US17/226,595 Active US11236163B2 (en) 2008-08-11 2021-04-09 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US17/226,624 Active US11236165B2 (en) 2008-08-11 2021-04-09 Human antibodies that bind Lymphocyte Activation Gene-3 (LAG-3), and uses thereof
US17/226,609 Active US11236164B2 (en) 2008-08-11 2021-04-09 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US17/544,534 Active US11530267B2 (en) 2008-08-11 2021-12-07 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US17/544,542 Active US11512130B2 (en) 2008-08-11 2021-12-07 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US18/050,336 Pending US20230322919A1 (en) 2008-08-11 2022-10-27 Human Antibodies that Bind Lymphocyte Activation Gene-3 (LAG-3), and Uses Thereof

Family Applications After (12)

Application Number Title Priority Date Filing Date
US15/730,363 Active US10344089B2 (en) 2008-08-11 2017-10-11 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US16/419,940 Abandoned US20190276539A1 (en) 2008-08-11 2019-05-22 Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
US16/419,938 Active US10988535B2 (en) 2008-08-11 2019-05-22 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US16/722,296 Abandoned US20200231671A1 (en) 2008-08-11 2019-12-20 Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
US16/999,488 Active US11001630B2 (en) 2008-08-11 2020-08-21 Human antibodies that bind lymphocyte activation Gene-3 (LAG-3), and uses thereof
US16/999,463 Active US10988536B2 (en) 2008-08-11 2020-08-21 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US17/226,595 Active US11236163B2 (en) 2008-08-11 2021-04-09 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US17/226,624 Active US11236165B2 (en) 2008-08-11 2021-04-09 Human antibodies that bind Lymphocyte Activation Gene-3 (LAG-3), and uses thereof
US17/226,609 Active US11236164B2 (en) 2008-08-11 2021-04-09 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US17/544,534 Active US11530267B2 (en) 2008-08-11 2021-12-07 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US17/544,542 Active US11512130B2 (en) 2008-08-11 2021-12-07 Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US18/050,336 Pending US20230322919A1 (en) 2008-08-11 2022-10-27 Human Antibodies that Bind Lymphocyte Activation Gene-3 (LAG-3), and Uses Thereof

Country Status (32)

Country Link
US (13) US20110150892A1 (pl)
EP (4) EP4147714A1 (pl)
JP (6) JP5647981B2 (pl)
KR (6) KR20170010901A (pl)
CN (4) CN103923213A (pl)
AR (3) AR072999A1 (pl)
AU (2) AU2009282134B2 (pl)
BR (1) BRPI0917470B8 (pl)
CA (1) CA2734335C (pl)
CL (4) CL2011000308A1 (pl)
CO (1) CO6351751A2 (pl)
CY (2) CY1116582T1 (pl)
DK (3) DK2905030T3 (pl)
EA (2) EA201590777A1 (pl)
ES (3) ES2537203T3 (pl)
HK (2) HK1151985A1 (pl)
HR (3) HRP20221191T1 (pl)
HU (2) HUE025250T2 (pl)
IL (4) IL210731A (pl)
LT (2) LT3597216T (pl)
MX (2) MX2011001250A (pl)
NZ (3) NZ623319A (pl)
PE (3) PE20190373A1 (pl)
PL (3) PL2320940T3 (pl)
PT (3) PT2320940E (pl)
SG (1) SG10201706497QA (pl)
SI (2) SI2905030T1 (pl)
SM (1) SMT201500125B (pl)
TN (1) TN2011000025A1 (pl)
TW (1) TWI491408B (pl)
WO (1) WO2010019570A2 (pl)
ZA (1) ZA201101009B (pl)

Cited By (238)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013003761A1 (en) * 2011-06-30 2013-01-03 Genzyme Corporation Inhibitors of t-cell activation
WO2014008218A1 (en) 2012-07-02 2014-01-09 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
US20140286935A1 (en) * 2013-03-15 2014-09-25 Glaxosmithkline Intellectual Property Development Limited Antigen binding proteins
WO2014179664A2 (en) 2013-05-02 2014-11-06 Anaptysbio, Inc. Antibodies directed against programmed death-1 (pd-1)
WO2015042246A1 (en) 2013-09-20 2015-03-26 Bristol-Myers Squibb Company Combination of anti-lag-3 antibodies and anti-pd-1 antibodies to treat tumors
WO2015048312A1 (en) * 2013-09-26 2015-04-02 Costim Pharmaceuticals Inc. Methods for treating hematologic cancers
WO2015066413A1 (en) 2013-11-01 2015-05-07 Novartis Ag Oxazolidinone hydroxamic acid compounds for the treatment of bacterial infections
WO2015107495A1 (en) 2014-01-17 2015-07-23 Novartis Ag N-azaspirocycloalkane substituted n-heteroaryl compounds and compositions for inhibiting the activity of shp2
WO2015116539A1 (en) 2014-01-28 2015-08-06 Bristol-Myers Squibb Company Anti-lag-3 antibodies to treat hematological malignancies
WO2015148379A1 (en) 2014-03-24 2015-10-01 Novartis Ag Monobactam organic compounds for the treatment of bacterial infections
WO2015184099A1 (en) 2014-05-28 2015-12-03 4-Antibody Ag Anti-gitr antibodies and methods of use thereof
WO2015187835A2 (en) 2014-06-06 2015-12-10 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
WO2016020836A1 (en) 2014-08-06 2016-02-11 Novartis Ag Quinolone derivatives as antibacterials
WO2016025642A1 (en) 2014-08-12 2016-02-18 Massachusetts Institute Of Technology Synergistic tumor treatment with il-2 and integrin-binding-fc-fusion protein
WO2016025647A1 (en) 2014-08-12 2016-02-18 Massachusetts Institute Of Technology Synergistic tumor treatment with il-2, a therapeutic antibody, and a cancer vaccine
WO2016040880A1 (en) 2014-09-13 2016-03-17 Novartis Ag Combination therapies of alk inhibitors
WO2016054555A2 (en) 2014-10-03 2016-04-07 Novartis Ag Combination therapies
WO2016057846A1 (en) 2014-10-08 2016-04-14 Novartis Ag Compositions and methods of use for augmented immune response and cancer therapy
WO2016061142A1 (en) 2014-10-14 2016-04-21 Novartis Ag Antibody molecules to pd-l1 and uses thereof
WO2016081748A2 (en) 2014-11-21 2016-05-26 Bristol-Myers Squibb Company Antibodies against cd73 and uses thereof
WO2016094639A1 (en) 2014-12-10 2016-06-16 Wisconsin Alumni Research Foundation Mini-intronic plasmid dna vaccines in combination with lag3 blockade
WO2016100882A1 (en) 2014-12-19 2016-06-23 Novartis Ag Combination therapies
WO2016097995A1 (en) 2014-12-16 2016-06-23 Novartis Ag Isoxazole hydroxamic acid compounds as lpxc inhibitors
WO2016127052A1 (en) 2015-02-05 2016-08-11 Bristol-Myers Squibb Company Cxcl11 and smica as predictive biomarkers for efficacy of anti-ctla4 immunotherapy
WO2016145102A1 (en) 2015-03-10 2016-09-15 Aduro Biotech, Inc. Compositions and methods for activating "stimulator of interferon gene" -dependent signalling
WO2016196228A1 (en) 2015-05-29 2016-12-08 Bristol-Myers Squibb Company Antibodies against ox40 and uses thereof
WO2016200782A1 (en) * 2015-06-08 2016-12-15 Macrogenics, Inc. Lag-3-binding molecules and methods of use thereof
WO2017004016A1 (en) 2015-06-29 2017-01-05 The Rockefeller University Antibodies to cd40 with enhanced agonist activity
WO2017009842A2 (en) 2015-07-16 2017-01-19 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
WO2017019897A1 (en) 2015-07-29 2017-02-02 Novartis Ag Combination therapies comprising antibody molecules to tim-3
WO2017019894A1 (en) 2015-07-29 2017-02-02 Novartis Ag Combination therapies comprising antibody molecules to lag-3
WO2017025871A1 (en) 2015-08-07 2017-02-16 Glaxosmithkline Intellectual Property Development Limited Combination therapy comprising anti ctla-4 antibodies
US9605070B2 (en) 2014-01-31 2017-03-28 Novartis Ag Antibody molecules to TIM-3 and uses thereof
WO2017062888A1 (en) 2015-10-09 2017-04-13 Regeneron Pharmaceuticals, Inc. Anti-lag3 antibodies and uses thereof
WO2017087678A2 (en) 2015-11-19 2017-05-26 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
US9683048B2 (en) 2014-01-24 2017-06-20 Novartis Ag Antibody molecules to PD-1 and uses thereof
WO2017106656A1 (en) 2015-12-17 2017-06-22 Novartis Ag Antibody molecules to pd-1 and uses thereof
WO2017103895A1 (en) 2015-12-18 2017-06-22 Novartis Ag Antibodies targeting cd32b and methods of use thereof
WO2017122130A1 (en) 2016-01-11 2017-07-20 Novartis Ag Immune-stimulating humanized monoclonal antibodies against human interleukin-2, and fusion proteins thereof
WO2017140821A1 (en) 2016-02-19 2017-08-24 Novartis Ag Tetracyclic pyridone compounds as antivirals
WO2017152085A1 (en) 2016-03-04 2017-09-08 Bristol-Myers Squibb Company Combination therapy with anti-cd73 antibodies
WO2017163186A1 (en) 2016-03-24 2017-09-28 Novartis Ag Alkynyl nucleoside analogs as inhibitors of human rhinovirus
WO2017178572A1 (en) 2016-04-13 2017-10-19 Vivia Biotech, S.L Ex vivo bite-activated t cells
WO2017184619A2 (en) 2016-04-18 2017-10-26 Celldex Therapeutics, Inc. Agonistic antibodies that bind human cd40 and uses thereof
WO2017201502A1 (en) 2016-05-20 2017-11-23 Biohaven Pharmaceutical Holding Company Ltd. Use of glutamate modulating agents with immunotherapies to treat cancer
WO2017216686A1 (en) 2016-06-16 2017-12-21 Novartis Ag 8,9-fused 2-oxo-6,7-dihydropyrido-isoquinoline compounds as antivirals
WO2017216705A1 (en) 2016-06-14 2017-12-21 Novartis Ag Crystalline form of (r)-4-(5-(cyclopropylethynyl)isoxazol-3-yl)-n-hydroxy-2-methyl-2-(methylsulfonyl)butanamide as an antibacterial agent
WO2017216685A1 (en) 2016-06-16 2017-12-21 Novartis Ag Pentacyclic pyridone compounds as antivirals
WO2017223422A1 (en) 2016-06-24 2017-12-28 Infinity Pharmaceuticals, Inc. Combination therapies
WO2018013818A2 (en) 2016-07-14 2018-01-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
US9907768B2 (en) 2016-06-10 2018-03-06 Io Therapeutics, Inc. Receptor subtype and function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US9908936B2 (en) 2014-03-14 2018-03-06 Novartis Ag Antibody molecules to LAG-3 and uses thereof
WO2018047109A1 (en) 2016-09-09 2018-03-15 Novartis Ag Polycyclic pyridone compounds as antivirals
WO2018057955A1 (en) 2016-09-23 2018-03-29 Elstar Therapeutics, Inc. Multispecific antibody molecules comprising lambda and kappa light chains
WO2018060926A1 (en) 2016-09-28 2018-04-05 Novartis Ag Beta-lactamase inhibitors
WO2018073753A1 (en) 2016-10-18 2018-04-26 Novartis Ag Fused tetracyclic pyridone compounds as antivirals
WO2018083087A2 (en) 2016-11-02 2018-05-11 Glaxosmithkline Intellectual Property (No.2) Limited Binding proteins
WO2018106862A1 (en) 2016-12-07 2018-06-14 Agenus Inc. Anti-ctla-4 antibodies and methods of use thereof
WO2018112266A1 (en) 2016-12-14 2018-06-21 The Board Of Trustees Of The Leland Stanford Junior University Il-13 superkine: immune cell targeting constructs and methods of use thereof
WO2018148476A1 (en) 2017-02-10 2018-08-16 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-lag3 antibodies for immuno-pet imaging
WO2018151820A1 (en) 2017-02-16 2018-08-23 Elstar Therapeutics, Inc. Multifunctional molecules comprising a trimeric ligand and uses thereof
WO2018151821A1 (en) 2017-02-17 2018-08-23 Bristol-Myers Squibb Company Antibodies to alpha-synuclein and uses thereof
JP2018527290A (ja) * 2015-11-13 2018-09-20 マクロジェニクス，インコーポレーテッド Ｌａｇ‐３結合分子及びその使用方法
WO2018183928A1 (en) 2017-03-31 2018-10-04 Bristol-Myers Squibb Company Methods of treating tumor
WO2018185046A1 (en) 2017-04-05 2018-10-11 F. Hoffmann-La Roche Ag Anti-lag3 antibodies
WO2018187613A2 (en) 2017-04-07 2018-10-11 Bristol-Myers Squibb Company Anti-icos agonist antibodies and uses thereof
WO2018195283A1 (en) 2017-04-19 2018-10-25 Elstar Therapeutics, Inc. Multispecific molecules and uses thereof
WO2018195552A1 (en) 2017-04-21 2018-10-25 Sillajen, Inc. Oncolytic vaccinia virus and checkpoint inhibitor combination therapy
WO2018201047A1 (en) 2017-04-28 2018-11-01 Elstar Therapeutics, Inc. Multispecific molecules comprising a non-immunoglobulin heterodimerization domain and uses thereof
WO2018200430A1 (en) 2017-04-26 2018-11-01 Bristol-Myers Squibb Company Methods of antibody production that minimize disulfide bond reduction
WO2018198079A1 (en) 2017-04-27 2018-11-01 Novartis Ag Fused indazole pyridone compounds as antivirals
WO2018198076A1 (en) 2017-04-28 2018-11-01 Aduro Biotech, Inc. Bis 2'-5'-rr-(3'f-a)(3'f-a) cyclic dinucleotide compound and uses thereof
WO2018203302A1 (en) 2017-05-05 2018-11-08 Novartis Ag Tricyclic 2-quinolinones as antibacterials
WO2018208868A1 (en) * 2017-05-10 2018-11-15 Smet Pharmaceutical Inc Human monoclonal antibodies against lag3 and uses thereof
WO2018213297A1 (en) 2017-05-16 2018-11-22 Bristol-Myers Squibb Company Treatment of cancer with anti-gitr agonist antibodies
WO2018218056A1 (en) 2017-05-25 2018-11-29 Birstol-Myers Squibb Company Antibodies comprising modified heavy constant regions
US10144779B2 (en) 2015-05-29 2018-12-04 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
WO2018222722A2 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Compositions comprising an anti-lag-3 antibody or an anti-lag-3 antibody and an anti-pd-1 or anti-pd-l1 antibody
WO2018222711A2 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Compositions comprising a combination of an anti-lag-3 antibody, a pd-1 pathway inhibitor, and an immunotherapeutic agent
WO2018223002A1 (en) 2017-06-01 2018-12-06 Xencor, Inc. Bispecific antibodies that bind cd 123 cd3
WO2018223004A1 (en) 2017-06-01 2018-12-06 Xencor, Inc. Bispecific antibodies that bind cd20 and cd3
WO2018222901A1 (en) 2017-05-31 2018-12-06 Elstar Therapeutics, Inc. Multispecific molecules that bind to myeloproliferative leukemia (mpl) protein and uses thereof
WO2018222718A1 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Treatment of lag-3 positive tumors
WO2019035938A1 (en) 2017-08-16 2019-02-21 Elstar Therapeutics, Inc. MULTISPECIFIC MOLECULES BINDING TO BCMA AND USES THEREOF
WO2019035985A1 (en) 2017-08-18 2019-02-21 Tragara Pharmaceuticals, Inc. POLYMORPHIC FORM OF TG02
US10213401B2 (en) 2017-07-13 2019-02-26 Io Therapeutics, Inc. Immunomodulatory and differentiating function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
WO2019075468A1 (en) 2017-10-15 2019-04-18 Bristol-Myers Squibb Company TUMOR TREATMENT METHODS
WO2019075090A1 (en) 2017-10-10 2019-04-18 Tilos Therapeutics, Inc. ANTI-LAP ANTIBODIES AND USES THEREOF
WO2019077062A1 (en) 2017-10-18 2019-04-25 Vivia Biotech, S.L. C-CELLS ACTIVATED BY BIT
WO2019089921A1 (en) 2017-11-01 2019-05-09 Bristol-Myers Squibb Company Immunostimulatory agonistic antibodies for use in treating cancer
WO2019097479A1 (en) 2017-11-17 2019-05-23 Novartis Ag Novel dihydroisoxazole compounds and their use for the treatment of hepatitis b
WO2019113464A1 (en) 2017-12-08 2019-06-13 Elstar Therapeutics, Inc. Multispecific molecules and uses thereof
WO2019123285A1 (en) 2017-12-20 2019-06-27 Novartis Ag Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals
WO2019133747A1 (en) 2017-12-27 2019-07-04 Bristol-Myers Squibb Company Anti-cd40 antibodies and uses thereof
US10344089B2 (en) 2008-08-11 2019-07-09 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US10350266B2 (en) 2017-01-10 2019-07-16 Nodus Therapeutics, Inc. Method of treating cancer with a multiple integrin binding Fc fusion protein
WO2019140229A1 (en) 2018-01-12 2019-07-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
US10363272B2 (en) 2017-08-31 2019-07-30 Io Therapeutics, Inc. RAR selective agonists in combination with immune modulators for cancer immunotherapy
WO2019149715A1 (en) 2018-01-31 2019-08-08 F. Hoffmann-La Roche Ag Stabilized immunoglobulin domains
WO2019149716A1 (en) 2018-01-31 2019-08-08 F. Hoffmann-La Roche Ag Bispecific antibodies comprising an antigen-binding site binding to lag3
WO2019166951A1 (en) 2018-02-28 2019-09-06 Novartis Ag Indole-2-carbonyl compounds and their use for the treatment of hepatitis b
WO2019178362A1 (en) 2018-03-14 2019-09-19 Elstar Therapeutics, Inc. Multifunctional molecules that bind to calreticulin and uses thereof
WO2019178364A2 (en) 2018-03-14 2019-09-19 Elstar Therapeutics, Inc. Multifunctional molecules and uses thereof
WO2019183040A1 (en) 2018-03-21 2019-09-26 Five Prime Therapeutics, Inc. ANTIBODIES BINDING TO VISTA AT ACIDIC pH
WO2019191676A1 (en) 2018-03-30 2019-10-03 Bristol-Myers Squibb Company Methods of treating tumor
WO2019192432A1 (zh) 2018-04-02 2019-10-10 上海博威生物医药有限公司 结合淋巴细胞活化基因-3(lag-3)的抗体及其用途
WO2019204592A1 (en) 2018-04-18 2019-10-24 Xencor, Inc. Il-15/il-15ra heterodimeric fc fusion proteins and uses thereof
WO2019204665A1 (en) 2018-04-18 2019-10-24 Xencor, Inc. Pd-1 targeted heterodimeric fusion proteins containing il-15/il-15ra fc-fusion proteins and pd-1 antigen binding domains and uses thereof
WO2019232528A1 (en) 2018-06-01 2019-12-05 Xencor, Inc. Dosing of a bispecific antibody that bind cd123 and cd3
US10512689B2 (en) 2015-04-17 2019-12-24 Bristol-Myers Squibb Company Compositions comprising a combination of nivolumab and ipilimumab
WO2020010250A2 (en) 2018-07-03 2020-01-09 Elstar Therapeutics, Inc. Anti-tcr antibody molecules and uses thereof
WO2020014327A2 (en) 2018-07-11 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to vista at acidic ph
WO2020014132A2 (en) 2018-07-09 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to ilt4
WO2020023707A1 (en) 2018-07-26 2020-01-30 Bristol-Myers Squibb Company Lag-3 combination therapy for the treatment of cancer
WO2020053654A1 (en) 2018-09-12 2020-03-19 Novartis Ag Antiviral pyridopyrazinedione compounds
WO2020057646A1 (zh) 2018-09-21 2020-03-26 信达生物制药(苏州)有限公司 新型白介素2及其用途
WO2020057645A1 (zh) 2018-09-21 2020-03-26 信达生物制药(苏州)有限公司 新型白介素2及其用途
US10603358B2 (en) 2017-01-10 2020-03-31 Nodus Therapeutics Combination tumor treatment with an integrin-binding-Fc fusion protein and immune stimulator
WO2020065453A1 (en) 2018-09-29 2020-04-02 Novartis Ag Process of manufacture of a compound for inhibiting the activity of shp2
WO2020069372A1 (en) 2018-09-27 2020-04-02 Elstar Therapeutics, Inc. Csf1r/ccr2 multispecific antibodies
WO2020072821A2 (en) 2018-10-03 2020-04-09 Xencor, Inc. Il-12 heterodimeric fc-fusion proteins
WO2020077276A2 (en) 2018-10-12 2020-04-16 Xencor, Inc. Pd-1 targeted il-15/il-15ralpha fc fusion proteins and uses in combination therapies thereof
WO2020076969A2 (en) 2018-10-10 2020-04-16 Tilos Therapeutics, Inc. Anti-lap antibody variants and uses thereof
WO2020081928A1 (en) 2018-10-19 2020-04-23 Bristol-Myers Squibb Company Combination therapy for melanoma
WO2020102501A1 (en) 2018-11-16 2020-05-22 Bristol-Myers Squibb Company Anti-nkg2a antibodies and uses thereof
WO2020132646A1 (en) 2018-12-20 2020-06-25 Xencor, Inc. Targeted heterodimeric fc fusion proteins containing il-15/il-15ra and nkg2d antigen binding domains
WO2020154032A1 (en) 2019-01-23 2020-07-30 Massachusetts Institute Of Technology Combination immunotherapy dosing regimen for immune checkpoint blockade
WO2020198435A1 (en) 2019-03-26 2020-10-01 The Regents Of The University Of Michigan Small molecule degraders of stat3
WO2020205467A1 (en) 2019-03-29 2020-10-08 The Regents Of The University Of Michigan Stat3 protein degraders
WO2020221928A1 (en) 2019-05-01 2020-11-05 Immutep S.A.S. Anti-lag-3 binding molecules
WO2020223121A1 (en) 2019-04-30 2020-11-05 Dana-Farber Cancer Institute, Inc. Methods for treating cancer using combinations of anti-cx3cr1 and immune checkpoint blockade agents
US10836830B2 (en) 2015-12-02 2020-11-17 Agenus Inc. Antibodies and methods of use thereof
US10836824B2 (en) 2015-02-03 2020-11-17 Anaptysbio, Inc. Antibodies directed against lymphocyte activation gene 3 (LAG-3)
WO2020232019A1 (en) 2019-05-13 2020-11-19 Regeneron Pharmaceuticals, Inc. Combination of pd-1 inhibitors and lag-3 inhibitors for enhanced efficacy in treating cancer
US10844119B2 (en) 2016-10-11 2020-11-24 Agenus Inc. Anti-LAG-3 antibodies and methods of use thereof
WO2020243570A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Cell localization signature and combination therapy
WO2020243568A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Methods of identifying a subject suitable for an immuno-oncology (i-o) therapy
WO2020243563A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Multi-tumor gene signatures for suitability to immuno-oncology therapy
WO2020252264A1 (en) 2019-06-12 2020-12-17 AskGene Pharma, Inc. Novel il-15 prodrugs and methods of use thereof
WO2020252353A1 (en) 2019-06-12 2020-12-17 Vanderbilt University Amino acid transport inhibitors and the uses thereof
WO2020252336A1 (en) 2019-06-12 2020-12-17 Vanderbilt University Dibenzylamines as amino acid transport inhibitors
CN112119094A (zh) * 2018-06-29 2020-12-22 Y 生物股份有限公司 与淋巴细胞活化基因3特异性结合的单克隆抗体及其用途
WO2020263399A1 (en) 2019-06-26 2020-12-30 Massachusetts Institute Of Technology Immunomodulatory fusion protein-metal hydroxide complexes and methods thereof
US10894830B2 (en) 2015-11-03 2021-01-19 Janssen Biotech, Inc. Antibodies specifically binding PD-1, TIM-3 or PD-1 and TIM-3 and their uses
WO2021011713A1 (en) 2019-07-16 2021-01-21 The Regents Of The University Of Michigan Imidazopyrimidines as eed inhibitors and the use thereof
WO2021024020A1 (en) 2019-08-06 2021-02-11 Astellas Pharma Inc. Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer
WO2021041664A1 (en) 2019-08-27 2021-03-04 The Regents Of The University Of Michigan Cereblon e3 ligase inhibitors
EP3789399A1 (en) 2014-11-21 2021-03-10 Bristol-Myers Squibb Company Antibodies comprising modified heavy constant regions
WO2021055756A1 (en) 2019-09-19 2021-03-25 The Regents Of The University Of Michigan Spirocyclic androgen receptor protein degraders
WO2021055994A1 (en) 2019-09-22 2021-03-25 Bristol-Myers Squibb Company Quantitative spatial profiling for lag-3 antagonist therapy
WO2021055698A1 (en) 2019-09-19 2021-03-25 Bristol-Myers Squibb Company Antibodies binding to vista at acidic ph
EP3798234A1 (en) 2015-09-02 2021-03-31 Immutep S.A.S. Anti-lag-3 agonistic antibodies
WO2021067863A2 (en) 2019-10-03 2021-04-08 Xencor, Inc. Targeted il-12 heterodimeric fc-fusion proteins
WO2021072298A1 (en) 2019-10-11 2021-04-15 Genentech, Inc. Pd-1 targeted il-15/il-15ralpha fc fusion proteins with improved properties
WO2021080682A1 (en) 2019-10-24 2021-04-29 Massachusetts Institute Of Technology Monoclonal antibodies that bind human cd161 and uses thereof
WO2021090146A1 (en) 2019-11-04 2021-05-14 Astrazeneca Ab Combination therapy for treating cancer
WO2021092380A1 (en) 2019-11-08 2021-05-14 Bristol-Myers Squibb Company Lag-3 antagonist therapy for melanoma
WO2021092221A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
WO2021092220A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
WO2021138407A2 (en) 2020-01-03 2021-07-08 Marengo Therapeutics, Inc. Multifunctional molecules that bind to cd33 and uses thereof
US11066483B2 (en) 2010-11-30 2021-07-20 Chugai Seiyaku Kabushiki Kaisha Cytotoxicity-inducing therapeutic agent
WO2021158938A1 (en) 2020-02-06 2021-08-12 Bristol-Myers Squibb Company Il-10 and uses thereof
US11090344B2 (en) 2016-05-27 2021-08-17 Dnatrix, Inc. Adenovirus and immunomodulator combination therapy
US11098077B2 (en) 2016-07-05 2021-08-24 Chinook Therapeutics, Inc. Locked nucleic acid cyclic dinucleotide compounds and uses thereof
WO2021171264A1 (en) 2020-02-28 2021-09-02 Novartis Ag Dosing of a bispecific antibody that binds cd123 and cd3
WO2021183428A1 (en) 2020-03-09 2021-09-16 Bristol-Myers Squibb Company Antibodies to cd40 with enhanced agonist activity
WO2021195481A1 (en) 2020-03-26 2021-09-30 The Regents Of The University Of Michigan Small molecule stat protein degraders
WO2021207449A1 (en) 2020-04-09 2021-10-14 Merck Sharp & Dohme Corp. Affinity matured anti-lap antibodies and uses thereof
US11155624B2 (en) 2016-11-01 2021-10-26 Anaptysbio, Inc. Antibodies directed against programmed death-1 (PD-1)
WO2021231732A1 (en) 2020-05-15 2021-11-18 Bristol-Myers Squibb Company Antibodies to garp
US11214619B2 (en) 2018-07-20 2022-01-04 Surface Oncology, Inc. Anti-CD112R compositions and methods
WO2022008519A1 (en) 2020-07-07 2022-01-13 BioNTech SE Therapeutic rna for hpv-positive cancer
WO2022011204A1 (en) 2020-07-10 2022-01-13 The Regents Of The University Of Michigan Small molecule androgen receptor protein degraders
WO2022011205A1 (en) 2020-07-10 2022-01-13 The Regents Of The University Of Michigan Androgen receptor protein degraders
US11242393B2 (en) 2018-03-23 2022-02-08 Bristol-Myers Squibb Company Antibodies against MICA and/or MICB and uses thereof
WO2022036079A1 (en) 2020-08-13 2022-02-17 Bristol-Myers Squibb Company Methods of redirecting of il-2 to target cells of interest
WO2022047189A1 (en) 2020-08-28 2022-03-03 Bristol-Myers Squibb Company Lag-3 antagonist therapy for hepatocellular carcinoma
WO2022047046A1 (en) 2020-08-26 2022-03-03 Marengo Therapeutics, Inc. Methods of detecting trbc1 or trbc2
WO2022047412A1 (en) 2020-08-31 2022-03-03 Bristol-Myers Squibb Company Cell localization signature and immunotherapy
WO2022087402A1 (en) 2020-10-23 2022-04-28 Bristol-Myers Squibb Company Lag-3 antagonist therapy for lung cancer
WO2022120179A1 (en) 2020-12-03 2022-06-09 Bristol-Myers Squibb Company Multi-tumor gene signatures and uses thereof
WO2022125497A1 (en) 2020-12-08 2022-06-16 Infinity Pharmaceuticals, Inc. Eganelisib for use in the treatment of pd-l1 negative cancer
WO2022136255A1 (en) 2020-12-21 2022-06-30 BioNTech SE Treatment schedule for cytokine proteins
WO2022136257A1 (en) 2020-12-21 2022-06-30 BioNTech SE Therapeutic rna for treating cancer
WO2022136266A1 (en) 2020-12-21 2022-06-30 BioNTech SE Therapeutic rna for treating cancer
WO2022146947A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2022146948A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Subcutaneous administration of pd1/pd-l1 antibodies
US11384131B2 (en) 2014-04-24 2022-07-12 The Board Of Trustees Of The Leland Stanford Junior University Superagonists, partial agonists and antagonists of interleukin-2
US11390679B2 (en) * 2017-08-30 2022-07-19 Phanes Therapeutics, Inc. Anti-LAG-3 antibodies and uses thereof
US11407830B2 (en) 2017-01-09 2022-08-09 Tesaro, Inc. Methods of treating cancer with anti-PD-1 antibodies
WO2022187423A1 (en) 2021-03-03 2022-09-09 The Regents Of The University Of Michigan Cereblon ligands
WO2022187419A1 (en) 2021-03-03 2022-09-09 The Regents Of The University Of Michigan Small molecule degraders of androgen receptor
WO2022212400A1 (en) 2021-03-29 2022-10-06 Juno Therapeutics, Inc. Methods for dosing and treatment with a combination of a checkpoint inhibitor therapy and a car t cell therapy
WO2022212876A1 (en) 2021-04-02 2022-10-06 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
WO2022216993A2 (en) 2021-04-08 2022-10-13 Marengo Therapeutics, Inc. Multifuntional molecules binding to tcr and uses thereof
US11485790B2 (en) 2014-04-07 2022-11-01 Chugai Seiyaku Kabushiki Kaisha Immunoactivating antigen-binding molecule
WO2022240741A1 (en) 2021-05-12 2022-11-17 Dana-Farber Cancer Institute, Inc. Lag3 and gal3 inhibitory agents, xbp1, cs1, and cd138 peptides, and methods of use thereof
US11505605B2 (en) 2014-05-13 2022-11-22 Chugai Seiyaku Kabushiki Kaisha T cell-redirected antigen-binding molecule for cells having immunosuppression function
US11542312B2 (en) 2017-06-19 2023-01-03 Medicenna Therapeutics, Inc. IL-2 superagonists in combination with anti-PD-1 antibodies
WO2023285552A1 (en) 2021-07-13 2023-01-19 BioNTech SE Multispecific binding agents against cd40 and cd137 in combination therapy for cancer
CN115667304A (zh) * 2020-05-27 2023-01-31 安捷伦科技有限公司 抗人lag-3抗体及其在免疫组织化学(ihc)中的用途
WO2023039089A1 (en) 2021-09-08 2023-03-16 Twentyeight-Seven, Inc. Papd5 and/or papd7 inhibiting 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives
US11607453B2 (en) 2017-05-12 2023-03-21 Harpoon Therapeutics, Inc. Mesothelin binding proteins
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
WO2023061930A1 (en) 2021-10-11 2023-04-20 BioNTech SE Therapeutic rna for lung cancer
WO2023077090A1 (en) 2021-10-29 2023-05-04 Bristol-Myers Squibb Company Lag-3 antagonist therapy for hematological cancer
US11649293B2 (en) 2015-11-18 2023-05-16 Chugai Seiyaku Kabushiki Kaisha Method for enhancing humoral immune response
US11660340B2 (en) 2015-11-18 2023-05-30 Chugai Seiyaku Kabushiki Kaisha Combination therapy using T cell redirection antigen binding molecule against cell having immunosuppressing function
US11661452B2 (en) 2018-03-20 2023-05-30 WuXi Biologics Ireland Limited Anti-lag-3 antibody polypeptide
US11667613B2 (en) 2019-09-26 2023-06-06 Novartis Ag Antiviral pyrazolopyridinone compounds
US11680090B2 (en) 2013-09-24 2023-06-20 Medicenna Therapeutics, Inc. Interleukin-2 fusion proteins and uses thereof
US11684654B2 (en) 2015-01-09 2023-06-27 Immutep S.A.S. Combined preparations for the treatment of cancer or infection
WO2023147371A1 (en) 2022-01-26 2023-08-03 Bristol-Myers Squibb Company Combination therapy for hepatocellular carcinoma
WO2023154905A1 (en) 2022-02-14 2023-08-17 Gilead Sciences, Inc. Antiviral pyrazolopyridinone compounds
WO2023164638A1 (en) 2022-02-25 2023-08-31 Bristol-Myers Squibb Company Combination therapy for colorectal carcinoma
WO2023168404A1 (en) 2022-03-04 2023-09-07 Bristol-Myers Squibb Company Methods of treating a tumor
WO2023170606A1 (en) 2022-03-08 2023-09-14 Alentis Therapeutics Ag Use of anti-claudin-1 antibodies to increase t cell availability
WO2023178329A1 (en) 2022-03-18 2023-09-21 Bristol-Myers Squibb Company Methods of isolating polypeptides
WO2023178192A1 (en) 2022-03-15 2023-09-21 Compugen Ltd. Il-18bp antagonist antibodies and their use in monotherapy and combination therapy in the treatment of cancer
EP4249066A2 (en) 2014-12-23 2023-09-27 Bristol-Myers Squibb Company Antibodies to tigit
US11795221B2 (en) 2018-02-28 2023-10-24 WuXi Biologics Ireland Limited Monoclonal antibody against human LAG-3, method for preparing the same, and use thereof
US11807692B2 (en) 2018-09-25 2023-11-07 Harpoon Therapeutics, Inc. DLL3 binding proteins and methods of use
WO2023235847A1 (en) 2022-06-02 2023-12-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2024040194A1 (en) 2022-08-17 2024-02-22 Capstan Therapeutics, Inc. Conditioning for in vivo immune cell engineering
WO2024089418A1 (en) 2022-10-24 2024-05-02 Cancer Research Technology Limited Tumour sensitisation to checkpoint inhibitors with redox status modifier
WO2024089417A1 (en) 2022-10-24 2024-05-02 Memorial Sloan-Kettering Cancer Center Tumour stratification for responsiveness to an immune checkpoint inhibitor
US11976125B2 (en) 2017-10-13 2024-05-07 Harpoon Therapeutics, Inc. B cell maturation antigen binding proteins
EP4378957A2 (en) 2015-07-29 2024-06-05 Novartis AG Combination therapies comprising antibody molecules to pd-1
WO2024116140A1 (en) 2022-12-01 2024-06-06 Medimmune Limited Combination therapy for treatment of cancer comprising anti-pd-l1 and anti-cd73 antibodies
US12006347B2 (en) 2010-12-22 2024-06-11 The Board Of Trustees Of The Leland Stanford Junior University Superagonists and antagonists of interleukin-2
WO2024126457A1 (en) 2022-12-14 2024-06-20 Astellas Pharma Europe Bv Combination therapy involving bispecific binding agents binding to cldn18.2 and cd3 and immune checkpoint inhibitors
WO2024137776A1 (en) 2022-12-21 2024-06-27 Bristol-Myers Squibb Company Combination therapy for lung cancer
WO2024150017A1 (en) 2023-01-13 2024-07-18 Akrivia Biomedics Limited Method of profiling diseases
WO2024173876A1 (en) 2023-02-17 2024-08-22 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-lag3 antibodies for immuno-pet imaging
US12084518B2 (en) 2015-05-21 2024-09-10 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use
WO2024192033A1 (en) 2023-03-13 2024-09-19 Regeneron Pharmaceuticals, Inc. Combination of pd-1 inhibitors and lag-3 inhibitors for enhanced efficacy in treating melanoma
WO2024196952A1 (en) 2023-03-20 2024-09-26 Bristol-Myers Squibb Company Tumor subtype assessment for cancer therapy
US12129297B2 (en) 2019-01-11 2024-10-29 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof

Families Citing this family (388)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101360761B (zh) 2005-12-08 2012-09-12 米德列斯公司 抗蛋白质酪氨酸激酶7（ptk7）的人单克隆抗体及其用途
CN103249833B (zh) * 2010-12-06 2016-06-29 大日本住友制药株式会社 人单克隆抗体
US8440797B2 (en) 2010-12-06 2013-05-14 Dainippon Sumitomo Pharma Co., Ltd. Human monoclonal antibody
DK2734205T3 (en) 2011-07-21 2018-06-14 Tolero Pharmaceuticals Inc Heterocyclic Protein Kinase Inhibitors
EP3404116B1 (en) 2013-03-15 2022-10-19 The University of Chicago Methods and compositions related to t-cell activity
TWI654206B (zh) 2013-03-16 2019-03-21 諾華公司 使用人類化抗－ｃｄ１９嵌合抗原受體治療癌症
DK3013350T3 (da) 2013-06-25 2020-04-14 Vaccinex Inc Anvendelse af semaphorin-4D-hæmmende molekyler i kombination med en immunmodulerende terapi for at hæmme tumorvækst og metastaser
EP3027210A1 (en) 2013-08-02 2016-06-08 Aduro Biotech Holdings, Europe B.V. Combining cd27 agonists and immune checkpoint inhibition for immune stimulation
HRP20212023T1 (hr) 2013-08-08 2022-04-01 Cytune Pharma Modulokini temeljeni na il-15 i il-15ralpha sushi domeni
PL3030262T3 (pl) 2013-08-08 2020-07-27 Cytune Pharma Złożona kompozycja farmaceutyczna
KR102447878B1 (ko) * 2013-12-17 2022-09-26 제넨테크, 인크. Pd-1 축 결합 길항제 및 탁산을 이용한 암 치료 방법
WO2015095410A1 (en) * 2013-12-17 2015-06-25 Genentech, Inc. Methods of treating cancer using pd-1 axis binding antagonists and an anti-cd20 antibody
AU2014366047B2 (en) 2013-12-19 2021-03-25 Novartis Ag Human mesothelin chimeric antigen receptors and uses thereof
GB201322626D0 (en) 2013-12-19 2014-02-05 Immutep S A Combined preparations for the treatment of cancer
AU2014369982B2 (en) 2013-12-24 2019-04-18 Bristol-Myers Squibb Company Tricyclic compounds as anticancer agents
US9394365B1 (en) 2014-03-12 2016-07-19 Yeda Research And Development Co., Ltd Reducing systemic regulatory T cell levels or activity for treatment of alzheimer's disease
AU2015228372B2 (en) 2014-03-12 2018-05-31 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
US10618963B2 (en) 2014-03-12 2020-04-14 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
US10519237B2 (en) 2014-03-12 2019-12-31 Yeda Research And Development Co. Ltd Reducing systemic regulatory T cell levels or activity for treatment of disease and injury of the CNS
JP2017513818A (ja) 2014-03-15 2017-06-01 ノバルティス アーゲー キメラ抗原受容体を使用する癌の処置
HRP20240874T1 (hr) 2014-04-07 2024-10-11 Novartis Ag Liječenje raka korištenjem kimernog antigenskog receptora anti-cd19
HUE050007T2 (hu) 2014-05-16 2020-11-30 Ablynx Nv Immunglobulin variábilis domének
CN106535884A (zh) 2014-06-06 2017-03-22 弗雷克萨斯生物科学公司 免疫调节剂
TWI693232B (zh) 2014-06-26 2020-05-11 美商宏觀基因股份有限公司 與pd-1和lag-3具有免疫反應性的共價結合的雙抗體和其使用方法
CA2955154C (en) 2014-07-21 2023-10-31 Novartis Ag Treatment of cancer using a cd33 chimeric antigen receptor
EP3193915A1 (en) 2014-07-21 2017-07-26 Novartis AG Combinations of low, immune enhancing. doses of mtor inhibitors and cars
WO2016014553A1 (en) 2014-07-21 2016-01-28 Novartis Ag Sortase synthesized chimeric antigen receptors
US20170209492A1 (en) 2014-07-31 2017-07-27 Novartis Ag Subset-optimized chimeric antigen receptor-containing t-cells
EP3180359A1 (en) 2014-08-14 2017-06-21 Novartis AG Treatment of cancer using gfr alpha-4 chimeric antigen receptor
ES2791248T3 (es) 2014-08-19 2020-11-03 Novartis Ag Receptor antigénico quimérico (CAR) anti-CD123 para su uso en el tratamiento del cáncer
JO3663B1 (ar) * 2014-08-19 2020-08-27 Merck Sharp & Dohme الأجسام المضادة لمضاد lag3 وأجزاء ربط الأنتيجين
AU2015317608B2 (en) 2014-09-17 2021-03-11 Novartis Ag Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
RU2743657C2 (ru) 2014-10-08 2021-02-20 Новартис Аг Биомаркеры, прогнозирующие способность к терапевтическому ответу на терапию химерным рецептором антигена, и их применение
WO2016057898A1 (en) 2014-10-10 2016-04-14 Idera Pharmaceuticals, Inc. Treatment of cancer using tlr9 agonist with checkpoint inhibitors
UY36390A (es) 2014-11-05 2016-06-01 Flexus Biosciences Inc Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido), sus métodos de síntesis y composiciones farmacéuticas que los contienen
EP3215141A4 (en) 2014-11-05 2018-06-06 Flexus Biosciences, Inc. Immunoregulatory agents
UY36391A (es) 2014-11-05 2016-06-01 Flexus Biosciences Inc Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido1), sus métodos de síntesis y composiciones farmacèuticas que las contienen
US20180334490A1 (en) 2014-12-03 2018-11-22 Qilong H. Wu Methods for b cell preconditioning in car therapy
TW201630907A (zh) 2014-12-22 2016-09-01 必治妥美雅史谷比公司 ＴＧＦβＲ拮抗劑
US11161907B2 (en) 2015-02-02 2021-11-02 Novartis Ag Car-expressing cells against multiple tumor antigens and uses thereof
PE20171789A1 (es) 2015-03-02 2017-12-28 Bristol Myers Squibb Co Inhibidores del factor beta de crecimiento de transformacion (tgf-beta)
US20180133327A1 (en) 2015-03-16 2018-05-17 Amal Therapeutics Sa Cell Penetrating Peptides and Complexes Comprising the Same
MX2017012738A (es) 2015-04-03 2017-11-15 Bristol Myers Squibb Co Inhibidores de indolamina 2.3-dioxigenasa (ido) para el tratamiento de cancer.
US20180140602A1 (en) 2015-04-07 2018-05-24 Novartis Ag Combination of chimeric antigen receptor therapy and amino pyrimidine derivatives
WO2016162505A1 (en) 2015-04-08 2016-10-13 F-Star Biotechnology Limited Her2 binding agent therapies
RU2752918C2 (ru) 2015-04-08 2021-08-11 Новартис Аг Cd20 терапия, cd22 терапия и комбинированная терапия клетками, экспрессирующими химерный антигенный рецептор (car) k cd19
EP3964527A3 (en) 2015-04-13 2022-06-15 Five Prime Therapeutics, Inc. Combination therapy for cancer
EP3283619B1 (en) 2015-04-17 2023-04-05 Novartis AG Methods for improving the efficacy and expansion of chimeric antigen receptor-expressing cells
EP3286211A1 (en) 2015-04-23 2018-02-28 Novartis AG Treatment of cancer using chimeric antigen receptor and protein kinase a blocker
EP3907285A1 (en) 2015-05-06 2021-11-10 Snipr Technologies Limited Altering microbial populations & modifying microbiota
EP3294736B1 (en) 2015-05-11 2020-07-22 Bristol-Myers Squibb Company Tricyclic compounds as anticancer agents
ES2770349T3 (es) 2015-05-12 2020-07-01 Bristol Myers Squibb Co Compuestos de 5H-pirido[3,2-b]indol como agentes antineoplásicos
US9725449B2 (en) 2015-05-12 2017-08-08 Bristol-Myers Squibb Company Tricyclic compounds as anticancer agents
EA039293B1 (ru) * 2015-06-05 2021-12-30 Мерк Шарп И Доум Корп. Антитела против lag3 и антигенсвязывающие фрагменты
FI3313441T3 (fi) 2015-06-24 2024-03-28 Janssen Biotech Inc Kiinteiden kasvainten immunomodulaatio ja hoito spesifisesti cd38:aa sitovilla vasta-aineilla
WO2017011666A1 (en) 2015-07-14 2017-01-19 Bristol-Myers Squibb Company Method of treating cancer using immune checkpoint inhibitor
CN109476722A (zh) 2015-07-21 2019-03-15 诺华股份有限公司 用于改善免疫细胞的功效和扩张的方法
US9902772B2 (en) * 2015-07-22 2018-02-27 Sorrento Therapeutics, Inc. Antibody therapeutics that bind LAG3
CN108137597A (zh) 2015-07-28 2018-06-08 百时美施贵宝公司 TGFβ受体拮抗剂
SG10201906059VA (en) 2015-07-30 2019-08-27 Macrogenics Inc Pd-1-binding molecules and methods of use thereof
US20180250303A1 (en) 2015-08-25 2018-09-06 Bristol-Myers Squibb Company Tgf beta receptor antagonists
PE20181322A1 (es) 2015-09-01 2018-08-14 Agenus Inc Anticuerpo anti-pd1 y sus metodos de uso
JP6905163B2 (ja) 2015-09-03 2021-07-21 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア サイトカイン放出症候群を予測するバイオマーカー
JP6622392B2 (ja) 2015-10-02 2019-12-18 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト Ｐｄ１とｔｉｍ３に特異的な二重特異性抗体
US10149887B2 (en) 2015-10-23 2018-12-11 Canbas Co., Ltd. Peptides and peptidomimetics in combination with t cell activating and/or checkpoint inhibiting agents for cancer treatment
TW201722985A (zh) 2015-11-02 2017-07-01 戊瑞治療有限公司 Cd80胞外域多肽及其用於癌症治療
KR20180104597A (ko) 2015-11-07 2018-09-21 멀티비르 인코포레이티드 암 치료를 위한 종양 억제 유전자 요법 및 면역관문 봉쇄를 포함하는 조성물
KR102220275B1 (ko) 2015-11-18 2021-02-26 머크 샤프 앤드 돔 코포레이션 Pd1 및/또는 lag3 결합제
EP3377533A2 (en) * 2015-11-19 2018-09-26 Sutro Biopharma, Inc. Anti-lag3 antibodies, compositions comprising anti-lag3 antibodies and methods of making and using anti-lag3 antibodies
BR112018010158A2 (pt) 2015-11-20 2018-11-21 Regeneron Pharma roedor, polipeptídeo lag-3 humanizado, célula ou tecido, célula-tronco embrionária e embrião de roedor, métodos para produzir um roedor, para avaliar a eficácia antitumoral e as propriedades farmacocinéticas de uma droga
CN116327924A (zh) 2015-11-23 2023-06-27 戊瑞治疗有限公司 用于癌症治疗的单独fgfr2抑制剂或与免疫刺激剂的组合
EP3389714A4 (en) 2015-12-14 2019-11-13 MacroGenics, Inc. BISPECIFIC MOLECULES HAVING IMMUNOREACTIVITY TO PD-1 AND CTLA-4 AND METHODS OF USE
US10450318B2 (en) 2015-12-15 2019-10-22 Bristol-Myers Squibb Company CXCR4 receptor antagonists
WO2017106129A1 (en) * 2015-12-16 2017-06-22 Merck Sharp & Dohme Corp. Anti-lag3 antibodies and antigen-binding fragments
US10392442B2 (en) 2015-12-17 2019-08-27 Bristol-Myers Squibb Company Use of anti-PD-1 antibody in combination with anti-CD27 antibody in cancer treatment
WO2017106630A1 (en) 2015-12-18 2017-06-22 The General Hospital Corporation Polyacetal polymers, conjugates, particles and uses thereof
JP7082055B2 (ja) 2015-12-22 2022-06-07 ノバルティス アーゲー 抗癌治療における組み合わせ使用のためのメソテリンキメラ抗原受容体（ｃａｒ）およびｐｄ－ｌ１阻害剤に対する抗体
EP3423482A1 (en) 2016-03-04 2019-01-09 Novartis AG Cells expressing multiple chimeric antigen receptor (car) molecules and uses therefore
SG10201601719RA (en) * 2016-03-04 2017-10-30 Agency Science Tech & Res Anti-LAG-3 Antibodies
MX2018011204A (es) 2016-03-15 2019-03-07 Mersana Therapeutics Inc Conjugados de anticuerpo-farmaco dirigidos a napi2b y sus metodos de uso.
HRP20240510T1 (hr) 2016-03-16 2024-07-05 Amal Therapeutics Sa Kombinacija modulatora imunosne kontrolne točke i kompleksa koji sadrži peptid koji prodire u stanicu, teretni i tlr peptidni agonist za uporabu u medicini
KR20190003686A (ko) 2016-05-04 2019-01-09 브리스톨-마이어스 스큅 컴퍼니 인돌아민 2,3-디옥시게나제의 억제제 및 그의 사용 방법
KR20190004743A (ko) 2016-05-04 2019-01-14 브리스톨-마이어스 스큅 컴퍼니 인돌아민 2,3-디옥시게나제의 억제제 및 그의 사용 방법
JP2019516687A (ja) 2016-05-04 2019-06-20 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ インドールアミン２，３−ジオキシゲナーゼ阻害剤およびその使用方法
EP3452030A4 (en) 2016-05-04 2019-11-13 Bristol-Myers Squibb Company INHIBITORS OF INDOLEAMINE-2,3-DIOXYGENASE AND METHOD FOR THEIR USE
EP3452450A1 (en) 2016-05-04 2019-03-13 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
KR20220103806A (ko) * 2016-05-18 2022-07-22 베링거 인겔하임 인터내셔날 게엠베하 암 치료용 항-pd1 및 항-lag3 항체
EP3468581A1 (en) 2016-06-13 2019-04-17 Torque Therapeutics, Inc. Methods and compositions for promoting immune cell function
WO2017220990A1 (en) 2016-06-20 2017-12-28 Kymab Limited Anti-pd-l1 antibodies
TW201831513A (zh) 2016-06-20 2018-09-01 Ｆ星貝塔有限公司 結合物件(一)
ES2858091T3 (es) * 2016-06-20 2021-09-29 F Star Therapeutics Ltd Moléculas de unión que se unen a PD-L1 y LAG-3
PL3476399T3 (pl) * 2016-06-23 2022-06-20 Jiangsu Hengrui Medicine Co. Ltd. Przeciwciało lag-3, jego fragment wiążący i jego zastosowanie farmaceutyczne
EP3478321A4 (en) 2016-06-30 2020-04-22 Oncorus, Inc. PSEUDOTYPIZED ONCOLYTIC VIRAL ADMINISTRATION OF THERAPEUTIC POLYPEPTIDES
GB201612520D0 (en) 2016-07-19 2016-08-31 F-Star Beta Ltd Binding molecules
CA3031542A1 (en) 2016-07-20 2018-01-25 University Of Utah Research Foundation Cd229 car t cells and methods of use thereof
US20190292179A1 (en) 2016-07-21 2019-09-26 Bristol-Myers Squibb Company TGF Beta RECEPTOR ANTAGONISTS
EA039718B1 (ru) * 2016-07-21 2022-03-03 Регенерон Фармасьютикалз, Инк. Антитела к lag3 и их применения
US11198730B2 (en) 2016-08-15 2021-12-14 Fuso Pharmaceutical Industries, Ltd. Anti-LAG-3 antibody
KR102585976B1 (ko) 2016-08-17 2023-10-05 컴퓨젠 엘티디. 항-tigit 항체, 항-pvrig 항체 및 이들의 조합
WO2018039518A1 (en) 2016-08-26 2018-03-01 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
UA126565C2 (uk) 2016-09-19 2022-11-02 Ай-Маб Байофарма (Ханчжоу) Ко., Лтд. Антитіло до гм-ксф
CA3031170A1 (en) 2016-09-21 2018-03-29 Amal Therapeutics Sa Fusion comprising a cell penetrating peptide, a multi epitope and a tlr peptide agonist for treatment of cancer
EP3518946A4 (en) 2016-09-27 2020-09-09 Board of Regents, The University of Texas System METHODS TO IMPROVE IMMUNE CHECKPOINT BLOCKING TREATMENT BY MODULATING THE MICROBIOME
TW202340473A (zh) 2016-10-07 2023-10-16 瑞士商諾華公司 利用嵌合抗原受體之癌症治療
KR102661905B1 (ko) 2016-10-12 2024-04-29 더 보드 오브 리젠츠 오브 더 유니버시티 오브 텍사스 시스템 Tusc2 면역요법을 위한 방법 및 조성물
EA201990912A1 (ru) * 2016-10-13 2019-10-31 Анти-lag-3 антитела и их композиции
US10660909B2 (en) 2016-11-17 2020-05-26 Syntrix Biosystems Inc. Method for treating cancer using chemokine antagonists
WO2018094275A1 (en) 2016-11-18 2018-05-24 Tolero Pharmaceuticals, Inc. Alvocidib prodrugs and their use as protein kinase inhibitors
US11135307B2 (en) 2016-11-23 2021-10-05 Mersana Therapeutics, Inc. Peptide-containing linkers for antibody-drug conjugates
BR112019010878A2 (pt) 2016-11-29 2019-10-01 Lindhofer Horst combinação de anticorpos multifuncionais de redirecionamento de células t com moduladores de ponto de verificação imunológico e usos dos mesmos
CN110248678A (zh) 2016-12-03 2019-09-17 朱诺治疗学股份有限公司 调节car-t细胞的方法
WO2018106738A1 (en) 2016-12-05 2018-06-14 Massachusetts Institute Of Technology Brush-arm star polymers, conjugates and particles, and uses thereof
BR112019011582A2 (pt) 2016-12-07 2019-10-22 Agenus Inc. anticorpos e métodos de utilização dos mesmos
JP2020510624A (ja) 2016-12-12 2020-04-09 マルチビア インコーポレイテッド がんおよび感染性疾患の治療および予防のための、ウイルス遺伝子治療および免疫チェックポイント阻害剤を含む方法および組成物
CN108204958A (zh) * 2016-12-19 2018-06-26 伊缪泰普有限公司 结合测定
WO2018132279A1 (en) 2017-01-05 2018-07-19 Bristol-Myers Squibb Company Tgf beta receptor antagonists
CA3047600A1 (en) 2017-01-20 2018-07-26 Arcus Biosciences, Inc. Azolopyrimidine for the treatment of cancer-related disorders
WO2018152687A1 (en) * 2017-02-22 2018-08-30 I-Mab Anti-lymphocyte activation gene-3 (lag-3) antibodies and uses thereof
KR102236259B1 (ko) * 2017-02-22 2021-04-06 아이-맵 바이오파마 유에스 리미티드 항-lag-3 항체 및 그것의 사용
WO2018160538A1 (en) 2017-02-28 2018-09-07 Mersana Therapeutics, Inc. Combination therapies of her2-targeted antibody-drug conjugates
CN110709420A (zh) 2017-03-31 2020-01-17 戊瑞治疗有限公司 使用抗gitr抗体的癌症组合疗法
RS63663B1 (sr) 2017-04-03 2022-11-30 Hoffmann La Roche Imunokonjugati anti-pd-1 antitela sa mutantom il-2 ili sa il-15
CA3052532A1 (en) * 2017-04-05 2018-10-11 F. Hoffmann-La Roche Ag Bispecific antibodies specifically binding to pd1 and lag3
JP2020513009A (ja) 2017-04-05 2020-04-30 シムフォゲン・アクティーゼルスカブＳｙｍｐｈｏｇｅｎ Ａ／Ｓ Ｐｄ−１、ｔｉｍ−３、およびｌａｇ−３を標的とする併用治療
BR112019021992A2 (pt) 2017-04-21 2020-06-09 Kyn Therapeutics inibidores de ahr de indol e usos dos mesmos
EP3615572A1 (en) * 2017-04-27 2020-03-04 Tesaro Inc. Antibody agents directed against lymphocyte activation gene-3 (lag-3) and uses thereof
AR111651A1 (es) 2017-04-28 2019-08-07 Novartis Ag Conjugados de anticuerpos que comprenden agonistas del receptor de tipo toll y terapias de combinación
MX2019012849A (es) 2017-04-28 2019-11-28 Five Prime Therapeutics Inc Metodos de tratamiento con polipeptidos del dominio extracelular del cd80.
US20200055948A1 (en) 2017-04-28 2020-02-20 Novartis Ag Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor
EP3615068A1 (en) 2017-04-28 2020-03-04 Novartis AG Bcma-targeting agent, and combination therapy with a gamma secretase inhibitor
WO2018209049A1 (en) 2017-05-12 2018-11-15 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US11220492B2 (en) 2017-05-17 2022-01-11 Arcus Biosciences, Inc. Quinazoline-pyrazole derivatives for the treatment of cancer-related disorders
CA3064333A1 (en) 2017-05-29 2018-12-06 Gamamabs Pharma Cancer-associated immunosuppression inhibitor
EP3630132A1 (en) 2017-06-02 2020-04-08 Juno Therapeutics, Inc. Articles of manufacture and methods for treatment using adoptive cell therapy
WO2018229715A1 (en) 2017-06-16 2018-12-20 Novartis Ag Compositions comprising anti-cd32b antibodies and methods of use thereof
JP2020524694A (ja) 2017-06-22 2020-08-20 ノバルティス アーゲー がんの処置における使用のためのＩＬ−１β結合性抗体
WO2018235056A1 (en) 2017-06-22 2018-12-27 Novartis Ag IL-1BETA BINDING ANTIBODIES FOR USE IN THE TREATMENT OF CANCER
MA49457A (fr) 2017-06-22 2020-04-29 Novartis Ag Molécules d'anticorps se liant à cd73 et leurs utilisations
WO2019006007A1 (en) 2017-06-27 2019-01-03 Novartis Ag POSOLOGICAL REGIMES FOR ANTI-TIM3 ANTIBODIES AND USES THEREOF
WO2019006427A1 (en) 2017-06-29 2019-01-03 Juno Therapeutics, Inc. WALL MODEL FOR ASSESSING TOXICITIES ASSOCIATED WITH IMMUNOTHERAPIES
EA202090119A1 (ru) 2017-06-30 2020-04-21 Бристол-Маерс Сквибб Компани Аморфные и кристаллические формы ido-ингибиторов
EP3649156A1 (en) 2017-07-06 2020-05-13 Merus N.V. Antibodies that modulate a biological activity expressed by a cell
EP3652212A4 (en) * 2017-07-13 2021-04-14 Nanjing Leads Biolabs Co., Ltd. LAG-3 BINDING ANTIBODIES AND USES THEREOF
AU2018302283A1 (en) 2017-07-20 2020-02-06 Novartis Ag Dosage regimens of anti-LAG-3 antibodies and uses thereof
JP7186764B2 (ja) 2017-07-28 2022-12-09 ブリストル－マイヤーズ スクイブ カンパニー 抗癌剤としての環状ジヌクレオチド
CN118772242A (zh) 2017-08-04 2024-10-15 拜斯科技术开发有限公司 Cd137特异性的双环肽配体
JP7269917B2 (ja) 2017-08-17 2023-05-09 イケナ オンコロジー， インコーポレイテッド Ａｈｒ阻害剤およびその使用
WO2019046496A1 (en) 2017-08-31 2019-03-07 Bristol-Myers Squibb Company CYCLIC DINUCLEOTIDES AS ANTICANCER AGENTS
KR102674630B1 (ko) 2017-08-31 2024-06-11 브리스톨-마이어스 스큅 컴퍼니 항암제로서의 시클릭 디뉴클레오티드
WO2019046498A1 (en) 2017-08-31 2019-03-07 Bristol-Myers Squibb Company CYCLIC DINUCLEOTIDES AS ANTICANCER AGENTS
WO2019055579A1 (en) 2017-09-12 2019-03-21 Tolero Pharmaceuticals, Inc. TREATMENT REGIME FOR CANCERS THAT ARE INSENSITIVE TO BCL-2 INHIBITORS USING THE MCL-1 ALVOCIDIB INHIBITOR
EP3684366A4 (en) 2017-09-22 2021-09-08 Kymera Therapeutics, Inc. CRBN LIGANDS AND USES OF THE LATEST
IL295603B2 (en) 2017-09-22 2024-03-01 Kymera Therapeutics Inc Protein compounds and their uses
US20200262917A1 (en) * 2017-10-05 2020-08-20 Daiichi Sankyo Company, Limited Composition for cytotoxic t cell depletion
US11203592B2 (en) 2017-10-09 2021-12-21 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2019074822A1 (en) 2017-10-09 2019-04-18 Bristol-Myers Squibb Company INDOLEAMINE 2,3-DIOXYGENASE INHIBITORS AND METHODS OF USE
US11660311B2 (en) 2017-10-10 2023-05-30 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
US11427610B2 (en) 2017-10-16 2022-08-30 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
CN111094339B (zh) * 2017-10-17 2023-01-24 江苏恒瑞医药股份有限公司 抗pd-1抗体和抗lag-3抗体联合在制备治疗肿瘤的药物中的用途
US20210040205A1 (en) 2017-10-25 2021-02-11 Novartis Ag Antibodies targeting cd32b and methods of use thereof
WO2019089969A2 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for b-cell maturation antigen
US12031975B2 (en) 2017-11-01 2024-07-09 Juno Therapeutics, Inc. Methods of assessing or monitoring a response to a cell therapy
CN111902159A (zh) 2017-11-01 2020-11-06 朱诺治疗学股份有限公司 对b细胞成熟抗原（bcma）具有特异性的嵌合抗原受体
WO2019090198A1 (en) 2017-11-06 2019-05-09 Bristol-Myers Squibb Company Isofuranone compounds useful as hpk1 inhibitors
KR20200089286A (ko) 2017-11-16 2020-07-24 노파르티스 아게 조합 요법
EP3717021A1 (en) 2017-11-27 2020-10-07 Mersana Therapeutics, Inc. Pyrrolobenzodiazepine antibody conjugates
RU2020121458A (ru) 2017-11-30 2021-12-30 Новартис Аг Химерный антигенный рецептор, нацеливающийся на bcma, и его пути применения
EP3724225A1 (en) 2017-12-15 2020-10-21 Juno Therapeutics, Inc. Anti-cct5 binding molecules and methods of use thereof
WO2019121906A1 (en) 2017-12-19 2019-06-27 F-Star Beta Limited Specific pd-l1 binding sequences inserted in a ch3 domain
EP3727463A1 (en) 2017-12-21 2020-10-28 Mersana Therapeutics, Inc. Pyrrolobenzodiazepine antibody conjugates
TW201927337A (zh) * 2017-12-22 2019-07-16 大陸商江蘇恆瑞醫藥股份有限公司 一種ｌａｇ－３抗體醫藥組成物及其用途
IL315310A (en) 2017-12-26 2024-10-01 Kymera Therapeutics Inc IRAK joints and used in them
WO2019129137A1 (zh) * 2017-12-27 2019-07-04 信达生物制药(苏州)有限公司 抗lag-3抗体及其用途
CN115925943A (zh) * 2017-12-27 2023-04-07 信达生物制药(苏州)有限公司 抗pd-l1抗体及其用途
CN109970856B (zh) * 2017-12-27 2022-08-23 信达生物制药(苏州)有限公司 抗lag-3抗体及其用途
WO2019133847A1 (en) 2017-12-29 2019-07-04 Oncorus, Inc. Oncolytic viral delivery of therapeutic polypeptides
US11447449B2 (en) 2018-01-05 2022-09-20 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN112218651A (zh) 2018-01-08 2021-01-12 诺华公司 用于与嵌合抗原受体疗法组合的免疫增强rna
US11512080B2 (en) 2018-01-12 2022-11-29 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
WO2019140380A1 (en) 2018-01-12 2019-07-18 Kymera Therapeutics, Inc. Protein degraders and uses thereof
CN111542546B (zh) * 2018-01-18 2022-08-16 四川科伦博泰生物医药股份有限公司 抗lag-3抗体及其用途
AU2019211485A1 (en) 2018-01-29 2020-08-06 Merck Patent Gmbh GCN2 inhibitors and uses thereof
CA3089769A1 (en) 2018-01-29 2019-08-01 Merck Patent Gmbh Gcn2 inhibitors and uses thereof
WO2019152660A1 (en) 2018-01-31 2019-08-08 Novartis Ag Combination therapy using a chimeric antigen receptor
JP7383620B2 (ja) 2018-01-31 2023-11-20 セルジーン コーポレイション 養子細胞療法およびチェックポイント阻害剤を使用する併用療法
EP3752203A1 (en) 2018-02-13 2020-12-23 Novartis AG Chimeric antigen receptor therapy in combination with il-15r and il15
US10519187B2 (en) 2018-02-13 2019-12-31 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
US12090142B2 (en) 2018-02-22 2024-09-17 Board Of Regents, The University Of Texas System Combination therapy for the treatment of cancer
WO2019165315A1 (en) 2018-02-23 2019-08-29 Syntrix Biosystems Inc. Method for treating cancer using chemokine antagonists alone or in combination
EP3762397B1 (en) 2018-03-08 2024-05-01 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
CA3094329A1 (en) 2018-03-19 2020-02-20 Multivir Inc. Methods and compositions comprising tumor suppressor gene therapy and cd122/cd132 agonists for the treatment of cancer
MX2020009550A (es) * 2018-03-22 2020-11-11 Keires Ag Proteinas de union a antigeno antagonistas.
US10760075B2 (en) 2018-04-30 2020-09-01 Snipr Biome Aps Treating and preventing microbial infections
AU2019246043B2 (en) 2018-03-25 2024-07-04 Snipr Biome Aps. Treating and preventing microbial infections
CN110343178B (zh) * 2018-04-03 2022-07-22 上海开拓者生物医药有限公司 抗人lag-3单克隆抗体及其应用
US20210147547A1 (en) 2018-04-13 2021-05-20 Novartis Ag Dosage Regimens For Anti-Pd-L1 Antibodies And Uses Thereof
US10973834B2 (en) 2018-04-16 2021-04-13 Arrys Therapeutics, Inc. EP4 inhibitors and use thereof
EP3784351A1 (en) 2018-04-27 2021-03-03 Novartis AG Car t cell therapies with enhanced efficacy
US20210396739A1 (en) 2018-05-01 2021-12-23 Novartis Ag Biomarkers for evaluating car-t cells to predict clinical outcome
US12037323B2 (en) 2018-05-03 2024-07-16 Bristol-Myers Squibb Company Uracil derivatives as Mer-AXL inhibitors
AR126019A1 (es) 2018-05-30 2023-09-06 Novartis Ag Anticuerpos frente a entpd2, terapias de combinación y métodos de uso de los anticuerpos y las terapias de combinación
WO2019232244A2 (en) 2018-05-31 2019-12-05 Novartis Ag Antibody molecules to cd73 and uses thereof
CN112384531B (zh) 2018-06-01 2024-05-14 诺华股份有限公司 针对bcma的结合分子及其用途
US20210171631A1 (en) * 2018-06-11 2021-06-10 Yale University Novel Immune Checkpoint Inhibitors
SG11202011830SA (en) 2018-06-13 2020-12-30 Novartis Ag Bcma chimeric antigen receptors and uses thereof
CN110606892B (zh) * 2018-06-14 2023-09-26 华博生物医药技术（上海）有限公司 一种高亲和力高生物活性的lag-3抗体及其应用
CN110615840A (zh) * 2018-06-19 2019-12-27 信达生物制药(苏州)有限公司 全人源的抗lag-3抗体及其应用
US11180531B2 (en) 2018-06-22 2021-11-23 Bicycletx Limited Bicyclic peptide ligands specific for Nectin-4
SG11202012972YA (en) 2018-06-27 2021-01-28 Bristol Myers Squibb Co Substituted naphthyridinone compounds useful as t cell activators
SI3814347T1 (sl) 2018-06-27 2023-07-31 Bristol-Myers Squibb Company Naftiridinonske spojine uporabne kot T celični aktivatorji
EP3817748A4 (en) 2018-07-06 2022-08-24 Kymera Therapeutics, Inc. TRICYCLIC CRBN LIGANDS AND USES THEREOF
AR116109A1 (es) 2018-07-10 2021-03-31 Novartis Ag Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos
JOP20210001A1 (ar) 2018-07-10 2021-01-05 Novartis Ag مشتقات 3-(5- هيدروكسي -1- أوكسو أيزو إندولين -2- يل) بيبريدين -2، 6- دايون واستخدامها لمعالجة أمراض مرتبطة ببروتين ذات أصبع الزنك من عائلة (ikaros 2 (ikzf2
GB201811408D0 (en) 2018-07-12 2018-08-29 F Star Beta Ltd CD137 Binding Molecules
EP3823989A2 (en) 2018-07-16 2021-05-26 Regeneron Pharmaceuticals, Inc. Anti-il36r antibodies
KR20210033503A (ko) 2018-07-18 2021-03-26 아르커스 바이오사이언시즈 인코포레이티드 아졸로피리미딘 화합물의 고체 형태
US12059420B2 (en) 2018-07-23 2024-08-13 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US20210355113A1 (en) 2018-07-23 2021-11-18 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2020021465A1 (en) 2018-07-25 2020-01-30 Advanced Accelerator Applications (Italy) S.R.L. Method of treatment of neuroendocrine tumors
KR102666754B1 (ko) * 2018-08-21 2024-05-17 에이비엘바이오 주식회사 항-pd-l1/항-lag3 이중 특이 항체 및 이의 용도
US11253525B2 (en) 2018-08-29 2022-02-22 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US10959986B2 (en) 2018-08-29 2021-03-30 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
JP2022500499A (ja) 2018-09-07 2022-01-04 ピク セラピューティクス， インコーポレイテッド Ｅｉｆ４ｅ阻害剤およびその使用
WO2020069409A1 (en) 2018-09-28 2020-04-02 Novartis Ag Cd19 chimeric antigen receptor (car) and cd22 car combination therapies
WO2020069405A1 (en) 2018-09-28 2020-04-02 Novartis Ag Cd22 chimeric antigen receptor (car) therapies
JP2022513400A (ja) 2018-10-29 2022-02-07 メルサナ セラピューティクス インコーポレイテッド ペプチド含有リンカーを有するシステイン操作抗体－薬物コンジュゲート
US20230053449A1 (en) 2018-10-31 2023-02-23 Novartis Ag Dc-sign antibody drug conjugates
MA54078A (fr) 2018-11-01 2021-09-15 Juno Therapeutics Inc Méthodes pour le traitement au moyen de récepteurs antigéniques chimériques spécifiques de l'antigene de maturation des lymphocytes b
JP2022506598A (ja) 2018-11-01 2022-01-17 ジュノー セラピューティクス インコーポレイテッド Ｇタンパク質共役受容体クラスｃグループ５メンバーｄ（ｇｐｒｃ５ｄ）に特異的なキメラ抗原受容体
WO2020102770A1 (en) 2018-11-16 2020-05-22 Juno Therapeutics, Inc. Methods of dosing engineered t cells for the treatment of b cell malignancies
SG11202105502RA (en) 2018-11-30 2021-06-29 Juno Therapeutics Inc Methods for treatment using adoptive cell therapy
EP3886904A4 (en) 2018-11-30 2022-07-13 Kymera Therapeutics, Inc. IRAQ-TYPE KINASE DEGRADING AGENTS AND THEIR USES
EP3890749A4 (en) 2018-12-04 2022-08-03 Sumitomo Dainippon Pharma Oncology, Inc. CDK9 INHIBITORS AND POLYMORPHS THEREOF FOR USE AS CANCER TREATMENT AGENT
LT3893924T (lt) * 2018-12-13 2024-10-10 argenx BV Antikūnai žmogaus komplemento faktoriui c2b ir jų panaudojimo būdai
EP3670659A1 (en) 2018-12-20 2020-06-24 Abivax Biomarkers, and uses in treatment of viral infections, inflammations, or cancer
JP2022514315A (ja) 2018-12-20 2022-02-10 ノバルティス アーゲー ３－（１－オキソイソインドリン－２－イル）ピペリジン－２，６－ジオン誘導体を含む投与計画及び薬剤組み合わせ
MX2021007271A (es) 2018-12-21 2021-07-15 Onxeo Nuevas moleculas de acido nucleico conjugado y sus usos.
EP3897613A1 (en) 2018-12-21 2021-10-27 Novartis AG Use of il-1beta binding antibodies
BR112021012037A2 (pt) 2018-12-21 2021-11-03 Ose Immunotherapeutics Molécula anti-pd-1/il-7 bifuncional
CA3119584A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1 beta antibodies in the treatment or prevention of myelodysplastic syndrome
WO2020128637A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1 binding antibodies in the treatment of a msi-h cancer
WO2020128620A1 (en) 2018-12-21 2020-06-25 Novartis Ag Use of il-1beta binding antibodies
JP2022518925A (ja) 2019-01-29 2022-03-17 ジュノー セラピューティクス インコーポレイテッド 受容体チロシンキナーゼ様オーファン受容体１（ｒｏｒ１）に特異的な抗体およびキメラ抗原受容体
WO2020167990A1 (en) 2019-02-12 2020-08-20 Tolero Pharmaceuticals, Inc. Formulations comprising heterocyclic protein kinase inhibitors
WO2020165374A1 (en) 2019-02-14 2020-08-20 Ose Immunotherapeutics Bifunctional molecule comprising il-15ra
JP7488826B2 (ja) 2019-02-15 2024-05-22 ノバルティス アーゲー 置換３－（１－オキソイソインドリン－２－イル）ピペリジン－２，６－ジオン誘導体及びその使用
JP7483732B2 (ja) 2019-02-15 2024-05-15 ノバルティス アーゲー ３－（１－オキソ－５－（ピペリジン－４－イル）イソインドリン－２－イル）ピペリジン－２，６－ジオン誘導体及びその使用
CN111620949A (zh) * 2019-02-28 2020-09-04 三生国健药业（上海）股份有限公司 结合人lag-3的抗体、其制备方法和用途
MX2021011320A (es) 2019-03-19 2021-12-10 Fundacio Privada Inst Dinvestigacio Oncològica De Vall Hebron Terapia de combinacion con omomyc y un anticuerpo que se une a pd-1 o a ctla-4 para el tratamiento del cancer.
WO2020191326A1 (en) 2019-03-20 2020-09-24 Sumitomo Dainippon Pharma Oncology, Inc. Treatment of acute myeloid leukemia (aml) with venetoclax failure
CA3133460A1 (en) 2019-03-22 2020-10-01 Sumitomo Dainippon Pharma Oncology, Inc. Compositions comprising pkm2 modulators and methods of treatment using the same
EP3946462A1 (en) 2019-04-02 2022-02-09 BicycleTX Limited Bicycle toxin conjugates and uses thereof
AU2020253633A1 (en) 2019-04-05 2021-11-04 Kymera Therapeutics, Inc. STAT degraders and uses thereof
EP3725370A1 (en) 2019-04-19 2020-10-21 ImmunoBrain Checkpoint, Inc. Modified anti-pd-l1 antibodies and methods and uses for treating a neurodegenerative disease
WO2020231713A1 (en) 2019-05-13 2020-11-19 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
WO2020231766A1 (en) 2019-05-13 2020-11-19 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
CN110320367A (zh) * 2019-05-30 2019-10-11 广州医科大学附属第一医院（广州呼吸中心） 基于lag-3的诊断试剂盒及其在帕金森病诊断产品上的应用
WO2020243423A1 (en) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Tead inhibitors and uses thereof
CN112079925A (zh) * 2019-06-13 2020-12-15 上海健信生物医药科技有限公司 靶向lag-3的抗体和双特异性抗体及其用途
JP2022539208A (ja) 2019-07-03 2022-09-07 スミトモ ファーマ オンコロジー， インコーポレイテッド チロシンキナーゼ非受容体１（ｔｎｋ１）阻害剤およびその使用
IT201900011676A1 (it) 2019-07-12 2021-01-12 St Superiore Di Sanita Anticorpo ricombinante umano contro il recettore di membrana LAG3, suoi usi medici e diagnostici.
WO2021026179A1 (en) 2019-08-06 2021-02-11 Bristol-Myers Squibb Company AGONISTS OF ROR GAMMAt
AR119821A1 (es) 2019-08-28 2022-01-12 Bristol Myers Squibb Co Compuestos de piridopirimidinonilo sustituidos útiles como activadores de células t
BR112022004451A2 (pt) 2019-09-13 2022-06-21 Nimbus Saturn Inc Antagonistas de hpk1 e usos dos mesmos
JP2022548881A (ja) 2019-09-18 2022-11-22 ノバルティス アーゲー Ｅｎｔｐｄ２抗体、組合せ療法並びに抗体及び組合せ療法を使用する方法
IL292347A (en) 2019-10-21 2022-06-01 Novartis Ag Combination treatments with ventoclax and tim-3 inhibitors
AU2020370832A1 (en) 2019-10-21 2022-05-19 Novartis Ag TIM-3 inhibitors and uses thereof
EP4049675A4 (en) * 2019-10-25 2023-11-22 Daiichi Sankyo Company, Limited COMBINATION OF ANTI-GARP ANTIBODY AND IMMUNOREGULATOR
BR112022009514A2 (pt) 2019-11-19 2022-08-16 Bristol Myers Squibb Co Compostos úteis como inibidores de proteína helios
CN115279764A (zh) 2019-11-26 2022-11-01 医肯纳肿瘤学公司 多晶型咔唑衍生物及其用途
US11975026B2 (en) 2019-11-26 2024-05-07 Novartis Ag CD19 and CD22 chimeric antigen receptors and uses thereof
US20230052523A1 (en) 2019-11-26 2023-02-16 Bristol-Myers Squibb Company Salts/cocrystals of (r)-n-(4-chlorophenyl)-2-((1s,4s)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide
WO2021113644A1 (en) 2019-12-05 2021-06-10 Multivir Inc. Combinations comprising a cd8+ t cell enhancer, an immune checkpoint inhibitor and radiotherapy for targeted and abscopal effects for the treatment of cancer
EP4076520A4 (en) 2019-12-17 2024-03-27 Kymera Therapeutics, Inc. IRAQ DEGRADERS AND USES THEREOF
EP4076524A4 (en) 2019-12-17 2023-11-29 Kymera Therapeutics, Inc. IRAQ DEGRADERS AND USES THEREOF
AU2020406083A1 (en) 2019-12-17 2022-06-16 Boehringer Ingelheim International Gmbh Bifunctional molecules comprising an IL-7 variant
CA3165399A1 (en) 2019-12-20 2021-06-24 Novartis Ag Uses of anti-tgf-beta antibodies and checkpoint inhibitors for the treatment of proliferative diseases
WO2021126967A1 (en) * 2019-12-20 2021-06-24 Merck Sharp & Dohme Corp. Lag3 antagonist cell based potency assay
WO2021133751A1 (en) 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Substituted quinazolinyl compounds useful as t cell activators
AR120823A1 (es) 2019-12-23 2022-03-23 Bristol Myers Squibb Co Compuestos bicíclicos sustituidos útiles como activadores de células t
IL294270A (en) 2019-12-23 2022-08-01 Bristol Myers Squibb Co Substituted piperazine derivatives are useful as t-cell activators
CN114846015B (zh) 2019-12-23 2024-07-30 百时美施贵宝公司 用作t细胞激活剂的经取代的杂芳基化合物
BR112022012410A2 (pt) 2019-12-23 2022-08-30 Kymera Therapeutics Inc Degradadores smarca e usos dos mesmos
JP2023508055A (ja) 2019-12-23 2023-02-28 ブリストル－マイヤーズ スクイブ カンパニー Ｔ細胞アクティベーターとして有用な置換キノリノニルピペラジン化合物
JP2023517794A (ja) 2020-01-06 2023-04-27 ハイファイバイオ（ホンコン）リミテッド 抗ｔｎｆｒ２抗体及びその使用
AR121047A1 (es) 2020-01-15 2022-04-13 Blueprint Medicines Corp Inhibidores de map4k1
US20230058489A1 (en) 2020-01-17 2023-02-23 Novartis Ag Combination comprising a tim-3 inhibitor and a hypomethylating agent for use in treating myelodysplastic syndrome or chronic myelomonocytic leukemia
MX2022010944A (es) 2020-03-03 2022-11-09 Pic Therapeutics Inc Inhibidores del factor de iniciacion de traduccion eucariotica 4e (eif4e) y sus usos.
KR20220155593A (ko) 2020-03-19 2022-11-23 아르커스 바이오사이언시즈 인코포레이티드 Hif-2알파의 억제제로서의 테트랄린 및 테트라히드로퀴놀린 화합물
BR112022018678A2 (pt) 2020-03-19 2022-11-01 Kymera Therapeutics Inc Degradadores de mdm2 e usos dos mesmos
TW202140441A (zh) 2020-03-23 2021-11-01 美商必治妥美雅史谷比公司 經取代之側氧基異吲哚啉化合物
KR20230009386A (ko) 2020-04-10 2023-01-17 주노 쎄러퓨티크스 인코퍼레이티드 Ｂ-세포 성숙 항원을 표적화하는 키메라 항원 수용체로 조작된 세포 요법 관련 방법 및 용도
AU2021284273A1 (en) 2020-06-02 2022-12-15 Arcus Biosciences, Inc. Antibodies to TIGIT
WO2021245071A1 (en) 2020-06-03 2021-12-09 Mv Biotherapeutics Sa Combination of an atp-hydrolyzing enzyme and an immune checkpoint modulator and uses thereof
TW202210483A (zh) 2020-06-03 2022-03-16 美商凱麥拉醫療公司 Irak降解劑之結晶型
CN111808192B (zh) 2020-06-05 2022-02-15 北京天广实生物技术股份有限公司 结合lag3的抗体及其用途
WO2021258010A1 (en) 2020-06-19 2021-12-23 Gossamer Bio Services, Inc. Oxime compounds useful as t cell activators
AR122644A1 (es) 2020-06-19 2022-09-28 Onxeo Nuevas moléculas de ácido nucleico conjugado y sus usos
US20230321067A1 (en) 2020-06-23 2023-10-12 Novartis Ag Dosing regimen comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
AU2021316053A1 (en) 2020-07-30 2023-03-02 Kymera Therapeutics, Inc. Methods of treating mutant lymphomas
JP2023536164A (ja) 2020-08-03 2023-08-23 ノバルティス アーゲー ヘテロアリール置換３－（１－オキソイソインドリン－２－イル）ピペリジン－２，６－ジオン誘導体及びその使用
CN116724051A (zh) 2020-08-10 2023-09-08 上海寻百会生物技术有限公司 用于通过靶向igsf8来治疗自身免疫性疾病和癌症的组合物和方法
KR20230074721A (ko) 2020-08-17 2023-05-31 바이사이클티엑스 리미티드 Nectin-4에 특이적인 이환 콘쥬게이트 및 이의 용도
US20230338587A1 (en) 2020-08-31 2023-10-26 Advanced Accelerator Applications International Sa Method of treating psma-expressing cancers
WO2022043557A1 (en) 2020-08-31 2022-03-03 Advanced Accelerator Applications International Sa Method of treating psma-expressing cancers
AU2021341521A1 (en) 2020-09-14 2023-03-30 Boehringer Ingelheim International Gmbh Heterologous prime boost vaccine
WO2022074206A1 (en) 2020-10-08 2022-04-14 Affimed Gmbh Trispecific binders
CA3198456A1 (en) 2020-10-14 2022-04-21 Five Prime Therapeutics, Inc. Anti-c-c chemokine receptor 8 (ccr8) antibodies and methods of use thereof
IL302569A (en) 2020-11-06 2023-07-01 Novartis Ag CD19 binding molecules and their uses
WO2022112198A1 (en) 2020-11-24 2022-06-02 Worldwide Innovative Network Method to select the optimal immune checkpoint therapies
JP2024508207A (ja) 2020-12-02 2024-02-26 ブイアイビー ブイゼットダブリュ がんに対する組み合わせ治療におけるｌｔｂｒアゴニスト
WO2022120353A1 (en) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Tead inhibitors and uses thereof
CN117015531A (zh) 2020-12-02 2023-11-07 医肯纳肿瘤学公司 Tead抑制剂及其用途
CN114621344B (zh) * 2020-12-10 2022-08-30 北京东方百泰生物科技股份有限公司 一种抗lag-3单克隆抗体的纯化方法
TW202237119A (zh) 2020-12-10 2022-10-01 美商住友製藥腫瘤公司 Ａｌｋ﹘５抑制劑和彼之用途
WO2022133083A1 (en) 2020-12-16 2022-06-23 Gossamer Bio Services, Inc. Compounds useful as t cell activators
WO2022148781A1 (en) 2021-01-05 2022-07-14 Institut Curie Combination of mcoln activators and immune checkpoint inhibitors
US20240325554A1 (en) 2021-01-11 2024-10-03 Bicycle TX Limited Methods for treating cancer
KR20230153387A (ko) 2021-02-02 2023-11-06 리미널 바이오사이언시스 리미티드 Gpr84 길항제 및 이의 용도
EP4288430A1 (en) 2021-02-02 2023-12-13 Liminal Biosciences Limited Gpr84 antagonists and uses thereof
MX2023009100A (es) 2021-02-03 2023-09-25 Mozart Therapeutics Inc Agentes aglutinantes y métodos para usar los mismos.
WO2022169921A1 (en) 2021-02-04 2022-08-11 Bristol-Myers Squibb Company Benzofuran compounds as sting agonists
CR20230382A (es) 2021-02-12 2023-09-06 Hoffmann La Roche Derivados de tetrahidroazepina bicíclicos para el tratamiento del cáncer
AU2022220869A1 (en) 2021-02-15 2023-08-24 Kymera Therapeutics, Inc. Irak4 degraders and uses thereof
US20220275090A1 (en) 2021-02-22 2022-09-01 Janssen Biotech, Inc. Combination Therapies with Anti-CD38 Antibodies and PARP or Adenosine Receptor Inhibitors
CN117295737A (zh) 2021-03-05 2023-12-26 林伯士萨顿公司 Hpk1拮抗剂和其用途
WO2022192145A1 (en) 2021-03-08 2022-09-15 Blueprint Medicines Corporation Map4k1 inhibitors
WO2022197641A1 (en) 2021-03-15 2022-09-22 Rapt Therapeutics, Inc. 1h-pyrazolo[3,4-d]pyrimidin-6-yl-amine derivatives as hematopoietic progenitor kinase 1 (hpk1) modulators and/or inhibitors for the treatment of cancer and other diseases
EP4313989A1 (en) 2021-03-29 2024-02-07 Nimbus Saturn, Inc. Hpk1 antagonists and uses thereof
AU2022253450A1 (en) 2021-04-05 2023-11-16 Bristol-Myers Squibb Company Pyridinyl substituted oxoisoindoline compounds for the treatment of cancer
TW202304881A (zh) 2021-04-06 2023-02-01 美商必治妥美雅史谷比公司 經吡啶基取代之側氧基異吲哚啉化合物
TW202304979A (zh) 2021-04-07 2023-02-01 瑞士商諾華公司 抗ＴＧＦβ抗體及其他治療劑用於治療增殖性疾病之用途
US20240182571A1 (en) 2021-04-09 2024-06-06 Ose Immunotherapeutics New scaffold for bifunctional molecules with improved properties
EP4320156A1 (en) 2021-04-09 2024-02-14 Ose Immunotherapeutics Scaffold for bifunctioanl molecules comprising pd-1 or cd28 and sirp binding domains
PE20240327A1 (es) 2021-04-13 2024-02-22 Nuvalent Inc Heterociclos con sustitucion amino para tratar canceres con mutaciones de egfr
IL307673A (en) 2021-04-16 2023-12-01 Ikena Oncology Inc MEK inhibitors and their use
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
AR125874A1 (es) 2021-05-18 2023-08-23 Novartis Ag Terapias de combinación
JP2024521706A (ja) 2021-05-21 2024-06-04 アーカス バイオサイエンシーズ，インコーポレーテッド Ａｘｌ化合物
JP2024521712A (ja) 2021-05-21 2024-06-04 アーカス バイオサイエンシーズ，インコーポレーテッド Ａｘｌ阻害化合物
CA3218786A1 (en) 2021-05-25 2022-12-01 Lifei HOU C-x-c motif chemokine receptor 6 (cxcr6) binding molecules, and methods of using the same
TW202307210A (zh) 2021-06-01 2023-02-16 瑞士商諾華公司 Ｃｄ１９和ｃｄ２２嵌合抗原受體及其用途
TW202321237A (zh) 2021-07-14 2023-06-01 美商纜圖藥品公司 Ｍａｐ４ｋ１抑制劑
CN117940406A (zh) 2021-07-15 2024-04-26 缆图药品公司 Map4k1抑制剂
JP2024529381A (ja) 2021-07-30 2024-08-06 アフィメド ゲーエムベーハー デュプレックスボディ
US20230134932A1 (en) 2021-08-25 2023-05-04 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
TW202315621A (zh) 2021-08-25 2023-04-16 美商皮克醫療公司 Ｅｉｆ４ｅ抑制劑及其用途
WO2023076876A1 (en) 2021-10-26 2023-05-04 Mozart Therapeutics, Inc. Modulation of immune responses to viral vectors
KR20240110814A (ko) 2021-10-29 2024-07-16 아르커스 바이오사이언시즈 인코포레이티드 Hif-2알파의 저해제 및 이의 사용 방법
US20230136301A1 (en) 2021-11-03 2023-05-04 Janssen Biotech, Inc. Corticosteriod Reduction in Treatment with Anti-CD38 Antibody
CN118660964A (zh) 2021-12-16 2024-09-17 瓦莱里奥治疗公司 新型缀合核酸分子及其用途
WO2023114984A1 (en) 2021-12-17 2023-06-22 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2023122777A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Oxime derivatives useful as t cell activators
WO2023122778A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Pyridazinone derivatives useful as t cell activators
WO2023122772A1 (en) 2021-12-22 2023-06-29 Gossamer Bio Services, Inc. Oxime derivatives useful as t cell activators
WO2023147594A2 (en) 2022-01-31 2023-08-03 Kymera Therapeutics, Inc. Irak degraders and uses thereof
WO2023150186A1 (en) 2022-02-01 2023-08-10 Arvinas Operations, Inc. Dgk targeting compounds and uses thereof
WO2023173053A1 (en) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Mek inhibitors and uses thereof
WO2023173057A1 (en) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Mek inhibitors and uses thereof
WO2023178201A2 (en) * 2022-03-15 2023-09-21 The Board Of Trustees Of The Leland Stanford Junior University Methods of identifying anti-lag-3 agents
WO2023211889A1 (en) 2022-04-25 2023-11-02 Ikena Oncology, Inc. Polymorphic compounds and uses thereof
WO2023214325A1 (en) 2022-05-05 2023-11-09 Novartis Ag Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors
TW202404581A (zh) 2022-05-25 2024-02-01 美商醫肯納腫瘤學公司 Ｍｅｋ抑制劑及其用途
WO2023250400A1 (en) 2022-06-22 2023-12-28 Juno Therapeutics, Inc. Treatment methods for second line therapy of cd19-targeted car t cells
GB202209518D0 (en) 2022-06-29 2022-08-10 Snipr Biome Aps Treating & preventing E coli infections
WO2024003360A1 (en) 2022-07-01 2024-01-04 Institut Curie Biomarkers and uses thereof for the treatment of neuroblastoma
US20240124490A1 (en) 2022-07-15 2024-04-18 Arcus Biosciences, Inc. Inhibitors of hpk1 and methods of use thereof
WO2024020034A1 (en) 2022-07-20 2024-01-25 Arcus Biosciences, Inc. Cbl-b inhibitors and methods of use thereof
TW202416972A (zh) 2022-08-02 2024-05-01 英商利米那生物科技有限公司 經取代之吡啶酮gpr84拮抗劑及其用途
WO2024028364A1 (en) 2022-08-02 2024-02-08 Liminal Biosciences Limited Aryl-triazolyl and related gpr84 antagonists and uses thereof
WO2024028386A1 (en) 2022-08-02 2024-02-08 Ose Immunotherapeutics Multifunctional molecule directed against cd28
TW202416950A (zh) 2022-08-02 2024-05-01 英商利米那生物科技有限公司 雜芳基甲醯胺及相關gpr84拮抗劑及其用途
WO2024031091A2 (en) 2022-08-05 2024-02-08 Juno Therapeutics, Inc. Chimeric antigen receptors specific for gprc5d and bcma
WO2024036100A1 (en) 2022-08-08 2024-02-15 Bristol-Myers Squibb Company Substituted tetrazolyl compounds useful as t cell activators
WO2024036101A1 (en) 2022-08-09 2024-02-15 Bristol-Myers Squibb Company Tertiary amine substituted bicyclic compounds useful as t cell activators
WO2024033388A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
TW202417001A (zh) 2022-08-11 2024-05-01 瑞士商赫孚孟拉羅股份公司 雙環四氫吖呯衍生物
WO2024033457A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024033389A1 (en) 2022-08-11 2024-02-15 F. Hoffmann-La Roche Ag Bicyclic tetrahydrothiazepine derivatives
WO2024059142A1 (en) 2022-09-14 2024-03-21 Arcus Biosciences, Inc. Dispersions of etrumadenant
WO2024081385A1 (en) 2022-10-14 2024-04-18 Arcus Biosciences, Inc. Hpk1 inhibitors and methods of use thereof
US20240180947A1 (en) 2022-10-20 2024-06-06 Arcus Biosciences, Inc. Lyophilized formulations of cd73 compounds
US20240208961A1 (en) 2022-11-22 2024-06-27 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
WO2024129778A2 (en) 2022-12-13 2024-06-20 Juno Therapeutics, Inc. Chimeric antigen receptors specific for baff-r and cd19 and methods and uses thereof
WO2024137865A1 (en) 2022-12-22 2024-06-27 Gossamer Bio Services, Inc. Compounds useful as t cell activators
WO2024163477A1 (en) 2023-01-31 2024-08-08 University Of Rochester Immune checkpoint blockade therapy for treating staphylococcus aureus infections
WO2024200826A1 (en) 2023-03-30 2024-10-03 Ose Immunotherapeutics Lipid-based nanoparticle targeted at activated immune cells for the expression of immune cell inhibiting molecule and use thereof
WO2024200823A1 (en) 2023-03-30 2024-10-03 Ose Immunotherapeutics Lipid-based nanoparticle targeted at activated immune cells for the expression of immune cell enhancing molecule and use thereof

Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5773578A (en) * 1990-01-08 1998-06-30 Institut National De La Sante Et De La Recherche Medicale Proteins produced by human lymphocytes, DNA sequence encoding these proteins and their pharmaceutical and biological use
USRE36313E (en) * 1993-07-23 1999-09-28 Westinghouse Air Brake Company Disc brake shoe assembly
US5976877A (en) * 1990-01-08 1999-11-02 Institut National De La Sante Et De La Recherche Medicale (Inserm) Proteins produced by human lymphocytes DNA sequence encoding these proteins and their pharmaceutical and biological uses
US6143273A (en) * 1994-05-06 2000-11-07 Institut Gustave Roussy Therapeutic composition containing antibodies to soluble polypeptide fractions of LAG-3 protein
US6197524B1 (en) * 1995-07-21 2001-03-06 Institute National De La Sante Et De La Recherche Medicale Methods for detecting, identifying, isolating, and selectively labelling and targeting TH1 lymphocyte by means of the LAG-3 protein
US20020086014A1 (en) * 1999-08-24 2002-07-04 Korman Alan J. Human CTLA-4 antibodies and their uses
US20020146753A1 (en) * 2001-04-06 2002-10-10 Henrik Ditzel Autoantibodies to glucose-6-phosphate isomerase and their participation in autoimmune disease
US6482925B1 (en) * 1996-11-28 2002-11-19 Applied Research Systems Ars Holding N.V. Mutants of the LAG-3 proteins and nucleotides encoding LAG-3 mutants
US20030059937A1 (en) * 2000-06-16 2003-03-27 Ruben Steven M. Antibodies that immunospecifically bind BLyS
US20030129601A1 (en) * 2001-02-22 2003-07-10 Cole Stewart T. Comparative mycobacterial genomics as a tool for identifying targets for the diagnosis, prophylaxis or treatment of mycobacterioses
US20040072164A1 (en) * 2001-09-19 2004-04-15 Toshiaki Maruyama Engineered templates and their use in single primer amplification
US20040171551A1 (en) * 2001-09-19 2004-09-02 Institut Gustave Roussy - Igr, A Corporation Of France Molecules binding to Glu-Pro motifs, therapeutic compositions containing them and their applications
US20050009136A1 (en) * 2003-02-19 2005-01-13 Dyax Corporation PAPP-A ligands
US20050226876A1 (en) * 2004-04-13 2005-10-13 Yvo Graus Anti-P-selectin antibodies
US20060177442A1 (en) * 2004-10-01 2006-08-10 Medarex, Inc. Method of treating CD30 positive lymphomas
US20060240024A1 (en) * 2003-02-28 2006-10-26 The Johns Hopkins University T cell regulation
US20070004910A1 (en) * 2004-08-03 2007-01-04 Sexton Daniel J HK1-binding proteins
US20070160598A1 (en) * 2005-11-07 2007-07-12 Dennis Mark S Binding polypeptides with diversified and consensus vh/vl hypervariable sequences
US20080069822A1 (en) * 2005-12-05 2008-03-20 Symphogen A/S Anti-orthopoxvirus recombinant polyclonal antibody
US20080260641A1 (en) * 2004-04-20 2008-10-23 Jessica Teeling Human Monoclonal Antibodies Against Cd20

Family Cites Families (132)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US153043A (en) 1874-07-14 Improvement in middlings-separators
US5179017A (en) 1980-02-25 1993-01-12 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4399216A (en) 1980-02-25 1983-08-16 The Trustees Of Columbia University Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4634665A (en) 1980-02-25 1987-01-06 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4475196A (en) 1981-03-06 1984-10-02 Zor Clair G Instrument for locating faults in aircraft passenger reading light and attendant call control system
US4447233A (en) 1981-04-10 1984-05-08 Parker-Hannifin Corporation Medication infusion pump
US4439196A (en) 1982-03-18 1984-03-27 Merck & Co., Inc. Osmotic drug delivery system
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US4447224A (en) 1982-09-20 1984-05-08 Infusaid Corporation Variable flow implantable infusion apparatus
US4487603A (en) 1982-11-26 1984-12-11 Cordis Corporation Implantable microinfusion pump system
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4486194A (en) 1983-06-08 1984-12-04 James Ferrara Therapeutic device for administering medicaments through the skin
DE3572982D1 (en) 1984-03-06 1989-10-19 Takeda Chemical Industries Ltd Chemically modified lymphokine and production thereof
US4596556A (en) 1985-03-25 1986-06-24 Bioject, Inc. Hypodermic injection apparatus
US5374548A (en) 1986-05-02 1994-12-20 Genentech, Inc. Methods and compositions for the attachment of proteins to liposomes using a glycophospholipid anchor
MX9203291A (es) 1985-06-26 1992-08-01 Liposome Co Inc Metodo para acoplamiento de liposomas.
GB8601597D0 (en) 1986-01-23 1986-02-26 Wilson R H Nucleotide sequences
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
JP3101690B2 (ja) 1987-03-18 2000-10-23 エス・ビィ・２・インコーポレイテッド 変性抗体の、または変性抗体に関する改良
US4790824A (en) 1987-06-19 1988-12-13 Bioject, Inc. Non-invasive hypodermic injection device
US4941880A (en) 1987-06-19 1990-07-17 Bioject, Inc. Pre-filled ampule and non-invasive hypodermic injection device assembly
GB8717430D0 (en) 1987-07-23 1987-08-26 Celltech Ltd Recombinant dna product
US5677425A (en) 1987-09-04 1997-10-14 Celltech Therapeutics Limited Recombinant antibody
GB8809129D0 (en) 1988-04-18 1988-05-18 Celltech Ltd Recombinant dna methods vectors and host cells
US5476996A (en) 1988-06-14 1995-12-19 Lidak Pharmaceuticals Human immune system in non-human animal
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
GB8823869D0 (en) 1988-10-12 1988-11-16 Medical Res Council Production of antibodies
CA2006596C (en) 1988-12-22 2000-09-05 Rika Ishikawa Chemically-modified g-csf
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5108921A (en) 1989-04-03 1992-04-28 Purdue Research Foundation Method for enhanced transmembrane transport of exogenous molecules
US5064413A (en) 1989-11-09 1991-11-12 Bioject, Inc. Needleless hypodermic injection device
US5312335A (en) 1989-11-09 1994-05-17 Bioject Inc. Needleless hypodermic injection device
DE69120146T2 (de) 1990-01-12 1996-12-12 Cell Genesys Inc Erzeugung xenogener antikörper
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
US6673986B1 (en) 1990-01-12 2004-01-06 Abgenix, Inc. Generation of xenogeneic antibodies
US6150584A (en) 1990-01-12 2000-11-21 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
US6172197B1 (en) 1991-07-10 2001-01-09 Medical Research Council Methods for producing members of specific binding pairs
GB9015198D0 (en) 1990-07-10 1990-08-29 Brien Caroline J O Binding substance
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5877397A (en) 1990-08-29 1999-03-02 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5789650A (en) 1990-08-29 1998-08-04 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5770429A (en) 1990-08-29 1998-06-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US6300129B1 (en) 1990-08-29 2001-10-09 Genpharm International Transgenic non-human animals for producing heterologous antibodies
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
US5874299A (en) 1990-08-29 1999-02-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
DK0814159T3 (da) 1990-08-29 2005-10-24 Genpharm Int Transgene, ikke-humane dyr, der er i stand til at danne heterologe antistoffer
US6255458B1 (en) 1990-08-29 2001-07-03 Genpharm International High affinity human antibodies and human antibodies against digoxin
GB9108652D0 (en) 1991-04-23 1991-06-12 Antisoma Ltd Immunoreactive compounds
ES2313867T3 (es) 1991-12-02 2009-03-16 Medical Research Council Produccion de anticuerpos anti-auto de repertorios de segmentos de anticuerpo expresados en la superficie de fagos.
CA2124967C (en) 1991-12-17 2008-04-08 Nils Lonberg Transgenic non-human animals capable of producing heterologous antibodies
US5714350A (en) 1992-03-09 1998-02-03 Protein Design Labs, Inc. Increasing antibody affinity by altering glycosylation in the immunoglobulin variable region
EP0640094A1 (en) 1992-04-24 1995-03-01 The Board Of Regents, The University Of Texas System Recombinant production of immunoglobulin-like domains in prokaryotic cells
US5383851A (en) 1992-07-24 1995-01-24 Bioject Inc. Needleless hypodermic injection device
EP0671927B1 (en) 1992-09-16 2003-01-15 The Scripps Research Institute Human neutralizing monoclonal antibodies to respiratory syncytial virus
JP3919830B2 (ja) 1992-11-28 2007-05-30 財団法人化学及血清療法研究所 抗ネコヘルペスウイルス−１組換え抗体および該抗体をコードする遺伝子断片
CA2161351C (en) 1993-04-26 2010-12-21 Nils Lonberg Transgenic non-human animals capable of producing heterologous antibodies
EP0714409A1 (en) 1993-06-16 1996-06-05 Celltech Therapeutics Limited Antibodies
AU1866895A (en) 1994-01-04 1995-08-01 Scripps Research Institute, The Human monoclonal antibodies to herpes simplex virus and methods therefor
US6121022A (en) 1995-04-14 2000-09-19 Genentech, Inc. Altered polypeptides with increased half-life
US5869046A (en) 1995-04-14 1999-02-09 Genentech, Inc. Altered polypeptides with increased half-life
US6410690B1 (en) 1995-06-07 2002-06-25 Medarex, Inc. Therapeutic compounds comprised of anti-Fc receptor antibodies
US5811097A (en) 1995-07-25 1998-09-22 The Regents Of The University Of California Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
US6090382A (en) 1996-02-09 2000-07-18 Basf Aktiengesellschaft Human antibodies that bind human TNFα
KR19990087557A (ko) * 1996-03-07 1999-12-27 그윈넬 해리 제이 근적외선 형광 비밀정보의 열전사 인쇄 및 표시용 리본
US5922845A (en) 1996-07-11 1999-07-13 Medarex, Inc. Therapeutic multispecific compounds comprised of anti-Fcα receptor antibodies
CA2272130C (en) * 1996-11-29 2007-10-23 Applied Research Systems Ars Holding N.V. Methods for preventing graft rejection in transplantation and for producing a universal gene therapy host cell using lymphocyte activation (lag-3)
US6277375B1 (en) 1997-03-03 2001-08-21 Board Of Regents, The University Of Texas System Immunoglobulin-like domains with increased half-lives
AU6703198A (en) 1997-03-21 1998-10-20 Brigham And Women's Hospital Immunotherapeutic ctla-4 binding peptides
DE69833755T2 (de) 1997-05-21 2006-12-28 Biovation Ltd. Verfahren zur herstellung von nicht-immunogenen proteinen
EP0900841A1 (en) 1997-06-18 1999-03-10 Institut National De La Sante Et De La Recherche Medicale (Inserm) LAG-3 splice variants
US6194551B1 (en) 1998-04-02 2001-02-27 Genentech, Inc. Polypeptide variants
AU3657899A (en) 1998-04-20 1999-11-08 James E. Bailey Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity
GB9814383D0 (en) 1998-07-02 1998-09-02 Cambridge Antibody Tech Improvements relating to antibodies
WO2000005266A1 (en) 1998-07-21 2000-02-03 Connex Gesellschaft Zur Optimierung Von Forschung Und Entwicklung Mbh Anti hepatitis c virus antibody and uses thereof
JP3793693B2 (ja) 1998-12-23 2006-07-05 ファイザー インコーポレーテッド Ｃｔｌａ−４に対するヒトモノクローナル抗体
KR101155191B1 (ko) 1999-01-15 2012-06-13 제넨테크, 인크. 효과기 기능이 변화된 폴리펩티드 변이체
US6914128B1 (en) 1999-03-25 2005-07-05 Abbott Gmbh & Co. Kg Human antibodies that bind human IL-12 and methods for producing
ES2571230T3 (es) 1999-04-09 2016-05-24 Kyowa Hakko Kirin Co Ltd Procedimiento para controlar la actividad de una molécula inmunofuncional
GB9911569D0 (en) * 1999-05-18 1999-07-21 Oxford Biomedica Ltd Antibodies
DE60037896D1 (de) 1999-07-29 2008-03-13 Medarex Inc Menschliche antikörper gegen her2/neu
EP2360254A1 (en) 1999-08-23 2011-08-24 Dana-Farber Cancer Institute, Inc. Assays for screening anti-pd-1 antibodies and uses thereof
US6984720B1 (en) 1999-08-24 2006-01-10 Medarex, Inc. Human CTLA-4 antibodies
US6794132B2 (en) 1999-10-02 2004-09-21 Biosite, Inc. Human antibodies
US6818216B2 (en) 2000-11-28 2004-11-16 Medimmune, Inc. Anti-RSV antibodies
EP1916303B1 (en) 2000-11-30 2013-02-27 Medarex, Inc. Nucleic acids encoding rearranged human immunoglobulin sequences from transgenic transchromosomal mice
KR100583331B1 (ko) 2001-05-11 2006-05-26 기린 비루 가부시키가이샤 인간 항체 λ 경쇄 유전자를 포함하는 인간 인공 염색체 및 자손 전달 가능한 상기 인간 인공 염색체를 포함하는 비인간 동물
WO2002092780A2 (en) 2001-05-17 2002-11-21 Diversa Corporation Novel antigen binding molecules for therapeutic, diagnostic, prophylactic, enzymatic, industrial, and agricultural applications, and methods for generating and screening thereof
MXPA03011094A (es) 2001-05-31 2004-12-06 Medarex Inc Citotoxinas, profarmacos, ligadores, y estabilizadores utiles para ello.
HUP0600342A3 (en) 2001-10-25 2011-03-28 Genentech Inc Glycoprotein compositions
JP2005535290A (ja) 2002-02-22 2005-11-24 ジェネンテック・インコーポレーテッド 免疫関連疾患の治療のための組成物と方法
US20040110226A1 (en) 2002-03-01 2004-06-10 Xencor Antibody optimization
PL373256A1 (pl) 2002-04-09 2005-08-22 Kyowa Hakko Kogyo Co, Ltd. Komórki, których genom jest zmodyfikowany
AU2003230874A1 (en) 2002-04-16 2003-11-03 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
JP4409430B2 (ja) 2002-07-03 2010-02-03 小野薬品工業株式会社 免疫賦活組成物
EP2322201A3 (en) 2002-10-29 2011-07-27 Genentech, Inc. Compositions and methods for the treatment of immune related diseases
ATE532861T1 (de) 2003-09-04 2011-11-15 Medarex Inc Expressionsvektor
WO2005034733A2 (en) * 2003-10-08 2005-04-21 North Shore-Long Island Jewish Research Institute Methods and compositions for diagnosis and treatment of b cell chronic lymphocytic leukemia
EP1747021B1 (en) 2004-05-19 2015-09-09 E. R. Squibb & Sons, L.L.C. Self-immolative linkers and drug conjugates
RU2402548C2 (ru) 2004-05-19 2010-10-27 Медарекс, Инк. Химические линкеры и их конъюгаты
BRPI0513706A (pt) * 2004-07-20 2008-05-13 Symphogen As anticorpo policlonal recombinante anti-rhesus d e métodos de produção
EP1793858A4 (en) * 2004-09-08 2008-12-10 Univ Ohio State Res Found HUMAN MONOCLONAL ANTI-CTLA4 ANTIBODIES FOR CANCER TREATMENT
MX2007004176A (es) 2004-10-06 2007-06-15 Mayo Foundation B7-h1 y metodos de diagnosis, prognosis, y tratamiento de cancer.
US7875278B2 (en) 2005-02-18 2011-01-25 Medarex, Inc. Monoclonal antibodies against prostate specific membrane antigen (PSMA) lacking in fucosyl residues
KR20070108259A (ko) * 2005-03-23 2007-11-08 화이자 프로덕츠 인크. Ｃｔｌａ-4 항체와 호르몬 요법에 의한 전립선암의 치료법
US7714016B2 (en) 2005-04-08 2010-05-11 Medarex, Inc. Cytotoxic compounds and conjugates with cleavable substrates
CN117534755A (zh) 2005-05-09 2024-02-09 小野药品工业株式会社 程序性死亡-1(pd-1)的人单克隆抗体及使用抗pd-1抗体来治疗癌症的方法
BRPI0611766A2 (pt) 2005-06-08 2011-12-20 Dana Farber Cancer Inst Inc métodos e composições para o tratamento de infecções persistentes e cáncer por inibição da rota de morte celular programada
KR101888321B1 (ko) 2005-07-01 2018-08-13 이. 알. 스퀴부 앤드 선즈, 엘.엘.씨. 예정 사멸 리간드 1 (피디-엘1)에 대한 인간 모노클로날 항체
BRPI0617546A2 (pt) 2005-09-26 2011-07-26 Medarex Inc conjugado de fÁrmaco-anticorpo, formulaÇço farmacÊutica, mÉtodo para matar uma cÉlula de tumor, mÉtodo para retardar ou interromper o crescimento de um tumor em um sujeito mamÍfero e composto
BRPI0619331A2 (pt) 2005-10-26 2011-09-27 Medarex Inc método para fazer um composto para preparar um análogo de cbi cc-1065, método para preparar um análogo de cbi cc-1065 e composto
WO2007059404A2 (en) 2005-11-10 2007-05-24 Medarex, Inc. Duocarmycin derivatives as novel cytotoxic compounds and conjugates
WO2008007648A1 (fr) * 2006-07-10 2008-01-17 Institute For Antibodies Co., Ltd. Procédé de classification d'antigène, procédé d'identification d'antigène, procédé d'obtention d' un ensemble d'antigènes ou d'anticorps, procédés de construction d'un panel d'anticorps, anticorps et ens
WO2008073160A2 (en) 2006-08-17 2008-06-19 The Trustees Of Columbia University In The City Of New York Methods for converting or inducing protective immunity
CL2007003622A1 (es) 2006-12-13 2009-08-07 Medarex Inc Anticuerpo monoclonal humano anti-cd19; composicion que lo comprende; y metodo de inhibicion del crecimiento de celulas tumorales.
TWI412367B (zh) 2006-12-28 2013-10-21 Medarex Llc 化學鏈接劑與可裂解基質以及其之綴合物
JP2010519310A (ja) 2007-02-21 2010-06-03 メダレックス インコーポレイテッド 単一のアミノ酸を有する化学リンカーおよびその複合体
EP1987839A1 (en) 2007-04-30 2008-11-05 I.N.S.E.R.M. Institut National de la Sante et de la Recherche Medicale Cytotoxic anti-LAG-3 monoclonal antibody and its use in the treatment or prevention of organ transplant rejection and autoimmune disease
US20090028857A1 (en) * 2007-07-23 2009-01-29 Cell Genesys, Inc. Pd-1 antibodies in combination with a cytokine-secreting cell and methods of use thereof
HUE029164T2 (hu) 2007-09-14 2017-02-28 Univ Brussel Vrije Humán antigén-prezentáló sejtek T-sejteket stimuláló képességének fokozása és azok alkalmazása vakcinázásra
AU2008308956B2 (en) 2007-10-01 2013-03-14 Bristol-Myers Squibb Company Human antibodies that bind mesothelin, and uses thereof
CN101939028A (zh) 2007-11-30 2011-01-05 百时美施贵宝公司 针对蛋白酪氨酸激酶7(ptk7)的单克隆抗体伴侣分子偶联物
EA201000910A1 (ru) 2007-11-30 2011-04-29 Бристоль-Мейерз Сквибб Компани Конъюгат "моноклональное антитело против в7н4/лекарственное средство" и способы его применения
AR072999A1 (es) 2008-08-11 2010-10-06 Medarex Inc Anticuerpos humanos que se unen al gen 3 de activacion linfocitaria (lag-3) y los usos de estos
SG11201407190TA (en) 2012-05-15 2014-12-30 Bristol Myers Squibb Co Cancer immunotherapy by disrupting pd-1/pd-l1 signaling
AR091649A1 (es) 2012-07-02 2015-02-18 Bristol Myers Squibb Co Optimizacion de anticuerpos que se fijan al gen de activacion de linfocitos 3 (lag-3) y sus usos
SG11201708223QA (en) 2015-04-17 2017-11-29 Bristol Myers Squibb Co Compositions comprising a combination of an anti-pd-1 antibody and another antibody
WO2017037203A1 (en) 2015-09-02 2017-03-09 Immutep S.A.S. Anti-LAG-3 Antibodies
TWI756187B (zh) 2015-10-09 2022-03-01 美商再生元醫藥公司 抗ｌａｇ３抗體及其用途

Patent Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5773578A (en) * 1990-01-08 1998-06-30 Institut National De La Sante Et De La Recherche Medicale Proteins produced by human lymphocytes, DNA sequence encoding these proteins and their pharmaceutical and biological use
US5874250A (en) * 1990-01-08 1999-02-23 Institut National De La Sante Et De La Recherche Medicale (Inserm) DNA encoding for a protein containing the extracellular domain of lymphocyte activation gene 3
US5976877A (en) * 1990-01-08 1999-11-02 Institut National De La Sante Et De La Recherche Medicale (Inserm) Proteins produced by human lymphocytes DNA sequence encoding these proteins and their pharmaceutical and biological uses
USRE36313E (en) * 1993-07-23 1999-09-28 Westinghouse Air Brake Company Disc brake shoe assembly
US6143273A (en) * 1994-05-06 2000-11-07 Institut Gustave Roussy Therapeutic composition containing antibodies to soluble polypeptide fractions of LAG-3 protein
US6197524B1 (en) * 1995-07-21 2001-03-06 Institute National De La Sante Et De La Recherche Medicale Methods for detecting, identifying, isolating, and selectively labelling and targeting TH1 lymphocyte by means of the LAG-3 protein
US6482925B1 (en) * 1996-11-28 2002-11-19 Applied Research Systems Ars Holding N.V. Mutants of the LAG-3 proteins and nucleotides encoding LAG-3 mutants
US20020086014A1 (en) * 1999-08-24 2002-07-04 Korman Alan J. Human CTLA-4 antibodies and their uses
US7605238B2 (en) * 1999-08-24 2009-10-20 Medarex, Inc. Human CTLA-4 antibodies and their uses
US20030059937A1 (en) * 2000-06-16 2003-03-27 Ruben Steven M. Antibodies that immunospecifically bind BLyS
US7138501B2 (en) * 2000-06-16 2006-11-21 Human Genome Sciences, Inc. Antibodies that immunospecifically bind BLyS
US20030129601A1 (en) * 2001-02-22 2003-07-10 Cole Stewart T. Comparative mycobacterial genomics as a tool for identifying targets for the diagnosis, prophylaxis or treatment of mycobacterioses
US20020146753A1 (en) * 2001-04-06 2002-10-10 Henrik Ditzel Autoantibodies to glucose-6-phosphate isomerase and their participation in autoimmune disease
US7306906B2 (en) * 2001-09-19 2007-12-11 Alexion Pharmaceuticals, Inc. Engineered templates and their use in single primer amplification
US20040072164A1 (en) * 2001-09-19 2004-04-15 Toshiaki Maruyama Engineered templates and their use in single primer amplification
US20040171551A1 (en) * 2001-09-19 2004-09-02 Institut Gustave Roussy - Igr, A Corporation Of France Molecules binding to Glu-Pro motifs, therapeutic compositions containing them and their applications
US20050009136A1 (en) * 2003-02-19 2005-01-13 Dyax Corporation PAPP-A ligands
US20060240024A1 (en) * 2003-02-28 2006-10-26 The Johns Hopkins University T cell regulation
US20050226876A1 (en) * 2004-04-13 2005-10-13 Yvo Graus Anti-P-selectin antibodies
US7563441B2 (en) * 2004-04-13 2009-07-21 Hoffman-La Roche Inc. Anti-P-selectin antibodies
US20080260641A1 (en) * 2004-04-20 2008-10-23 Jessica Teeling Human Monoclonal Antibodies Against Cd20
US20070004910A1 (en) * 2004-08-03 2007-01-04 Sexton Daniel J HK1-binding proteins
US7329737B2 (en) * 2004-08-03 2008-02-12 Dyax Corp. Antibodies that bind hK-1
US20060177442A1 (en) * 2004-10-01 2006-08-10 Medarex, Inc. Method of treating CD30 positive lymphomas
US7790160B2 (en) * 2004-10-01 2010-09-07 Medarex, Inc. Method of treating CD30 positive lymphomas
US20070160598A1 (en) * 2005-11-07 2007-07-12 Dennis Mark S Binding polypeptides with diversified and consensus vh/vl hypervariable sequences
US20080069822A1 (en) * 2005-12-05 2008-03-20 Symphogen A/S Anti-orthopoxvirus recombinant polyclonal antibody
US7850965B2 (en) * 2005-12-05 2010-12-14 Symphogen A/S Anti-orthopoxvirus recombinant polyclonal antibody

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DE PASCALIS et al. "Grafting of abbreviated complementarity determining regions containing specificity determining residuesessential for ligand contact to engineer a less immunogenic humanzied monoclonal antibody", Journal of Immunology, 2002,Vol. 169, pages 3076- 3084. *
Edwards, B.M., et al. J. Mol. Biol. 2003;334:103-118 *
Khan, T., and Salunke, D.M. J. Immunol. 2014;192:5398-5405 *
MACCALLUM et al. "Antibody-antigen interactions: contact analysis and binding site topography",Journal of Molecular Biology, 1996. Vol. 262, pages 732-745. *
Poosarla, V.G., et al. Biotechnol. Bioengin. 2017;114(6):1331-1342 *
Torres, M., and Casadevall, A. Trends Immunol. 2008;91-97 *

Cited By (404)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10344089B2 (en) 2008-08-11 2019-07-09 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11512130B2 (en) 2008-08-11 2022-11-29 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11530267B2 (en) 2008-08-11 2022-12-20 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11236165B2 (en) 2008-08-11 2022-02-01 E.R. Squibb & Sons, L.L.C. Human antibodies that bind Lymphocyte Activation Gene-3 (LAG-3), and uses thereof
US11236164B2 (en) 2008-08-11 2022-02-01 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11236163B2 (en) 2008-08-11 2022-02-01 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11001630B2 (en) 2008-08-11 2021-05-11 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation Gene-3 (LAG-3), and uses thereof
US10988535B2 (en) 2008-08-11 2021-04-27 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US10988536B2 (en) 2008-08-11 2021-04-27 E.R. Squibb & Sons, L.L.C. Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US11066483B2 (en) 2010-11-30 2021-07-20 Chugai Seiyaku Kabushiki Kaisha Cytotoxicity-inducing therapeutic agent
US12006347B2 (en) 2010-12-22 2024-06-11 The Board Of Trustees Of The Leland Stanford Junior University Superagonists and antagonists of interleukin-2
AU2012275133B2 (en) * 2011-06-30 2017-08-17 Genzyme Corporation Inhibitors of T-cell activation
CN107988156A (zh) * 2011-06-30 2018-05-04 建新公司 T细胞活化的抑制剂
US9834604B2 (en) 2011-06-30 2017-12-05 Genzyme Corporation Inhibitors of T-cell activation
US12043665B2 (en) 2011-06-30 2024-07-23 Genzyme Corporation Inhibitors of T-cell activation
US11028170B2 (en) 2011-06-30 2021-06-08 Genzyme Corporation Inhibitors of T-cell activation
WO2013003761A1 (en) * 2011-06-30 2013-01-03 Genzyme Corporation Inhibitors of t-cell activation
CN103796681A (zh) * 2011-06-30 2014-05-14 建新公司 T细胞活化的抑制剂
RU2657440C2 (ru) * 2011-06-30 2018-06-13 Джензим Корпорейшн Ингибиторы т-клеточной активации
US9505839B2 (en) 2012-07-02 2016-11-29 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US10266591B2 (en) 2012-07-02 2019-04-23 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
WO2014008218A1 (en) 2012-07-02 2014-01-09 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
EP3795592A1 (en) 2012-07-02 2021-03-24 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
EP3275899A1 (en) 2012-07-02 2018-01-31 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
US11345752B2 (en) 2012-07-02 2022-05-31 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US10377824B2 (en) 2012-07-02 2019-08-13 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof
US10280221B2 (en) 2013-03-15 2019-05-07 Glaxosmithkline Intellectual Property Development Limited Anti-LAG-3 binding proteins
US20140286935A1 (en) * 2013-03-15 2014-09-25 Glaxosmithkline Intellectual Property Development Limited Antigen binding proteins
CN105209494A (zh) * 2013-03-15 2015-12-30 葛兰素史克知识产权开发有限公司 抗lag-3结合蛋白
US10344088B2 (en) * 2013-03-15 2019-07-09 Glaxosmithkline Intellectual Property Development Limited Antigen binding proteins
US9815897B2 (en) 2013-05-02 2017-11-14 Anaptysbio, Inc. Antibodies directed against programmed death-1 (PD-1)
EP3770176A1 (en) 2013-05-02 2021-01-27 AnaptysBio, Inc. Antibodies directed against programmed death-1 (pd-1)
WO2014179664A2 (en) 2013-05-02 2014-11-06 Anaptysbio, Inc. Antibodies directed against programmed death-1 (pd-1)
US10738117B2 (en) 2013-05-02 2020-08-11 Anaptysbio, Inc. Antibodies directed against programmed death-1 (PD-1)
EP3178849A1 (en) 2013-09-20 2017-06-14 Bristol-Myers Squibb Company Combination of anti-lag-3 antibodies and anti-pd-1 antibodies to treat tumors
US11274152B2 (en) 2013-09-20 2022-03-15 Bristol-Myers Squibb Company Combination of anti-LAG-3 antibodies and anti-PD-1 antibodies to treat tumors
EP4249065A2 (en) 2013-09-20 2023-09-27 Bristol-Myers Squibb Company Combination of anti-lag-3 antibodies and anti-pd-1 antibodies to treat tumors
EP3508502A1 (en) 2013-09-20 2019-07-10 Bristol-Myers Squibb Company Combination of anti-lag-3 antibodies and anti-pd-1 antibodies to treat tumors
WO2015042246A1 (en) 2013-09-20 2015-03-26 Bristol-Myers Squibb Company Combination of anti-lag-3 antibodies and anti-pd-1 antibodies to treat tumors
US10081681B2 (en) 2013-09-20 2018-09-25 Bristol-Myers Squibb Company Combination of anti-LAG-3 antibodies and anti-PD-1 antibodies to treat tumors
US11680090B2 (en) 2013-09-24 2023-06-20 Medicenna Therapeutics, Inc. Interleukin-2 fusion proteins and uses thereof
US20200377600A1 (en) * 2013-09-26 2020-12-03 Novartis Ag Methods for treating hematologic cancers
US10570204B2 (en) 2013-09-26 2020-02-25 The Medical College Of Wisconsin, Inc. Methods for treating hematologic cancers
WO2015048312A1 (en) * 2013-09-26 2015-04-02 Costim Pharmaceuticals Inc. Methods for treating hematologic cancers
EP3757130A1 (en) 2013-09-26 2020-12-30 Costim Pharmaceuticals Inc. Methods for treating hematologic cancers
US11708412B2 (en) * 2013-09-26 2023-07-25 Novartis Ag Methods for treating hematologic cancers
WO2015066413A1 (en) 2013-11-01 2015-05-07 Novartis Ag Oxazolidinone hydroxamic acid compounds for the treatment of bacterial infections
WO2015107495A1 (en) 2014-01-17 2015-07-23 Novartis Ag N-azaspirocycloalkane substituted n-heteroaryl compounds and compositions for inhibiting the activity of shp2
US9815898B2 (en) 2014-01-24 2017-11-14 Novartis Ag Antibody molecules to PD-1 and uses thereof
US9683048B2 (en) 2014-01-24 2017-06-20 Novartis Ag Antibody molecules to PD-1 and uses thereof
US11827704B2 (en) 2014-01-24 2023-11-28 Novartis Ag Antibody molecules to PD-1 and uses thereof
US10752687B2 (en) 2014-01-24 2020-08-25 Novartis Ag Antibody molecules to PD-1 and uses thereof
US20160326248A1 (en) * 2014-01-28 2016-11-10 Bristol-Myers Squibb Company Anti-lag-3 antibodies to treat hematological malignancies
EP3556775A1 (en) 2014-01-28 2019-10-23 Bristol-Myers Squibb Company Anti-lag-3 antibodies to treat hematological malignancies
US20180244773A1 (en) * 2014-01-28 2018-08-30 Bristol-Myers Squibb Company Anti-lag-3 antibodies to treat hematological malignancies
EP3988572A1 (en) 2014-01-28 2022-04-27 Bristol-Myers Squibb Company Anti-lag-3 antibodies to treat hematological malignancies
WO2015116539A1 (en) 2014-01-28 2015-08-06 Bristol-Myers Squibb Company Anti-lag-3 antibodies to treat hematological malignancies
US9605070B2 (en) 2014-01-31 2017-03-28 Novartis Ag Antibody molecules to TIM-3 and uses thereof
US10981990B2 (en) 2014-01-31 2021-04-20 Novartis Ag Antibody molecules to TIM-3 and uses thereof
US11155620B2 (en) 2014-01-31 2021-10-26 Novartis Ag Method of detecting TIM-3 using antibody molecules to TIM-3
US10472419B2 (en) 2014-01-31 2019-11-12 Novartis Ag Antibody molecules to TIM-3 and uses thereof
US9884913B2 (en) 2014-01-31 2018-02-06 Novartis Ag Antibody molecules to TIM-3 and uses thereof
US10711060B2 (en) 2014-03-14 2020-07-14 Novartis Ag Antibody molecules to LAG-3 and uses thereof
US9908936B2 (en) 2014-03-14 2018-03-06 Novartis Ag Antibody molecules to LAG-3 and uses thereof
WO2015148379A1 (en) 2014-03-24 2015-10-01 Novartis Ag Monobactam organic compounds for the treatment of bacterial infections
EP3511328A1 (en) 2014-03-24 2019-07-17 Novartis AG Monobactam organic compounds for the treatment of bacterial infections
US11485790B2 (en) 2014-04-07 2022-11-01 Chugai Seiyaku Kabushiki Kaisha Immunoactivating antigen-binding molecule
US11384131B2 (en) 2014-04-24 2022-07-12 The Board Of Trustees Of The Leland Stanford Junior University Superagonists, partial agonists and antagonists of interleukin-2
US11505605B2 (en) 2014-05-13 2022-11-22 Chugai Seiyaku Kabushiki Kaisha T cell-redirected antigen-binding molecule for cells having immunosuppression function
EP3498295A1 (en) 2014-05-28 2019-06-19 Agenus Inc. Anti-gitr antibodies and methods of use thereof
US10155818B2 (en) 2014-05-28 2018-12-18 Agenus Inc. Anti-GITR antibodies and methods of use thereof
US10800849B2 (en) 2014-05-28 2020-10-13 Agenus Inc. Anti-GITR antibodies and methods of use thereof
WO2015184099A1 (en) 2014-05-28 2015-12-03 4-Antibody Ag Anti-gitr antibodies and methods of use thereof
US11401335B2 (en) 2014-05-28 2022-08-02 Agenus Inc. Anti-GITR antibodies and methods of use thereof
US11897962B2 (en) 2014-05-28 2024-02-13 Agenus Inc. Anti-GITR antibodies and methods of use thereof
US10280226B2 (en) 2014-05-28 2019-05-07 Agenus Inc. Anti-GITR antibodies and methods of use thereof
US10577426B2 (en) 2014-05-28 2020-03-03 Agenus Inc. Anti-GITR antibodies and methods of use thereof
US10829559B2 (en) 2014-05-28 2020-11-10 Agenus Inc. Anti-GITR antibodies and methods of use thereof
WO2015187835A2 (en) 2014-06-06 2015-12-10 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
EP3610924A1 (en) 2014-06-06 2020-02-19 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
EP3998079A1 (en) 2014-06-06 2022-05-18 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
WO2016020836A1 (en) 2014-08-06 2016-02-11 Novartis Ag Quinolone derivatives as antibacterials
WO2016025645A1 (en) 2014-08-12 2016-02-18 Massachusetts Institute Of Technology Synergistic tumor treatment with il-2, a therapeutic antibody, and an immune checkpoint blocker
WO2016025647A1 (en) 2014-08-12 2016-02-18 Massachusetts Institute Of Technology Synergistic tumor treatment with il-2, a therapeutic antibody, and a cancer vaccine
WO2016025642A1 (en) 2014-08-12 2016-02-18 Massachusetts Institute Of Technology Synergistic tumor treatment with il-2 and integrin-binding-fc-fusion protein
US10166273B2 (en) 2014-08-12 2019-01-01 The Board Of Trustees Of The Leland Stanford Junior University Synergistic tumor treatment with antibodies targeting PD-1, PD-L1 or CTLA4 and integrin-binding-Fc-fusion protein
US11096989B2 (en) 2014-08-12 2021-08-24 The Board Of Trustees Of The Leland Stanford Junior University Synergistic tumor treatment with an extended pharmacokinetic IL-2 and integrin-binding-Fc fusion protein
EP3646879A1 (en) 2014-08-12 2020-05-06 Massachusetts Institute Of Technology Synergistic tumor treatment with il-2 and integrin-binding-fc-fusion protein
WO2016040880A1 (en) 2014-09-13 2016-03-17 Novartis Ag Combination therapies of alk inhibitors
EP3659621A1 (en) 2014-09-13 2020-06-03 Novartis AG Combination therapies for cancer
WO2016040892A1 (en) 2014-09-13 2016-03-17 Novartis Ag Combination therapies
EP3925622A1 (en) 2014-09-13 2021-12-22 Novartis AG Combination therapies
US11344620B2 (en) 2014-09-13 2022-05-31 Novartis Ag Combination therapies
EP3662903A2 (en) 2014-10-03 2020-06-10 Novartis AG Combination therapies
WO2016054555A2 (en) 2014-10-03 2016-04-07 Novartis Ag Combination therapies
WO2016057846A1 (en) 2014-10-08 2016-04-14 Novartis Ag Compositions and methods of use for augmented immune response and cancer therapy
WO2016057841A1 (en) 2014-10-08 2016-04-14 Novartis Ag Compositions and methods of use for augmented immune response and cancer therapy
WO2016061142A1 (en) 2014-10-14 2016-04-21 Novartis Ag Antibody molecules to pd-l1 and uses thereof
EP4245376A2 (en) 2014-10-14 2023-09-20 Novartis AG Antibody molecules to pd-l1 and uses thereof
US9988452B2 (en) 2014-10-14 2018-06-05 Novartis Ag Antibody molecules to PD-L1 and uses thereof
US10851165B2 (en) 2014-10-14 2020-12-01 Novartis Ag Antibody molecules to PD-L1 and methods of treating cancer
EP3725808A1 (en) 2014-11-21 2020-10-21 Bristol-Myers Squibb Company Antibodies against cd73 and uses thereof
EP3789399A1 (en) 2014-11-21 2021-03-10 Bristol-Myers Squibb Company Antibodies comprising modified heavy constant regions
WO2016081748A2 (en) 2014-11-21 2016-05-26 Bristol-Myers Squibb Company Antibodies against cd73 and uses thereof
WO2016094639A1 (en) 2014-12-10 2016-06-16 Wisconsin Alumni Research Foundation Mini-intronic plasmid dna vaccines in combination with lag3 blockade
US9827308B2 (en) 2014-12-10 2017-11-28 Wisconsin Alumni Research Foundation Mini-intronic plasmid DNA vaccines in combination with LAG3 blockade
WO2016097995A1 (en) 2014-12-16 2016-06-23 Novartis Ag Isoxazole hydroxamic acid compounds as lpxc inhibitors
WO2016100882A1 (en) 2014-12-19 2016-06-23 Novartis Ag Combination therapies
EP4249066A2 (en) 2014-12-23 2023-09-27 Bristol-Myers Squibb Company Antibodies to tigit
US11684654B2 (en) 2015-01-09 2023-06-27 Immutep S.A.S. Combined preparations for the treatment of cancer or infection
US10836824B2 (en) 2015-02-03 2020-11-17 Anaptysbio, Inc. Antibodies directed against lymphocyte activation gene 3 (LAG-3)
WO2016127052A1 (en) 2015-02-05 2016-08-11 Bristol-Myers Squibb Company Cxcl11 and smica as predictive biomarkers for efficacy of anti-ctla4 immunotherapy
WO2016145102A1 (en) 2015-03-10 2016-09-15 Aduro Biotech, Inc. Compositions and methods for activating "stimulator of interferon gene" -dependent signalling
US10449211B2 (en) 2015-03-10 2019-10-22 Aduro Biotech, Inc. Compositions and methods for activating “stimulator of interferon gene”—dependent signalling
US11040053B2 (en) 2015-03-10 2021-06-22 Chinook Therapeutics, Inc. Compositions and methods for activating “stimulator of interferon gene”13 dependent signalling
EP3738610A1 (en) 2015-04-17 2020-11-18 Bristol-Myers Squibb Company Compositions comprising a combination of ipilimumab and nivolumab
US10512689B2 (en) 2015-04-17 2019-12-24 Bristol-Myers Squibb Company Compositions comprising a combination of nivolumab and ipilimumab
US11612654B2 (en) 2015-04-17 2023-03-28 Bristol-Myers Squibb Company Combination therapy comprising nivolumab and ipilimumab
US12084518B2 (en) 2015-05-21 2024-09-10 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use
US11267889B2 (en) 2015-05-29 2022-03-08 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
WO2016196228A1 (en) 2015-05-29 2016-12-08 Bristol-Myers Squibb Company Antibodies against ox40 and uses thereof
US10144779B2 (en) 2015-05-29 2018-12-04 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
EP3736290A1 (en) 2015-05-29 2020-11-11 Agenus Inc. Anti-ctla-4 antibodies and methods of use thereof
US10479833B2 (en) 2015-05-29 2019-11-19 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
IL256179B2 (en) * 2015-06-08 2024-03-01 Macrogenics Inc LAG-3 binding molecules and methods of using them
WO2016200782A1 (en) * 2015-06-08 2016-12-15 Macrogenics, Inc. Lag-3-binding molecules and methods of use thereof
AU2016274485B2 (en) * 2015-06-08 2022-02-17 Macrogenics, Inc. LAG-3-binding molecules and methods of use thereof
US11072653B2 (en) 2015-06-08 2021-07-27 Macrogenics, Inc. LAG-3-binding molecules and methods of use thereof
US11858991B2 (en) 2015-06-08 2024-01-02 Macrogenics, Inc. LAG-3-binding molecules and methods of use thereof
IL256179B1 (en) * 2015-06-08 2023-11-01 Macrogenics Inc LAG-3 binding molecules and methods of using them
WO2017004016A1 (en) 2015-06-29 2017-01-05 The Rockefeller University Antibodies to cd40 with enhanced agonist activity
EP3943098A2 (en) 2015-07-16 2022-01-26 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
WO2017009842A2 (en) 2015-07-16 2017-01-19 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
EP3744340A2 (en) 2015-07-16 2020-12-02 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US20180340025A1 (en) * 2015-07-29 2018-11-29 Novartis Ag Combination therapies comprising antibody molecules to lag-3
WO2017019897A1 (en) 2015-07-29 2017-02-02 Novartis Ag Combination therapies comprising antibody molecules to tim-3
WO2017019894A1 (en) 2015-07-29 2017-02-02 Novartis Ag Combination therapies comprising antibody molecules to lag-3
EP4378957A2 (en) 2015-07-29 2024-06-05 Novartis AG Combination therapies comprising antibody molecules to pd-1
EP3964528A1 (en) 2015-07-29 2022-03-09 Novartis AG Combination therapies comprising antibody molecules to lag-3
EP3878465A1 (en) 2015-07-29 2021-09-15 Novartis AG Combination therapies comprising antibody molecules to tim-3
WO2017025871A1 (en) 2015-08-07 2017-02-16 Glaxosmithkline Intellectual Property Development Limited Combination therapy comprising anti ctla-4 antibodies
US11680104B2 (en) 2015-09-02 2023-06-20 Immutep S.A.S. Anti-LAG-3 antibodies
EP3798234A1 (en) 2015-09-02 2021-03-31 Immutep S.A.S. Anti-lag-3 agonistic antibodies
US11692032B2 (en) 2015-10-09 2023-07-04 Regeneron Pharmaceuticals, Inc. Anti-LAG3 antibodies and uses thereof
US10358495B2 (en) 2015-10-09 2019-07-23 Regeneron Pharmaceuticals, Inc. Anti-LAG3 antibodies and uses thereof
WO2017062888A1 (en) 2015-10-09 2017-04-13 Regeneron Pharmaceuticals, Inc. Anti-lag3 antibodies and uses thereof
US10894830B2 (en) 2015-11-03 2021-01-19 Janssen Biotech, Inc. Antibodies specifically binding PD-1, TIM-3 or PD-1 and TIM-3 and their uses
JP7378567B2 (ja) 2015-11-13 2023-11-13 マクロジェニクス，インコーポレーテッド Ｌａｇ‐３結合分子及びその使用方法
JP2023025220A (ja) * 2015-11-13 2023-02-21 マクロジェニクス，インコーポレーテッド Ｌａｇ‐３結合分子及びその使用方法
JP2018527290A (ja) * 2015-11-13 2018-09-20 マクロジェニクス，インコーポレーテッド Ｌａｇ‐３結合分子及びその使用方法
JP2021165275A (ja) * 2015-11-13 2021-10-14 マクロジェニクス，インコーポレーテッド Ｌａｇ‐３結合分子及びその使用方法
JP7192042B2 (ja) 2015-11-13 2022-12-19 マクロジェニクス，インコーポレーテッド Ｌａｇ‐３結合分子及びその使用方法
US11660340B2 (en) 2015-11-18 2023-05-30 Chugai Seiyaku Kabushiki Kaisha Combination therapy using T cell redirection antigen binding molecule against cell having immunosuppressing function
US11649293B2 (en) 2015-11-18 2023-05-16 Chugai Seiyaku Kabushiki Kaisha Method for enhancing humoral immune response
WO2017087678A2 (en) 2015-11-19 2017-05-26 Bristol-Myers Squibb Company Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof
US11447557B2 (en) 2015-12-02 2022-09-20 Agenus Inc. Antibodies and methods of use thereof
US10836830B2 (en) 2015-12-02 2020-11-17 Agenus Inc. Antibodies and methods of use thereof
WO2017106656A1 (en) 2015-12-17 2017-06-22 Novartis Ag Antibody molecules to pd-1 and uses thereof
EP4424322A2 (en) 2015-12-17 2024-09-04 Novartis AG Antibody molecules to pd-1 and uses thereof
WO2017103895A1 (en) 2015-12-18 2017-06-22 Novartis Ag Antibodies targeting cd32b and methods of use thereof
WO2017122130A1 (en) 2016-01-11 2017-07-20 Novartis Ag Immune-stimulating humanized monoclonal antibodies against human interleukin-2, and fusion proteins thereof
WO2017140821A1 (en) 2016-02-19 2017-08-24 Novartis Ag Tetracyclic pyridone compounds as antivirals
WO2017152085A1 (en) 2016-03-04 2017-09-08 Bristol-Myers Squibb Company Combination therapy with anti-cd73 antibodies
WO2017163186A1 (en) 2016-03-24 2017-09-28 Novartis Ag Alkynyl nucleoside analogs as inhibitors of human rhinovirus
EP4292658A2 (en) 2016-03-24 2023-12-20 Novartis AG Alkynyl nucleoside analogs as inhibitors of human rhinovirus
WO2017178572A1 (en) 2016-04-13 2017-10-19 Vivia Biotech, S.L Ex vivo bite-activated t cells
WO2017184619A2 (en) 2016-04-18 2017-10-26 Celldex Therapeutics, Inc. Agonistic antibodies that bind human cd40 and uses thereof
WO2017201502A1 (en) 2016-05-20 2017-11-23 Biohaven Pharmaceutical Holding Company Ltd. Use of glutamate modulating agents with immunotherapies to treat cancer
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
US11090344B2 (en) 2016-05-27 2021-08-17 Dnatrix, Inc. Adenovirus and immunomodulator combination therapy
US9907768B2 (en) 2016-06-10 2018-03-06 Io Therapeutics, Inc. Receptor subtype and function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US10004708B2 (en) 2016-06-10 2018-06-26 Io Therapeutics, Inc. Receptor subtype and function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US11648223B2 (en) 2016-06-10 2023-05-16 Io Therapeutics, Inc. Receptor subtype and function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US10004709B2 (en) 2016-06-10 2018-06-26 Io Therapeutics, Inc. Receptor subtype and function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US10123982B2 (en) 2016-06-10 2018-11-13 Io Therapeutics, Inc. Receptor subtype and function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US10071973B2 (en) 2016-06-14 2018-09-11 Novartis Ag Crystalline isoxazole hydroxamic acid compounds
WO2017216705A1 (en) 2016-06-14 2017-12-21 Novartis Ag Crystalline form of (r)-4-(5-(cyclopropylethynyl)isoxazol-3-yl)-n-hydroxy-2-methyl-2-(methylsulfonyl)butanamide as an antibacterial agent
WO2017216686A1 (en) 2016-06-16 2017-12-21 Novartis Ag 8,9-fused 2-oxo-6,7-dihydropyrido-isoquinoline compounds as antivirals
WO2017216685A1 (en) 2016-06-16 2017-12-21 Novartis Ag Pentacyclic pyridone compounds as antivirals
WO2017223422A1 (en) 2016-06-24 2017-12-28 Infinity Pharmaceuticals, Inc. Combination therapies
US11098077B2 (en) 2016-07-05 2021-08-24 Chinook Therapeutics, Inc. Locked nucleic acid cyclic dinucleotide compounds and uses thereof
WO2018013818A2 (en) 2016-07-14 2018-01-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
US10077306B2 (en) 2016-07-14 2018-09-18 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof
US10533052B2 (en) 2016-07-14 2020-01-14 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof
US11591392B2 (en) 2016-07-14 2023-02-28 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof
WO2018047109A1 (en) 2016-09-09 2018-03-15 Novartis Ag Polycyclic pyridone compounds as antivirals
WO2018057955A1 (en) 2016-09-23 2018-03-29 Elstar Therapeutics, Inc. Multispecific antibody molecules comprising lambda and kappa light chains
US11673971B2 (en) 2016-09-23 2023-06-13 Marengo Therapeutics, Inc. Multispecific antibody molecules comprising lambda and kappa light chains
EP3698796A1 (en) 2016-09-28 2020-08-26 Novartis AG Pharmaceutical combination of a tricyclic beta-lactamase inhibitor with specific beta-lactam antibiotics
WO2018060926A1 (en) 2016-09-28 2018-04-05 Novartis Ag Beta-lactamase inhibitors
US10844119B2 (en) 2016-10-11 2020-11-24 Agenus Inc. Anti-LAG-3 antibodies and methods of use thereof
US10882908B2 (en) 2016-10-11 2021-01-05 Agenus Inc. Anti-LAG-3 antibodies and methods of use thereof
US11993651B2 (en) 2016-10-11 2024-05-28 Agenus Inc. Anti-lag-3 antibodies and methods of use thereof
WO2018073753A1 (en) 2016-10-18 2018-04-26 Novartis Ag Fused tetracyclic pyridone compounds as antivirals
US11155624B2 (en) 2016-11-01 2021-10-26 Anaptysbio, Inc. Antibodies directed against programmed death-1 (PD-1)
WO2018083087A2 (en) 2016-11-02 2018-05-11 Glaxosmithkline Intellectual Property (No.2) Limited Binding proteins
WO2018106862A1 (en) 2016-12-07 2018-06-14 Agenus Inc. Anti-ctla-4 antibodies and methods of use thereof
US10912831B1 (en) 2016-12-07 2021-02-09 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
US11638755B2 (en) 2016-12-07 2023-05-02 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
US11013802B2 (en) 2016-12-07 2021-05-25 Agenus Inc. Anti-CTLA-4 antibodies and methods of use thereof
EP4289484A2 (en) 2016-12-07 2023-12-13 Agenus Inc. Anti-ctla-4 antibodies and methods of use thereof
WO2018112266A1 (en) 2016-12-14 2018-06-21 The Board Of Trustees Of The Leland Stanford Junior University Il-13 superkine: immune cell targeting constructs and methods of use thereof
US11407830B2 (en) 2017-01-09 2022-08-09 Tesaro, Inc. Methods of treating cancer with anti-PD-1 antibodies
US10603358B2 (en) 2017-01-10 2020-03-31 Nodus Therapeutics Combination tumor treatment with an integrin-binding-Fc fusion protein and immune stimulator
US10350266B2 (en) 2017-01-10 2019-07-16 Nodus Therapeutics, Inc. Method of treating cancer with a multiple integrin binding Fc fusion protein
US10905784B2 (en) 2017-02-10 2021-02-02 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-LAG3 antibodies for immuno-PET imaging
WO2018148476A1 (en) 2017-02-10 2018-08-16 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-lag3 antibodies for immuno-pet imaging
US11511001B2 (en) 2017-02-10 2022-11-29 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-LAG3 antibodies for immuno-PET imaging
WO2018151820A1 (en) 2017-02-16 2018-08-23 Elstar Therapeutics, Inc. Multifunctional molecules comprising a trimeric ligand and uses thereof
WO2018151821A1 (en) 2017-02-17 2018-08-23 Bristol-Myers Squibb Company Antibodies to alpha-synuclein and uses thereof
US11142570B2 (en) 2017-02-17 2021-10-12 Bristol-Myers Squibb Company Antibodies to alpha-synuclein and uses thereof
US11827695B2 (en) 2017-02-17 2023-11-28 Bristol-Myers Squibb Company Antibodies to alpha-synuclein and uses thereof
WO2018183928A1 (en) 2017-03-31 2018-10-04 Bristol-Myers Squibb Company Methods of treating tumor
WO2018185046A1 (en) 2017-04-05 2018-10-11 F. Hoffmann-La Roche Ag Anti-lag3 antibodies
WO2018187613A2 (en) 2017-04-07 2018-10-11 Bristol-Myers Squibb Company Anti-icos agonist antibodies and uses thereof
WO2018195283A1 (en) 2017-04-19 2018-10-25 Elstar Therapeutics, Inc. Multispecific molecules and uses thereof
WO2018195552A1 (en) 2017-04-21 2018-10-25 Sillajen, Inc. Oncolytic vaccinia virus and checkpoint inhibitor combination therapy
EP4286009A2 (en) 2017-04-21 2023-12-06 Sillajen, Inc. Oncolytic vaccinia virus and checkpoint inhibitor combination therapy
WO2018200430A1 (en) 2017-04-26 2018-11-01 Bristol-Myers Squibb Company Methods of antibody production that minimize disulfide bond reduction
EP3998269A1 (en) 2017-04-27 2022-05-18 Novartis AG Fused indazole pyridone compounds as antivirals
US10975078B2 (en) 2017-04-27 2021-04-13 Novartis Ag Fused indazole pyridone compounds as antivirals
WO2018198079A1 (en) 2017-04-27 2018-11-01 Novartis Ag Fused indazole pyridone compounds as antivirals
US10301312B2 (en) 2017-04-27 2019-05-28 Novartis Ag Fused indazole pyridone compounds as antivirals
WO2018201047A1 (en) 2017-04-28 2018-11-01 Elstar Therapeutics, Inc. Multispecific molecules comprising a non-immunoglobulin heterodimerization domain and uses thereof
WO2018198076A1 (en) 2017-04-28 2018-11-01 Aduro Biotech, Inc. Bis 2'-5'-rr-(3'f-a)(3'f-a) cyclic dinucleotide compound and uses thereof
US10975114B2 (en) 2017-04-28 2021-04-13 Chinook Therapeutics, Inc. Bis 2′-5′-RR-(3′F-A)(3′F-A) cyclic dinucleotide compound and uses thereof
EP4328241A2 (en) 2017-04-28 2024-02-28 Marengo Therapeutics, Inc. Multispecific molecules comprising a non-immunoglobulin heterodimerization domain and uses thereof
WO2018203302A1 (en) 2017-05-05 2018-11-08 Novartis Ag Tricyclic 2-quinolinones as antibacterials
WO2018208868A1 (en) * 2017-05-10 2018-11-15 Smet Pharmaceutical Inc Human monoclonal antibodies against lag3 and uses thereof
US11339218B2 (en) 2017-05-10 2022-05-24 Zhejiang Shimai Pharmaceutical Co., Ltd. Human monoclonal antibodies against LAG3 and uses thereof
CN110621337A (zh) * 2017-05-10 2019-12-27 时迈药业 抗lag3人单克隆抗体及其用途
US11607453B2 (en) 2017-05-12 2023-03-21 Harpoon Therapeutics, Inc. Mesothelin binding proteins
WO2018213297A1 (en) 2017-05-16 2018-11-22 Bristol-Myers Squibb Company Treatment of cancer with anti-gitr agonist antibodies
WO2018218056A1 (en) 2017-05-25 2018-11-29 Birstol-Myers Squibb Company Antibodies comprising modified heavy constant regions
EP4098662A1 (en) 2017-05-25 2022-12-07 Bristol-Myers Squibb Company Antibodies comprising modified heavy constant regions
WO2018222722A2 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Compositions comprising an anti-lag-3 antibody or an anti-lag-3 antibody and an anti-pd-1 or anti-pd-l1 antibody
US12049503B2 (en) 2017-05-30 2024-07-30 Bristol-Myers Squibb Company Treatment of LAG-3 positive tumors
WO2018222711A2 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Compositions comprising a combination of an anti-lag-3 antibody, a pd-1 pathway inhibitor, and an immunotherapeutic agent
EP4306542A2 (en) 2017-05-30 2024-01-17 Bristol-Myers Squibb Company Treatment of lag-3 positive tumors
US11807686B2 (en) 2017-05-30 2023-11-07 Bristol-Myers Squibb Company Treatment of LAG-3 positive tumors
WO2018222718A1 (en) 2017-05-30 2018-12-06 Bristol-Myers Squibb Company Treatment of lag-3 positive tumors
EP4245375A2 (en) 2017-05-30 2023-09-20 Bristol-Myers Squibb Company Compositions comprising a combination of an anti-lag-3 antibody, a pd-1 pathway inhibitor, and an immunotherapeutic agent
US11723975B2 (en) 2017-05-30 2023-08-15 Bristol-Myers Squibb Company Compositions comprising an anti-LAG-3 antibody or an anti-LAG-3 antibody and an anti-PD-1 or anti-PD-L1 antibody
WO2018222901A1 (en) 2017-05-31 2018-12-06 Elstar Therapeutics, Inc. Multispecific molecules that bind to myeloproliferative leukemia (mpl) protein and uses thereof
WO2018223002A1 (en) 2017-06-01 2018-12-06 Xencor, Inc. Bispecific antibodies that bind cd 123 cd3
WO2018223004A1 (en) 2017-06-01 2018-12-06 Xencor, Inc. Bispecific antibodies that bind cd20 and cd3
US11542312B2 (en) 2017-06-19 2023-01-03 Medicenna Therapeutics, Inc. IL-2 superagonists in combination with anti-PD-1 antibodies
US10874627B2 (en) 2017-07-13 2020-12-29 Io Therapeutics, Inc. Immunomodulatory and differentiating function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US10517843B2 (en) 2017-07-13 2019-12-31 Io Therapeutics, Inc. Receptor subtype and function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US10213401B2 (en) 2017-07-13 2019-02-26 Io Therapeutics, Inc. Immunomodulatory and differentiating function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US10881628B2 (en) 2017-07-13 2021-01-05 Io Therapeutics, Inc. Receptor subtype and function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US10471030B2 (en) 2017-07-13 2019-11-12 lo Therapeutics, Inc. Immunomodulatory and differentiating function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US10485775B2 (en) 2017-07-13 2019-11-26 Io Therapeutics, Inc. Receptor subtype and function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US10231944B2 (en) 2017-07-13 2019-03-19 Io Therapeutics, Inc. Receptor subtype and function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US10874628B2 (en) 2017-07-13 2020-12-29 Io Therapeutics, Inc. Receptor subtype and function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US11779558B2 (en) 2017-07-13 2023-10-10 Io Therapeutics, Inc. Receptor subtype and function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
US11737996B2 (en) 2017-07-13 2023-08-29 Io Therapeutics, Inc. Immunomodulatory and differentiating function selective retinoid and rexinoid compounds in combination with immune modulators for cancer immunotherapy
WO2019035938A1 (en) 2017-08-16 2019-02-21 Elstar Therapeutics, Inc. MULTISPECIFIC MOLECULES BINDING TO BCMA AND USES THEREOF
WO2019035985A1 (en) 2017-08-18 2019-02-21 Tragara Pharmaceuticals, Inc. POLYMORPHIC FORM OF TG02
EP4364741A2 (en) 2017-08-18 2024-05-08 Cothera Bioscience, Inc. Polymorphic form of tg02
US11390679B2 (en) * 2017-08-30 2022-07-19 Phanes Therapeutics, Inc. Anti-LAG-3 antibodies and uses thereof
US11786555B2 (en) 2017-08-31 2023-10-17 Io Therapeutics, Inc. RAR selective agonists in combination with immune modulators for cancer immunotherapy
US10532073B2 (en) 2017-08-31 2020-01-14 Io Therapeutics, Inc. RAR selective agonists in combination with immune modulators for cancer immunotherapy
US10874694B2 (en) 2017-08-31 2020-12-29 Io Therapeutics, Inc. RAR selective agonists in combination with immune modulators for cancer immunotherapy
US10363272B2 (en) 2017-08-31 2019-07-30 Io Therapeutics, Inc. RAR selective agonists in combination with immune modulators for cancer immunotherapy
WO2019075090A1 (en) 2017-10-10 2019-04-18 Tilos Therapeutics, Inc. ANTI-LAP ANTIBODIES AND USES THEREOF
US11230601B2 (en) 2017-10-10 2022-01-25 Tilos Therapeutics, Inc. Methods of using anti-lap antibodies
US11976125B2 (en) 2017-10-13 2024-05-07 Harpoon Therapeutics, Inc. B cell maturation antigen binding proteins
WO2019075468A1 (en) 2017-10-15 2019-04-18 Bristol-Myers Squibb Company TUMOR TREATMENT METHODS
US11919957B2 (en) 2017-10-15 2024-03-05 Bristol-Myers Squibb Company Methods of treating tumor
WO2019077062A1 (en) 2017-10-18 2019-04-25 Vivia Biotech, S.L. C-CELLS ACTIVATED BY BIT
WO2019089921A1 (en) 2017-11-01 2019-05-09 Bristol-Myers Squibb Company Immunostimulatory agonistic antibodies for use in treating cancer
WO2019097479A1 (en) 2017-11-17 2019-05-23 Novartis Ag Novel dihydroisoxazole compounds and their use for the treatment of hepatitis b
WO2019113464A1 (en) 2017-12-08 2019-06-13 Elstar Therapeutics, Inc. Multispecific molecules and uses thereof
US11234977B2 (en) 2017-12-20 2022-02-01 Novartis Ag Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals
WO2019123285A1 (en) 2017-12-20 2019-06-27 Novartis Ag Fused tricyclic pyrazolo-dihydropyrazinyl-pyridone compounds as antivirals
US11306149B2 (en) 2017-12-27 2022-04-19 Bristol-Myers Squibb Company Anti-CD40 antibodies and uses thereof
WO2019133747A1 (en) 2017-12-27 2019-07-04 Bristol-Myers Squibb Company Anti-cd40 antibodies and uses thereof
US11952427B2 (en) 2017-12-27 2024-04-09 Bristol-Myers Squibb Company Anti-CD40 antibodies and uses thereof
WO2019140229A1 (en) 2018-01-12 2019-07-18 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
WO2019149715A1 (en) 2018-01-31 2019-08-08 F. Hoffmann-La Roche Ag Stabilized immunoglobulin domains
WO2019149716A1 (en) 2018-01-31 2019-08-08 F. Hoffmann-La Roche Ag Bispecific antibodies comprising an antigen-binding site binding to lag3
WO2019166951A1 (en) 2018-02-28 2019-09-06 Novartis Ag Indole-2-carbonyl compounds and their use for the treatment of hepatitis b
US11795221B2 (en) 2018-02-28 2023-10-24 WuXi Biologics Ireland Limited Monoclonal antibody against human LAG-3, method for preparing the same, and use thereof
WO2019178364A2 (en) 2018-03-14 2019-09-19 Elstar Therapeutics, Inc. Multifunctional molecules and uses thereof
WO2019178362A1 (en) 2018-03-14 2019-09-19 Elstar Therapeutics, Inc. Multifunctional molecules that bind to calreticulin and uses thereof
US11661452B2 (en) 2018-03-20 2023-05-30 WuXi Biologics Ireland Limited Anti-lag-3 antibody polypeptide
WO2019183040A1 (en) 2018-03-21 2019-09-26 Five Prime Therapeutics, Inc. ANTIBODIES BINDING TO VISTA AT ACIDIC pH
US11242393B2 (en) 2018-03-23 2022-02-08 Bristol-Myers Squibb Company Antibodies against MICA and/or MICB and uses thereof
WO2019191676A1 (en) 2018-03-30 2019-10-03 Bristol-Myers Squibb Company Methods of treating tumor
WO2019192432A1 (zh) 2018-04-02 2019-10-10 上海博威生物医药有限公司 结合淋巴细胞活化基因-3(lag-3)的抗体及其用途
WO2019204592A1 (en) 2018-04-18 2019-10-24 Xencor, Inc. Il-15/il-15ra heterodimeric fc fusion proteins and uses thereof
WO2019204665A1 (en) 2018-04-18 2019-10-24 Xencor, Inc. Pd-1 targeted heterodimeric fusion proteins containing il-15/il-15ra fc-fusion proteins and pd-1 antigen binding domains and uses thereof
WO2019232528A1 (en) 2018-06-01 2019-12-05 Xencor, Inc. Dosing of a bispecific antibody that bind cd123 and cd3
CN112119094A (zh) * 2018-06-29 2020-12-22 Y 生物股份有限公司 与淋巴细胞活化基因3特异性结合的单克隆抗体及其用途
DE202019005887U1 (de) 2018-07-03 2023-06-14 Marengo Therapeutics, Inc. Anti-TCR-Antikörpermoleküle und Verwendungen davon
US11845797B2 (en) 2018-07-03 2023-12-19 Marengo Therapeutics, Inc. Anti-TCR antibody molecules and uses thereof
WO2020010250A2 (en) 2018-07-03 2020-01-09 Elstar Therapeutics, Inc. Anti-tcr antibody molecules and uses thereof
US11965025B2 (en) 2018-07-03 2024-04-23 Marengo Therapeutics, Inc. Method of treating solid cancers with bispecific interleukin-anti-TCRß molecules
WO2020014132A2 (en) 2018-07-09 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to ilt4
WO2020014327A2 (en) 2018-07-11 2020-01-16 Five Prime Therapeutics, Inc. Antibodies binding to vista at acidic ph
US11279758B2 (en) 2018-07-20 2022-03-22 Surface Oncology, Inc. Anti-CD112R compositions and methods
US11214619B2 (en) 2018-07-20 2022-01-04 Surface Oncology, Inc. Anti-CD112R compositions and methods
WO2020023707A1 (en) 2018-07-26 2020-01-30 Bristol-Myers Squibb Company Lag-3 combination therapy for the treatment of cancer
WO2020053654A1 (en) 2018-09-12 2020-03-19 Novartis Ag Antiviral pyridopyrazinedione compounds
US11072610B2 (en) 2018-09-12 2021-07-27 Novartis Ag Antiviral pyridopyrazinedione compounds
WO2020057645A1 (zh) 2018-09-21 2020-03-26 信达生物制药(苏州)有限公司 新型白介素2及其用途
WO2020057646A1 (zh) 2018-09-21 2020-03-26 信达生物制药(苏州)有限公司 新型白介素2及其用途
US11807692B2 (en) 2018-09-25 2023-11-07 Harpoon Therapeutics, Inc. DLL3 binding proteins and methods of use
WO2020069372A1 (en) 2018-09-27 2020-04-02 Elstar Therapeutics, Inc. Csf1r/ccr2 multispecific antibodies
WO2020065453A1 (en) 2018-09-29 2020-04-02 Novartis Ag Process of manufacture of a compound for inhibiting the activity of shp2
EP4282416A2 (en) 2018-09-29 2023-11-29 Novartis AG Process of manufacture of a compound for inhibiting the activity of shp2
WO2020072821A2 (en) 2018-10-03 2020-04-09 Xencor, Inc. Il-12 heterodimeric fc-fusion proteins
US11130802B2 (en) 2018-10-10 2021-09-28 Tilos Therapeutics, Inc. Anti-lap antibody variants
WO2020076969A2 (en) 2018-10-10 2020-04-16 Tilos Therapeutics, Inc. Anti-lap antibody variants and uses thereof
WO2020077276A2 (en) 2018-10-12 2020-04-16 Xencor, Inc. Pd-1 targeted il-15/il-15ralpha fc fusion proteins and uses in combination therapies thereof
WO2020081928A1 (en) 2018-10-19 2020-04-23 Bristol-Myers Squibb Company Combination therapy for melanoma
EP4445958A2 (en) 2018-10-19 2024-10-16 Bristol-Myers Squibb Company Combination therapy for melanoma
WO2020102501A1 (en) 2018-11-16 2020-05-22 Bristol-Myers Squibb Company Anti-nkg2a antibodies and uses thereof
WO2020132646A1 (en) 2018-12-20 2020-06-25 Xencor, Inc. Targeted heterodimeric fc fusion proteins containing il-15/il-15ra and nkg2d antigen binding domains
US12129297B2 (en) 2019-01-11 2024-10-29 Bristol-Myers Squibb Company Antibodies against TIM3 and uses thereof
WO2020154032A1 (en) 2019-01-23 2020-07-30 Massachusetts Institute Of Technology Combination immunotherapy dosing regimen for immune checkpoint blockade
WO2020198435A1 (en) 2019-03-26 2020-10-01 The Regents Of The University Of Michigan Small molecule degraders of stat3
WO2020205467A1 (en) 2019-03-29 2020-10-08 The Regents Of The University Of Michigan Stat3 protein degraders
WO2020223121A1 (en) 2019-04-30 2020-11-05 Dana-Farber Cancer Institute, Inc. Methods for treating cancer using combinations of anti-cx3cr1 and immune checkpoint blockade agents
WO2020221927A1 (en) 2019-05-01 2020-11-05 Immutep S.A.S. Anti-lag-3 binding molecules
WO2020221928A1 (en) 2019-05-01 2020-11-05 Immutep S.A.S. Anti-lag-3 binding molecules
WO2020232019A1 (en) 2019-05-13 2020-11-19 Regeneron Pharmaceuticals, Inc. Combination of pd-1 inhibitors and lag-3 inhibitors for enhanced efficacy in treating cancer
WO2020243563A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Multi-tumor gene signatures for suitability to immuno-oncology therapy
WO2020243568A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Methods of identifying a subject suitable for an immuno-oncology (i-o) therapy
WO2020243570A1 (en) 2019-05-30 2020-12-03 Bristol-Myers Squibb Company Cell localization signature and combination therapy
WO2020252264A1 (en) 2019-06-12 2020-12-17 AskGene Pharma, Inc. Novel il-15 prodrugs and methods of use thereof
WO2020252336A1 (en) 2019-06-12 2020-12-17 Vanderbilt University Dibenzylamines as amino acid transport inhibitors
WO2020252353A1 (en) 2019-06-12 2020-12-17 Vanderbilt University Amino acid transport inhibitors and the uses thereof
WO2020263399A1 (en) 2019-06-26 2020-12-30 Massachusetts Institute Of Technology Immunomodulatory fusion protein-metal hydroxide complexes and methods thereof
WO2021011713A1 (en) 2019-07-16 2021-01-21 The Regents Of The University Of Michigan Imidazopyrimidines as eed inhibitors and the use thereof
WO2021024020A1 (en) 2019-08-06 2021-02-11 Astellas Pharma Inc. Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer
WO2021025177A1 (en) 2019-08-06 2021-02-11 Astellas Pharma Inc. Combination therapy involving antibodies against claudin 18.2 and immune checkpoint inhibitors for treatment of cancer
WO2021041664A1 (en) 2019-08-27 2021-03-04 The Regents Of The University Of Michigan Cereblon e3 ligase inhibitors
WO2021055698A1 (en) 2019-09-19 2021-03-25 Bristol-Myers Squibb Company Antibodies binding to vista at acidic ph
WO2021055756A1 (en) 2019-09-19 2021-03-25 The Regents Of The University Of Michigan Spirocyclic androgen receptor protein degraders
WO2021055994A1 (en) 2019-09-22 2021-03-25 Bristol-Myers Squibb Company Quantitative spatial profiling for lag-3 antagonist therapy
US11667613B2 (en) 2019-09-26 2023-06-06 Novartis Ag Antiviral pyrazolopyridinone compounds
WO2021067863A2 (en) 2019-10-03 2021-04-08 Xencor, Inc. Targeted il-12 heterodimeric fc-fusion proteins
WO2021072298A1 (en) 2019-10-11 2021-04-15 Genentech, Inc. Pd-1 targeted il-15/il-15ralpha fc fusion proteins with improved properties
WO2021080682A1 (en) 2019-10-24 2021-04-29 Massachusetts Institute Of Technology Monoclonal antibodies that bind human cd161 and uses thereof
WO2021090146A1 (en) 2019-11-04 2021-05-14 Astrazeneca Ab Combination therapy for treating cancer
WO2021092220A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
WO2021092221A1 (en) 2019-11-06 2021-05-14 Bristol-Myers Squibb Company Methods of identifying a subject with a tumor suitable for a checkpoint inhibitor therapy
WO2021092380A1 (en) 2019-11-08 2021-05-14 Bristol-Myers Squibb Company Lag-3 antagonist therapy for melanoma
WO2021138407A2 (en) 2020-01-03 2021-07-08 Marengo Therapeutics, Inc. Multifunctional molecules that bind to cd33 and uses thereof
WO2021158938A1 (en) 2020-02-06 2021-08-12 Bristol-Myers Squibb Company Il-10 and uses thereof
WO2021171264A1 (en) 2020-02-28 2021-09-02 Novartis Ag Dosing of a bispecific antibody that binds cd123 and cd3
WO2021183428A1 (en) 2020-03-09 2021-09-16 Bristol-Myers Squibb Company Antibodies to cd40 with enhanced agonist activity
WO2021195481A1 (en) 2020-03-26 2021-09-30 The Regents Of The University Of Michigan Small molecule stat protein degraders
WO2021207449A1 (en) 2020-04-09 2021-10-14 Merck Sharp & Dohme Corp. Affinity matured anti-lap antibodies and uses thereof
WO2021231732A1 (en) 2020-05-15 2021-11-18 Bristol-Myers Squibb Company Antibodies to garp
CN115667304A (zh) * 2020-05-27 2023-01-31 安捷伦科技有限公司 抗人lag-3抗体及其在免疫组织化学(ihc)中的用途
WO2022008519A1 (en) 2020-07-07 2022-01-13 BioNTech SE Therapeutic rna for hpv-positive cancer
WO2022011205A1 (en) 2020-07-10 2022-01-13 The Regents Of The University Of Michigan Androgen receptor protein degraders
WO2022011204A1 (en) 2020-07-10 2022-01-13 The Regents Of The University Of Michigan Small molecule androgen receptor protein degraders
WO2022036079A1 (en) 2020-08-13 2022-02-17 Bristol-Myers Squibb Company Methods of redirecting of il-2 to target cells of interest
WO2022047046A1 (en) 2020-08-26 2022-03-03 Marengo Therapeutics, Inc. Methods of detecting trbc1 or trbc2
WO2022047189A1 (en) 2020-08-28 2022-03-03 Bristol-Myers Squibb Company Lag-3 antagonist therapy for hepatocellular carcinoma
WO2022047412A1 (en) 2020-08-31 2022-03-03 Bristol-Myers Squibb Company Cell localization signature and immunotherapy
WO2022087402A1 (en) 2020-10-23 2022-04-28 Bristol-Myers Squibb Company Lag-3 antagonist therapy for lung cancer
WO2022120179A1 (en) 2020-12-03 2022-06-09 Bristol-Myers Squibb Company Multi-tumor gene signatures and uses thereof
WO2022125497A1 (en) 2020-12-08 2022-06-16 Infinity Pharmaceuticals, Inc. Eganelisib for use in the treatment of pd-l1 negative cancer
WO2022136255A1 (en) 2020-12-21 2022-06-30 BioNTech SE Treatment schedule for cytokine proteins
WO2022135666A1 (en) 2020-12-21 2022-06-30 BioNTech SE Treatment schedule for cytokine proteins
WO2022136266A1 (en) 2020-12-21 2022-06-30 BioNTech SE Therapeutic rna for treating cancer
WO2022135667A1 (en) 2020-12-21 2022-06-30 BioNTech SE Therapeutic rna for treating cancer
WO2022136257A1 (en) 2020-12-21 2022-06-30 BioNTech SE Therapeutic rna for treating cancer
WO2022146947A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2022146948A1 (en) 2020-12-28 2022-07-07 Bristol-Myers Squibb Company Subcutaneous administration of pd1/pd-l1 antibodies
WO2022187419A1 (en) 2021-03-03 2022-09-09 The Regents Of The University Of Michigan Small molecule degraders of androgen receptor
WO2022187423A1 (en) 2021-03-03 2022-09-09 The Regents Of The University Of Michigan Cereblon ligands
WO2022212400A1 (en) 2021-03-29 2022-10-06 Juno Therapeutics, Inc. Methods for dosing and treatment with a combination of a checkpoint inhibitor therapy and a car t cell therapy
WO2022212876A1 (en) 2021-04-02 2022-10-06 The Regents Of The University Of California Antibodies against cleaved cdcp1 and uses thereof
WO2022216993A2 (en) 2021-04-08 2022-10-13 Marengo Therapeutics, Inc. Multifuntional molecules binding to tcr and uses thereof
WO2022240741A1 (en) 2021-05-12 2022-11-17 Dana-Farber Cancer Institute, Inc. Lag3 and gal3 inhibitory agents, xbp1, cs1, and cd138 peptides, and methods of use thereof
WO2023285552A1 (en) 2021-07-13 2023-01-19 BioNTech SE Multispecific binding agents against cd40 and cd137 in combination therapy for cancer
WO2023039089A1 (en) 2021-09-08 2023-03-16 Twentyeight-Seven, Inc. Papd5 and/or papd7 inhibiting 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives
WO2023061930A1 (en) 2021-10-11 2023-04-20 BioNTech SE Therapeutic rna for lung cancer
WO2023077090A1 (en) 2021-10-29 2023-05-04 Bristol-Myers Squibb Company Lag-3 antagonist therapy for hematological cancer
WO2023147371A1 (en) 2022-01-26 2023-08-03 Bristol-Myers Squibb Company Combination therapy for hepatocellular carcinoma
WO2023154905A1 (en) 2022-02-14 2023-08-17 Gilead Sciences, Inc. Antiviral pyrazolopyridinone compounds
WO2023164638A1 (en) 2022-02-25 2023-08-31 Bristol-Myers Squibb Company Combination therapy for colorectal carcinoma
WO2023168404A1 (en) 2022-03-04 2023-09-07 Bristol-Myers Squibb Company Methods of treating a tumor
WO2023170606A1 (en) 2022-03-08 2023-09-14 Alentis Therapeutics Ag Use of anti-claudin-1 antibodies to increase t cell availability
WO2023178192A1 (en) 2022-03-15 2023-09-21 Compugen Ltd. Il-18bp antagonist antibodies and their use in monotherapy and combination therapy in the treatment of cancer
WO2023178329A1 (en) 2022-03-18 2023-09-21 Bristol-Myers Squibb Company Methods of isolating polypeptides
WO2023235847A1 (en) 2022-06-02 2023-12-07 Bristol-Myers Squibb Company Antibody compositions and methods of use thereof
WO2024040195A1 (en) 2022-08-17 2024-02-22 Capstan Therapeutics, Inc. Conditioning for in vivo immune cell engineering
WO2024040194A1 (en) 2022-08-17 2024-02-22 Capstan Therapeutics, Inc. Conditioning for in vivo immune cell engineering
WO2024089417A1 (en) 2022-10-24 2024-05-02 Memorial Sloan-Kettering Cancer Center Tumour stratification for responsiveness to an immune checkpoint inhibitor
WO2024089418A1 (en) 2022-10-24 2024-05-02 Cancer Research Technology Limited Tumour sensitisation to checkpoint inhibitors with redox status modifier
WO2024116140A1 (en) 2022-12-01 2024-06-06 Medimmune Limited Combination therapy for treatment of cancer comprising anti-pd-l1 and anti-cd73 antibodies
WO2024126457A1 (en) 2022-12-14 2024-06-20 Astellas Pharma Europe Bv Combination therapy involving bispecific binding agents binding to cldn18.2 and cd3 and immune checkpoint inhibitors
WO2024137776A1 (en) 2022-12-21 2024-06-27 Bristol-Myers Squibb Company Combination therapy for lung cancer
WO2024150017A1 (en) 2023-01-13 2024-07-18 Akrivia Biomedics Limited Method of profiling diseases
WO2024173876A1 (en) 2023-02-17 2024-08-22 Regeneron Pharmaceuticals, Inc. Radiolabeled anti-lag3 antibodies for immuno-pet imaging
WO2024192033A1 (en) 2023-03-13 2024-09-19 Regeneron Pharmaceuticals, Inc. Combination of pd-1 inhibitors and lag-3 inhibitors for enhanced efficacy in treating melanoma
WO2024196952A1 (en) 2023-03-20 2024-09-26 Bristol-Myers Squibb Company Tumor subtype assessment for cancer therapy

Also Published As

Publication number Publication date
CL2018001903A1 (es) 2018-11-09
SI2905030T1 (sl) 2020-02-28
CA2734335C (en) 2018-01-16
PE20190373A1 (es) 2019-03-08
US20200231671A1 (en) 2020-07-23
US11236163B2 (en) 2022-02-01
EP2320940A2 (en) 2011-05-18
PL3597216T3 (pl) 2022-11-14
BRPI0917470A2 (pt) 2015-12-01
AU2009282134A1 (en) 2010-02-18
HK1212911A1 (zh) 2016-06-24
KR101700459B1 (ko) 2017-01-26
PL2320940T3 (pl) 2015-08-31
BRPI0917470B8 (pt) 2021-05-25
CN107474137A (zh) 2017-12-15
JP5647981B2 (ja) 2015-01-07
PT2905030T (pt) 2020-01-29
LT2905030T (lt) 2020-02-10
US11001630B2 (en) 2021-05-11
US11236165B2 (en) 2022-02-01
AR072999A1 (es) 2010-10-06
US20200385466A1 (en) 2020-12-10
US11512130B2 (en) 2022-11-29
ES2927547T3 (es) 2022-11-08
DK3597216T3 (da) 2022-10-31
EP3597216B1 (en) 2022-08-24
KR102370201B1 (ko) 2022-03-04
US20200385467A1 (en) 2020-12-10
EP2320940B1 (en) 2015-03-04
US20180066054A1 (en) 2018-03-08
US20210261660A1 (en) 2021-08-26
HUE025250T2 (en) 2016-02-29
JP2015096503A (ja) 2015-05-21
CL2016002624A1 (es) 2017-06-09
KR20190000922A (ko) 2019-01-03
EA023032B1 (ru) 2016-04-29
JP7286692B2 (ja) 2023-06-05
US10988536B2 (en) 2021-04-27
AR115072A2 (es) 2020-11-25
IL261718A (en) 2018-10-31
TWI491408B (zh) 2015-07-11
EA201590777A1 (ru) 2016-01-29
US20190276538A1 (en) 2019-09-12
JP2017052765A (ja) 2017-03-16
CN102176921A (zh) 2011-09-07
AU2009282134B2 (en) 2014-07-03
CN113773386A (zh) 2021-12-10
TN2011000025A1 (en) 2012-09-05
SI2320940T1 (sl) 2015-07-31
HRP20150453T1 (hr) 2015-06-19
HRP20200070T8 (hr) 2021-03-05
CL2011000308A1 (es) 2011-05-27
AU2014221286A1 (en) 2014-10-02
SMT201500125B (it) 2015-07-09
CA2734335A1 (en) 2010-02-18
JP2023113722A (ja) 2023-08-16
US11530267B2 (en) 2022-12-20
CO6351751A2 (es) 2011-12-20
NZ623319A (en) 2015-08-28
EP2905030A1 (en) 2015-08-12
TW201019958A (en) 2010-06-01
US10988535B2 (en) 2021-04-27
SG10201706497QA (en) 2017-09-28
EP3597216A1 (en) 2020-01-22
IL210731A0 (en) 2011-03-31
KR102121141B1 (ko) 2020-06-10
BRPI0917470B1 (pt) 2020-09-24
WO2010019570A3 (en) 2010-06-17
EP4147714A1 (en) 2023-03-15
WO2010019570A2 (en) 2010-02-18
CN102176921B (zh) 2014-05-07
CY1116582T1 (el) 2017-03-15
PL2905030T3 (pl) 2020-04-30
NZ602780A (en) 2014-04-30
HRP20221191T1 (hr) 2022-12-09
NZ590991A (en) 2012-11-30
KR20220032636A (ko) 2022-03-15
CY1122576T1 (el) 2021-01-27
EP2320940A4 (en) 2013-01-23
ZA201101009B (en) 2012-11-28
HUE060029T2 (hu) 2023-01-28
EP2905030B1 (en) 2019-11-06
MX2019000094A (es) 2023-04-12
DK2320940T3 (en) 2015-05-26
IL210731A (en) 2017-08-31
KR20200068749A (ko) 2020-06-15
EA201100340A1 (ru) 2011-08-30
CN103923213A (zh) 2014-07-16
JP2021091696A (ja) 2021-06-17
AR117774A2 (es) 2021-08-25
IL253868A0 (en) 2017-10-31
ES2537203T3 (es) 2015-06-03
US20210261661A1 (en) 2021-08-26
US10344089B2 (en) 2019-07-09
US20220195040A1 (en) 2022-06-23
PT2320940E (pt) 2015-06-19
US20230322919A1 (en) 2023-10-12
KR20230165352A (ko) 2023-12-05
HRP20200070T1 (hr) 2020-04-03
PE20141658A1 (es) 2014-11-08
JP2019030307A (ja) 2019-02-28
US11236164B2 (en) 2022-02-01
PT3597216T (pt) 2022-09-28
MX2011001250A (es) 2011-03-29
IL281876A (en) 2021-05-31
KR20170010901A (ko) 2017-02-01
DK2905030T3 (da) 2020-02-17
US20220204612A1 (en) 2022-06-30
HK1151985A1 (en) 2012-02-17
US20190276539A1 (en) 2019-09-12
JP2012500006A (ja) 2012-01-05
KR20110050507A (ko) 2011-05-13
CL2013002062A1 (es) 2014-01-10
ES2768576T3 (es) 2020-06-23
LT3597216T (lt) 2022-11-10
PE20110306A1 (es) 2011-05-21
US20210261662A1 (en) 2021-08-26

Similar Documents

Publication Publication Date Title
US11530267B2 (en) Human antibodies that bind lymphocyte activation gene-3 (LAG-3), and uses thereof

Legal Events

Date Code Title Description
AS Assignment

Owner name: MEDAREX, L.L.C., NEW JERSEY

Free format text: MERGER;ASSIGNOR:MEDAREX, INC.;REEL/FRAME:030603/0924

Effective date: 20121231

AS Assignment

Owner name: E. R. SQUIBB & SONS, L.L.C., NEW JERSEY

Free format text: MERGER;ASSIGNOR:MEDAREX, L.L.C.;REEL/FRAME:035226/0690

Effective date: 20140930

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION